CASE REPORT

MELATONIN FOR THE TREATMENT OFGASTROESOPHAGEAL REFLUX DISEASE

Melvyn R. Werbach, MD

The enterochromaffin cells of the gastrointestinal (GI) tractsecrete 400 times as much melatonin as the pineal gland; there-fore, it is not surprising that research is finding that this indoleplays an important role in GI functioning. In animal studies, itprotects against GI ulcérations, and randomized clinical trialssuggest its efficacy in treating functional dyspepsia and irritablebowel syndrome. Melatonin administration has been shown toprotect against esophageal lesions in animals. Moreover, in arandomized, single-blind clinical trial of subjects with gastroe-sophageal reflux disease (GERD), the combination of melatoninwith other natural supplements was found to be superior toomeprazole, a proton pump inhibitor (PPI). Its administration asa single treatment for GERD has not been previously reported.

A 64-year-old Caucasian female who required treatment

with a PPI for symptoms of GERD wished to substitute a natu-ral treatment because of the risk of worsening her osteoporosis.

She experienced a return of symptoms following each of three20-day trials of a proprietary blend of D-limonene whenattempts were made to discontinue the PPI. She then under-went a trial of a natural formula consisting of melatonin 6 mg,5-hydroxytryptophan 100 mg, D.L-methionine 500 mg, betaine100 mg, L-taurine 50 mg. riboflavin 1.7 mg, vitamin B̂ ; 0.8 mg,folie acid 400 pg. and calcium 50 mg. After 40 days, the PPI waswithdrawn without a return of symptoms. Subsequently, anattempt to reduce melatonin to 3 mg resulted in symptoms,while all other ingredients were withdrawn with minimal symp-toms during 10 months of follow-up. {Allem Ther Heallh Med.2008:14(4):54-58.)

Melvyn R. Werbach, MD, is an associate editor of AlternativeTherapies in Health and Medicine. He is also the author of se\ eralbooks on natural medicines, including Nutritional Influences onIllness (Keats Publishing, 1990) and Textbook of NutritionalMediane (Third line Press, 1999).

Gastroesophageal reflux disease (GERD) can bedefined as symptoms of mucosal damage pro-duced by the abnormal reflux of gastric contentsinto the esophagus.' It is one of the most commondiseases in the Western world.- Eor adults in the

United States, symptoms of esophageal reflux are reported tooccur in 44% of the population once a month,' in 20% once aweek,' and in about 10% daily.-

Medical treatment has focused on combating stomachacid, the primary cause of inflammation of the esophagealmucosa. Proton pump inhibitors (PPIs) are currently the mostpotent acid suppressants and are a major source of income forthe pharmaceutical industry. In the United States only the lipidregulating drugs have greater sales/

Despite the popularity of PPIs, there are a growing numberof concerns about their safety. Their long-term safety is not com-pletely known, as studies investigating their long-term use havefollowed up their subjects for no more than 10 years.' In additionto common side effects (such as headaches, nausea, and diar-

rhea) that cease as soon as medication is stopped, they may beassociated with a number of longer lasting adverse efFects, whichmay be due to their profound acid suppression and the elevatedlevel of gastrin that results from it. These include a significantincrease in risk for hip fracture. For example, a large case-controlstudy found a 44% increase in hip fracture risk in patients overage 50 who had received PPIs for more than 1 year. For thosewho received high doses, the risk increased 2.6 times."

Another case-control study found that patients receivingPPIs had a 50% increase in risk for community-acquired pneumo-nia. In contrast to the increasing risk for hip fracture with contin-ued intake of PPIs, patients who started ingesting PPIs within thepast week had the greatest elevation in risk (500%), and the riskdecreased over time to 33%." Similarly, the use of PPIs is associat-ed with an increased risk of Clostridium dijpcite-assocxateá diar-rhea among hospital patients.^ PPIs are also the most commoncause of drug-related acute interstitial nephritis,'" and there iscompelling evidence that PPIs may cause myopathies."

Hypergastrinemia causes rebound hyperacidity when thedrug is stopped, and animal studies suggest that it may eventu-ally cause enterocbromaffin-like ceil hyperplasia and carcino-ids,'^ whereas drug-induced gastric hypoacidity increases gutbacterial infections and may possibly increase the risk of viraland prion infections."

Finally, gastric acid is needed for the proper absorption ofseveral important nutrients, and thus potent acid suppression

54 ALTERNATIVE THERAPIES, |UL/AUG 2008, VOL 14, NO, 4 Melatoiiin for ¡lie Treatnienl of GERD

may provoke deficiencies. Vitamins whose absorption is acid-dependent include vitamin Bj^" and vitamin C ' Acid-dependent minerals include calcium, iron, magnesium,phosphorus, and zinc'

There is thus a rieed lor a safer approach to treating CiERD.This article presents the first report of melatonin administration,l̂ ,1 irfalmenl for the symptoms of (lERD and reviews the e\i-dtntf for the efficacy of the indole in this disorder.

Melatonin is widely recognized as :i pineal hormone. Mosthealthcare professionals are unaware, however, that this indole issecreted not only in the pineal glund hut also in the gut. In fact,tilt' quantity of melalonin secreted by the en le roch rom affin cellsin the gastrointestinal ((11) tract is 400 times that of the pineal."In contrast to pineal melatonin, ihe release of Gl melatoninappears to be related lo the periodicity of food intake."

Compared to pharmaceutitals. melatonin is toleratedextremely well,' One study found no harmfiil side effects at dosesas liigh as fiO mg daily." In a safety analysis that iiuludcii 487participants in 10 studies, 9 of which were randomized con-trolled trials, the occurrences of the most cunnnonly reportedadverse events (headache, dizziness, nausea, and drowsiness) didnot differ significantly from those associated with placebo.'"

Due to its immunostinïulatini! effects, " however, melatoninshould Iw avoided In people with autoimmune disorders and.due to its possible effects on female hormones, il is not recom-mended for pregnant or nursing mothers. Moreover, although ithas been found to be relatively safe over the short term (days toweeks), its safety over the long term has not heen established.-'

Melatonin has been shown to protect against Cil ulcérationsby several actions. It is a potent ¡intioxidant,-' it inhibits thesecretion of hydrochloric acid and pepsin," and it stimulates (heimmune system." These actions increase microcirculation andpromote regeneration of the luminal epithetiuni."

Randomized clinical trials have (bund melatonin to be elfec-tive in treating functional dyspepsia, a disorder of the upper Gltract. Functional dyspepsia was studied in till patients aged 19 to39 years without ¡klicohacter pylon. ' The patients randomlyreceived either melatonin 5 mg in the evening or placebo. Bothgroups were on an equivalent diet and were only to take an alka-line drug in case of abdominal pain, .\fter 12 weeks, the dyspep-tic symptoms completely subsided in 17 patients (56.(i%) in themelatonin group, and another 9 patients (30%) showed a partialimprovement. Ihis contrasted with the placebo group, in which93.3% failed to improve. Multivariate analysis indicated thatmelatonin correlated independently with significantly improvedpatient health. Past inlectioti with ///y/ori decreased the positiveeffect of melatonin.-*

Two studies also found melatonin to bf effective in treatinga lower Gl disorder, namely irritable bowel syndrome (IBS).Findings from both suggest that the indole's efficacy was not dueto improvements in sleep, anxiety, or depression. In the firststudy, 17 female patients randomly received either S mg of mela-tonin each evening or placebo for 8 weeks, followed by a 4-weekwashout period, and then melatonin or placebo in reverse order

for another 8 weeks. Improvements in mean Gl symptom scores(but not anxiety/depression or sleep scores) were signílicantlygreater after treatment with melatonin than alter placebo (3.9 vs1.3; /*=.0:Í7). The percentage of patients achieving a mild-to-excellent improvement was also greater after the melatonin-treatment ami (88% vs 47%: P=.O4).̂ ''

In the second study of IBS patients, this time of patientswith sleep disturbances, 40 patients (24 fcniiilc*) aged 20 to 64years randomly received either 3 mg of mclalonin or placebo atbedtime for 2 weeks. Compared with placebo, melatonin signifi-cantly decreased mean abdominal pain score (2.35 vs 0.70;P<.001) and increased mean rectal pain threshold (8.9 vs -1.2mm Hg; /'<.O1). Bloating, stool ty[>e. stool frequency, and anxietyand depression scores were similar after treatment in bothgroups. Moreover, sleep parameters were unchanged.'

Evidence that melatonin specifically protects against csoph-ageal damage comes fn)m a study of acute esophageal injur\' inrats in wliich the esophagus was perhised with an acid-pepsin-bile solution. Pretreatment with melatonin was found to preventesophageal injury in a dose-dependent manner.'' Compared tohealthy suhjects, suhjetts with GERD found to have esophageallesions also have diminished nocturnal melatonin secretion,although subjects with symptoms of (ÍI:RI) hut normal esopha-geal findings have elevated noclunial melatonin secretion.' Thissuggests that hi populations prone to esophageal reflux disease,reduced melatonin secretion may fail to protect the esophagealmucosa from ulcération due to the adverse ettects of acid-pepsinand bite salts.

Although no previous human study has provided mekitoninas a single therapeutic agent to suhjects with GERD, it wasincluded as part of a nutritional formula in a randomized, single-blind, experimental study.-"

Patients with heartburn, régurgitation, dy.sphagia, and chestpain were enrolled in the study if they experienced at least 1 peri-od of moderate-to-very-severe heartburn or regurgitatitïn in the7 days prior to the experimental treatment. In addition to ii mgolmeiatonin. the formula contained seM-ral other nutrients.These ingredients, their dosages, and the author's rationales forthem are as follows:

i-tryptophan (200 mg). vitamin B^ (25 mg). and vita-min ¡iy, (50 meg) may alleviate acute pain due toenhanird ovailahility and/or efficacy of the muroin-hibitors noradrenaline and serotonin. Folie add W mgprotects against (¡I cancers. These substances, in combi-nation with hetaine (¡00 mg) and methionine (¡00 mg).probably induced synthesis of S-adenosyL-i-methionine(SAMt). a methyl donor with anti-inthimmatory andanalgesic activity, which has successfully treated gastriculcer in animals. '"

A total ol 351 patients entered the study. After randomiza-tion, 176 patients received the formula (group A), and 175patients received 20 mg omeprazole (group B), each taken after

Mdaionin for Ihc ircatnienl of GERl> ALTERNATIVE THERAPIES, )UL/AUG 2008. VOL. 14. NO, 4 55

the evening meal for 40 days. Before the study 18.2% of patientsin group A vs 10.8''ii of patients in group B liad received medica-tion for retlux disease. No other medication was allowed for theduration of the study.

Seven da\'s after starting the formula, all subjects in group Areported s)inptoiii relief, and b) the end of the stud}' (following40 days of treatment), all subjects in group A rated themselves asmarkedl)- impnived (ic, as)'mptomatic"). Of the 176 subjects, 1̂ 9(9O'Üi) noted what tlic)- described as eitlier somnolence or sleepimpro\'t'ment.

In ii^oup B, 11,'t subjects (65.7%) reported symptom relief 9days after starting oineprazole treatment, and 2.3% reported par-tial relief (ie, slight improvement): tbe remainder reported nochange. Two subjects in the group (1,1%) withdrew from thestud)' because of persistent headache. .Moreover. 7 subjects (4%)noted diarrhea. 4 subjects (2.3%) noted somnolence or sleepimprovement, and A subjects(1.7%) noted hypertension.

Following completion of the randomized stud), the 60 sub-jects (34.3%) in group B who reported persistence of their symp-toms received the formula for 40 days. Ail subjects in thissubgroup reported disappearance of all GERD symptoms by tbeend of tbe 4()-da\' period.'

Although he was impressed b\- the results of this stud)', theauthor was suspicious tbat melatonin was the key ingredient oftbe formula. Through the means of an unblinded case study, heconducted a preliminary investigation of the efficacy of mela-tonin alone as a trenttiient for GERD.

CASE REPORT

TliL' patient was a 64-year-old Caucasian female who. afterfasting .siiici- the previous night's dinner, experienced a suddenepisode of severe pain in her chest and up into her mouth around1 PM. She ate food and tbe pain largely dissipated, althoughslight discomfort remained.

She received a medical evaluation 2 days later and was start-ed on 40 mg daily of pantoprazole, a PPl, with full symptomrelief TUD weeks later, liouf\'er, mild pain returned in the sameareas despite continuation of the medication. She took calciumcarbonate 1000 mg, and the symptoms stopped.

Concerned that pantoprazole tiiight not full)' control symp-toms and that long-term use of a PPI could worsen her osteopo-rosis, her physician decided to attempt to substitute a naturaltreatment. The plan was to first add the natural treatment for aperiod of time and then to attempt to discontinue medication inthe hope that symptoms would not return.

D-limonene was selected for tbe initial trial and was pro\'Íd-ed in the form of a proprietary extract of orange peel (Citrus sin-ensis) that was standardized to contain a minimum of 98,5% ofD-limonene. This selection was made because although there areno published studies, the manufacturer has reported excellentresults in its proprietary study. Specifically, 89% of 19 subjects inthe manufacturer's study reported resolution of most of theirgastric distress after taking one 1000-mg gelcap of standardizedD-limonene ever\' other dav.

In the controlled, double-blind, second pbase of the study,22 subjects randomly received either the standardized extract orplacebo. Seventy fi\x' percent of subjects receiving standardizedD-limonene reported significant relief after 2 weeks compared to20% of those recei\1no placebo. No adverse effects were reported,and some participants reported relief lasting up to 6 months(Willette RC, Barrow L, Doster R, VVitkins J, VVilkins JS. MeggersiP, unptiblislied data).

I'he patient was placed on the manufacturer's recommend-ed 20-day course of 1000 mg of D-limonene every other day andstDfiped pantoprazole following the conclusion of the course ofD-limoneiie. Ten days later sharp pain suddenly started underher right breast at 6 PJM. She immediately took famotidine U) mg(a histamlne 112-receptor antagonist) and calcium carbonateKKK) nig. with relief after 15 minutes. She was theti switched toesomeprazole. a PPl. 20 mg daily, and remained asymptomatic.

After being asymptomatic for 12 days, esophagoscopyshowed e\'idence of a hiatal hernia with minimal gastritis and anormal duodenum. Ciastric biopsies were normal and negativefor // pylori. She was told to continue on esomeprazole 20 mgdaily. After 1 month, she stopped esomeprazole on her ownw itiiout a return of symptoms.

Two and a half months later, in order to improve her lipidprofile, she was started on 20 mg daily of lovastatin (ati liMG-CoA reductase enzyme inhibitor which may cause upper Glsymptoms such as nausea, "gas pains." and chest pain). Sheik'\'t'lnped "gas pains" S days later and took cakium carbonate1000 nig. Although she had full symptom relief, the ne,\t day shenoted moderate pain under her right breast that continued untilshe returned to esomeprazole 20 mg daily.

Two further trials of substituting D-tinionene for the medi-cation also were unsuccessful. She was then switched to 20 mgdaily of otneprazole. another PPl. and continued to be totallyasyiuptiimatjc.

Eighteen months later, however, she sought a trial nl anoth-er natural treattiient. This time she was placed on a combinationof dietar)- supplements modeled after the formula described ear-lier in this article. ' Ingredients consisted of 5-hvdroxytrypto-plian (S-HTP) 100 mg, a proprietär)' methionine complex(consisting of D.L-methionine 500 mg, betaine 100 mg, L-taurine50 mg, ribofiavin 1.7 mg. vitamin B̂^ 0.8 mg, folie acid 400 pg,and calcium 50 tng) 1 capsule, and melatonin 6 mg, all to betaken at bedtime, (See the Table for a side-by-side comparison ofthe 2 formulas.) Eorty days later, she stopped otneprazole with-out the return of symptoms.

It was decided after 1 month that the combination formulaappeared to be effective, and a series of trials were begun toattempt to minimize the ingredients of her anti-GERD supple-ment. Initially, an attempt was made to reduce the melatonindosage to half (3 mg) by doubling the dosage of 5-HTP (a mela-tonin precursor) to 200 mg. She developed nausea for 30 min-utes, bowever. around the middle of the next 2 mornings whilestill fasting. Omeprazole 20 mg daily was restarted along withthe anti-GERD formula.

56 ALTERNATIVE THER,A,PIES, ) U L / A U G 2008, VOL 14, NO, 4 Melatonin tor the Treatment of GERD

Comparison of Anti-GERD Experimental Formulas

(le Souza Pereira anti-(iERD Modified anti-GERD Formula

Formula

Melatoniii 6 mg

L-tr\^ptophan2f)nmg

D,i.-methionint 100 mg

Betaine 100 mg

FoUc acid 10 mg

Vitamin

Vitamin

Mc'latonin

5-hydraxylrypto[)han UMl mg

Proprietär, inelhii-iniiie ciimpl

n,L-nu'thionine 500 mg

Betaine 100 mg

I'olic acid 40n jig

\itaniiii B̂ 0.8 nig

Riboflavin 1.7 mg

Calcium 50 mg

L-tauriiie 50 mg

A second attempt to reduce the melatonin dosage was made2 weeks later. Omeprazole was discontinued, and melatonin wasreduced again to 3 mg daih', but this time tbe 5-1ITP dosage wastripled to 3()Ü mg. Around midday tbe fallowing day, she sud-denly experienced sharp pain between her breasts and in hermouth and tongue. Omeprazole 20 mg daih' was inunediatelyrestarted, with full symptom relief, and she returned once againto the initial anti-GERD formula. One month later, she stoppedomeprazole without the return of symptoms.

Next, attempts were made to discontiime tbe other ingredi-ents of tbe anti-tiERD formula while continuing melatonin at thesame dosage. First the methionine complex was stopped success-fully, and tben the 5-HTP was stopped successfully, so tbat hertreatment now consisted solel)' of melatonin.

Two montbs later she was on a trip and awoke at 5 .\\\ withsharp pain bet^veen her breasts (7 on a 1-10 scale) that lessenedupon standing. She counted tbe number of melatonin tablets sbehad brought with her and discovered that she had forgotten to taketbe supplement tbe night before. For 1 week she returned toomeprazole 20 mg dail) in acidition to melatonin (i mgat bedtime.

Over the next B months of follow-up, she has continued onmeiatoiiin (i mg at bedtime. Except for 3 episodes of mild sub-sternal chest pain awakening her during the middle ot the night.she has remained asymptomatic. (During each episode she tookomeprazole 20 mg, experienced full pain relief in about 30 min-utes, and tben returned to sleep.)

DISCUSSIONThis a|)pears to be the tirst publislu'd study to record the

successful substitution of melatonin ti mg at bedtime for themaximum recommended dosage o[ a IMM in a patient withGKRD. The report suflers from 2 serious limitations. Tirst. sinceit documents only a single case, it pro\ides no indication ofwhether the findings can be generalized to other patietits.Second, it fails tn control for the placebo ctfect, so it is not piissi-ble to know whether tbe active treatment or a concurrent lum-specilic factor is responsible for her response.

Perhaps the strong<"̂ t indication that her response was unlike-ly to be due to tbe placebo eliect was her discovery after the symp-toms started that sbe had skipped taking melatonin the nightbefore: thus her s)'mptoms occurred even though she thought shewas being protected by the pill. Further evidence suggesting thather response was not simply a placebo effect was her poor priorresponse to multiple trials of D-iimonene, another natural agentthat liad been presented to tbe patient in a similar manner.

Asymptomatic on the combination supplement witbout thePPI, she was successfully weaned off of afl of its ingredientsexcept for melatonin, for which a 50% decrease in dosage led tothe rapid return of s\inptoms. VVe cannot conclude, however,that the other ingredients were ineflective as it is possible tbatthey had an initial role in repairing mucosal defenses so thatmelatonin alone would become adequate for treatment.

It appears that, through various mechanisms, melatoninprotects the esophageal mucosa from injury due to the assault ofacid reflux. Daily administration appears to be necessary, orsymptoms immediately recur.

Despite its efficacy in preventing symptoms for almost ayear, it is possible tbat symptoms may recur at a later date, per-haps due to worsening of the underlying disorder.

This report also addressed the question of whether 5-HTP, amelatonin precursor, could be substituted fur melatonin inrelieving the symptoms of GERD. The oral administration ofL-tryptopban. the immediate precursor to 5-HTP, to chicks andrats has been found to cause a rapid, dose-dependent ele\ation ofcirculating melatonln, and the major source of the increase in cir-culating melatonin was not the pineal gland but the enterocbro-niaffm cells of the Gl tract." Other studies suggest that thisincrease may be roughly 4-fold compared to baseline levels. " "

In the case presented here, an attempt was made to reducetbe initial melatonin dosage b\ doubling and then by tripling tbedosage of fi-HTl*. However, 300 mg of 5-1 ITP. a dosage usuall)'considered to be adequate for clinical applications, failed to per-mit melatonin to he reduced from iS mg to 3 mg daily, and dis-continuation of 5-1 ITP alone did not cause a return of symptoms.Tbese findings suggest that the usual clinical dosages ot 5-HTPare ineffective as a substitute for melatonin.

CONCLUSIONSFindings of this single case study In addition to a review of

the literature suggest tbat melatonin 6 mg al bedtime may bf aneffective treatment for GERD with fewer and less serious adverseeffects than acid-reducing medications so long as anti-GERDmedications are (1) contiiuu-d during the first 40 days of treat-ment and (2) resumed for at least 1 dose whenever symptomsrecur. Further studies, inchnling randomized controlled trials.are needed to \alidate and extend these earlv ft

REFKRENCKS1. ne\aull KR.taMrlirx): American ("iiilege oil .a.striifmerokigi..l'pdaled guidelines for

the diagnosis and Irealmciit oiga sir oesophages I retlux diseaw. Am I CiKlroenlrroI.

2. Orlando Kl\ Diseases oflhe esopha¡:m. In: (kildman L, AusiHlo D, ed-s. Odl Textbook

of Medium: a2nd vA. Philadelphia, l'A: SaiindiTv 2<MM.

Melytoiiin for the Treatment of GERD ALTERNATIVE THERAPIES. [UL/AUG 2008, VOL. 14. NO. 4 57

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lx>cke GR 3rd, Talley N), Fell SL, Zinsmeister AR, Mi-lion LJ 5rd, Provalpnce and clini-cal spedrum of pastniesopha^i-al refliw: a populaiion-based siudy ¡n OlmsleadQuiTily. Minnewia-irVwii-ivn/iw/iigv, 1997;il2(5J:144«-H5e.Tlie Gallup 0rnaiiÍ7.alion, A GiiSufi Survey im Heartburn Aanss .immm. Princelon, NJ. I!lf48.IMS National Sale.-. Prnpectim. 2007 Top Therapeut:! Classes by US Sah. Available at:liIt[i://im5healih.ci)m/vgn/iniagei/p(>rtai/dT_40O(IO87V.19/6O/83433fl392O07%2OTop'*,20TherapeuliA20Cla.sies%20b^^20Salt^.pdf. ,\ccessed Mayl4,2008,Malal>' V\', Stiglcman S, Majw.), liuthmann R,\, Clinical inquiries, h ihe long-tenn useof priiion pump inhibitiirï sate? / Turn Pract. 2O04;53(9):74l>-742,Vang VX, I.PWÍS JD, Epslein S, Mpl/ DC. l.ong-lenn ¡jmUm puniji iiiliiliitor ilieraji)and risk ofhiptraiUirv, M.IÍ4,2(MH¡:29W24):294?-295,Í.

(iiilmez 5E, lioliti A, l-rederiksen I I , Jensen TG, Pfdersen C, Hallas I. I V (if protonpump iiiliibitiir. and ilie itsk ot icmimuniivaiquired pneumonia: a popuiation-ba.'iedLaif •( iintrol study, inVi Inlem Mtd. 21 MJ7:167(9):950-955,Veanley KA, Gilby IJ, Ramadas AV. Kubiak EM. Fone PI., Aliison MV. Proton pumpinhibitor therapy U a risk factor (or (.losiiridiuni difficile-assodaied diarrhea, .AlimcnlPhiirmacol Ther. 2(XI6:24(4):6l:i-tiliJ,RrewMer I'C. Perazdia MA. Proton pump inhibitors and the kidney: critical review,t Im Sephml. 20(17:(i8(2):ti5-72.(lark DW, Strandell J, Mrapathy itiiliiding pol>Tn>t)sitis: a likely clas.s adverse effect ofprnioii pump inhibitors? EurJCIiii PImrmacd. 2(Xlt):tl2(6):473-479,Norsfii KG, la'greid A, Ungaas M, tt al. Molecular characterization of rat gastriciiuiriisal responst' in jxitent acid i nil i lii I ion, Physwl Ccnomici. 2OO5:22t 11:24-32,Waldum HE, Brenna E, Sandvik AK. long-term salety of proton pump inhibitors: risksofgasiricnmplasiaand infections./i,t;wriOpi/( Drat;.Vif;,2IX12:l(l);29-.iK.Valuck RJ, Rusciii JM, A case contnil study on adverse etfects: H2 blix-ker or protonpump inhibitor and risk of vitamin B,̂ deficiemy in old« a<Jults,y (VJ« Fpidcmiol2[KI4:57(4):422428.

Henry EB, Carsuell A, Wjrz A. FyHe \. McColl KE. Proton pump inhibitors reduce thebill avail ability ol dietary vitamin C. Aliment Pharmai nl Ther. 2 (H).S: 22(6 ):,'>,! 9-r>4S,Bubenik GA, Gastrointestinal melatonin: localization, function, and clinical relevance./)!,!,' /)j,v .SV-f, 2{KI2:47( in): 233fi-234«.Mardeland R, Kandi-i'erumal SK. ,Mclatoniii, a piHeiit ajifiit in antiomiiatii* defense:actions as a naiufal food constituent, gastroiniesiinal factor, drug and prodrug,S'utritii'i! Met.ib H.md). 2005 Sep 10,2:22.Jacob .S, Poegi;i>liT B, Weishaupt JH, et al. Metatûnin as a candidate compound forncuriiprolection in .mmitrophic lateral sclerosis (ALS): hi^h tolerability ol daily iiralmelatonin adminisiralion in AI.S¡)atii-nts,/Pj>rfíi//¡n,20Ü2:33(3):18(;-I87,Buscemi N, \and('rmeer B, Hooinn \ , et al, Eíficaci aiui safety ofexogenou.s melatoninfor secondary sleep disorders and slt-ep disorden, aicompanying sleep reslriclion:mcla-analysis. BMI. 2rxib:.132(7r>.i8):.i8,S393,

Currillo-Vico A, ( lurrrero JM, Eardone PJ, Reiter RJ. A review of the multiple actions ofmelalonin on the immune system, Endt\ rJw.2005:27(2):]89-200.Huscenii N, \aiidcrmei-f B, Pandya K, et al, Melütonin jar Treatment of Sleep Disordm,•\HRQPublicatioti No, n5-E0O2-2, Ko.kiille, MD: Agencj- for Heallhcare Research andQuality, US Depanment nf Health anit Human Services; 20(14.Kciter RJ, Tan OX, Mayo JC, Saints KM, Eeon J, Qarnocki Z, Melatonin as an antioxi-ilant: hiocheniical mechanisms and |)atbuphysiological implications in humans, .AituB / / ' / 2 i

23, Kato K, Murai J. Asai S, et al, C entrai nen'ous system anión of melatonin on gaslricacid and pepsin sitretion in pylorus-ligated rats, Xeurureport. 1998;9ll7)::î989-3992,

24, Klupinska Cl, Poplawski T, Drï.emiski J, et al. Therapeutic effect of melatonin inpatients with functional dyspepsia,/(/m <;nrfri)('H/m:/.2OO7;41(3):27O-274,

25, Eu WZ, Gwee KA, Mixichhalla S. Ho KV. .Metatonin improves kiwel symptoms infemale patients niih irritable bowel syndrome: a double-blind placehii-controlled(ludy, Ahment Pharmmnl Ther. 2(M)5:22(l(l)i927934,

26, Song GH, Eeng Pi I, i.lwee KA, Moochlala SM, Ho K>, Melatonin improves abdominalpain in irritable bowel syndmmr ¡latients who have sleep disturbatices: a randomised,doLible blind, pidicki controlled stndy. í.'uí. 2flfl5:54(l(l):1402-1407,

27, KoDturek SJ, Zajachki\ska Ü. Havryluk \ 0 , el al. Protective influence of melatoninagainsi acute esophageal lesions involves prostaglandins, nitric oxide and sen.sorynerves,/PAv,si,i//'A,ji-m,j,y/, 2007:58(21:361-377,

28, KlujMnska G, VVisniuw,iska-Jarosinsk;i M, liarasiuk A. et al, Nimurnal secretion of melatoninin patientsHiihup|)prdigestive trad divirders.//¥i|'ijii//ïnimjiiiii/,20ub:r>7Sui^l 5:41-50,

29, (le Souza Peceira R, Regression nt gaslroesophafical rellux disease svmptoms usingdietary supplementation with melatonin, vitamins and ammoacids: comparison withomeprazole.y/>iii,vj/ftv 2006:41(31:19.v2(H),

30, GERli, melatonin, viiamins and Jininn acids: Kirk Hamilton interviews Ricardo deSoii7aPereira|transcript|, rííí'/:'.i;/j,rf.í.S/)«iil:, Available at: http://^vww,vitasearch,^om/CP/experLs/RI1SPereiraAT10-3(>-(lti,litni, ,Vcessed May 14, 2008.

31, Huether G, Poei^fler B, Reimer A, ( Iturge A. Effect of trypiophan administration oncirculating melatonin levels in chiiks and rats: evidence for stimulation of melatoninsynthesis and release in the gastrointestinal tract. Lift Si 1.1992:5» 12):ÍM5-!I53,

32, Yaga K, Reiter RI, Richardson MA, Tryptophan loading increases daytime scrum niela-tiinin levels in intact and pinealeitoniiied rats. Life Sei. 1993:52{14):Í2:il-1238.

33, Br^ozowski T, Konturek PC. Koniurek SJ, et al. The rule of melatotiin and E-lryptophanin prevention of acule gastric lesions induced bi strevs, ethanol, ischemia, and aspirin,./ Pmeal fíís. I997:2:((2}:79-B9,

Heavy Metal Delox System

Melatotiin fur itie Treatment ofCiERU