SUMMARY

Chitosan preparations are available as dietary aids in slimming. In vitro, in vivo and clinical studies have demonstrated its ability to bind to triglyceride fats. Observations have been made with a hypocalorific diet, whilst no benefits were seen with dietary restrictions.

The study in dispute investigated LipoSan Ultra^TM, which in my opinion, does show positive results in conjunction with an unaltered diet. The participants of the study were all female and were overweight or slightly obese and 30% or more of their diet consisted of fat. Equal to and over this percentage is considered to be a health risk.

The study showed that there was a significant increase in body weight and body mass index in the placebo group whilst the opposite was true for the treatment group. Although an increase in percent body fat and a decrease in lean body mass was observed in the treatment group, it was not statistically significant although, a significant increase was observed in the placebo group.

LipoSan Ultra^TM appears to prevent a gain in weight, whilst also encouraging weight loss, even without the reduction of calorie intake.

INTRODUCTION

The causes of weight gain include an increased availability of food, lack of exercise, increased stress, decreased motivation and increased alcohol consumption. A person's susceptibility to weight gain plays an essential factor. Obesity is defined as a body fat % greater than 32% in females and greater than 25% in males, (Lohman, 1992). Obesity can lead to a variety of disorders such as coronary artery disease, hypertension, strokes and abnormalities in the blood lipid profile. Other consequences of obesity include non-insulin dependent diabetes mellitus, increased cancer risk, osteoarthritis, degenerative joint disease and menstrual irregularities, (National Institute of Health, 1985). Furthermore, psychological effects often accompany weight gain, which may consist of low self-esteem, depression or feelings of guilt.

There are pharmaceutical agents to facilitate weight management but consumers are searching for safer, natural and effective slimming agents. A potential candidate is chitosan, which is already available as a dietary supplement and is used to facilitate weight control, (Muzzarelli and De Vincenza, 1997; Muzzarelli, 2000; Furda, 2000; Wadstein et al., 2000).

Chitosan occurs naturally in some filamentous fungi and is also formed by the deacetylation of chitin found in crustaceae shells. The enzymes that catalyse the latter are found in plants and microorganisms. Chitosan formation from chitin can also be performed by the use of hot alkali solutions. Scientific studies reveal that this cationic polysaccharide binds to dietary fats and bile acids, (Sugano et al., 1978; Nauss et al., 1983; Maezeki et al., 1993; Furda, 2000;).

One of the chitosan products currently available is LipoSan Ultra^TM, which is highly soluble and possesses a high density, (Johnson and Nichols, 2000). The solubility rate, molecular weight and concentration probably affects the efficacy of chitosan, and consequently in both in vitro studies, and clinical trials, LipoSan Ultra^TM demonstrated greater efficacy than chitosan itself in binding fat (Nichols 2001).

This suggests that it has greater potential in the treatment of obesity and weight gain than chitosan itself. Despite these findings, the positive results of the LipoSan Ultra^TM study have received criticism, and in this report these will be discussed.

[NOTE: Criticisms appear in the text as italics and in bold.]

THE STUDY

The study (Nichols et al., 2001) investigated the effects of LipoSan Ultra^TM on weight loss and body composition in overweight and mildly obese subjects. A double blind placebo-controlled trial was performed using 69 healthy females who were overweight or mildly obese. The treatment group received 3 capsules containing 500mg chitosan twice daily for 8 weeks, whilst the other group received the placebo equivalent.

In other trials, chitosan administration, in conjunction with a low calorie, diet was shown to produce significant weight loss, (Sciutto and Colombo, 1995; Colombo and Sciutto, 1996). However, such results have not been observed when the amount of calories consumed was restricted, (Pittler et al., 1999; Ho et al., 2001).

As mentioned already, LipoSan Ultra^TM demonstrates a greater efficacy in binding fat than chitosan, and in the criticized study, no dietary restrictions or modifications were imposed.

"We are also unclear as to whether a routine 30% intake of dietary fat is normal for your target market (given that it is inappropriate to target obese people in general advertising)".

The individuals recruited had a routine fat intake that constituted at least 30% of their daily calories. It is recommended that our dietary intake of fat should not be more than 30% of our calorie intake, (Howley and Franks, 1997), and thus, this is a suitable parameter for subject recruitment.

"It is not clear if the subjects were really blind to their treatment allocation..."

The group to which the subjects were assigned was determined using a random numbers table. Both the subjects and the investigators did not know which group a subject was allocated to, i.e. they were blind to group assignment. Neither was aware of whether the capsules received contained drug or placebo because both were of identical appearance. The study was approved by the Human Subjects Review Committee of the American Institute for Biosocial and Medical Research (Puyallup, WA), which conducts independent clinical trials in the field of natural medicines.

Furthermore, personal communication with the center’s director Dr Alex Schauss, has confirmed that there was no evidence that the trial was "unblended" at anytime and that the study was approved by an outside independent review committee that follows standard protocols that you would find in any institution that conducts clinical trials.

"We are unclear as to how a 'stable weight history' has been defined and whether the system of diet diaries is a sufficiently rigorous means to assess subjects' daily calorific intake. This particularly concerns us giving that the average weight loss by the Liposan group was only 1kg over the 8-week period of the trial".

Potential participants were assessed for suitability to the study. The exclusion criteria were 1) history of metabolic, hepatic, renal, autoimmune, gastrointestinal or neurological disease; 2) consumption of OTC products and/or pharmaceutical products; 3) history of eating disorders, bipolar disorder, severe depression; 4) experiencing peri-menopausal or menopausal symptoms; 5) pregnant or nursing. Through these criteria, healthy individuals with a 'stable weight history' were selected.

Furthermore, participants were asked to fill out the Beck Depression Inventory and the Medical Outcome Survey, (Short Form 36) both prior to and after the study to validate their suitability.

The subjects completed 3-day diet diaries at baseline and weeks 4 and 8; these revealed no significant changes in dietary fat intake in either the placebo or the treatment group. A diet diary, or food log, is most commonly used to assess dietary intake and consists of a record of everything a person has eaten, which includes methods of preparation, e.g. fried in olive oil, (Howley and Franks, 1997). A record of 1 day is not sufficient and they are usually kept for 3 or 7 days. This data can then be analysed by one of the software packages available.

Typical problems include the tendency to not record everything that is consumed. This may be due to guilt, forgetfulness or embarrassment of their eating habits. Measures against this include the emphasis that the records are essential for the outcome of the study.

In the study the Nutritionist IV software programme was used to assess the subject's food intake, (version 4.0 First Databank, San Bruno, CA). This is a well-used & reputable package that displays the nutrient analysis of any food or combination of foods selected.

It was found that there was a significant increase in weight gain in the placebo group of 1.5kg (p<0.01). Whilst in the treatment group a significant decrease of 1.0kg was seen (p<0.005). In respect of the observations made it would appear that LipoSan Ultra^TM both prevented weight gain and actually caused a weight loss. By comparing placebo and treatment groups it could be said that the average weight loss induced by the treatment is roughly 2.5kg. This is validated but there being no significant differences in demographics (age), anthropometrics (height, weight, body mass index, body fat %, lean body mass %), and dietary and caloric intake between the 2 groups.

"It is our understanding that Chitosan binds and expels fat. Given this, we are unclear as to why the average percentage of body fat increased in the Liposan group, despite weight loss".

Using the impedance data a significant increase in percent body fat (p<0.005), and body mass index (p<0.01), as well as a significant decrease in percent lean body mass (p<0.005), was seen in the placebo group. Percent body fat is most frequently used to assess body composition; it refers to the total body weight that is constituted by fat. It is estimated rather than measured, which would require tissue dissection, (Howley and Franks, 1997).

Although a 0.6% increase in body fat and a 0.5% loss of lean body mass was also observed in the treatment group, statistical analysis shows that these are not statistically significant results. In consideration of the results for the placebo group it would appear that LipoSan Ultra^TM prevents an increase in the percent body fat, rather than actually decreasing it.

Another parameter used to assess body composition was waist-to-hip ratio (WHR), which requires measurements of the waist and hip, (Howley and Franks, 1997). An increase in WHR is associated with an increase in girth. Although the WHR does not inform one of the bodily fat and non-fat components, the results in this study did indicate that they were lower at week 8 in the treatment group compared to baseline, whereas in the placebo group the values had increased.

These observations indicate that girth size was reduced in the treatment group compared to an increase in the placebo group. These results were shown to be significant using statistical analysis (1-tailed paired student t-test).

Furthermore, in the treatment group there was a significant decrease in the body mass index (BMI) (p<0.05). This parameter, also referred to as the Quetelet Index, is commonly used to clinically assess the suitability of a person's weight. The U.S. Centers for Disease Control utilise the BMI to assess obesity risk. It is derived by dividing weight (kg) by height squared (m²). Negative health consequences, such as cardiovascular disease, are associated with an increase in BMI, (Howley and Franks, 1997).

At the end of the study (week 8) the BMI of the placebo group had increased whilst that of the treatment group had decreased, both of which were found to be significant. This is in accordance with the weight loss observed in the treatment group and weight gain in the placebo group. Furthermore, a decrease in BMI indicates that the treatment group are less at risk of negative health consequences. This suggests that LipoSan Ultra^TM possesses properties that are potentially beneficial for overweight and mildly obese individuals whose BMI is high.

"Since the effect of the treatment is small there may be no difference between Ostrin and placebo on weight loss if the 5 lost from the Ostrin group had lost little weight, and those on placebo were better losers. Analysis should have been on intention to treat, not on completers only".

Seven subjects were excluded from completing the study due to non-compliance with the study protocol, whilst one experienced illness, not related to the study. Their results are not included because they did not complete the study, as they were not in compliance of the study protocol. The outcome of these patients is therefore irrelevant to this study.

It would be inappropriate to include them in this kind of preliminary study as their results would unjustifiably weaken or strengthen the assessment of the effect of LipoSan as a fat reducing agent, after all this material is a dietary supplement and cannot be assessed, based on pharmaceutical drug - like protocols.

For example, cosmetic and food products have less stringent requirements for their safety and efficacy compared to pharmaceutical drugs and with natural products supporting data is even acceptable to the MCA and the Novel Foods Committee that relies on a previous history of use. To judge this product by pharmaceutical standards is therefore inappropriate.

The other two subjects that were not included in the results were lost during the follow-up. Furthermore, Chi-squared analysis indicates that significantly more people in the treatment group than in the placebo group experienced a weight loss, 62.8% and 17.0% respectively.

"Although the marketing material states that each tablet contains 500mg of Chitosan, (Liposan Ultra) 20mg of Vitamin C and 18mcg of Chromium (GTF), we note that in the study, each tablet contained >90% Chitosan and <10% succinic acid'. It is our understanding that succinic acid plays a role in the metabolic process and we are concerned that the difference in formulation could have affected the results of the trial."

There is evidence to suggest that ascorbic acid is synergistic to chitosan in its effects as a lipid binder (Kanachi et al., 1995). Therefore it is possible that succinic acid could also synergise chitosan in the same way. However the scientific literature has shown that lactic acid does not act as a synergist while in fact sodium ascorbate does. Therefore, if anything, it is likely that since the new formulation contains vitamin C, it would probably be more effective than the formulation used in the study due to possible synergy effects, justifying further the supporting data for the product.

So the criticisms about succinic acid seemed to lack foundation here. Succinic acid is of course an intermediate in the respiration process and may increase metabolism or energy release from carbohydrates and fats etc., but I am not aware of any studies that validate the use of succinic acid to facilitate weight loss.

"Chitosan is neither natural nor new. It is derived from chitin by a chemical process".

Chitosan is synthesised through the deacetylation of chitin, which is the major structural polysaccharide found in the shell of crustaceans. After cellulose chitin is the second most abundant biomass. The main difference between chitosan and chitin is the degree of acetylation. The enzymes, (deacetylases), that catalyse this conversion occur naturally in plants and microorganisms. Chitosan is also present in the cell wall of filamentous fungi that belong to the Mucoraceae family, (Bartnicki-Garcia, 1968).

The fungi are treated with hot aqueous alkali solutions, such as sodium hydroxide, and the resulting alkali insoluble substances are reacted with organic acids to isolate chitosan. Chitosan is also manufactured commercially via the deacetylation of chitin using hot alkali solutions, (Johnson and Peniston, 1980). Chitin is obtained from crustacean shells via the removal of protein, using hot aqueous alkali solutions, and minerals, using hydrochloric acid, (Mukherjee, 2001).

It would therefore be more correct to refer to chitosan in LipoSan Ultra^TM as 'naturally derived', since chitin has been chemically modified to produce chitosan itself. It could also be referred to as a "Natural identical".

The question of a product as being natural has not been fully defined and one can ask where do you draw the line. Is orange juice a natural product since by expressing the juice the composition of the juice changes compared to that found in the plant. Essential oils, which are steam extracted from plants, are also regarded as natural products but in fact often have different phytochemical compositions compared to those found in the plant. Therefore there is a strong argument to support the description of the product as natural or "naturally derived."

CONCLUSION

The results do suggest that LipoSan Ultra^TM causes a significant loss in body weight and a reduction in body mass index (BMI). Furthermore, comparison with the placebo group shows that it also prevents weight gain, which is highly desirable for those wishing to lose it.

Associated with weight gain are health complications, which can have serious consequences, for example, heart disease and non-insulin dependent diabetes mellitus. The decrease in BMI in the treatment group further highlight its potential benefits in overweight and mildly obese people. Whilst there was a significant increase in percent body fat and a significant decrease in lean body mass in the placebo treated group, no significant changes were seen in those receiving LipoSan Ultra^TM.

The selection criteria requiring a fat intake of greater than 30% of the diet is sensible considering that above this value is considered to be a health risk. Furthermore, the use of dietary diaries is also common practice for assessing weight management. Whilst impedance parameters such as body mass index are recognised by the U.S. Centers for Disease Control.

The study indicates that LipoSan Ultra^TM can facilitate weight loss. Positive results have been seen before with chitosan preparations but in these studies the calorie intake was reduced. Here, positive results were observed even though there was no modification of the diet, which is very exciting and indicates its beneficial use to consumers that want to lose weight without changing their diets or undertaking extra exercise.

Report written by Dr John A. Wilkinson BSc PhD DIC MRSC C Chem

Date: 25.303

AUTHOR DETAILS

Dr John Wilkinson is Senior Lecturer in Pharmacognosy and Phytochemistry at Middlesex University, UK. He program led the Western World's first degree in herbal medicine in 1994. He is also director of Herbal Sciences International Ltd a company that conducts R & D on natural products through clinical trials, in vitro testing and chemical analysis. He has over 15 years experience in the research and development of organic compounds and natural products for use as pharmaceuticals, cosmetics, health foods, herbal medicines and dietary supplements. He previously worked in the drug development departments of Beecham's Pharmaceuticals and the Welcome Research Laboratories, both of which are now part of GSK pharmaceuticals. He obtained his PhD at Imperial College of Science Technology and Medicine and was also an SERC NATO post doctoral research fellow with the Nobel Prize Winner, Professor George Olah at the University of Southern California, Los Angeles, CA USA.