The effects of an artificially enhanced clinoptilolite in patients with irritable bowel syndrome

Irritable Bowel Syndrome (IBS) is a common gastrointestinal (GI) disorder characterised by recurrent abdominal pain or discomfort, bloating and stool irregularities (constipation and/or diarrhoea).1 IBS tends to affect women more than men, 2 probably due to sexual or biological differences.3 Almost a decade ago, Farthing contended that, “from the diverse collection of symptoms it seems unlikely that a single medication can reliably treat all aspects of the syndrome”.4


Introduction
Irritable Bowel Syndrome (IBS) is a common gastrointestinal (GI) disorder characterised by recurrent abdominal pain or discomfort, bloating and stool irregularities (constipation and/or diarrhoea). 1 IBS tends to affect women more than men, 2 probably due to sexual or biological differences. 3Almost a decade ago, Farthing contended that, "from the diverse collection of symptoms it seems unlikely that a single medication can reliably treat all aspects of the syndrome". 4S may be accompanied by other clinical manifestations, associated with the GI-tract.Population based and large case studies have shown that one to two thirds of subjects with IBS have symptoms that overlap with functional dyspepsia.Other gut symptoms that were reported among IBS patients were heartburn, nausea, vomiting and early satiety. 5e objective of this trial was to explore the possibility of Absorbatox ® , a potentiated clinoptilolite (mineral device) with unique adsorptive and absorption properties as treatment for IBS.A specific objective was measuring adequate relief as primary outcome.
The exact pharmacological action of Absorbatox ® is not completely clear but the substance may play a role as an ameliorating agent in the ad-and absorption of certain endogenous chemicals which can cause GI symptoms such as diarrhoea, bloating, distension and abdominal discomfort.
The page number in the footer is not for bibliographic referencing www.tandfonline.com/oemd19 possible alternative treatment in IBS.Absorbatox ® is essentially a sorptive, inert device which is not absorbed from the GIT but ad-and absorbs selective products in the GIT.The latter has been identified in in vitro assays specifically for Absorbatox ® , such as E. coli exotoxins, heavy metals, some allergens, fungal toxins (aflatoxin, zearalenone and ochratoxin) and biological autacoids (amines) such as histamine (data on file Absorbatox (Pty) Ltd).

Absorbatox
Absorbatox ® is a patented name of an aluminosilicate belonging to the zeolite family (US Pat#8758775 and 13177298 and 13943056).It is a potentiated clinoptilolite by means of exposing the natural zeolite to the physiochemical procedures, thereby improving the unique physiognomies.It has a significantly enhanced CEC of around 2-4 times higher than that found in nature.
Clinoptilolite is the most common natural zeolite found in sedimentary rock of volcanic origin. 14The clinoptilolite structure is a typical three-dimensional network of AlO4 and SiO4 arranged in a tetrahedral. 15This non-toxic zeolite has a monoclinic crystal symmetry, strong adsorptive and ion exchange capacity, and has been widely utilised by the industrial, agricultural and environmental industry. 16The zeolite has the ability to adsorb bile acids, 17 harmful toxins, 18 gasses including CO 2 , CH 4 , H 2 , 19 NH 3 20 and it also has been shown to reduce bacterial contamination of the gut. 21 is established that some zeolites have antidiarrhoeal, 22 immunostimulatory and antioxidative, 23 antibacterial and antifungal, 24 antacid 25 as well as glucose adsorbent-like properties. 26imal and human data demonstrated the safety of clinoptilolite consumption.A laboratory animal study demonstrated that it was not associated with any toxic effects or biological damage. 22 safety report published in the International Journal of Toxicology did not mention any toxicity of particular concern with clinoptilolite. 27wdered zeolites are inert and whenever ingested do not react chemically with food or body fluids or their metabolites.The risk of any associated adverse effects is therefore said to be insignificant. 28olites and in particular Absorbatox ® have been the topic of many safety studies both in vitro and in vivo demonstrating its safety.Extensive human exposure to clinoptilolites such as Absorbatox ® is documented in various clinical conditions such as diarrhoea.Dosages of 5-31.1 g/kg showed no accumulation or organ toxicity in test animals.Absorption is minimal and only < 1% of silicone is excreted in the urine of any dose and 99% was excreted in the faeces of rodents. 29e active product for this study consisted of 750 mg Absorbatox ® [(Na,Ca,K) 6 Si 30 Al 6 O 72 .NH2O] per capsule.

Methodology
Clinical trials in IBS are difficult to design because, unlike other organic disease entities, IBS lacks a biological marker and its diagnosis is based on symptom criteria, therefore subjective scoring. 30The high placebo response seen in IBS patients enrolled in trials is also bothersome.Researchers are further challenged by selecting the most appropriate study duration and by being able to recruit appropriate patients. 30,31is study screened 94 patients for inclusion.After ethics committee approval (North West University ethics committee) and informed consent was signed.Recruited participants were assigned to the 2-week run-in phase of the study to assess baseline symptoms.Thereafter, participants were randomly assigned to either the active or placebo arms.This was a doubleblind, placebo-controlled study.Participants had to attend five study visits that were distributed over six weeks.It was expected of participants to complete a diary (booklet) throughout the trial period.This diary contained questionnaires that enabled the investigators to assess treatment effect.Participants were treated for four consecutive weeks after the initial run-in period (30 days).
A population sample size (N=54) was finally enrolled in the trial before randomisation.Of the initial 94 patients screened as possible candidates, 40 were disqualified as they either did not meet the Rome III criteria for inclusion or refused participation in a placebo controlled study.During the treatment phase another four participants were disqualified for reasons of: one being noncompliant; one contracted influenza; one's questionnaire was not completed during the baseline phase and one withdrew for personal reasons.
The final statistical analysis was performed on a sample size of 50 subjects, 25 subjects were on placebo and 25 on the active moiety.

Inclusion and Exclusion criteria
IBS may be considered a valid diagnosis if the patient complains of abdominal pain and altered bowel habits in the absence of a structure or biochemical markers.Using extensive and expensive testing procedures is sometimes not valuable when patients, without alarm systems, fulfil the Rome III criteria. 32It is advisable to include as broad a spectrum of patients as possible, as commended by the Rome III criteria. 27tients with alarm symptoms/conditions (weight loss, nocturnal predominant symptoms, progressive deterioration of symptoms, family history of colorectal cancer or inflammatory bowel disease) were excluded from recruitment.The main indications for exclusion as postulated by Corazziari were used: 30 • Patients over 50 years of age who have not had a colonoscopy and patients of 50 years or younger who have not had a colonoscopy or sigmoidoscopy after the onset of IBS symptoms and within the previous 5 years; • Patients with relevant abnormalities on physical examination; • Patients with an abnormal blood count or elevated sedimentation rate; • Clinically evident disturbed behaviour and major psychiatric disorders; • Female patients whose symptoms are suggestive of an underlying gynaecological disorder; • Patients with suspected lactose intolerance, and; • Patients with celiac disease.
Moreover, medication containing cations such as Lithium were also regarded as a criterion for exclusion in this particular study given the sorption nature of the test product.

Participants
Male and female participants over the age of 18 years were recruited in the North-West Province, South Africa, making use of recruitment from medical private practices and in pharmacies by means of flyers, and electronic invitations through mass mailing systems.

Treatment
Participants in the trial received 750 mg Absorbatox ® or placebo capsules three times daily as oral soft gelatine capsules.This dosage was based on the founding of an unpublished study by Koot and associates in which 30 enterotoxin-induced NMRI mice were given different dosages of Absorbatox ® to assess efficacy (reduction in toxicity and stool frequency) 33 as well as a study in patients with NGORD. 34e placebo capsules were similar in form, colour, taste, size and packaging to the potentiated clinoptilolite capsules.

Statistical methods
The StatSoft, Inc. (2013).STASTICA (data analysis software system), version 11. www.statsoft.comwas used for analysis and the Chi-square test was used to determine associations between group membership and outcomes for each week.

Demographics
Two thirds (68%) of the population presented with IBS-M (mixed IBS symptoms) and IBS-D (predominant diarrhoea symptoms) and only a third (32%) presented with constipation as a predominant IBS-symptom (IBS-C).Interestingly, it was noticeable that more than half the participants (56%) were overweight according to their BMI index.
Table 1 illustrates the demographic profiles before analysis.The method of randomisation ensured equal representation of characteristics among treatment groups.Although participants in the Absorbatox ® group were on average older than participants in the Placebo group, no significant differences were observed in the duration of IBS symptoms (described as the number of years that patients are aware of bowel symptoms) and BMI index.In terms of bowel habit subtype (according to Rome III criteria), patients with mixed IBS (IBS-M) were almost equally represented throughout the treatment groups.Thirteen ( 13) IBS-M patients were allocated to the Placebo group, and sixteen ( 16) were allocated to the Absorbatox ® .

Primary Outcomes (Adequate relief)
Participants who qualified as overall responders were defined as the participants who indicated a positive response to treatment in > 50% of the 4 treatment weeks.
At the end of the 28-day treatment (last 4 weeks), 40% (10/25) of participants from the Placebo and 67% (16/24) of participants from the Absorbatox ® group were classified as overall responders.
Table 2 is a summary of responders reported in both active and placebo arm.
A pronounced placebo effect was observed in the placebo arm that coincides with the findings in literature.However, the response to treatment in the active arm increased over time and reached significance in week three (p=0.048)and borderline significance after four weeks of treatment (p=0.06).
Over the four weeks of the trial, around 40% of those on the placebo arm experienced adequate relief in each of the four weeks.In the first week, approximately 32% of participants on the active treatment experienced adequate relief.This steadily increased to 67% in the final week on active treatment.

Secondary endpoints
It was not possible to obtain statistical significance in measuring secondary endpoints in this trial, as expected from the small number of participants in the trial.Some of the secondary endpoints measured were: 1) Bowel habit satisfactions; 2) Number of days with pain over the last 10 days and; 3) Interference with life (quality of life) The page number in the footer is not for bibliographic referencing www.tandfonline.com/oemd21

Discussion
This trial recruited patients from various resources using inclusion and exclusion criteria in concordance with literature recommendations. 8,30,357][38] However, due to logistic reasons and with the intention to keep this trial as non-invasive as possible and naturalistic within the general practitioner environment, laboratory and radiological tests were not performed on IBS candidates unless clinically indicated and requested by the treating doctor.
At the end of treatment 67% and 40% of patients were classified as overall responders in the Absorbatox ® and Placebo groups respectively (N=50) (see Figure 1).After week three and week four of treatment, the number of weekly responders was significantly higher (p < 0.5) in the Absorbatox ® group compared to the Placebo group.
When patients with predominant constipation were excluded, IBS-C (constipation dominant group), then 74% of overall responders were found to be in the active group compared to 29% of overall responders in the placebo group (p=0.01)(see Figure 2).Absorbatox ® treatment was more effective in the treatment of IBS-D (diarrhoea dominant) and IBS-M (mixed group) testing for adequate relief.Absorbatox ® showed clinical benefit and warrants further exploration within the mentioned groups.
Although the placebo effect was largely present during the trial, the active treatment showed clinical benefit.The mechanism of action is not clear.However, as Absorbatox ® has the ability to ad-or absorb bile acids, harmful toxins, gasses (CO 2 , CH 4 , NH 3 ) and bacterial toxins in vitro may partially explain its efficacy in IBS.This warrants further exploration in larger clinical trials.

Ethical considerations
Guidelines set out by the ICH Good Clinical Practice Guidelines and the World Medical Association Declaration of Helsinki (2004) were followed in the preparation of the study protocol.The protocol was authorised by the Ethics Committee of the North-West University, Potchefstroom, South Africa (Ethical approval no.nwu-0001-08-S5).The trial was also registered with the South African Clinical Trial Register (SANCTR) online at www.sanctr.gov.za, the application ID no.1631.All participants gave written informed consent for participation.
• Jesslee du Plessis, medical physician, who consulted the patients medically.
• JR Kloppers primary researcher for concluding an interim analysis of the trial for the purposes of a dissertation submitted in partial fulfilment of the requirements for the degree Magister Pharmaciae. 22Co-supervisors, Mr GK John and Prof JR Snyman, the mentioned dissertation submitted at the NWU, with special thanks to Mr George John for partnering with the National Research Foundation and allowing the primary researcher to NRF funding.
• Sponsors of the active and placebo substances manufactured by Brunel Farmaseutika (Pty) Ltd. available in South Africa from Absorbatox (Pty) Ltd. as a non-scheduled substance and

Table 1 :
Demographic characteristics before analysis