Letters to the Editor
To the Editor: The recent paper by Janssen et al. (1) fails to find significant correlations between the abilities of metoclopramide, domperidone, cisapride, erythromycin, botulinum toxin, and levosulpiride (grouped as ‘‘prokinetics’’) to accelerate gastric emptying and improve symptoms associated with gastroparesis. These drugs have an extraordinary range of actions (see Table 1), sometimes discovered only after registration, so was this a fair grouping? Antiemetic activity may be attributed to D2 ( + D3) antagonism within the area postrema, and links between nausea and gastric hypo-motility may explain how domperidone can promote gastric emptying and alleviate gastroparesis. Metoclopramide, which unlike domperidone crosses the blood– brain barrier, also directly inhibits emesis (D2 and 5-HT3 antagonism), but central D2 antagonism can cause extra-pyramidal side effects, complicating patient perception of symptom improvement. Further, metoclopramide, and also cisapride and levosulpiride, directly increase gastric motility by 5-HT4 activation (not D2 antagonism, as stated by the authors), and this can reduce various symptoms, including nausea (2). Cisapride’s additional ability to antagonize at 5-HT3 receptors was said to endow antiemetic activity, but poor affinity for this receptor makes this unlikely. Instead, cisapride acts at α1 and 5-HT2A/B receptors at therapeutically relevant concentrations. Finally, botulinum toxin acts completely differently, improving gastric emptying by reducing pyloric sphincter resistance when applied topically (6). Different pharmacological activities within individual drugs means that the
correct dose for particular symptoms is not always clear. When prescribing erythromycin for gastroparesis, for example, the advice is to use doses ‘‘lower’’ than those used to treat infections, paradoxically reversing a tendency to cause emesis and reducing the nausea of gastroparesis. Similar problems apply to the D2/5-HT3 antagonists/5-HT4 agonists: has the best dose been chosen to maximize activities at one or other receptor when treating gastroparesis? Thus, was it correct to consider all these drugs as just ‘‘prokinetics’’? Perhaps not, as this classification hides important differences that define the drugs and doses needed to directly inhibit emesis, directly improve gastric emptying, and/or directly/indirectly alleviate dysrhythmia and improve gastroduodenal coordination. Understanding both the drugs and the patients is essential before asking new research questions in this important area of medicine. CONFLICT OF INTEREST
G.J.S. has received funding from GlaxoSmithKline to study the mechanisms of action of motilin receptor agonists, from Shire Pharmaceuticals, Protexin, and Tioga, and in the past 2 years consulted for Novartis, Theravance, and Proximagen.
Cisapride
D3
5-HT2A
5-HT2B
↓
Metoclopramide Domperidone
D2
(↓)
↓
↓
(↓)
1. Janssen P, Harris MS, Jones M et al. The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis. Am J Gastroenterol 2013;108:1382–91. 2. Sanger GJ, Broad J, Andrews PLR. The relationship between gastric motility and nausea: gastric prokinetic agents as treatments. Eur J Pharmacol 2013;715:10–4.
5-HT3
5-HT4
↓
↑
(↓)
↑
Motilin
P2X
Transmitter release
↑
↓
(↓)
↓ ↓
↓
Erythromycin
↓
Botulinum toxin Levosulpiride
↓
↓
↑
α1, α1 adrenoceptor; D, dopamine; 5-HT, 5-hydroxytryptamine; P, purinergic. In parentheses: relatively high concentrations. References (2–6).
© 2014 by the American College of Gastroenterology
1
Neurogastroenterology Group, National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Correspondence: G.J. Sanger, DSc, Neurogastroenterology Group, Barts and The London School of Medicine and Dentistry, National Centre for Bowel Research and Surgical Innovation, Blizard Institute, 1st Floor, Abernethy Building, 2 Newark Street, London E1 2AT, UK. E-mail: [email protected]
Response to Sanger Jan Tack, MD, PhD1 (on behalf of Pieter Janssen, PhD, M. Scott Harris, MD, Mike Jones, PhD, Tatsuhiro Masaoka, MD, PhD, Ricard Farré, PhD, Hans Törnblom, MD, PhD, Lukas Van Oudenhove, MD, PhD, Magnus Simrén, MD, PhD)
REFERENCES
Table 1. Receptors and mechanisms antagonized ↓ or stimulated ↑ at therapeutically relevant concentrations α1
3. Sanger GJ. Translating 5-HT4 receptor pharmacology. Neurogastroenterol Motil 2009;21:1235–8. 4. Tonini M, De Giorgio R, Spelta V et al. 5-HT4 receptors contribute to the motor stimulating effect of levosulpiride in the guinea-pig gastrointestinal tract. Dig Liver Dis 2003;35: 244–50. 5. Sanger GJ, Andrews PLR. Treatment of nausea and vomiting: gaps in our knowledge. Auton Neurosci 2006;129:3–16. 6. Gil RA, Hwynn N, Fabian T et al. Botulinum toxin type A for the treatment of gastroparesis in Parkinson’s disease patients. Parkinsonism Relat Disord 2011;17:285–7.
doi:10.1038/ajg.2014.17
To the Editor: We thank Dr Sanger for his interest in our manuscript and his comments on the grouping of drugs under the label “prokinetics”. The term (gastro-) prokinetics dates from the early eighties and refers to “drugs that work to speed up the emptying of the stomach and the motility of the intestines” (1–4). Early prokinetics like metoclopramide and domperidone were preferentially developed and used for the treatment of gastroparesis, a condition characterized by delayed gastric emptying in the absence of an underlying mechanical disorder (5). On the basis of the dual rationale that symptoms in these patients were attributable to the delay in gastric emptying, and that pharmacologically enhancing gastric emptying improved The American Journal of GASTROENTEROLOGY
445
446
Letters to the Editor
symptoms, a number of novel prokinetics were developed such as cisapride and several other 5-HT4 receptor agonists (2–4). Assuming that stronger stimulation of gastric contractility would lead to superior control of symptoms, several motilin receptor agonists and later also ghrelin receptor agonists were developed, with disappointing clinical outcomes (2–4,6,7). Our aim was to review the hypothesis that the magnitude of improvement of gastric emptying rate is a predictor of the magnitude of symptom relief in gastroparesis, and our meta-regression analysis failed to confirm this hypothesis (5). This has important implications not only for clinical practice, by questioning the rationale for (repeated) gastric emptying testing, but also for drug development. Drugs that enhance gastric emptying in animal models will not necessarily convey symptomatic benefits to gastroparesis patients and, more importantly, measuring the effect on gastric emptying rate is less likely to identify the optimal dose range to be used in symptom-driven clinical trials. Our systematic review confirmed overall improvement of symptoms with prokinetic drugs without correlation to changes in gastric emptying rate suggests that the symptom-ameliorating effects are attributable to other aspects of these drugs’ actions (8). Indeed, as pointed by Dr Sanger and others, gastroprokinetics are a heterogenous class of agents with different receptor affinities and selectivities and different effects on multiple aspects of gastric sensorimotor function (2–4,6,8,9). Hence, other modes of action underlying the therapeutic benefit of “prokinetics” such as enhancement of gastric accommodation (5-HT4 agonists), changes in gastric sensitivity, or suppression of nausea and vomiting (D2 antagonists) deserve further studies (2–4). Indeed, drugs in the so-called class of prokinetics have variable effects on these aspects of gastric function (2–8). Such studies may lead to a better understanding of the therapeutic efficacy of “prokinetics”, identification of better predictors of their symptomatic efficacy than gastric emptying rate and, perhaps, reclassification into a more appropriately named new class. We are currently pursuing the hypothesis that effects on gastric accommodation have The American Journal of GASTROENTEROLOGY
a major role in the magnitude of symptomatic benefit with motility-modifying agents, and recent pharmacological and technical advances provide a potential for better applicability and understanding of these factors in the near future (10–13). CONFLICT OF INTEREST
The author declares no conflict of interest. REFERENCES 1. Gale Encyclopedia of Medicine Copyright 2008 The Gale Group Inc. http://medical-dictionary. thefreedictionary.com. 2. Saad RJ, Chey WD. Review article: current and emerging therapies for functional dyspepsia. Aliment Pharmacol Ther 2006;24:475–92. 3. Karamanolis G, Tack J. Promotility medications--now and in the future. Dig Dis 2006;24:297–307. 4. Tack J. Prokinetics and fundic relaxants in upper functional GI disorders. Curr Opin Pharmacol 2008;8:690–6. 5. Parkman HP, Camilleri M, Farrugia G et al. Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting. Neurogastroenterol Motil 2010;22:113–33. 6. Tack J, Peeters T. What comes after macrolides and other motilin stimulants? Gut 2001;49:317–8. 7. Avau B, Carbone F, Tack J et al. Ghrelin signaling in the gut, its physiological properties, and therapeutic potential. Neurogastroenterol Motil 2013;25:720–32. 8. Janssen P, Harris MS, Jones M et al. The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis. Am J Gastroenterol 2013;108:1382–91. 9. Sanger G. The relation between symptom improvement and gastric emptying in the treatment of gastroparesis: remember the pharmacology. Am J Gastroenterol 2014; 109:444–5 (this issue). 10. Bisschops R, Tack J. Dysaccommodation of the stomach: therapeutic nirvana? Neurogastroenterol Motil 2007;19:85–93. 11. Tack J, Janssen P, Masaoka T et al. Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin Gastroenterol Hepatol 2012;10:1239–45. 12. Kusunoki H, Haruma K, Manabe N et al. Therapeutic efficacy of acotiamide in patients with functional dyspepsia based on enhanced postprandial gastric accommodation and emptying: randomized controlled study evaluation by real-time ultrasonography. Neurogastroenterol Motil 2012;24:540–5, e250-1. 13. Janssen P, Verschueren S, Ly HG et al. Intragastric pressure during food intake: a physiological and minimally invasive method to assess gastric accommodation. Neurogastroenterol Motil 2011;23:316–22, e153-4. 1 University Leuven—Gastroenterology, Leuven, Belgium. Correspondence: Jan Tack, MD, PhD, University Leuven—Gastroenterology, Herestraat 49, Leuven 3000, Belgium. E-mail: [email protected]
Is Intraductal Papillary Mucinous Neoplasm of the Pancreas Just a Precursor or Identical With Pancreatic Ductal Adenocarcinoma? Kazumichi Kawakubo, MD, PhD1, Hiroshi Kawakami, MD, PhD1, Masaki Kuwatani, MD, PhD1 and Naoya Sakamoto, MD, PhD1 doi:10.1038/ajg.2013.468
To the Editor: We read with great interest the article by Capurso et al. (1), a multicenter case–control study about risk factors associated with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. They concluded that a previous history of diabetes, chronic pancreatitis, and family history of pancreatic ductal adenocarcinoma (PDAC) are risk factors for IPMN, and overlaps with those of PDAC. IPMN and PDAC were reported to be significantly associated with each other. PDAC developed both synchronously and metachronously with IPMN (2,3). It is a matter of course that the risk factors of IPMN and PDAC overlapped with each other. Really important thing to be clarified is that the patients who have such kind of risk factor will develop only IPMN, or both IPMN and PDAC. As previously reported, the comorbidity score was significantly associated with mortality other than pancreatic cancer in patients with IPMN, so those patients will die of disease other than PDAC (4). The prognosis of IPMN was better than that of PDAC, so it would be very helpful for those patients to know the risk of PDAC rather than that of IPMN. In the study by Capuro et al. (1), the main issue is the prevalence of the risk factors of IPMN. The prevalence is important information, but the incidence of IPMN in patients who have such kind of risk factor is not clarified. Therefore, the prospective study will be necessary to evaluate the incidence, not the prevalence, of IPMN and PDAC. VOLUME 109 | MARCH 2014 www.amjgastro.com
To the Editor: The recent paper by Janssen et al. (1) fails to find significant correlations between the abilities of metoclopramide, domperidone, cisapride, erythromycin, botulinum toxin, and levosulpiride (grouped as ‘‘prokinetics’’) to accelerate gastric emptying and improve symptoms associated with gastroparesis. These drugs have an extraordinary range of actions (see Table 1), sometimes discovered only after registration, so was this a fair grouping? Antiemetic activity may be attributed to D2 ( + D3) antagonism within the area postrema, and links between nausea and gastric hypo-motility may explain how domperidone can promote gastric emptying and alleviate gastroparesis. Metoclopramide, which unlike domperidone crosses the blood– brain barrier, also directly inhibits emesis (D2 and 5-HT3 antagonism), but central D2 antagonism can cause extra-pyramidal side effects, complicating patient perception of symptom improvement. Further, metoclopramide, and also cisapride and levosulpiride, directly increase gastric motility by 5-HT4 activation (not D2 antagonism, as stated by the authors), and this can reduce various symptoms, including nausea (2). Cisapride’s additional ability to antagonize at 5-HT3 receptors was said to endow antiemetic activity, but poor affinity for this receptor makes this unlikely. Instead, cisapride acts at α1 and 5-HT2A/B receptors at therapeutically relevant concentrations. Finally, botulinum toxin acts completely differently, improving gastric emptying by reducing pyloric sphincter resistance when applied topically (6). Different pharmacological activities within individual drugs means that the
correct dose for particular symptoms is not always clear. When prescribing erythromycin for gastroparesis, for example, the advice is to use doses ‘‘lower’’ than those used to treat infections, paradoxically reversing a tendency to cause emesis and reducing the nausea of gastroparesis. Similar problems apply to the D2/5-HT3 antagonists/5-HT4 agonists: has the best dose been chosen to maximize activities at one or other receptor when treating gastroparesis? Thus, was it correct to consider all these drugs as just ‘‘prokinetics’’? Perhaps not, as this classification hides important differences that define the drugs and doses needed to directly inhibit emesis, directly improve gastric emptying, and/or directly/indirectly alleviate dysrhythmia and improve gastroduodenal coordination. Understanding both the drugs and the patients is essential before asking new research questions in this important area of medicine. CONFLICT OF INTEREST
G.J.S. has received funding from GlaxoSmithKline to study the mechanisms of action of motilin receptor agonists, from Shire Pharmaceuticals, Protexin, and Tioga, and in the past 2 years consulted for Novartis, Theravance, and Proximagen.
Cisapride
D3
5-HT2A
5-HT2B
↓
Metoclopramide Domperidone
D2
(↓)
↓
↓
(↓)
1. Janssen P, Harris MS, Jones M et al. The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis. Am J Gastroenterol 2013;108:1382–91. 2. Sanger GJ, Broad J, Andrews PLR. The relationship between gastric motility and nausea: gastric prokinetic agents as treatments. Eur J Pharmacol 2013;715:10–4.
5-HT3
5-HT4
↓
↑
(↓)
↑
Motilin
P2X
Transmitter release
↑
↓
(↓)
↓ ↓
↓
Erythromycin
↓
Botulinum toxin Levosulpiride
↓
↓
↑
α1, α1 adrenoceptor; D, dopamine; 5-HT, 5-hydroxytryptamine; P, purinergic. In parentheses: relatively high concentrations. References (2–6).
© 2014 by the American College of Gastroenterology
1
Neurogastroenterology Group, National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Correspondence: G.J. Sanger, DSc, Neurogastroenterology Group, Barts and The London School of Medicine and Dentistry, National Centre for Bowel Research and Surgical Innovation, Blizard Institute, 1st Floor, Abernethy Building, 2 Newark Street, London E1 2AT, UK. E-mail: [email protected]
Response to Sanger Jan Tack, MD, PhD1 (on behalf of Pieter Janssen, PhD, M. Scott Harris, MD, Mike Jones, PhD, Tatsuhiro Masaoka, MD, PhD, Ricard Farré, PhD, Hans Törnblom, MD, PhD, Lukas Van Oudenhove, MD, PhD, Magnus Simrén, MD, PhD)
REFERENCES
Table 1. Receptors and mechanisms antagonized ↓ or stimulated ↑ at therapeutically relevant concentrations α1
3. Sanger GJ. Translating 5-HT4 receptor pharmacology. Neurogastroenterol Motil 2009;21:1235–8. 4. Tonini M, De Giorgio R, Spelta V et al. 5-HT4 receptors contribute to the motor stimulating effect of levosulpiride in the guinea-pig gastrointestinal tract. Dig Liver Dis 2003;35: 244–50. 5. Sanger GJ, Andrews PLR. Treatment of nausea and vomiting: gaps in our knowledge. Auton Neurosci 2006;129:3–16. 6. Gil RA, Hwynn N, Fabian T et al. Botulinum toxin type A for the treatment of gastroparesis in Parkinson’s disease patients. Parkinsonism Relat Disord 2011;17:285–7.
doi:10.1038/ajg.2014.17
To the Editor: We thank Dr Sanger for his interest in our manuscript and his comments on the grouping of drugs under the label “prokinetics”. The term (gastro-) prokinetics dates from the early eighties and refers to “drugs that work to speed up the emptying of the stomach and the motility of the intestines” (1–4). Early prokinetics like metoclopramide and domperidone were preferentially developed and used for the treatment of gastroparesis, a condition characterized by delayed gastric emptying in the absence of an underlying mechanical disorder (5). On the basis of the dual rationale that symptoms in these patients were attributable to the delay in gastric emptying, and that pharmacologically enhancing gastric emptying improved The American Journal of GASTROENTEROLOGY
445
446
Letters to the Editor
symptoms, a number of novel prokinetics were developed such as cisapride and several other 5-HT4 receptor agonists (2–4). Assuming that stronger stimulation of gastric contractility would lead to superior control of symptoms, several motilin receptor agonists and later also ghrelin receptor agonists were developed, with disappointing clinical outcomes (2–4,6,7). Our aim was to review the hypothesis that the magnitude of improvement of gastric emptying rate is a predictor of the magnitude of symptom relief in gastroparesis, and our meta-regression analysis failed to confirm this hypothesis (5). This has important implications not only for clinical practice, by questioning the rationale for (repeated) gastric emptying testing, but also for drug development. Drugs that enhance gastric emptying in animal models will not necessarily convey symptomatic benefits to gastroparesis patients and, more importantly, measuring the effect on gastric emptying rate is less likely to identify the optimal dose range to be used in symptom-driven clinical trials. Our systematic review confirmed overall improvement of symptoms with prokinetic drugs without correlation to changes in gastric emptying rate suggests that the symptom-ameliorating effects are attributable to other aspects of these drugs’ actions (8). Indeed, as pointed by Dr Sanger and others, gastroprokinetics are a heterogenous class of agents with different receptor affinities and selectivities and different effects on multiple aspects of gastric sensorimotor function (2–4,6,8,9). Hence, other modes of action underlying the therapeutic benefit of “prokinetics” such as enhancement of gastric accommodation (5-HT4 agonists), changes in gastric sensitivity, or suppression of nausea and vomiting (D2 antagonists) deserve further studies (2–4). Indeed, drugs in the so-called class of prokinetics have variable effects on these aspects of gastric function (2–8). Such studies may lead to a better understanding of the therapeutic efficacy of “prokinetics”, identification of better predictors of their symptomatic efficacy than gastric emptying rate and, perhaps, reclassification into a more appropriately named new class. We are currently pursuing the hypothesis that effects on gastric accommodation have The American Journal of GASTROENTEROLOGY
a major role in the magnitude of symptomatic benefit with motility-modifying agents, and recent pharmacological and technical advances provide a potential for better applicability and understanding of these factors in the near future (10–13). CONFLICT OF INTEREST
The author declares no conflict of interest. REFERENCES 1. Gale Encyclopedia of Medicine Copyright 2008 The Gale Group Inc. http://medical-dictionary. thefreedictionary.com. 2. Saad RJ, Chey WD. Review article: current and emerging therapies for functional dyspepsia. Aliment Pharmacol Ther 2006;24:475–92. 3. Karamanolis G, Tack J. Promotility medications--now and in the future. Dig Dis 2006;24:297–307. 4. Tack J. Prokinetics and fundic relaxants in upper functional GI disorders. Curr Opin Pharmacol 2008;8:690–6. 5. Parkman HP, Camilleri M, Farrugia G et al. Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting. Neurogastroenterol Motil 2010;22:113–33. 6. Tack J, Peeters T. What comes after macrolides and other motilin stimulants? Gut 2001;49:317–8. 7. Avau B, Carbone F, Tack J et al. Ghrelin signaling in the gut, its physiological properties, and therapeutic potential. Neurogastroenterol Motil 2013;25:720–32. 8. Janssen P, Harris MS, Jones M et al. The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis. Am J Gastroenterol 2013;108:1382–91. 9. Sanger G. The relation between symptom improvement and gastric emptying in the treatment of gastroparesis: remember the pharmacology. Am J Gastroenterol 2014; 109:444–5 (this issue). 10. Bisschops R, Tack J. Dysaccommodation of the stomach: therapeutic nirvana? Neurogastroenterol Motil 2007;19:85–93. 11. Tack J, Janssen P, Masaoka T et al. Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin Gastroenterol Hepatol 2012;10:1239–45. 12. Kusunoki H, Haruma K, Manabe N et al. Therapeutic efficacy of acotiamide in patients with functional dyspepsia based on enhanced postprandial gastric accommodation and emptying: randomized controlled study evaluation by real-time ultrasonography. Neurogastroenterol Motil 2012;24:540–5, e250-1. 13. Janssen P, Verschueren S, Ly HG et al. Intragastric pressure during food intake: a physiological and minimally invasive method to assess gastric accommodation. Neurogastroenterol Motil 2011;23:316–22, e153-4. 1 University Leuven—Gastroenterology, Leuven, Belgium. Correspondence: Jan Tack, MD, PhD, University Leuven—Gastroenterology, Herestraat 49, Leuven 3000, Belgium. E-mail: [email protected]
Is Intraductal Papillary Mucinous Neoplasm of the Pancreas Just a Precursor or Identical With Pancreatic Ductal Adenocarcinoma? Kazumichi Kawakubo, MD, PhD1, Hiroshi Kawakami, MD, PhD1, Masaki Kuwatani, MD, PhD1 and Naoya Sakamoto, MD, PhD1 doi:10.1038/ajg.2013.468
To the Editor: We read with great interest the article by Capurso et al. (1), a multicenter case–control study about risk factors associated with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. They concluded that a previous history of diabetes, chronic pancreatitis, and family history of pancreatic ductal adenocarcinoma (PDAC) are risk factors for IPMN, and overlaps with those of PDAC. IPMN and PDAC were reported to be significantly associated with each other. PDAC developed both synchronously and metachronously with IPMN (2,3). It is a matter of course that the risk factors of IPMN and PDAC overlapped with each other. Really important thing to be clarified is that the patients who have such kind of risk factor will develop only IPMN, or both IPMN and PDAC. As previously reported, the comorbidity score was significantly associated with mortality other than pancreatic cancer in patients with IPMN, so those patients will die of disease other than PDAC (4). The prognosis of IPMN was better than that of PDAC, so it would be very helpful for those patients to know the risk of PDAC rather than that of IPMN. In the study by Capuro et al. (1), the main issue is the prevalence of the risk factors of IPMN. The prevalence is important information, but the incidence of IPMN in patients who have such kind of risk factor is not clarified. Therefore, the prospective study will be necessary to evaluate the incidence, not the prevalence, of IPMN and PDAC. VOLUME 109 | MARCH 2014 www.amjgastro.com
