Search Article Keyword:  

PubMed Submission Abstract PDF Feed Back Count: 1600 Download Count: 462 

ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2008 March 28; 14(12): 1805-1809
                                                                                                                                         
                         EDITORIAL
Intragastric injection of botulinum toxin for the treatment of obesity. Where are we?

Diego Garcia-Compean, Hector Maldonado Garza


Diego Garcia-Compean, Hector Maldonado Garza, Department of Gastroenterology, Faculty of Medicine, University Hospital. Ave Madero y Gonzalitos, Col Mitras Centro, Monterrey 64700, Mexico

Author contributions: Jaquez Quintana JO and Reyes Cabello E contributed equally to this work.

Correspondence to: Diego Garcia-Compean, Department of Gastroenterology, Faculty of Medicine, University Hospital, Ave Madero y Gonzalitos, Col Mitras Centro, Monterrey 64700, Mexico. digarciacompean@prodigy.net.mx

Telephone: +52-81-83487315  Fax: +52-81-89891381

Received: January 4, 2008      Revised: January 29, 2008

 

Abstract

Obesity has reached epidemic proportions particularly in western countries. Most non-surgical treatments of this condition are disappointing. Since 2005, several studies evaluating the effect of Botulinum Toxin type A (BT-A) in gastric antrum by means of endoscopy for the treatment of obesity have been published. This treatment modality was based on the observation that gastric injection of BT-A in laparatomized rats induced a significant reduction of food intake and body weight. Nowadays, 6 studies have been published yielding conflicting results. Differences in selection of patients, doses of BT-A, method of administration of the toxin and instruments of evaluation of some parameters among these studies may be the cause of divergent results. We discuss herein some important features of these studies pointing out on differences among them. At the same time, based on the knowledge of physiological characteristics of normal and abnormal gastric function related with feeding, we discuss the probable causes of failure observed in these trials. Finally, we give some guidelines concerning the way that future research in this field may follow, not without calling attention to disadvantages of this treatment.

 

© 2008 WJG. All rights reserved.

 

Key words: Botulinum toxin; Obesity; Gastric emptying; Gastric motility; Gastroparesis

 

Peer reviewers: Yvan Vandenplas, Professor, Department of Pediatrics, AZ-VUB, Laarbeeklaan 101, Brussels 1090, Belgium; Andrew Ukleja, MD, Assistant Professor, Clinical Assistant Professor of Medicine, Director of Nutrition Support Team, Director of Esophageal Motility Laboratory, Cleveland Clinic Florida, Department of Gastroenterology, 2950 Cleveland Clinic Blvd., Weston, FL 33331, United States

 

Garcia-Compean D, Maldonado Garza H. Intragastric injection of botulinum toxin for the treatment of obesity. Where are we? World J Gastroenterol 2008; 14(12): 1805-1809  Available from: URL: http://www.wjgnet.com/1007-9327/14/1805.asp  DOI: http://dx.doi.org/10.3748/wjg.14.1805

 

INTRODUCTION

The prevalence of obesity has increased in western countries in the last few decades, reaching epidemic proportions[1]. It affects more than 30% of general population in the US.  In this country, the costs attributed to obesity amounts to 100 billion dollars per year[2] and the number of deaths attributed to obesity is approximately 280000 annually[3]. Obesity increases the risk of morbidity and mortality, since some disorders such as diabetes, arterial hypertension, cardiovascular and cerebral illnesses, as well as hepatobiliary disorders, are particularly frequent in obese individuals[2].

The dietetic, pharmacological and behavioral treatments have demonstrated to have limited effect and duration[4]. The intragastric balloon applied by endoscopy has equally given partial and transitory results[5]. Surgical treatments (gastric banding and gastric by-pass), even if they are the most effective in some patients, particularly those with morbid obesity, are invasive procedures and may have complications, some of them fatal[6]. In view of the above, the search for new methods for weight reduction is completely justified.

In the year 2000, Gui et al published a pioneering study in which they show that intra-muscular injections of Botulínum Toxin type A (BT-A) in the gastric wall of laparatomized normal-weight rats significantly reduced their food intake and body weight[7]. Subsequently, such findings were confirmed in 2005, by Coskun et al in obese rats. This group also observed a significant delay of gastric emptying in rats that had received BT-A[8]; therefore, they attributed body weight reduction to an effect of early satiety probably induced by the pharmacologically induced gastroparesis.

 

BOTULINUM TOXIN

Botulínum Toxin is produced by the bacterium Clostridium botulinum. There are several serotypes from A to G. When this toxin is ingested by the human being it can produce a form of food poisoning known as botulism. The BT-A has a powerful inhibiting effect of long duration on the muscular contractions of smooth and striated muscles[9]. This pharmacological property has been used in the treatment of some digestive illnesses characterized by muscular spasm, particularly achalasia and anal fissure[10,11]. BT-A binds with high affinity to cholinergic nerve endings and selectively inhibits their activity. Acetylcholine is considered the most important stimulating agent both in intrinsic (myenteric) and extrinsic (vagal) nervous systems[12].

 

SATIETY AND GASTRIC MOTILITY

Additionally, the mechanisms that induce the gastric satiety are complex and they are related to the motor function of the stomach as well as to endocrine and paracrine effects acting in interrelated form. It is known that several mechanisms are involved in the induction of satiety such as distension and accommodation of the stomach, as well as hormones such as cholecystokinin (CCK), glucagon-like peptide (GLP-1), bombesin, liberating-gastrin peptide and somatostatin. It has also been observed that ghrelin, which is a peptide produced in the stomach, has orexigenic effect that probably controls the appetite at a central hypothalamic level. Other factors also intervene for the control of appetite as glycemia and some hormones such as insulin, leptin and enterostatin. It has been observed, for example, that duodenal infusion of fat induces a delay of gastric emptying and sensation of satiety[13]. Additionally, gastric banding increases the cholecystokinin plasma levels[14], the Roux-en Y gastric by-pass inhibits basal and postprandial ghrelin plasma levels and increases peptide YY (PYY) concentrations[15]. The jejunoileal by-pass increases cholecystokinin, motilin, GLP-1 and PYY[16], delays gastric emptying and reduces hunger sensation. As cholecystokinin, ghrelin and PYY also influence the gastrointestinal motility, it may be possible that a mechanism related to modifications of the gastric emptying is responsible for the early satiety and reduction of body weight observed in these operated patients.

Also the patterns of the gastric motility are well known. The fundus and proximal portion of the gastric body relax during the prandial and postprandial period; therefore, the intra gastric pressure is not modified in a significant form at the beginning of food ingestion. This phenomenon is known as “gastric accommodation”, a term which was introduced almost 100 years ago[17]. It consists of a receptive relaxation induced by the bolus deglutition and an adaptive relaxation influenced by the increase of the intragastric pressure due to food accumulation into the stomach. The impairment of the gastric accommodation seems to be initially responsible for the sensation of fullness and satiety[18]. Meanwhile, gastric antrum muscles contract in concentric form by means of rings of distal displacement impelling the gastric content to the duodenum. Nevertheless, the pylorus in postprandial period contracts preventing the early passage of solid meals to the duodenum. Thus, meals are returned to the gastric body in repeated form[19]. The speed with which the stomach empties depends on the nature of meals (the solids retain more time than the liquids), of the osmolarity (the isosmotic meals retain less time than the hypo-osmotic and hyper-osmotic) and of the chemical composition (the fats retain the most time). The hormonal mediators previously mentioned are produced by means of chemical and mechanic stimuli triggered by meals in the stomach and the proximal intestine and their main function is regulation of the gastrointestinal motility.

 

GASTROPARESIS

Gastroparesis is a gastric disorder characterized by a delay in the gastric emptying. The etiology is very diverse. The typical clinical manifestations are eructation, early satiety and sensation of gastric fullness, epigastric discomfort, nausea and vomiting and reduction of body weight[20]. It has been found that the patients with anorexia nervosa have a significant delay of gastric emptying compared to normal individuals or those with bulimia[21].

 

CLINICAL STUDIES OF BT-A FOR TREATMENT OF OBESITY

In accordance with all mentioned above, the clinical use of the BT-A injected into the gastric antrum in obese patients for inducing gastric emptying delay and body weight reduction seemed logical.

This idea was reinforced from the report of Rollnik et al, of a patient in whom the injection of BT-A in the gastric antrum by endoscopy was associated with a reduction of 9 kg of body weight and 32.5% of the caloric daily intake 4 mo after treatment[22].

In the last two years, 6 studies evaluating this novel treatment have been published[23-28]. Three were open pilot and 3 were randomized double blind controlled trials (one of them performed by our group[23]) of which in only one, beneficial effect of BT-A on body weight reduction was observed[27]. Nevertheless, important differences among these studies deserve to be discussed in detail (Table 1).

 

The dose of BT-A

The dose of BT-A used in all the studies was highly variable. It ranged from 100 UI to 300 UI. However, in the study in which the maximum dose was used no effect on body weight reduction was observed. Perhaps more important than the dose of BT-A was the method of application.

 

Method of application of BT-A

In all the studies, BT-A was administered by means of endoscopic antral injections in a number of punctures that ranged from 8 to 24 in circular disposition. Probably, it was expected that the more the punctures performed the more intra muscular diffusion of the toxin might have been obtained. Nevertheless, this factor was not crucial since in the study in which the greatest number of punctures was done, (24 punctures) the results were negative.

It is important to point out that BT-A were injected both into the antrum and the gastric fundus in the only study in which positive results were obtained (in the rest of the studies only antral injections were done). If we remember, the gastric fundus does not have a propulsive effect as the antrum, injections in this place to cause gastric emptying delay would not seem to have justification. Notwithstanding, the existence of other mechanisms related to satiety that might have origin in the fundus must be considered as we will discuss later.

 

Early satiety

Of 4 studies in which early satiety was evaluated after therapy, a positive effect was observed in 3 (two of them were randomized double blind controlled trials). However, only in 1 of these 3 studies a significant body weight reduction was observed. This incongruousness between early satiety and absence of weight reduction observed in some studies may be due to the difficulties of measuring a subjective parameter like this, or perhaps the intensity of the early satiety was not enough to produce significant body weight loss.

 

Gastric emptying

In only 1 of 5 studies in which gastric emptying after therapy was evaluated a significant delay was observed. Notwithstanding, diverse methods were used for measuring this parameter: octanoic acid breath test, gastric emptying scintigraphy for solids and liquids labeled with Technetium 99 and Indium 111, respectively. It is well known that results of these procedures can be affected by several factors (type of test meals, chemical composition and osmolarity of the test meals, quantity of liquid, etc.). For this reason these procedures must be carefully standardized in every laboratory. In regards to the above mentioned, presently highly sensitive and specific procedures for measuring gastric emptying are not available[29].

 

HOW TO EXPLAIN THE DIFFERENCES OF RESULTS BETWEEN THE ONLY POSITIVE AND THE 5 NEGATIVE STUDIES?

In the only positive study performed by the Italian group, 8 injections of BT-A were done in the gastric fundus in addition to the injections in gastric antrum. Conversely in the other studies, injections in the antrum were only done. In this positive study a significant modification of all the evaluated parameters were observed after treatment: presence of early satiety, a delay in gastric emptying, a reduction of the maximal gastric capacity for liquids and more importantly: a significant reduction of body weight. As authors of this study pointed out, gastric fundus is the principal source of ghrelin[30] and it also has sensory activity that regulates the total gastric capacity[31]. Ghrelin is a 28 amino acids peptide produced by the stomach with orexigenic effect acting on the arquatte nucleus of the hypothalamus. Ghrelin plasma levels increase during periods of fasting and reduce after a meal, in other words, this peptide seems to have a regulatory effect of hunger. However, published studies have shown that ghrelin expression in gastric mucosa, measured by histochemistry, increased one year after gastric banding in obese patients who maintained body weight loss; this would discard the physio-pathogenic role of ghrelin in body weight loss of these patients[32]. Similarly, in another study, high ghrelin plasma levels did not predict a minor loss of body weight in patients with gastric banding compared to patients with normal plasma ghrelin levels[33]. Conversely, Roux-en Y gastric by-pass inhibits basal and postprandial ghrelin plasma levels[15]. Additionally, ghrelin increases gastric emptying and stimulates gastric motility during fasting[34]. For all the above mentioned, it is difficult to clarify the role of ghrelin in body weight reduction of the patients in the positive study, particularly when plasma levels of this peptide were not measured.

The reduction of the maximal capacity for liquids after BT-A treatment may be explained by impairment of the gastric fundus accommodation inducing early satiety. Nevertheless, the test of gastric maximal capacity for liquids has poor reproducibility for measuring gastric accommodation. Recently, a novel scintigraphic method for simultaneously assessing gastric accommodation and emptying has been developed using dual-isotopes, either (99m)Tc-pertechnetate intravenously and (111) In-diethylenetriaminepentaacertic acid in a liquid nutrient drink or an (111) In-oxine-labeled egg sandwich meal. Emptying and accommodation were measured using single positron emission computer tomography (SPECT) every 20 min and up to 240 min[35].

On the other side, the mean delay of gastric emptying observed in patients after BT-A, although significant, was short. Therefore, it makes it difficult to attribute early satiety and body weight reduction to this mechanism.

Finally, treated and untreated patients were given reductive diets of 1200 kcal/day. This may explain the reason why non treated patients also had a significant body weight reduction. Therefore, it is very probable that in treated patients a combined effect of reductive diet and toxin was observed.

 

FUTURE OF BT-A IN THE TREATMENT OF OBESITY

In the context of all the above discussed, the following question arises: What is the future of the endoscopic gastric injections of BT-A for the treatment of obesity?

In our opinion the method of antral injections has a very uncertain future. If we take into account that this drug is expensive (100 UI cost about 350 Euros or $530 dollars), the performance of a study on a major scale is very difficult to achieve given the present circumstances.

Notwithstanding, it remains to be clarified if BT-A injections in the gastric fundus have better results in body weight reduction in obese patients. Perhaps the mechanism of action would be more difficult to explain. Modifications of gastric accommodation inducing early satiety may be an attractive hypothesis. Nevertheless, the measurement of this parameter in future studies by means of reliable tests will be the obstacle to overcome.

If gastric injections of BT-A demonstrate to be effective for the treatment of obese patients in the future, there is another disadvantage that must be considered: the limited duration of its effect (3 mo-6 mo). Therefore, for long-term administration by repeated administration of this drug, the cost-benefit relation has to be taken into account.

In medical science, it is frequent to find an agent that works and less frequent to know how it works. Consequently, we considerably learn from the test error method.

 

REFERENCES

1     Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA 2002; 288: 1723-1727   PubMed

2     Wolf AM. What is the economic case for treating obesity? Obes Res 1998; 6 Suppl 1: 2S-7S   PubMed

3     Allison DB, Fontaine KR, Manson JE, Stevens J, VanItallie TB. Annual deaths attributable to obesity in the United States. JAMA 1999; 282: 1530-1538   PubMed

4     Weigle DS. Pharmacological therapy of obesity: past, present, and future. J Clin Endocrinol Metab 2003; 88: 2462-2469   PubMed

5     Fernandes M, Atallah AN, Soares BG, Humberto S, Guimaraes S, Matos D, Monteiro L, Richter B. Intragastric balloon for obesity. Cochrane Database Syst Rev 2007; CD004931   PubMed

6     Livingston EH. Obesity and its surgical management. Am J Surg 2002; 184: 103-113   PubMed

7     Gui D, De Gaetano A, Spada PL, Viggiano A, Cassetta E, Albanese A. Botulinum toxin injected in the gastric wall reduces body weight and food intake in rats. Aliment Pharmacol Ther 2000; 14: 829-834   PubMed

8     Coskun H, Duran Y, Dilege E, Mihmanli M, Seymen H, Demirkol MO. Effect on gastric emptying and weight reduction of botulinum toxin-A injection into the gastric antral layer: an experimental study in the obese rat model. Obes Surg 2005; 15: 1137-1143   PubMed

9     Hallett M. One man's poison--clinical applications of botulinum toxin. N Engl J Med 1999; 341: 118-120   PubMed

10   Bhutani MS. Gastrointestinal uses of botulinum toxin. Am J Gastroenterol 1997; 92: 929-933   PubMed

11   Lemiere S, Bruley Des Varannes S. Pharmacologic actions and therapeutic importance of botulinum toxin in digestive diseases. Gastroenterol Clin Biol 1999; 23: 229-237   PubMed

12   Ward AB, Molenaers G, Colosimo C, Berardelli A. Clinical value of botulinum toxin in neurological indications. Eur J Neurol 2006; 13 Suppl 4: 20-26   PubMed

13   Barbera R, Peracchi M, Brighenti F, Cesana B, Bianchi PA, Basilisco G. Sensations induced by medium and long chain triglycerides: role of gastric tone and hormones. Gut 2000; 46: 32-36   PubMed

14   Foschi D, Corsi F, Pisoni L, Vago T, Bevilacqua M, Asti E, Righi I, Trabucchi E. Plasma cholecystokinin levels after vertical banded gastroplasty: effects of an acidified meal. Obes Surg 2004; 14: 644-647   PubMed

15   Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002; 346: 1623-1630   PubMed

16   Naslund E, Gryback P, Hellstrom PM, Jacobsson H, Holst JJ, Theodorsson E, Backman L. Gastrointestinal hormones and gastric emptying 20 years after jejunoileal bypass for massive obesity. Int J Obes Relat Metab Disord 1997; 21: 387-392   PubMed

17   Cannon WB, Washburn AL. An explanation of hunger. 1911. Obes Res 1993; 1: 494-500   PubMed

18   Mundt MW, Hausken T, Smout AJ, Samsom M. Relationships between gastric accommodation and gastrointestinal sensations in healthy volunteers. A study using the barostat technique and two- and three-dimensional ultrasonography. Dig Dis Sci 2005; 50: 1654-1660   PubMed

19   Quigley EM. Gastroduodenal motility. Curr Opin Gastroenterol 2000; 16: 479-488   PubMed

20   Hasler WL. Gastroparesis: symptoms, evaluation, and treatment. Gastroenterol Clin North Am 2007; 36: 619-647, ix   PubMed

21   Hutson WR, Wald A. Gastric emptying in patients with bulimia nervosa and anorexia nervosa. Am J Gastroenterol 1990; 85: 41-46   PubMed

22   Rollnik JD, Meier PN, Manns MP, Goke M. Antral injections of botulinum a toxin for the treatment of obesity. Ann Intern Med 2003; 138: 359-360   PubMed

23   Garcia-Compean D, Mendoza-Fuerte E, Martinez JA, Villarreal I, Maldonado H. Endoscopic injection of botulinum toxin in the gastric antrum for the treatment of obesity. Results of a pilot study. Gastroenterol Clin Biol 2005; 29: 789-791   PubMed

24   Albani G, Petroni ML, Mauro A, Liuzzi A, Lezzi G, Verti B, Marzullo P, Cattani L. Safety and efficacy of therapy with botulinum toxin in obesity: a pilot study. J Gastroenterol 2005; 40: 833-835   PubMed

25   Gui D, Mingrone G, Valenza V, Spada PL, Mutignani M, Runfola M, Scarfone A, Di Mugno M, Panunzi S. Effect of botulinum toxin antral injection on gastric emptying and weight reduction in obese patients: a pilot study. Aliment Pharmacol Ther 2006; 23: 675-680   PubMed

26   Junior AC, Savassi-Rocha PR, Coelho LG, Sposito MM, Albuquerque W, Diniz MT, Paixao Ade M, Garcia FD, Lasmar LF. Botulinum A toxin injected into the gastric wall for the treatment of class III obesity: a pilot study. Obes Surg 2006; 16: 335-343   PubMed

27   Foschi D, Corsi F, Lazzaroni M, Sangaletti O, Riva P, La Tartara G, Bevilacqua M, Osio M, Alciati A, Bianchi Porro G, Trabucchi E. Treatment of morbid obesity by intraparietogastric administration of botulinum toxin: a randomized, double-blind, controlled study. Int J Obes (Lond) 2007; 31: 707-712   PubMed

28   Mittermair R, Keller C, Geibel J. Intragastric injection of botulinum toxin A for the treatment of obesity. Obes Surg 2007; 17: 732-736   PubMed

29   Abell TL, Camilleri M, Donohoe K, Hasler WL, Lin HC, Maurer AH, McCallum RW, Nowak T, Nusynowitz ML, Parkman HP, Shreve P, Szarka LA, Snape WJ Jr, Ziessman HA. Consensus Recommendations for Gastric Emptying Scintigraphy: A Joint Report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. J Nucl Med Technol 2008; 36: 44-54   PubMed

30   Fruhbeck G, Diez-Caballero A, Gil MJ, Montero I, Gomez-Ambrosi J, Salvador J, Cienfuegos JA. The decrease in plasma ghrelin concentrations following bariatric surgery depends on the functional integrity of the fundus. Obes Surg 2004; 14: 606-612   PubMed

31   Kim DY, Camilleri M, Murray JA, Stephens DA, Levine JA, Burton DD. Is there a role for gastric accommodation and satiety in asymptomatic obese people? Obes Res 2001; 9: 655-661   PubMed

32   Uzzan B, Catheline JM, Lagorce C, Airinei G, Bon C, Cohen R, Perret GY, Aparicio T, Benamouzig R. Expression of ghrelin in fundus is increased after gastric banding in morbidly obese patients. Obes Surg 2007; 17: 1159-1164   PubMed

33   Busetto L, Segato G, De Luca M, Foletto M, Pigozzo S, Favretti F, Enzi G. High ghrelin concentration is not a predictor of less weight loss in morbidly obese women treated with laparoscopic adjustable gastric banding. Obes Surg 2006; 16: 1068-1074   PubMed

34   Peeters TL. Potential of ghrelin as a therapeutic approach for gastrointestinal motility disorders. Curr Opin Pharmacol 2006; 6: 553-558   PubMed

35   Simonian HP, Maurer AH, Knight LC, Kantor S, Kontos D, Megalooikonomou V, Fisher RS, Parkman HP. Simultaneous assessment of gastric accommodation and emptying: studies with liquid and solid meals. J Nucl Med 2004; 45: 1155-1160   PubMed

 

            S- Editor  Zhong XY    L- Editor  Rippe RA    E- Editor  Lu W

                                                                                             

 

Reviews Add
more>>


Related Articles:
Intragastric injection of botulinum toxin for the treatment of obesity. Where are we?
more>>