Anti-CGRP antibodies block CGRP-induced diarrhea in mice

Kaiser, Eric A.; Rea, Brandon J.; Kuburas, Adisa; Kovacevich, Brian R.; Garcı́a-Martı́nez, León F.; Recober, Ana; Russo, Andrew F.

doi:10.1016/j.npep.2016.11.004

Cited by 30 publications

(36 citation statements)

References 37 publications

(63 reference statements)

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“…Previous studies have shown that CGRP can induce diarrhea and intestinal inflammation in rodents 26,27 and that CGRP antibodies can block this GI hyperactivity 27 …”

Section: Discussionmentioning

confidence: 97%

Two‐Hour CGRP Infusion Causes Gastrointestinal Hyperactivity: Possible Relevance for CGRP Antibody Treatment

2020

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Objective.-The monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor are new antimigraine drugs from which many patients already benefit. Very few side effects have been reported from the antibody trials, including very few gastrointestinal (GI) side effects. The current data derive from a double-blind cross-over study of CGRP infusion for 2 hours. We present the GI side effects of the infusion and raise the question if underreporting of GI symptoms in CGRP antibody trials has occurred. We also discuss why constipation may be more likely with CGRP receptor blockade than with CGRP neutralizing antibodies.Methods.-Thirty healthy volunteers were recruited to receive a 2-hour infusion of CGRP 1.5 µg/minutes on 2 different days. The participants were pretreated with sumatriptan tablets (2 × 50 mg) 1 day and with placebo the other day. During the infusion, the participants were asked about side effects including a detailed description about their GI symptoms. Clinical observations like flatulence, rumbling, and use of bedpan were also noted. After the infusion, the participants filled out a questionnaire about side effects at home until 12-hour after the infusion start. The study was conducted at the Danish Headache Center at Rigshospitalet Glostrup in the period February 2018 to July 2018.Results.-On both study days 93% (27/29 participants) experienced symptoms from the GI system during the infusion. Rumbling, stomach pain, nausea, diarrhea, and an urge to defecate were the most commonly experienced GI side effects. There was no difference in symptoms between placebo and sumatriptan pretreatment.Conclusion.-We conclude that a 2-hour infusion of CGRP causes frequent and sometimes severe symptoms from the GI system. The symptoms are not antagonized by sumatriptan. More attention should be paid to constipation as a possible side effect of CGRP receptor antagonists.

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“…Previous studies have shown that CGRP can induce diarrhea and intestinal inflammation in rodents 26,27 and that CGRP antibodies can block this GI hyperactivity 27 …”

Section: Discussionmentioning

confidence: 97%

Two‐Hour CGRP Infusion Causes Gastrointestinal Hyperactivity: Possible Relevance for CGRP Antibody Treatment

2020

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“…107 Exogenously administered αCGRP has been shown to cause diarrhea in mice that was blocked by a CGRP neutralizing antibody and the small molecule CGRP-RA olcegepant, suggesting a potential to treat diarrhea in disease or treatments that result in elevated CGRP. 108,109 Interestingly, a case report of a patient with irritable bowel syndrome (IBS) and a history of migraine headaches showed that low-dose triptan medication relieved GI hypermotility symptoms of IBS, consistent with a role for CGRP in increased GI motility and the known pharmacology of the triptans to inhibit sensory (visceral) afferent CGRP release. 110 We acknowledge that this CGRP-hypermotility hypothesis is not consistent with some early experimental preclinical observations that CGRP neutralizing antibodies ameliorate ileus in the small bowel and colon postoperatively, 111,112 but this may reflect the differential involvement of CGRP released from visceral afferent neurons when activated by nociceptive stimuli or inflammatory stimuli produced during abdominal surgery vs the enteric and myenteric CGRP receptors that respond to an excess of circulating CGRP.…”

Section: -Antimigraine and Gi Sites Of Action Of Cgrp Modulators At Cmentioning

confidence: 96%

“…In the GI tract, CGRP acts as a sensory transmitter to promote GI motility via the extrinsic sensory and intrinsic pathways that mediate the peristaltic response to muscle stretch and to mucosal simulation, respectively . Exogenously administered αCGRP has been shown to cause diarrhea in mice that was blocked by a CGRP neutralizing antibody and the small molecule CGRP‐RA olcegepant, suggesting a potential to treat diarrhea in disease or treatments that result in elevated CGRP …”

Section: Comparing the Cgrp Antibodies Clinicallymentioning

confidence: 99%

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

2019

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Several lines of evidence pointed to an important role for CGRP in migraine. These included the anatomic colocalization of CGRP and its receptor in sensory fibers innervating pain‐producing meningeal blood vessels, its release by trigeminal stimulation, the observation of elevated CGRP in the cranial circulation during migraine with normalization concomitant with headache relief by sumatriptan, and translational studies with intravenous (IV) CGRP that evoked migraine only in migraineurs. The development of small molecule CGRP receptor antagonists (CGRP‐RAs) that showed clinical antimigraine efficacy acutely and prophylactically in randomized placebo‐controlled clinical trials subsequently gave definitive pharmacological proof of the importance of CGRP in migraine. More recently, CGRP target engagement imaging studies using a CGRP receptor PET ligand [11C]MK‐4232 demonstrated that there was no brain CGRP receptor occupancy at clinically effective antimigraine doses of telcagepant, a prototypic CGRP‐RA. Taken together, these data indicated that (1) the therapeutic site of action of the CGRP‐RAs was peripheral not central; (2) that IV CGRP had most likely evoked migraine through an action at sites outside the blood‐brain barrier; and (3) that migraine pain was therefore, at least in part, peripheral in origin. The evolution of CGRP migraine science gave impetus to the development of peripherally acting drugs that could modulate CGRP chronically to prevent frequent episodic and chronic migraine. Large molecule biologic antibody (mAb) approaches that are given subcutaneously to neutralize circulating CGRP peptide (fremanezumab, galcanezumab) or block CGRP receptors (erenumab) have shown consistent efficacy and tolerability in multicenter migraine prevention trials and are now approved for clinical use. Eptinezumab, a CGRP neutralizing antibody given IV, shows promise in late stage clinical development. Recently, orally administered next‐generation small molecule CGRP‐RAs have been shown to have safety and efficacy in acute treatment (ubrogepant and rimegepant) and prevention (atogepant) of migraine, giving additional CGRP‐based therapeutic options for migraine patients.

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“…[17][18][19] Slower rates of gastric emptying have also been correlated with greater headache severity in migraine. 29 Constipation has been reported with anti-CGRP receptor antibodies in humans. [21][22][23] The etiology of gastroparesis in patients with migraine is unclear.…”

Section: Introductionmentioning

confidence: 99%

“…28 In mice, CGRP has been shown to induce diarrhea, which can be prevented with concurrent anti-CGRP receptor antibodies, but the mechanisms that cause this effect are not known. 29 Constipation has been reported with anti-CGRP receptor antibodies in humans. 30,31 An animal model of migraine-related gastroparesis would be useful to further elucidate the mechanisms underlying this finding.…”

Section: Introductionmentioning

confidence: 99%

No Gastrointestinal Dysmotility in Transgenic Mouse Models of Migraine

et al. 2019

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Objective.-To determine whether transgenic mouse models of migraine exhibit upper gastrointestinal dysmotility comparable to those observed in migraine patients.Background.-There is considerable evidence supporting the comorbidity of gastrointestinal dysmotility and migraine. Gastrointestinal motility, however, has never been investigated in transgenic mouse models of migraine.Methods.-Three transgenic mouse strains that express pathogenic gene mutations linked to monogenic migraine-relevant phenotypes were studied: CADASIL (Notch3-Tg88), FASP (CSNK1D-T44A), and FHM1 (CACNA1A-S218L). Upper gastrointestinal motility was quantified by measuring gastric emptying and small intestinal transit in mutant and control animals. Gastrointestinal motility was measured at baseline and after pretreatment with 10 mg/kg nitroglycerin (NTG).Results. -No significant differences were observed for gastric emptying or small intestinal transit at baseline for any of the 3 transgenic strains when compared to appropriate controls or after pretreatment with NTG when compared to vehicle.Conclusions.-We detected no evidence of upper gastrointestinal dysmotility in mice that express mutations in genes linked to monogenic migraine-relevant phenotypes. Future studies seeking to understand why humans with migraine experience delayed gastric emptying may benefit from pursuing other modifiers of gastrointestinal motility, such as epigenetic or microbiome-related factors.Abbreviations: CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, FASP familial advanced sleep phase, FHM familial hemiplegic migraine, IBS irritable bowel syndrome, IG idiopathic gastroparesis, NTG nitroglycerin (Headache 2020;60:396-404) Headache

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Anti-CGRP antibodies block CGRP-induced diarrhea in mice

Cited by 30 publications

References 37 publications

Two‐Hour CGRP Infusion Causes Gastrointestinal Hyperactivity: Possible Relevance for CGRP Antibody Treatment

Two‐Hour CGRP Infusion Causes Gastrointestinal Hyperactivity: Possible Relevance for CGRP Antibody Treatment

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

No Gastrointestinal Dysmotility in Transgenic Mouse Models of Migraine

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