Perspective

Desperately Seeking Serotonin… A Commentary on the Withdrawal of Tegaserod and the State of Drug Development for Functional and Motility Disorders

Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are common gastrointestinal disorders imposing considerable impact on the quality of life and well-being of affected individuals. A paucity of evidence-based treatment options exist for CIC and IBS-C sufferers. Tegaserod, a 5-HT₄ agonist, has a substantial body of preclinical and clinical study evidence to support its beneficial role in modulating sensorimotor function of the luminal gastrointestinal tract. Tegaserod was first approved for use by the U.S. Food and Drug Administration for the management of IBS-C and CIC in 2002 and 2004, respectively. Tegaserod enjoyed a successful uptake in the management of these disorders during its first several years of availability in the United States, but was later withdrawn from the market in 2007 over concerns related to adverse cardiovascular events. Since then, additional safety data has been generated, and following a resubmission and review by the Food and Drug Administration, in April 2019, tegaserod was once again approved for use in IBS-C under a more restricted labeling, confining use to women under 65 years of age without heart disease or additional cardiovascular risk factors. This review summarizes the regulatory journey of tegaserod and details the existing pharmacokinetic, physiologic, clinical, and safety data of tegaserod generated over the last 2 decades. The discussion also examines the future of tegaserod in the treatment of these constipation disorders, as well as its potential role in other related disorders of brain-gut interaction.

Treatment options for irritable bowel syndrome with constipation (IBS-C) are limited—new prokinetic drugs are needed. We evaluated the efficacy and safety of minesapride (DSP-6952), a partial agonist with high affinity for 5-HT4 receptors, in patients with IBS-C in Japan.

We performed a double-blind phase 2 study of 171 patients with Rome III-defined IBS-C at 33 centers in Japan, from December 2012 through August 2013. Patients were randomly assigned to groups given minesapride (1, 4, 12, or 40 mg) or placebo once daily for 4 weeks. The primary outcome was efficacy, defined as improvement in the weekly frequency of complete spontaneous bowel movements (CSBMs), abdominal symptoms, and IBS-C symptoms (according to the Japanese version of the IBS severity index score). For evaluation of safety, adverse events (AEs) were recorded.

The least squares mean change from baseline in the weekly frequency of CSBMs was greater in all minesapride groups than in the placebo group at week 4 (40 mg vs placebo, P = .040). The abdominal symptoms score improved in minesapride 40 mg group. The overall IBS severity index score decreased from baseline to week 4 in all treatment groups—especially in the 12 mg and 40 mg groups (P = .048 and <.001 vs placebo, respectively). The proportions of patients with treatment-emergent AEs in the pooled minesapride and placebo groups were 55.0% and 60.0%, respectively. The most common treatment-emergent AE was diarrhea (in 42.9% and 37.1% of patients in the pooled minesapride and placebo groups, respectively).

In a phase 2 trial of patients with IBS-C in Japan, minesapride increased stool frequency (measured by CSBMs), reduced abdominal and overall IBS-C symptoms, and was well tolerated. Japan Pharmaceutical Information Center trial no: JapicCTI-122041.

The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5-hydroxytryptamine₄ (5-HT₄) receptor agonists. DSP-6952 had a strong affinity of Ki = 51.9 nM for 5-HT_4(b) receptor, and produced contraction in the isolated guinea pig colon with EC₅₀ of 271.6 nM and low intrinsic activity of 57%, similar to tegaserod and mosapride. In the development of the 5-HT₄ receptor agonists, cardiovascular risk was deliberately evaluated, because some related prokinetics were reported to cause with cardiovascular adverse events, such as ventricular arrhythmias or ischemia. DSP-6952 showed minimal effects up to 100 μM in human ether-a-go-go-related gene (hERG) channels or guinea pig cardiomyocytes. In telemetered conscious monkeys, DSP-6952 did not affect blood pressure or any electrocardiogram (ECG) up to 180 mg/kg, p.o.; however, DSP-6952 transiently increased heart rate, as well as in anesthetized dogs. The positive chronotropic effects of DSP-6952 were completely antagonized by a 5-HT₄ receptor antagonist, and another 5-HT₄ receptor agonist, TD-5108 also increased heart rate. These effects are considered a class effect seen in clinically developing and marketed 5-HT₄ receptor agonists, and have not been regarded as a critical issue in clinical use. DSP-6952 did not induce contraction in the rabbit coronary artery up to 100 μM, which differed from tegaserod or sumatriptan. These results show that DSP-6952 does not have cardiac ischemic risk via coronary vasoconstriction. In conclusion, DSP-6952 is a promising GI prokinetic compound with partial 5-HT₄ receptor agonistic activity as well as a favorable cardiovascular safety profile.

Intestinal ischemia and reperfusion (I/R) is a potentially life-threatening disease, ensuing from various clinical conditions. Experimentally, either protective or detrimental roles have been attributed to 5-HT in the functional and morphological injury caused by mesenteric I/R. Recently, we proved the involvement of 5-HT_2A receptors in the intestinal dysmotility and leukocyte recruitment induced by 45 min occlusion of the superior mesenteric artery (SMA) followed by 24 h reperfusion in mice. Starting from these premises, the aim of our present work was to investigate the role played by endogenous 5-HT in the same experimental model where 45 min SMA clamping was followed by 5 h reflow. To this end, we first observed that ischemic preconditioning before I/R injury (IPC + I/R) reverted the increase in 5-HT tissue content and in inflammatory parameters induced by I/R in mice. Second, the effects produced by intravenous administration of 5-HT_1A ligands (partial agonist buspirone 10 mg kg⁻¹, antagonist WAY100135 0.5–5 mg kg⁻¹), 5-HT_2A antagonist sarpogrelate (10 mg kg⁻¹), 5-HT₃ antagonist alosetron (0.1 mg kg⁻¹), 5-HT₄ antagonist GR125487 (5 mg kg⁻¹) and 5-HT re-uptake inhibitor fluoxetine (10 mg kg⁻¹) on I/R-induced inflammatory response were investigated in I/R mice and compared to those obtained in sham-operated animals (S). Our results confirmed the significant role played by 5-HT_2A receptors not only in the late but also in the early I/R-induced microcirculatory dysfunction and showed that blockade of 5-HT_1A receptors protected against the intestinal leukocyte recruitment, plasma extravasation and reactive oxygen species formation triggered by SMA occlusion and reflow. The ability of α7 nicotinic receptor (α7nAchR) antagonist methyllycaconitine (5 mg kg⁻¹) to counteract the beneficial action provided by buspirone on I/R-induced neutrophil infiltration suggests that the anti-inflammatory effect produced by 5-HT_1A receptor antagonism could be partly ascribed to the indirect activation of α7nAch receptors.

This chapter reviews the spectrum and mechanisms of neurologic adverse effects of commonly used gastrointestinal drugs including antiemetics, promotility drugs, laxatives, antimotility drugs, and drugs for acid-related disorders. The commonly used gastrointestinal drugs as a group are considered safe and are widely used. A range of neurologic complications are reported following use of various gastrointestinal drugs. Acute neurotoxicities, including transient akathisias, oculogyric crisis, delirium, seizures, and strokes, can develop after use of certain gastrointestinal medications, while disabling and pervasive tardive syndromes are described following long-term and often unsupervised use of phenothiazines, metoclopramide, and other drugs. In rare instances, some of the antiemetics can precipitate life-threating extrapyramidal reactions, neuroleptic malignant syndrome, or serotonin syndrome. In contrast, concerns about the cardiovascular toxicity of drugs such as cisapride and tegaserod have been grave enough to lead to their withdrawal from many world markets. Awareness and recognition of the neurotoxicity of gastrointestinal drugs is essential to help weigh the benefit of their use against possible adverse effects, even if uncommon. Furthermore, as far as possible, drugs such as metoclopramide and others that can lead to tardive dyskinesias should be used for as short time as possible, with close clinical monitoring and patient education.