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Effects of intramural administration of Botulinum Toxin A on gastric emptying and eating capacity in obese patients
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Digestive and Liver Disease 40 (2008) 667–672
Alimentary Tract
Effects of intramural administration of Botulinum Toxin A on gastric emptying and eating capacity in obese patients D. Foschi a,∗ , M. Lazzaroni b , O. Sangaletti b , F. Corsi a , E. Trabucchi a , G. Bianchi Porro a a
Department of Clinical Sciences, L.Sacco Hospital, University of Milan, Milan, Italy b Unit of Gastroenterology, Department of Surgery, L.Sacco Hospital, Milan, Italy Received 18 August 2007; accepted 18 February 2008 Available online 17 April 2008
Abstract Background. Intraparietal gastric administration of Botulinum Toxin A has been studied in open trials to induce satiety and increase weight loss of obese patients with contradictory results. In previous studies only the antrum was the target for Botulinum Toxin A, whereas the fundus, which exerts important activity on gastric accommodation, was excluded. In this study we report the effects of injection into both gastric regions on solid gastric capacity and emptying of the stomach. Materials and methods. In this study we extended our previous investigations to include 30 obese patients who received Botulinum Toxin A (120 U into the antrum and 80 U into the fundus) or saline by intraparietal endoscopic injection. The two groups were homogeneous for age, gender, body weight and body mass index. Body weight and body mass index, solid gastric emptying (T1/2 and Tlag at the octanoic acid breath test) and maximal gastric capacity for solids (kcal) were determined before injection and 2 months later. The results were expressed as mean values (S.E.M.). t-Test or Wilcoxon test was used for statistical analysis, p < 0.05 being considered significant. Results. Both treatments induced a significant reduction of body weight and body mass index but Botulinum Toxin A exerted a significantly greater effect (body weight −11.8 ± 0.9 kg vs. −5.5 ± 1.1 kg, p < 0.0002; body mass index −4.1 ± 0.2 vs. −2.2 ± 0.4, p < 0.001). The maximal gastric capacity for solids was also reduced by both Botulinum Toxin A and placebo, the former being significantly more effective (679 ± 114 kcal vs. 237 ± 94 kcal, p < 0.008). Botulinum Toxin A also significantly increased T1/2 from 83.4 ± 3.9 to 101.6 ± 9.9 min, p < 0.03) but Tlag was unchanged. Placebo had no effect on either of these parameters. Conclusions. Our results demonstrated that Botulinum Toxin A makes weight loss easier in obese patients. It acts by increasing the solid gastric emptying time and reducing the solid eating capacity of the stomach. © 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Botulinum toxin; Gastric capacity; Gastric emptying; Obesity; Octanoic acid test
1. Introduction Topical Botulinum toxin (Btx) administration into the muscle layer of the gastrointestinal tract exerts therapeutic effects in patients with achalasia, gastric paresis, spasm of Oddi’ s sphincter, anal fissure and pelvic floor disorders [1,2]. In 2000, Gui et al. [3] demonstrated in rodents that intraparietal administration of Btx-A into the gastric antrum causes significant reduction of food intake and decrease of body weight in comparison to sham-operated animals. Coskun et ∗
Corresponding author. Tel.: +39 02 39043204; fax: +39 02 50319846. E-mail address: [email protected] (D. Foschi).
al. [4] also demonstrated that Botulinum toxin injection into the antrum of obese rats leads to weight loss through reduction of gastric emptying. In 2003, Rollnik et al. [5] reported a case of an obese patient who had a significant reduction of food intake and body weight following antral injection of 500 mU of Btx-A. Two further open studies [6,7] extended this observation, but in the series studied by Garcia-Compean et al. [6] no significant effects on body weight and gastric emptying were observed. Recently, Gui et al. [8] found in a double blind pilot study that Btx-A, injected into the gastric antrum of obese patients at two dose levels (133 U and 200 U) reduced appetite, had variable effects on gastric emptying and caused weight reduction, although the loss was
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D. Foschi et al. / Digestive and Liver Disease 40 (2008) 667–672
not statistically significant. Junior et al. [9] investigated the effects of Btx-A injected into the antrum at different dose levels (100, 200 and 300 U) on the solid and semisolid gastric emptying. Although no significant effects of each Btx-A dose were demonstrated, the data for the patients as a whole demonstrated significant slowing of solid emptying at week 8 and semisolid emptying at weeks 2 and 4, respectively. Furthermore, all treated patients reported a feeling of early satiety, but they were not on a calorie-restricted diet and did not lose weight. We also investigated whether or not administration of Btx-A into the gastric wall [10] can help obese patients to adhere strictly to dietary prescriptions and obtain significant body weight reduction. In this study, intended to extend our previous observations, we investigated the effects of intraparietal Btx-A on solid gastric emptying and solideating capacity of patients with a body mass index greater than 35.
2. Materials and methods The investigation, intended to complete our previous observations [10] was performed at the L.Sacco Hospital in Milan, Italy, between January 2004 and November 2005. The protocol was approved by the Ethics Committee of the L.Sacco Hospital and conducted according to the Declaration of Helsinki. All patients gave their written informed consent to the diagnostic and therapeutic procedures according to the study design. 2.1. Admission criteria Age between 18 and 65 years, body mass index (BMI) between 35 and 40 with two complications of obesity or BMI >40. Pregnancy (even potential), a history of malignancy, surgery of the stomach or gastro-intestinal disease refractory to medical treatment were considered preliminary exclusion criteria, as was recent (<3 months) treatment for obesity or weight change. All patients had preliminary dietological, endocrinological, neurological and psychiatric examination to exclude further contraindications to the therapeutic procedure, including:
2.2. Diagnostic procedures 2.2.1. Clinical measurements BW (kg) and height (m) were measured at the first visit with the patient wearing standard light clothing and no shoes. BMI was also calculated as body weight (kg)/height (m2 ). 2.2.2. Gastric emptying evaluation All tests were performed after an overnight fast. The test meal consisted in a standard bun (5.8% protein, 33.3% lipid and 57.5% carbohydrate, 378 kcal), with 100 mg of 2 Ci of octanoic acid (I-13 C) added (Expiroger, Sofar, Italy). The test meal was followed immediately by 250 ml of water. Breath samples were taken immediately before the test meal and every 30 min thereafter for 3 h. Samples were analysed by a mass spectrometer (Breath mass plus, Finnigan, Germany) to measure 13 CO2 . The percentages of 13 CO2 cumulative values over 3 h were fit according to the equation described by Ghoos et al. [11]: y = m(1 − e−kt )β , where y is the cumulative percentage of 13 CO excretion in breath at time t (h) and m, k and β 2 are estimated parameters. In this model, m represents the total cumulative recovery of octanoic acid for time = ∞. The duration of the lag time was defined as the time when 10% of the test meal was emptied from the stomach. The results were measured as half-emptying time (min) [T1/2 = (−1/k) × ln(1 − (0.5)1/β ] and lag-time (min) [Tlag = (−1/k) × ln(1 − (0.1)1/β ]. 2.2.3. Maximal solid gastric capacity At 0:30 p.m., patients were asked to eat ham rolls (210 kcal per roll) until they experienced a sensation of complete fullness or abdominal discomfort. The results were expressed as kcal. 2.3. Study design After completion of the diagnostic procedures, patients were randomized in a double-blind fashion to receive intragastric administration of Btx-A (200 U) (12 patients) or placebo (saline, 12 patients). Six further patients were recruited according to the general selection criteria and assigned to the Btx-A group to increase our observations on the maximal solid gastric capacity test. 2.4. Therapeutic procedure
- heavy binge-eating; - previous botulism, neurological and neuromuscular diseases; - psychotic disorders, alcohol or substance abuse or dependence; - endocrine obesity. On the basis of these selection criteria, 6 patients were added to the previous series of 24 patients and completed the diagnostic and therapeutic procedures.
All therapeutic procedures were performed between 2 and 3 p.m. after a 6 h fast and under diazepam sedation. An Olympus GIF IT 130 operative gastroscope was used for a preliminary evaluation of the oesophagus, stomach and duodenum. Seventeen patients had sliding hiatus hernia, in three cases associated with oesophagitis, three patients had antral gastritis and one patient had pseudopolyps of the fundus. One patient had a gastric ulcer and another duodenitis suggesting Crohn’s disease. These last two patients
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Table 1 General characteristics of the treatment groups
had negative biopsies and were treated with Proton Pump Inhibitors for 45 days before the procedure was successfully performed. Btx-A (Botox, Allergan, USA, 10 IU in 0.5 saline) or saline (0.5 ml) was injected into the submucosa using an Endoflex needle, 2.3 mm in thickness and 230 cm in length. The microinjections were performed at the four cardinal points starting 3 cm from the pyloric ring, and repeated three times moving 2 cm towards the angulus each time. Four more microinjections were performed 2 cm below the cardias, and the last four doses were injected into the fundus of the stomach. The total dose was 200 U, given by 20 microinjections. The time to accomplish the procedure was always less than 10 min. No significant acute side effects were recorded. All patients were observed for 1 h. Only one patient complaining of abdominal pain had to be observed for 12 h.
Gender (M/F) Age (years) BW (kg) BMI (kg2 /m) Tlag (min) T1/2 (min) Maximal solid eating gastric capacity (kcal)
Btx-A (n: 18)
Placebo (n: 12)
1/3 42 ± 3.5 125.7 ± 6.1 44.6 ± 1.4 29.3 ± 2.5 83.4 ± 3.9 1350 ± 150
1/3 45.2 ± 3.7 118.2 ± 5.3 44.1 ± 1.5 35.6 ± 2.3 103.4 ± 4.5* 925 ± 139
*p < 0.05, Wilcoxon rank test.
using a two-tailed Student’s t-test for unpaired data. Differences between times in the same group were compared using a two-tailed Student’s t-test for paired data. Gastric emptying time differences between groups were evaluated using the Wilcoxon rank test. Differences with p < 0.05 were considered significant.
2.5. Diet A 1200 kcal liquid diet (protein 15%, lipid 33%, carbohydrate 52%) was prescribed starting immediately after the endoscopic procedure. The diet was based on a personal choice between several market components for each meal, with a weekly balance between the daily meals. The patients were instructed to follow the diet for 8 weeks.
3. Results The two groups of patients were similar for gender, age, BW, lag time of solid gastric emptying and maximal solid eating capacity before treatment. They differed only for the T1/2 of solid gastric emptying, which was shorter in patients randomized to the Btx-A treatment (Table 1). Both groups of patients had a significant decrease in BW and BMI at the end of the follow-up period, but these decreases were greater in those who had undergone intraparietal administration of Btx-A into the fundus and the antrum of the stomach (Table 2). The effects of Btx-A on gastric emptying were characterized by a significant increase in T1/2 , (from 83.46 ± 3.98 to 101.6 ± 9.9 min, p < 0.03) whereas the Tlag was not significantly modified. Patients treated with saline had no significant increase in either of these gastric emptying parameters (Table 3). Furthermore, Btx-A significantly decreased the maximal gastric capacity of obese patients (Fig. 1). Both groups of patients had a significant reduction of the
2.6. Follow-up Every week, the patients attended our outpatient department to evaluate body weight and BMI. Final body weight measurement, anthropometric measures, maximal liquid gastric capacity test and the octanoic acid breath test were performed 8 weeks after treatment. All patients completed the scheduled follow-up. 2.7. Statistical analysis Results were expressed as mean ± standard error of the mean (S.E.M.). Differences between groups were compared Table 2 Effects of Btx-A on BW and BMI
BW (kg) BMI (kg2 /m) BW reduction BMI reduction
Btx-A pre
Btx-A post
125.7 ± 6.1 44.6 ± 1.4
113.9 40.5 11.8 4.1
± ± ± ±
5.6* 1.4* 0.9 0.2
Placebo pre
Placebo post
118.2 ± 5.3 44.1 ± 1.5
112.4 42.5 5.5 2.2
± ± ± ±
4.9** 1.3*** 1.1ˆ 0.4ˆˆ
*p < 0.0001, **p < 0.0003, ***p < 0.0008 between times. ˆp < 0.0002, ˆˆp < 0.001 between groups. Table 3 Effects of Btx-A on solid gastric emptying
Tlag (min) T1/2 (min) *p < 0.03, Wilcoxon rank test.
Btx-A pre
Btx-A post
Placebo pre
Placebo-post
29.3 ± 2.5 83.4 ± 3.9
32.3 ± 2.3 101.6 ± 9.9*
35.6 ± 2.3 103.4 ± 4.5
34.9 ± 2.5 96.6 ± 5.6
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D. Foschi et al. / Digestive and Liver Disease 40 (2008) 667–672
Fig. 1. Effect of Btx-A on the maximal gastric capacity for solids. Both BtxA and placebo significantly reduced the maximal gastric capacity for solids; Btx-A showed a significant advantage (p < 0.008) on placebo. *p < 0.03 post vs. pre; **p < 0.001 post vs. pre; •p < 0.008 Botox vs. Placebo.
maximal ingested solid charge, but comparison of the two groups of treatment demonstrated a significant advantage (679 ± 114 kcal vs. 237 ± 94 kcal, p < 0.008) after Btx-A treatment.
4. Discussion Obesity strongly affects gastrointestinal functions by direct and indirect mechanisms, resulting in a reinforcement of the ability of patients to increase food intake progressively through inhibition of satiety signals [12]. Geliebter et al. [13–15] and Granstrom and Backman [16] demonstrated that the acute maximal gastric capacity of bulimic and obese patients was higher than that of lean controls, but it remains to be established whether or not it is an adaptive response to overeating or a causative factor of increased food intake [17]. It is generally considered that gastric accommodation is more important than gastric capacity as a factor limiting meal size [17], but only Kim et al. [18] have determined the ratio between postprandial and fasting gastric volume after a liquid meal in obese patients and overweight controls: he found no differences between the two groups of subjects as far as the satiety score and maximal ingested liquid volume are concerned. These results suggest that gastric accommodation does not provide an important contribution to the development of obesity, but some bias in the study protocol could reduce the strength of this conclusion [17]. More light is thrown on the gastric ability to store food and release it into the duodenum of obese patients by the study of gastric emptying. Old studies based on scintigraphic determinations are contradictory [17], but it is generally accepted that accelerated gastric emptying is typical of obese patients and contributes to their overeating [17,18–20]. Recently, Cardoso-Junior et al. [21] demonstrated that morbidly obese patients show enhanced gastric emptying of solids with a direct correlation with BMI. Although modification of gas-
tric capacity and emptying is not a target for development of anti-obesity agents [22], we must consider that some herbal preparations [23], the intragastric balloon [24] and the implantable gastric stimulation device [25] act on gastric motility to reduce food intake and aid weight loss. For this reason we felt it worthwhile to investigate the effects of Btx-A on gastric emptying and capacity in order to establish its ability to modify the eating behaviour of obese patients. Btx-A, a site-specific spasmolytic agent that blocks acethylcholine release, is able to reduce muscle tone in the gastrointestinal tract. When injected into the lower oesophageal sphincter, Btx-A increases oesophageal emptying in achalasia and, when injected into the pyloric sphincter, it increases gastric emptying in patients with gastroparesis [1]. Gui et al. [3] used Btx-A injected into the antrum to reduce food intake in rodents and hypothesized that it acts by reducing gastric emptying. We believe that the site of injection of Btx-A is very important in obtaining the best results. In the early 1970s Maki et al. [26] proposed that a short antral cuff should be preserved above the pyloric sphincter to avoid dumping and related disorders after gastrectomy; however, if this cuff was more than 2 cm in length, gastric stasis occurred. In our opinion, Btx-A should be injected more than 2 cm from the pylorus to obtain loss of gastric coordination and to avoid loss of pyloric sphincter resistance. Although several studies [5–9] investigated the effects of Btx-A on gastric emptying, only Junior et al. [9], in a study devoted to finding the optimal dose of Btx-A, specified the site of microinjections and the minimal distance from the pyloric sphincter (2 cm). It is noteworthy that Junior was the only one who, like us, found an effect of Btx-A on gastric emptying in his series as a whole. We believe the different protocols used for injection and the absence of dietary prescriptions could explain the different effects obtained in terms of weight loss. Furthermore, in the study by Gui et al. [8] a beta-type error (only four and five patients in the two Botulinum toxin groups) invalidates the conclusion that Btx-A has only a potential role in the treatment of obesity. In our investigations, preservation of the pre-pyloric zone from the effects of acetylcholine block significantly delayed gastric emptying. Although our results do not support the hypothesis of rapid food transit through the stomach in obese patients, reduction of gastric emptying seems to be the mechanism through which Btx-A acts to reduce body weight [27]. Further consideration should be given to the fundus as a target for Btx-A administration, since it is the region of the stomach that is involved in gastric accommodation and strongly influences gastric capacity [17]. Both patients treated with placebo and those treated with Btx-A had a significant reduction in maximal gastric capacity for solids, but Btx-A had a significantly greater effect. Our results confirm those of previous investigations which showed a decrease in gastric capacity after calorie restriction and suggest that changes in gastric tone and accommodation could contribute
D. Foschi et al. / Digestive and Liver Disease 40 (2008) 667–672
to the reduction of the patients’ propensity to eat food ad libitum. The fundus is also the site of the endocrine gastric system, which is involved in the mechanisms of hunger and satiety regulation by the central nervous system [28]. It releases both leptin and ghrelin into the blood stream in response to food [29,30]. Albani et al. [7] found no effect of Btx-A on satiety after injection into the antrum only, but Gui et al. [8] found a significant reduction of appetite and Junior et al. [9] described early satiety. In our previous observations [10], patients showed no changes in hunger and meal initiation but an increase in satiety and easier compliance with dietary prescriptions. The effects of BtxA administration into the gastric fundus on the endocrine patterns involved in satiety regulation should be further investigated. In conclusion, our study demonstrated that Btx-A given by direct endoscopic intraparietal application into the antrum and fundus of the stomach makes weight loss easier thanks to functional changes in gastric motility, with a decrease in gastric emptying and capacity.
Practice points • Intraparietal administration of Btx-A into the gastric antrum and fundus of obese patients enhances T1/2 of solid gastric emptying and reduces the maximal eating capacity of the stomach. • This treatment can be useful in reducing the body weight of obese patients
Research agenda • The role of the fundus of the stomach in achieving postprandial satiety deserves further investigation. • The long-term effects of repeated intraparietal administration of Btx-A in obese patients are unknown and should be investigated.
Conflict of interest statement None declared.
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Acknowledgement This study was supported by a grant from the Fondazione Romeo ed Enrica Invernizzi, Milan, Italy.
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[25] Chen J. Mechanisms of action of the implantable gastric stimulator for obesity. Obes Surg 2004;14:S28–32. [26] Maki T, Shiratori T, Hatafuki T, Suganuma K. Pylorus preserving gastrectomy as an improved operation for gastric ulcer. Surgery 1967;61:838–45. [27] Geliebter A, Schacter S, Lohmann Walter C, Feldman H, Hashim S. Reduced stomach capacity in obese subjects after dieting. Am J Clin Nutr 1966;63:170–3. [28] Badman MK, Flier JS. The gut and energy balance: visceral allies in the obesity wars. Science 2005;307:1909–14. [29] Cinti S, De Matteis R, Pico C, Ceresi E, Obrador A, Maffeis C, et al. Secretory granules of endocrine and chief cells of human stomach contain leptin. Intern J Obes 2000;24:789–93. [30] Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656–60.
Digestive and Liver Disease 40 (2008) 667–672
Alimentary Tract
Effects of intramural administration of Botulinum Toxin A on gastric emptying and eating capacity in obese patients D. Foschi a,∗ , M. Lazzaroni b , O. Sangaletti b , F. Corsi a , E. Trabucchi a , G. Bianchi Porro a a
Department of Clinical Sciences, L.Sacco Hospital, University of Milan, Milan, Italy b Unit of Gastroenterology, Department of Surgery, L.Sacco Hospital, Milan, Italy Received 18 August 2007; accepted 18 February 2008 Available online 17 April 2008
Abstract Background. Intraparietal gastric administration of Botulinum Toxin A has been studied in open trials to induce satiety and increase weight loss of obese patients with contradictory results. In previous studies only the antrum was the target for Botulinum Toxin A, whereas the fundus, which exerts important activity on gastric accommodation, was excluded. In this study we report the effects of injection into both gastric regions on solid gastric capacity and emptying of the stomach. Materials and methods. In this study we extended our previous investigations to include 30 obese patients who received Botulinum Toxin A (120 U into the antrum and 80 U into the fundus) or saline by intraparietal endoscopic injection. The two groups were homogeneous for age, gender, body weight and body mass index. Body weight and body mass index, solid gastric emptying (T1/2 and Tlag at the octanoic acid breath test) and maximal gastric capacity for solids (kcal) were determined before injection and 2 months later. The results were expressed as mean values (S.E.M.). t-Test or Wilcoxon test was used for statistical analysis, p < 0.05 being considered significant. Results. Both treatments induced a significant reduction of body weight and body mass index but Botulinum Toxin A exerted a significantly greater effect (body weight −11.8 ± 0.9 kg vs. −5.5 ± 1.1 kg, p < 0.0002; body mass index −4.1 ± 0.2 vs. −2.2 ± 0.4, p < 0.001). The maximal gastric capacity for solids was also reduced by both Botulinum Toxin A and placebo, the former being significantly more effective (679 ± 114 kcal vs. 237 ± 94 kcal, p < 0.008). Botulinum Toxin A also significantly increased T1/2 from 83.4 ± 3.9 to 101.6 ± 9.9 min, p < 0.03) but Tlag was unchanged. Placebo had no effect on either of these parameters. Conclusions. Our results demonstrated that Botulinum Toxin A makes weight loss easier in obese patients. It acts by increasing the solid gastric emptying time and reducing the solid eating capacity of the stomach. © 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Botulinum toxin; Gastric capacity; Gastric emptying; Obesity; Octanoic acid test
1. Introduction Topical Botulinum toxin (Btx) administration into the muscle layer of the gastrointestinal tract exerts therapeutic effects in patients with achalasia, gastric paresis, spasm of Oddi’ s sphincter, anal fissure and pelvic floor disorders [1,2]. In 2000, Gui et al. [3] demonstrated in rodents that intraparietal administration of Btx-A into the gastric antrum causes significant reduction of food intake and decrease of body weight in comparison to sham-operated animals. Coskun et ∗
Corresponding author. Tel.: +39 02 39043204; fax: +39 02 50319846. E-mail address: [email protected] (D. Foschi).
al. [4] also demonstrated that Botulinum toxin injection into the antrum of obese rats leads to weight loss through reduction of gastric emptying. In 2003, Rollnik et al. [5] reported a case of an obese patient who had a significant reduction of food intake and body weight following antral injection of 500 mU of Btx-A. Two further open studies [6,7] extended this observation, but in the series studied by Garcia-Compean et al. [6] no significant effects on body weight and gastric emptying were observed. Recently, Gui et al. [8] found in a double blind pilot study that Btx-A, injected into the gastric antrum of obese patients at two dose levels (133 U and 200 U) reduced appetite, had variable effects on gastric emptying and caused weight reduction, although the loss was
1590-8658/$30 © 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2008.02.040
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not statistically significant. Junior et al. [9] investigated the effects of Btx-A injected into the antrum at different dose levels (100, 200 and 300 U) on the solid and semisolid gastric emptying. Although no significant effects of each Btx-A dose were demonstrated, the data for the patients as a whole demonstrated significant slowing of solid emptying at week 8 and semisolid emptying at weeks 2 and 4, respectively. Furthermore, all treated patients reported a feeling of early satiety, but they were not on a calorie-restricted diet and did not lose weight. We also investigated whether or not administration of Btx-A into the gastric wall [10] can help obese patients to adhere strictly to dietary prescriptions and obtain significant body weight reduction. In this study, intended to extend our previous observations, we investigated the effects of intraparietal Btx-A on solid gastric emptying and solideating capacity of patients with a body mass index greater than 35.
2. Materials and methods The investigation, intended to complete our previous observations [10] was performed at the L.Sacco Hospital in Milan, Italy, between January 2004 and November 2005. The protocol was approved by the Ethics Committee of the L.Sacco Hospital and conducted according to the Declaration of Helsinki. All patients gave their written informed consent to the diagnostic and therapeutic procedures according to the study design. 2.1. Admission criteria Age between 18 and 65 years, body mass index (BMI) between 35 and 40 with two complications of obesity or BMI >40. Pregnancy (even potential), a history of malignancy, surgery of the stomach or gastro-intestinal disease refractory to medical treatment were considered preliminary exclusion criteria, as was recent (<3 months) treatment for obesity or weight change. All patients had preliminary dietological, endocrinological, neurological and psychiatric examination to exclude further contraindications to the therapeutic procedure, including:
2.2. Diagnostic procedures 2.2.1. Clinical measurements BW (kg) and height (m) were measured at the first visit with the patient wearing standard light clothing and no shoes. BMI was also calculated as body weight (kg)/height (m2 ). 2.2.2. Gastric emptying evaluation All tests were performed after an overnight fast. The test meal consisted in a standard bun (5.8% protein, 33.3% lipid and 57.5% carbohydrate, 378 kcal), with 100 mg of 2 Ci of octanoic acid (I-13 C) added (Expiroger, Sofar, Italy). The test meal was followed immediately by 250 ml of water. Breath samples were taken immediately before the test meal and every 30 min thereafter for 3 h. Samples were analysed by a mass spectrometer (Breath mass plus, Finnigan, Germany) to measure 13 CO2 . The percentages of 13 CO2 cumulative values over 3 h were fit according to the equation described by Ghoos et al. [11]: y = m(1 − e−kt )β , where y is the cumulative percentage of 13 CO excretion in breath at time t (h) and m, k and β 2 are estimated parameters. In this model, m represents the total cumulative recovery of octanoic acid for time = ∞. The duration of the lag time was defined as the time when 10% of the test meal was emptied from the stomach. The results were measured as half-emptying time (min) [T1/2 = (−1/k) × ln(1 − (0.5)1/β ] and lag-time (min) [Tlag = (−1/k) × ln(1 − (0.1)1/β ]. 2.2.3. Maximal solid gastric capacity At 0:30 p.m., patients were asked to eat ham rolls (210 kcal per roll) until they experienced a sensation of complete fullness or abdominal discomfort. The results were expressed as kcal. 2.3. Study design After completion of the diagnostic procedures, patients were randomized in a double-blind fashion to receive intragastric administration of Btx-A (200 U) (12 patients) or placebo (saline, 12 patients). Six further patients were recruited according to the general selection criteria and assigned to the Btx-A group to increase our observations on the maximal solid gastric capacity test. 2.4. Therapeutic procedure
- heavy binge-eating; - previous botulism, neurological and neuromuscular diseases; - psychotic disorders, alcohol or substance abuse or dependence; - endocrine obesity. On the basis of these selection criteria, 6 patients were added to the previous series of 24 patients and completed the diagnostic and therapeutic procedures.
All therapeutic procedures were performed between 2 and 3 p.m. after a 6 h fast and under diazepam sedation. An Olympus GIF IT 130 operative gastroscope was used for a preliminary evaluation of the oesophagus, stomach and duodenum. Seventeen patients had sliding hiatus hernia, in three cases associated with oesophagitis, three patients had antral gastritis and one patient had pseudopolyps of the fundus. One patient had a gastric ulcer and another duodenitis suggesting Crohn’s disease. These last two patients
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Table 1 General characteristics of the treatment groups
had negative biopsies and were treated with Proton Pump Inhibitors for 45 days before the procedure was successfully performed. Btx-A (Botox, Allergan, USA, 10 IU in 0.5 saline) or saline (0.5 ml) was injected into the submucosa using an Endoflex needle, 2.3 mm in thickness and 230 cm in length. The microinjections were performed at the four cardinal points starting 3 cm from the pyloric ring, and repeated three times moving 2 cm towards the angulus each time. Four more microinjections were performed 2 cm below the cardias, and the last four doses were injected into the fundus of the stomach. The total dose was 200 U, given by 20 microinjections. The time to accomplish the procedure was always less than 10 min. No significant acute side effects were recorded. All patients were observed for 1 h. Only one patient complaining of abdominal pain had to be observed for 12 h.
Gender (M/F) Age (years) BW (kg) BMI (kg2 /m) Tlag (min) T1/2 (min) Maximal solid eating gastric capacity (kcal)
Btx-A (n: 18)
Placebo (n: 12)
1/3 42 ± 3.5 125.7 ± 6.1 44.6 ± 1.4 29.3 ± 2.5 83.4 ± 3.9 1350 ± 150
1/3 45.2 ± 3.7 118.2 ± 5.3 44.1 ± 1.5 35.6 ± 2.3 103.4 ± 4.5* 925 ± 139
*p < 0.05, Wilcoxon rank test.
using a two-tailed Student’s t-test for unpaired data. Differences between times in the same group were compared using a two-tailed Student’s t-test for paired data. Gastric emptying time differences between groups were evaluated using the Wilcoxon rank test. Differences with p < 0.05 were considered significant.
2.5. Diet A 1200 kcal liquid diet (protein 15%, lipid 33%, carbohydrate 52%) was prescribed starting immediately after the endoscopic procedure. The diet was based on a personal choice between several market components for each meal, with a weekly balance between the daily meals. The patients were instructed to follow the diet for 8 weeks.
3. Results The two groups of patients were similar for gender, age, BW, lag time of solid gastric emptying and maximal solid eating capacity before treatment. They differed only for the T1/2 of solid gastric emptying, which was shorter in patients randomized to the Btx-A treatment (Table 1). Both groups of patients had a significant decrease in BW and BMI at the end of the follow-up period, but these decreases were greater in those who had undergone intraparietal administration of Btx-A into the fundus and the antrum of the stomach (Table 2). The effects of Btx-A on gastric emptying were characterized by a significant increase in T1/2 , (from 83.46 ± 3.98 to 101.6 ± 9.9 min, p < 0.03) whereas the Tlag was not significantly modified. Patients treated with saline had no significant increase in either of these gastric emptying parameters (Table 3). Furthermore, Btx-A significantly decreased the maximal gastric capacity of obese patients (Fig. 1). Both groups of patients had a significant reduction of the
2.6. Follow-up Every week, the patients attended our outpatient department to evaluate body weight and BMI. Final body weight measurement, anthropometric measures, maximal liquid gastric capacity test and the octanoic acid breath test were performed 8 weeks after treatment. All patients completed the scheduled follow-up. 2.7. Statistical analysis Results were expressed as mean ± standard error of the mean (S.E.M.). Differences between groups were compared Table 2 Effects of Btx-A on BW and BMI
BW (kg) BMI (kg2 /m) BW reduction BMI reduction
Btx-A pre
Btx-A post
125.7 ± 6.1 44.6 ± 1.4
113.9 40.5 11.8 4.1
± ± ± ±
5.6* 1.4* 0.9 0.2
Placebo pre
Placebo post
118.2 ± 5.3 44.1 ± 1.5
112.4 42.5 5.5 2.2
± ± ± ±
4.9** 1.3*** 1.1ˆ 0.4ˆˆ
*p < 0.0001, **p < 0.0003, ***p < 0.0008 between times. ˆp < 0.0002, ˆˆp < 0.001 between groups. Table 3 Effects of Btx-A on solid gastric emptying
Tlag (min) T1/2 (min) *p < 0.03, Wilcoxon rank test.
Btx-A pre
Btx-A post
Placebo pre
Placebo-post
29.3 ± 2.5 83.4 ± 3.9
32.3 ± 2.3 101.6 ± 9.9*
35.6 ± 2.3 103.4 ± 4.5
34.9 ± 2.5 96.6 ± 5.6
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Fig. 1. Effect of Btx-A on the maximal gastric capacity for solids. Both BtxA and placebo significantly reduced the maximal gastric capacity for solids; Btx-A showed a significant advantage (p < 0.008) on placebo. *p < 0.03 post vs. pre; **p < 0.001 post vs. pre; •p < 0.008 Botox vs. Placebo.
maximal ingested solid charge, but comparison of the two groups of treatment demonstrated a significant advantage (679 ± 114 kcal vs. 237 ± 94 kcal, p < 0.008) after Btx-A treatment.
4. Discussion Obesity strongly affects gastrointestinal functions by direct and indirect mechanisms, resulting in a reinforcement of the ability of patients to increase food intake progressively through inhibition of satiety signals [12]. Geliebter et al. [13–15] and Granstrom and Backman [16] demonstrated that the acute maximal gastric capacity of bulimic and obese patients was higher than that of lean controls, but it remains to be established whether or not it is an adaptive response to overeating or a causative factor of increased food intake [17]. It is generally considered that gastric accommodation is more important than gastric capacity as a factor limiting meal size [17], but only Kim et al. [18] have determined the ratio between postprandial and fasting gastric volume after a liquid meal in obese patients and overweight controls: he found no differences between the two groups of subjects as far as the satiety score and maximal ingested liquid volume are concerned. These results suggest that gastric accommodation does not provide an important contribution to the development of obesity, but some bias in the study protocol could reduce the strength of this conclusion [17]. More light is thrown on the gastric ability to store food and release it into the duodenum of obese patients by the study of gastric emptying. Old studies based on scintigraphic determinations are contradictory [17], but it is generally accepted that accelerated gastric emptying is typical of obese patients and contributes to their overeating [17,18–20]. Recently, Cardoso-Junior et al. [21] demonstrated that morbidly obese patients show enhanced gastric emptying of solids with a direct correlation with BMI. Although modification of gas-
tric capacity and emptying is not a target for development of anti-obesity agents [22], we must consider that some herbal preparations [23], the intragastric balloon [24] and the implantable gastric stimulation device [25] act on gastric motility to reduce food intake and aid weight loss. For this reason we felt it worthwhile to investigate the effects of Btx-A on gastric emptying and capacity in order to establish its ability to modify the eating behaviour of obese patients. Btx-A, a site-specific spasmolytic agent that blocks acethylcholine release, is able to reduce muscle tone in the gastrointestinal tract. When injected into the lower oesophageal sphincter, Btx-A increases oesophageal emptying in achalasia and, when injected into the pyloric sphincter, it increases gastric emptying in patients with gastroparesis [1]. Gui et al. [3] used Btx-A injected into the antrum to reduce food intake in rodents and hypothesized that it acts by reducing gastric emptying. We believe that the site of injection of Btx-A is very important in obtaining the best results. In the early 1970s Maki et al. [26] proposed that a short antral cuff should be preserved above the pyloric sphincter to avoid dumping and related disorders after gastrectomy; however, if this cuff was more than 2 cm in length, gastric stasis occurred. In our opinion, Btx-A should be injected more than 2 cm from the pylorus to obtain loss of gastric coordination and to avoid loss of pyloric sphincter resistance. Although several studies [5–9] investigated the effects of Btx-A on gastric emptying, only Junior et al. [9], in a study devoted to finding the optimal dose of Btx-A, specified the site of microinjections and the minimal distance from the pyloric sphincter (2 cm). It is noteworthy that Junior was the only one who, like us, found an effect of Btx-A on gastric emptying in his series as a whole. We believe the different protocols used for injection and the absence of dietary prescriptions could explain the different effects obtained in terms of weight loss. Furthermore, in the study by Gui et al. [8] a beta-type error (only four and five patients in the two Botulinum toxin groups) invalidates the conclusion that Btx-A has only a potential role in the treatment of obesity. In our investigations, preservation of the pre-pyloric zone from the effects of acetylcholine block significantly delayed gastric emptying. Although our results do not support the hypothesis of rapid food transit through the stomach in obese patients, reduction of gastric emptying seems to be the mechanism through which Btx-A acts to reduce body weight [27]. Further consideration should be given to the fundus as a target for Btx-A administration, since it is the region of the stomach that is involved in gastric accommodation and strongly influences gastric capacity [17]. Both patients treated with placebo and those treated with Btx-A had a significant reduction in maximal gastric capacity for solids, but Btx-A had a significantly greater effect. Our results confirm those of previous investigations which showed a decrease in gastric capacity after calorie restriction and suggest that changes in gastric tone and accommodation could contribute
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to the reduction of the patients’ propensity to eat food ad libitum. The fundus is also the site of the endocrine gastric system, which is involved in the mechanisms of hunger and satiety regulation by the central nervous system [28]. It releases both leptin and ghrelin into the blood stream in response to food [29,30]. Albani et al. [7] found no effect of Btx-A on satiety after injection into the antrum only, but Gui et al. [8] found a significant reduction of appetite and Junior et al. [9] described early satiety. In our previous observations [10], patients showed no changes in hunger and meal initiation but an increase in satiety and easier compliance with dietary prescriptions. The effects of BtxA administration into the gastric fundus on the endocrine patterns involved in satiety regulation should be further investigated. In conclusion, our study demonstrated that Btx-A given by direct endoscopic intraparietal application into the antrum and fundus of the stomach makes weight loss easier thanks to functional changes in gastric motility, with a decrease in gastric emptying and capacity.
Practice points • Intraparietal administration of Btx-A into the gastric antrum and fundus of obese patients enhances T1/2 of solid gastric emptying and reduces the maximal eating capacity of the stomach. • This treatment can be useful in reducing the body weight of obese patients
Research agenda • The role of the fundus of the stomach in achieving postprandial satiety deserves further investigation. • The long-term effects of repeated intraparietal administration of Btx-A in obese patients are unknown and should be investigated.
Conflict of interest statement None declared.
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Acknowledgement This study was supported by a grant from the Fondazione Romeo ed Enrica Invernizzi, Milan, Italy.
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