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European Review for Medical and Pharmacological Sciences 2008; 12(Suppl 1): 119-127 New approaches to the treatment of -induced

P. HOLZER

Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz (Austria)

Abstract. – are indispensable Introduction for the treatment of moderate to severe pain. The gastrointestinal tract is one of the major derived from the unripe seed capsules victims of the undesired effects of opiates, be- cause the enteric nervous system expresses of has been used since an- all major subtypes of opioid receptors. As a cient times to treat diarrhoea. We now know that result, propulsive motility and secretory the biological effects of opium are due not only processes in the gut are inhibited by opioid to and but also other , and the ensuing constipation is such as papaverine, all of which affect the func- one of the most frequent and troublesome ad- tion of the gastrointestinal (GI) tract. Despite verse reactions. Many treatments involving , prokinetic drugs and opioid-sparing many attempts to develop other strong pain ther- regimens have been explored to circumvent apeutics, opioid analgesics have remained the opioid-induced bowel dysfunction, but the mainstay of therapy in many patients with mod- outcome has in general been unsatisfactory. erate to severe pain. However, the use of opioid Specific antagonism of peripheral opioid re- analgesics is associated with a number of adverse ceptors offers a more rational approach to the effects among which those on the GI tract are management of the adverse actions of opioid most troublesome in terms of frequency and analgesics in the gut. This goal is currently addressed by the use of an- severity. The constipation associated with opioid tagonists with limited absorption such as oral medication can be disabling to a degree that opi- and by the development of peripher- oid treatment needs to be reduced or even aban- ally restricted opioid receptor antagonists doned. The traditional approach to ameliorate such as and . opioid-induced constipation is co-med- These investigational drugs hold considerable ication which, however, can be both ineffective promise in preventing constipation due to opi- 1-3 ate treatment, whereas the action of and distasteful to the patient . opiates remains unabated. Postoperative ileus The spectrum of adverse opioid actions on the associated with opioid-induced postsurgical gut reflects the ability of these analgesic drugs to pain control is likewise ameliorated by the directly interact with pathways of the enteric ner- compounds. With this proof of concept, sever- vous system that regulate GI motility and secre- al phase III studies are under way to define op- tion4-8. In addition, there is evidence that some GI timal dosage, dosing regimen as well as long- effects of opioid receptor agonists can be mediat- term efficacy and safety of methylnaltrexone 9 and alvimopan. In addition, there is prelimi- ed by opioid receptors in the brain . However, ex- nary evidence that these peripherally restrict- perimental and clinical studies with opioid recep- ed opioid receptor antagonists may act as tor antagonists that are unable to enter the brain prokinetic drugs in their own right. have shown that the adverse GI effect profile of opioid receptor agonists is essentially peripheral Key Words: in origin9. Consequently, peripherally restricted Alvimopan, Methylnaltrexone, Naloxone, Opioid opioid receptor antagonists (PRORAs) such as peptides, Enteric nervous system, Opioid-induced N-methylnaltrexone and alvimopan represent a bowel dysfunction, Constipation, Peripherally re- significant advance in improving therapy stricted opioid receptor antagonists, Prokinetic ef- of pain2,7. The current review starts by providing fects. a brief overview of the neurobiological mecha-

Corresponding Author: Peter Holzer, PhD; e-mail: [email protected] 119 P. Holzer nisms whereby cause constipation. After The presence of an elaborate opioid system (Fig- describing the clinical features of opioid-induced ure 1) in the gut explains why exogenous opioid bowel dysfunction (OBD) the article goes on to analgesics inhibit GI function. Met-, discuss the emerging strategies to avoid OBD leu-enkephalin, β-endorphin and are and the expanding range of indications in which among the endogenous opioid peptides occurring PRORAs are likely to be of therapeutic benefit. in the GI tract where they have been localized to both neurons and endocrine cells of the mu- cosa2,4,5,8,13. Further analysis has revealed that The Opioid System in opioid peptides are present in distinct classes of the Gastrointestinal Tract enteric neurons, notably in myenteric neurons projecting to the circular muscle and in neurons Independently of their plant, mammalian or of descending enteric pathways11-13. Opioid re- synthetic origin, opioids are neuroactive sub- ceptors of the µ-, κ- and δ-subtype have been lo- stances, the actions of which are mediated by the calized to the GI tract of rodents and humans, but principal µ-, κ- and δ-opioid receptors. Many their relative distribution varies with GI layer, GI neuroactive drugs act on the gut because the ali- region and species2,8,13. In the human gut, µ-opi- mentary canal is equipped with the largest collec- oid receptors are present on myenteric and sub- tion of neurons outside the brain, known as the mucosal neurons and on immune cells in the enteric nervous system (ENS). The enteric neu- lamina propria13. rons originate from the myenteric and submucos- al plexuses, supply all layers of the alimentary canal and thus are in a position to regulate virtu- Opioid Physiology and Pharmacology in ally each aspect of digestion10-12. Many of the the Gastrointestinal Tract transmitters and neuropeptides occurring in the brain are also expressed by the ENS, and the When released from enteric neurons, opioid same is true for transmitter and neuropeptide re- peptides modify GI function by interaction with ceptors. Thus, enteric neurons synthesize and re- opioid receptors present on the enteric circuitry lease not only acetylcholine, substance P, nitric controlling motility and secretion. The inhibitory oxide, adenosine triphosphate, vasoactive intesti- effect of opioid receptor agonists on peristalsis in nal polypeptide and 5-hydroxytryptamine but al- the guinea-pig small intestine is thought to arise so opioid peptides as their transmitters. primarily from interruption of transmission with-

Figure 1. Schematic overview of the gastrointestinal opioid system rele- vant to constipation.

120 New approaches to the treatment of opioid-induced constipation in enteric nerve pathways governing muscle ac- duced inhibition of muscle activity2,8. Propulsive tivity7,8,14. Transmission is blocked both via motility in the rat intestine is blocked by δ- and µ-, presynaptic and postsynaptic sites of action on but not κ-, opioid receptor agonists5, whereas enteric neurons, whereby the release and action peristalsis in the guinea-pig intestine is sup- of transmitters are attenuated5,14. It is important pressed by activation of κ- and µ-, but not δ-, opi- to realize that opioid receptor agonists can inter- oid receptors18, much as opiate-induced inhibition rupt both excitatory and inhibitory neural inputs of cholinergic transmission in the guinea-pig gut to GI muscle14. Suppression of excitatory neural is mediated by µ- and κ-opioid receptors. inputs causes inhibition of the release of excitato- Although the available evidence indicates that ry transmitters such as acetylcholine and block- OBD is mediated by opioid receptors in the ade of distension-induced peristaltic contrac- gut2,8, there are experimental data to show that tions, whereas blockade of inhibitory neural in- opioids acting within the brain can also influence puts results in depression of nitric oxide release GI function. Thus, intradural injection of opioid from inhibitory motor neurons, disinhibition of analgesics delays intestinal transit at doses that GI muscle activity, elevation of resting muscle are considerably lower than equieffective intra- tone and non-propulsive motility patterns5,7,8,14,15. venous doses9. However, opiate-induced block- Depending on whether interruption of excita- ade of gut motility correlates better with opiate tory or inhibitory neural pathways is prevailing, concentrations in the gut than with opiate con- muscle relaxation or spasm will ensue in re- centrations in the brain19. In addition, the N- sponse to opiate administration. In addition, opi- methyl quaternary analogues of naloxone and oids may directly activate the interstitial , which do not cross the blood-brain cell–muscle network. As a result, µ-opioid recep- barrier, are able to fully antagonize the effects of tor agonists inhibit gastric emptying, increase py- morphine in the canine and rat intestine2,9. It fol- loric muscle tone, induce pyloric and duodenoje- lows that the adverse influence of opiates on GI junal phasic pressure activity, disturb the migrat- function results primarily from interaction with ing myoelectrical complex, delay transit through opioid receptors in the gut, an inference that is the small and large intestine, and elevate the rest- backed by the experimental and clinical effects ing anal sphincter pressure2,8,14. The halt in of PRORAs. propulsive motility combines with inhibition of GI ion and fluid transport. Through prolonged contact of the intestinal contents with the mucosa Opioid-Induced Bowel Dysfunction and interruption of prosecretory enteric reflexes, opioids attenuate the secretion of electrolytes and A delay in GI transit and constipation are the water and facilitate the net absorption of flu- most common and often disabling side effects of id2,5,8,16,17. As a result, the patient experiences opioid analgesics. However, constipation is just constipation and abdominal discomfort, two ma- one symptom of OBD, whose manifestations jor aspects of OBD. comprise incomplete evacuation, abdominal dis- When pharmacological measures to control tension, bloating, abdominal discomfort and in- OBD are considered, the question arises as to creased gastro-oesophageal reflux. In addition, which opioid receptor subtypes are involved. Opi- OBD may lead to secondary complications such oid receptors belong to the family of metabotrop- as pseudo-obstruction of the bowel, anorexia, ic membrane receptors that couple via the Gi/Go nausea, vomiting and interference with oral subtypes of G-proteins to cellular transduction administration and absorption2,8. The symptoms processes. Once activated by agonists, µ-opioid associated with OBD can profoundly impair the receptors undergo endocytosis in a concentration- quality of life and in some patients can be so se- dependent manner13,14. The cellular effects of vere that they prefer to discontinue analgesic myenteric µ-opioid receptor activation are therapy rather than experience the discomfort brought about by a multiplicity of signalling path- arising from OBD2. Unlike other adverse effects ways including activation of potassium channels, of chronic opioid therapy such as sedation, nau- membrane hyperpolarization, inhibition of calci- sea and vomiting which often resolve with con- um channels and reduced production of cyclic tinued use, OBD generally persists throughout adenosine monophosphate14. Studies with isolated treatment2. However, tolerance to the effects of tissues from the human intestine show that δ-, κ- morphine on enteric neurons has been found to and µ-opioid receptors contribute to opiate-in- occur under experimental conditions14.

121 P. Holzer

Specific Management of Opioid-Induced opioid receptor antagonists that cannot penetrate Bowel Dysfunction the blood-brain barrier. As a result, the adverse effects of opioid analgesics on the GI system The pharmacological management of OBD in- would be suppressed whereas their central anal- volves two approaches (Figure 2): non-specific gesic action would be preserved. This approach treatment with laxatives and prokinetic drugs and has been validated by the use of opioid receptor specific treatment with opioid receptor antago- antagonists with limited systemic absorption and nists1,2,20. Since the non-specific regimens often by the development of PRORAs such a N- do not provide satisfactory relief from the GI methylnaltrexone and alvimopan2,8,22,23. The latter manifestations of opioid-induced analgesia, vari- two compounds are currently in clinical trials for ous opportunities in the specific treatment of the management of OBD and postoperative ileus OBD have been explored. The primary objective and may also turn out to become prokinetic drugs of these approaches is to prevent GI symptoms to relieve intestinal stasis unrelated to opiate use. rather than treat established motor stasis due to opioid use2. For this reason, many opioid-sparing Opioid Receptor Antagonists with Limited regimens such as non-steroidal anti-inflammato- Systemic Absorption: Oral Naloxone ry drugs have been tested to circumvent the ad- The first attempt to selectively target opioid re- verse GI sequelae of opioid use. However, these ceptors in the periphery was made with naloxone regimens lack efficacy in severe pain states and and related tertiary opioid receptor antagonists themselves have adverse effects on the gut. such as nalmefene2. Naloxone is a pan-opioid re- Transdermal administration of opiates such as ceptor antagonist24 whose systemic has also been reported to cause less con- following oral administration is as low as 2% be- stipation and to result in a better quality of life cause of extensive first-pass metabolism. Conse- rating than oral administration of morphine2,21. quently, oral naloxone has been found to reduce However, none of these attempts is able to solve constipation but not antinociception caused by the problem of OBD in a satisfactory manner. morphine in rats25. These observations have been Since opioid-induced analgesia is primarily confirmed in clinical studies in which oral nalox- mediated by µ-opioid receptors in the central ner- one turned out to improve OBD without necessar- vous system, the rational approach to prevent ily compromising opiate-induced analgesia1,26,27. OBD would be to combine opioid analgesics with It needs to be realized, however, that naloxone

Figure 2. Non-specific and specific treatment of opioid-induced bowel dysfunction.

122 New approaches to the treatment of opioid-induced constipation can easily cross the blood-brain barrier and Methylnaltrexone hence, despite its low oral bioavailability, can re- Attaching a methyl group to the amine config- verse analgesia if given at sufficient doses2. Thus, uration in naltrexone results in N-methylnaltrex- the therapeutic range of naloxone is rather narrow one (in brief methylnaltrexone), a drug that has because of the need to titrate peripherally versus greater polarity and lower lipid solubility than its centrally active doses26. Despite this limitation, a parent compound. As a result, methylnaltrexone combination of oral and naloxone at exhibits low oral bioavailability due to limited ab- the weight ratio of 2:1 has been licensed in Ger- sorption and does not cross the blood-brain barri- many, given that a phase III trial had shown that er8,22,34,35. Consequently, this µ-opioid receptor- the combination has a low potential to induce preferring antagonist (IC50 at human µ-opioid re- OBD whereas the analgesic effect is preserved28. ceptors = 70 nM) offers the potential to prevent or One of the major metabolites of naloxone is reverse the undesired side effects of opioids in the naloxone-3-glucuronide which following oral ad- gut without compromising analgesia or precipitat- ministration to rodents is absorbed to a negligible ing opioid withdrawal symptoms that are predom- degree but can counteract opiate-induced inhibi- inantly mediated by opioid receptors in the tion of GI motility29,30. Experimental observa- brain22,34. This claim has been supported by sever- tions similar to those with naloxone glucuronide al studies which show that, following subcuta- have been made with glucuronide, a neous or intravenous administration of methylnal- metabolite of the µ-opioid trexone together with a centrally active opiate, the nalmefene29. A pilot study in humans, however, adverse effect of the opiate on GI function is pre- indicates that oral nalmefene glucuronide is not vented without attenuation of analgesia in dogs sufficiently selective for the gut in order to be and humans, whereas in rats analgesia is appre- clinically useful31. ciably compromised22,34,35. This species-depen- dence of the peripheral selectivity of methylnal- Peripherally Restricted Opioid trexone arises from its demethylation to naltrex- Receptor Antagonists one which readily penetrates the blood-brain bar- Quaternary analogues of opioid receptor an- rier: demethylation occurs in mice and rats but is tagonists such as naloxone and naltrexone dis- negligible in dogs and humans36. play a pharmacokinetic profile of limited absorp- A number of phase I and II studies has estab- tion from the gut and inability to enter the lished the pharmacodynamic, pharmacokinetic, brain2,22. Thus, intraluminal administration of N- therapeutic and safety profile of methylnaltrex- methylnaloxone to an isolated vascularly per- one22,34,35,37. The drug has been formulated as a fused segment of the rat colon prevents intravas- solution for intravenous or subcutaneous admin- cularly administered morphine from depressing istration and as capsules/tablets for oral adminis- motility, although the compound is not absorbed tration. Both the parenteral and oral formulations from the lumen to a degree that it becomes mea- as well as single and repeated dosage regimens surable in the vasculature30. Similarly, N-methyl- have been found efficacious in preventing the naloxone and N-methylnaltrexone attenuate mor- morphine-induced prolongation of gastric empty- phine-evoked electrical activity in the canine ing and orocaecal transit time without signifi- duodenum at doses that are devoid of effects on cantly attenuating morphine-induced analge- the central nervous system32. N-methylnaltrexone sia22,34,35. In this context it is worth noting that and another highly polar opioid receptor antago- methylnaltrexone is also able to ameliorate opi- nist, alvimopan, also fail to enter the brain in hu- oid-induced urinary retention38. mans and have a promising potential to relieve Phase II studies have shown that methylnal- OBD in a well-tolerated manner without compro- trexone is capable of relieving constipation in mising central analgesia. It is worth noting, how- -maintained, opioid-dependent volun- ever, that N-methylnaltrexone and alvimopan dif- teers. In a double-blind, randomized and place- fer in their opioid receptor subtype selectivity bo-controlled trial it has been found that intra- and intrinsic activity on the isolated guinea-pig venous methylnaltrexone shortens the orocaecal ileum33. While N-methylnaltrexone reduces elec- transit time and causes laxation, but does not trically induced contractions and spontaneous ac- elicit opioid withdrawal39. The utility of tivity of the muscle, alvimopan increases these methylnaltrexone to selectively counteract opi- parameters. The action of alvimopan appears to ate-induced stasis in the GI tract has also been involve both µ- and κ-opioid receptors33. proven in phase II and III studies of patients with

123 P. Holzer advanced illness requiring high doses of opiates vent opioid receptor agonists from delaying GI for pain control34,35. As a result, methylnaltrexone transit in healthy subjects without antagonizing has been approved in Europe, Canada and the central opioid effects such as analgesia and USA for the treatment of opioid-induced consti- pupillary constriction43-45. pation in patients with advanced illness. In subsequent phase II trials the utility of Postoperative ileus could be another indication alvimopan in preventing or treating OBD was for methylnaltrexone. This condition is thought to explored8,22,44,46,47. In patients on chronic opioid involve activation of opioid mechanisms in the gut therapy for non-malignant pain or opioid addic- and to be exacerbated by the use of opioid anal- tion, alvimopan (0.5 or 1 mg once daily for 21 gesics for the control of postoperative pain40,41. A days) was found to ameliorate constipation phase II trial has shown that patients with postop- without attenuating opioid analgesia46. These erative ileus following open segmental colonic re- results were confirmed in a phase III trial in- section benefit from treatment with methylnaltrex- volving more than 500 subjects taking opioids one, since upper and lower bowel function recover for non-cancer pain47. Alvimopan (0.5 or 1 mg approximately 1 day earlier than in placebo-treated twice daily for 6 weeks) was able to increase patients, whereas no difference in opioid use or spontaneous bowel movements during the ini- mean pain scores was observed34. Two phase III tial 3 weeks of treatment and to improve other studies are currently under way to establish the ef- symptoms of OBD (straining, stool consistency, ficacy and safety of methylnaltrexone in postopera- incomplete evacuation, abdominal bloating and tive ileus35. discomfort and decreased appetite) over the At therapeutic doses (0.3-0.45 mg/kg intra- whole treatment period, while analgesia was venously and up to 19.2 mg/kg per os) methylnal- not compromised47. trexone is well tolerated, an outcome that is also Since opioid mechanisms and OBD are true when methylnaltrexone is repeatedly admin- thought to contribute to postoperative ileus2,40,41, istered at 0.3 mg/kg intravenously every 6 h37. several phase II and III studies have addressed Thus far, only two types of adverse reactions to the ability of alvimopan to improve postopera- methylnaltrexone have been reported. One of tive bowel function2,8,22,44,48,49. The results of them relates to the vascular system, given that these studies indicate that alvimopan can shorten transient orthostatic hypotension can occur at postoperative ileus, although with somewhat supra-therapeutic doses8,22,34,35. This reaction may varying results. This may in part be due to the be related to facial flushing and mild light-head- rather wide range of doses (1-12 mg) tested as edness, symptoms that have occasionally been re- well as to differences in , given ported35. The other type of adverse effect com- that the rate of alvimopan absorption is slowed prises gut-related reactions such as abdominal in surgical patients, relative to healthy controls50. cramps, soft stools and diarrhoea8,22,34,35,37. The patients enrolled in the studies underwent radical abdominal hysterectomy or bowel resec- Alvimopan tion, and in most studies the initial dose of alvi- Alvimopan is a µ-opioid receptor-preferring mopan was given 2 h before surgery, and the antagonist with a peripherally restricted site of drug subsequently dosed twice daily. Postopera- action and a potency (IC50 at human µ-opioid re- tively, patient-controlled analgesia with intra- ceptors = 0.77 nM) considerably higher than that venous opioids was instituted. Alvimopan (12 of methynaltrexone. Given its polar structure, mg) was found to shorten both the time to first alvimopan exhibits both low systemic absorption bowel movement and the duration of hospitalisa- (oral bioavailability of 0.03% in dogs and 6% in tion on average by 18 h49. The drug has recently humans) and a limited ability to enter the been approved in the USA for the short-term brain22,42-44. Since it is rapidly degraded after in- treatment of postoperative ileus in hospitalised travenous injection, alvimopan is formulated for patients. oral intake, in which case it potently blocks µ- Studies addressing the acute safety of alvi- opioid receptors in the gut with a prolonged du- mopan in patients with OBD have shown that the ration of action. Several preclinical and phase I drug is well tolerated, the adverse effects being studies have established the pharmacokinetics, primarily bowel-related and including nausea, safety, efficacy and selectivity of alvimopan in its vomiting and abdominal discomfort43. When antagonism of peripheral opioid receptors2,8,22,42- alvimopan was tested for 3-6 weeks, the most 44. In these studies, alvimopan was found to pre- prevalent adverse reactions comprised abdominal

124 New approaches to the treatment of opioid-induced constipation pain, nausea and diarrhoea and occurred pre- intestinal pseudo-obstruction and constipation- dominantly during the initial period of treat- predominant irritable bowel syndrome8,22. PRO- ment46,47. It is at present too early to judge the RAs may hence be able to normalize pathologi- long-term safety of alvimopan, given that a cal inhibition of gut function that arises from an phase III trial revealed a numerical imbalance in upregulation and/or overactivity of the opioid the number of ischaemic cardiovascular events system in the GI tract6,8. and neoplasm cases in patients on alvimopan, relative to placebo3.

Conclusions Opioid Receptor Antagonists as Potential Prokinetics The GI tract is one of the major targets of the undesired effects of opiates, because the ENS ex- From the effects of opioid receptor antagonists presses all major subtypes of opioid receptors on GI function it would appear that endogenous which when activated dampen GI function. This opioid peptides play a role in the fine tuning of di- may be physiologically meaningful under condi- gestion. For example, distension-evoked peristalsis tions where the endogenous opioid system is ac- can be facilitated by naloxone in various prepara- tivated, but represents a nuisance when exoge- tions of the guinea-pig, rabbit, cat and rat isolated nous opiates are administered for therapeutic small intestine5,7,18. In the guinea-pig small intes- purposes. The development of opioid receptor tine, the effect of naloxone is mimicked by selective antagonists with restricted access to the central antagonists at µ- and κ-opioid receptors, but not by nervous system has opened up a new avenue to antagonism at δ-opioid receptors18. It follows that selectively control the adverse actions of opioid endogenous opioid peptides released in the course analgesics in the gut. This concept has been vali- of propulsive motility participate in the neural con- dated by the clinical efficacy of oral naloxone, trol of peristalsis as they dampen peristaltic perfor- parenteral methylnaltrexone and oral alvimopan, mance via activation of µ- and κ-opioid which are able to prevent the undesired opioid ef- receptors8,18. Naloxone has been found to accelerate fects on GI function while the desired action of transit in the colon but not small intestine of healthy opiates on central pain control is preserved. With human volunteers, this effect being shared by the µ- this proof of concept, further studies defining op- opioid receptor-preferring antagonists methylnal- timal dosage, dosing regimen as well as long- trexone and alvimopan37,45. Thus, PRORAs have the term efficacy and safety are needed8,23. These potential to act as prokinetics in their own right and studies will also reveal whether PRORAs could to alleviate intestinal motor stasis unrelated to opi- act as prokinetic drugs in their own right. ate use, such as chronic idiopathic constipation and intestinal pseudo-obstruction6,8,34,43. There is emerging evidence that GI pathophys- –––––––––––––––––––––––– iology leading to GI motor inhibition is associat- Acknowledgements ed with upregulation and/or overactivity of the opioid system in the alimentary canal. For in- Work in the authors' laboratory is supported by FWF – stance, experimental inflammation enhances the The Austrian Scientific Research Funds, the Austrian Federal Ministry of Science and Research, and the potency of µ-opioid receptor agonists to inhibit Zukunftsfonds Steiermark. The author thanks Ulrike GI transit and increases the expression of µ-opi- Holzer-Petsche for critically reading the manuscript. oid receptors in the intestine of mice51,52. Abdom- inal surgery leads to an increase in the circulating levels of in humans53 and causes δ internalization of -opioid receptors in the myen- References teric plexus of the guinea-pig intestine13. These observations reflect a role of endogenous opioids in the pathophysiology of postoperative motor 1) MEISSNER W, S CHMIDT U, HARTMANN M, KATH R, REIN- HART K. Oral naloxone reverses opioid-associat- disturbances. Consistent with this concept is a ed constipation. Pain 2000; 84: 105-109. limited number of small studies showing that 2) KURZ A, SESSLER DI. Opioid-induced bowel dys- naloxone can reverse idiopathic chronic constipa- function: pathophysiology and potential new tion and have beneficial activity in patients with therapies. Drugs 2003; 63: 649-671.

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