Preliminary clinical experience with a new natural compound in the treatment of oesophagitis and gastritis: symptomatic effect

Lunedì, 13 Luglio 2015

The Authors describe a preliminary clinical investigation on forty patients with oesophagitic and gastric symp-toms, ten of them affected of reflux disease.After oesophagogastroscopy and urea breath test they were submitted to administration of a natural productbased on Hyaluric acid and Chondroitin sulphate. The design of the study was a double blind drug versusplacebo trial. The results, based on symptoms analysis, showed statistically significance effectiveness of thenatural compound against placebo. Also the pre-post treatment endoscopic investigations showed improve-ment of inflammation and healing of the mucosa either in oesophageal or gastroduodenal pathology.

Gastroesophageal reflux disease (GERD) is anacid-related disorder triggered by reflux of ga-stric contents into the oesophagus whose lowersphyncter (LES) becomes incompetent due tomultiple causes. Hearthburn, the most com-mon and distinctive symptom affects roughly20-40% of western people whose 7% complainsof daily symptoms; the seasonal prevalence ofthe disease in the general practice reaches evenmore than 50% of the population, and poten-tial complications enclose erosive oesophagi-tis, Barretts oesophagus and adenocarcinoma.Functional dyspepsia is the commonest causeof dyspeptic symptoms in the world affectingroughly 25% of the population: its main fea-tures are recurrent pain or discomfort in theepigastric area, without coexisting irritablebowel syndrome, or ulcers; very often hyper-chloridric secretion, gastric motility disturban-ces and psychosocial reactivity have been advo-cated in the physiopathology of such a so cal-led gastritis and duodenitis. A very recent pa-per of Tomomitsu et al investigated the asso-ciation between dyspeptic symptoms and en-doscopic appearances enrolling 87 dyspepticpatients and 93 asymptomatic controls1.They found that friability in the antrum andduodenal ulcer scarring were independentlyassociated with dyspeptic symptoms. The logistic regression analysis showed that both of these endoscopic appearances were significan-tly more likely to be associated with dyspep-tic symptoms. Among 18 dyspeptic patientswith friability in the antrum, H. pylori infec-tion was present in only three, and inflamma-tion activity and severity of atrophy in theantrum by the updated Sydney System weremild in most patients. On this basis friabilityin the antrum was almost characterized bynormal or high gastric acid secretion and, po-tentially hypergastrinemia. The symptomatictreatment of oesophagitis and gastritis is pri-marily approached with proton pump inhibi-tors to reduce the acid output and with buffe-ring products that counteracts the hydrogenio-nic damage to the mucosa.A recent our original approach to the problemwas dedicated to identify and use some natu-ral compounds able to buffer the acidity of thegastric fluid, as well as to inhibit the pepsin-induced mucosal rebound damage, but speci-fically addressed to steadily coat the epithelialsurface as long as possible by means of an acti-ve principle able to stimulate the healing pro-cess with a very well known physiological re-pair mechanism.The chemical composition of the compoundinvestigated in our trial encloses Chondroitinsulphate (CS) and Hyaluronic acid (HyA) plusan adhesivity enhancer with the following ra-tionale:a) Chondroitin sulphate is a chemically safeand atoxic glycosaminoglycan family com-ponent with repeated disaccharide unitsmade of glucuronic acid and galactosamine1-beta sulphated group; the molecular struc-ture had been identified by Babkin and Ko-marov, as an effective inhibitor of pepsininduced damage on the gastroduodenalmucosa, being with mucoitinsulphate, amain chemical component of the spontane-ously secreted mucous by the parietal cells2.A primary attempt to Chondrotin sulphatetreatment by mouth in gastroduodenal di-seases was primarily tried on the man byCrandall & Roberts on 22 patients affectedby duodenal peptic ulcer, with a definitesymptoms improvement in 45%3. Levey andSheinfeld, blocked in the Shay-ulcer modelpf  the rat, the gastric damage administering25 mg Chondroitin sulphate by mouth4.b) Hyaluronic acid is an other outstanding ato-xic biological molecule, characterized by along dimeric cross-linked sugar (N-acetyl-D-glucosamine) linked with â-glucoronicacid.One of its natural functions is to control epi-thelial cells  turnover by means of the CD44and RAHMM receptors and to inactivate thefree radicals and the reactive oxygen species(ROS) in the skin layer5.This molecule has largely been used as an ef-fective skin ulcer healing compound, and se-veral years ago we hypotesized that it mightbe beneficial also in oesophageal erosions andgastroduodenal ulcers6.In a previously unpublished clinical pilot trialwe treated 20 adult patients affected by erosi-ve oesophagitis and reflux with Hyaluronicacid by mouth twice daily along two weeksachieving a 76 % control of the symptoms. Weused a 10% Hyaluronic acid sodium salt witha dynamic viscosity proportional to 4500mPa*s administered with a spoon 3 hours af-ter meals.The plan to mix the molecules of HyA andCS, within an adhesive biopolymer, whichmight increase the mucosal surface adhesivi-ty, was addressed to enhance the mucosa bar-rier either in the oesophagus or in the gastricand duodenal lumen.

Materials and methods

Trial design
Our study (double blind, crossing over drugversus placebo) enclosed 40 randomly selectedpatients (16 females and 24 males), aged betwe-en 6 and 87 years (average 55-85), with oesopha-gitis and gastritis symptoms characterized byheartburn, epigastric pain, dyspepsia, meteo-rism and belching; 22 patients had long stan-ding reflux disease unadequately treated withproton pump inhibitors and antiacids. Tencases underwent primarily the experimentalprotocol without any previous medical treat-ment. All the enrolled patients had such a se-vere symptoms score (see below) to require theuse of PPI alone or PPI plus antacids. An in-formed consent was signed by each patientwith the formal acceptance to self-administra-tion of the nutriceutical  compound under in-vestigation,  accepting the challenge of a twoweeks placebo administration.

Before being enrolled in the study, oesopha-gogastroscopy and urea breath test were perfomed on each one, to rule out any Helico-bacter positive patient. Endoscopic reexami-nation was allowed twice. The patients signedan informed consent, and any previous disea-se-specific drug treatment was withdrawn 5days before the start up of the investigation.They were randomized in two groups: 20 pa-tients each, and submitted to oral administra-tion of the drug to be tested and placebo.The composition of our syrup was:• Hyaluronic acid: 120 mg;• Chondroitin sulphate: 300 mg;• Excipients: Viscosity enhancers; preservati-ves; aroma; water q.s. 1200 mgThe viscosity of the syrup was 60 mPa.
Composition of the placebo was:• 10% vaseline-oil/water emulsion;
• Viscosity enhancer;• Preservatives;• Aroma;• Water q.s.:1200 mg.
The product and the placebo were manufac-tured in a private pharmacy accordingly witha galenic formula planned by one of the Au-thors (Palmieri), on the bases of a previous unpu-blished veterinary experimental trial on gastrooesophageal lesions healing in the horse.The compounds were blindly administeredwith the following schedule: one spoon every8 hours (far from meals) and two spoons atthe bed time along two weeks. One week in-terval without administration. Two furtherweeks of treatment switching placebo and pu-tative active principle in the groups. Symptoms were scored daily as follows:• +++ = complete disappearance of hearth-burn and epigastric pain during the treatment• ++ = less than 60 % reduction of hearth-burn and epigastric pain with no more thanthree attacks of the symptoms admitted andvery rare need of add antiacids to the experi-mental treatment• + = less than 30 % reduction of hearthburnand gastritis with recurrent use of PPI andantiacids.A final evaluation of  symptoms relieve, as welas endoscopic shortterm check-upOn a 4 patients samplewas done 4 weeks after the end of the trial
Statistical data interpretation
All the data groups aredistributed normally, sowe decided to used theanalysis of variance (Anova). This statisticalmethod evaluates data group of different po-pulations. In all the comparison between pla-cebo and drug, after crossing over, the p-valueis minor than 0,05 and F obtained is major F-crit, thus reaching statistical significance.

The treatment was completely safe and no dro-pout happened during the investigation. The compliance of the product (viscosity taste and swallowing difficulty), was very favourable.The effectiveness was meaningful and impres-sive especially in kids with reflux and adultswith biliary gastritis probably due to promptneutralization of alkaline biliary fluid:• 12 patients total symptoms remission;• 7 patients less than 60 % symptoms reduction;  1 less than 30 % symp-toms reduction.
Individual patients resul-ts are shown in Table1,2,3,4 where we descri-be the diagnosis and thedrug versus placebo orplacebo versus drug com-parison, in terms of dif-ferent scores for eachgroup: a remarkable effect of the nutriceuticalcompound has been observed, when admini-stered at the trial start up, in the first group,and a minor benefit if adminstered after theplacebo switch off, probably due to the pro-longed impending  symptoms along the trialcourse .The hyaluronic-condroitinsulphate association 
was more effective in oesophagitic symptoms,control, but also gastroduodenitic improvedduring the treatment and in the short termfollow-up (4 weeks) a smart improvement andexcellent compliance was scored in the 7 yearsold kid with drug-resistent oesophagitis ( casen°8).

Our treatment schedule achieved quick symp-toms improvement, accordingly with previousstudy of Bonfils & Cow who described therelationship between endoscopy7, and patho-logical findings from the surgical specimen:accordingly with this Author the efficacy ofChondroitin sulphate, should be due not onlyto the affinity between its sulphonated  mole-cular structure and the aminic groups of pep-sin molecule, but also to the induction of awide range of proteinated complexes (withhaemoglobin and serum-globulins, for instan-ce), coating steadily and protecting the deepi-thelized or ulcerated gastroduodenal areas8.Fialkova et al described skin ulcer healing pro-moter effect of the same compound in the ratwith topical or systemic administration9. Har-rison SE showed that Chondroitin sulphate isan excellent coating for intraocular lens im-plantation to avoid any damage to corneal epi-thelium10; according with this Author Chon-droitin sulfate surpassed by far the protectivequalities of other compounds: albumin wassecond best; Hyaluronic acid third. Compari-sons with the commercially available Healonstill revealed Chondroitin sulphate to be themost efficacious protective agent 40 hours la-sting its effect. The concept of a protectivelayer by Chondroitin sulphate upon the sur-
faceal mucosal lesions of either oesophagus andstomach, are actually very appealing , becausethe good affinity of the compound for the inju-ryed surfaces, affords a very effective andstrong protection11-14.More recently a clinical study of Steinhoff andCow, in patients with interstitial cystitis, re-ported favourable symptomatic outcome byintravescical instillation of 0,2% highly puri-fied Chondroitin sulphate solution with mo-lecular weight 20-40.000 Daltons confirmingantiinflammatory and healing properties of thecompound in an other muscular-epithelial con-tractile organ15.The putative Ha action mechanism stronglysupports the theory of  inducing epithelial cel-ls shifting (due to their increased motility atadequate Hyaluronic acid concentrations) tocover the submucosal connective tissue (whi-ch becomes more soft and  hydrophylic dueto the Hyaluronic acid availability) beneaththe fibrin crust to repair the damaged mucosallayer.The ulcers and erosions healing effect of Chon-droitin sulphate is thus synergistically co-pro-moted by the Hyaluronic acid and the addedadhesive biopolymer with a wide range of in-dications.

The nutriceutical product we tried has beenshown very useful to control oesophageal andgastric symptoms of reflux and inflammation,even if we lack long term results and the finaloutcome of a long-run treatment. Our pre-posttrial endoscopic investigations showed a smartimprovement of the mucosa either in oesopha-geal or gastroduodenal pathology.
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