Tropisetron (ICS 205-930)

Chemical identity and where it is a medicine

Nothing about tropisetron's identity is contested. The only wrinkle is how its stereochemistry gets written down. PubChem holds a single compound record for the name: CID 656665, formula C17H20N2O2, molecular weight 284.35, InChIKey ZNRGQMMCGHDTEI-FUNVUKJBSA-N. The IUPAC name field on that record reads, exactly as written, [(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] 1H-indole-3-carboxylate, describing a tropane alcohol esterified to an indole-3-carboxylic acid. The fuller stereodescriptor 1R,3r,5S turns up among the synonyms on that same record and on several other database entries, but never in the IUPAC name field itself; its lower-case r marks a pseudo-asymmetric centre rather than genuine chirality, and the compound is the endo isomer of the tropanyl ester. The FDA Global Substance Registration System carries the same molecule under UNII 6I819NIK1W with CAS registry number 89565-68-4, INN number 6535, ChEMBL identifier CHEMBL56564 and WHO ATC code A04AA03.

The synonym list attached to that PubChem record carries two CAS-like strings, 89565-68-4 and 89565-86-6. Only the first is registered as primary in the FDA substance record. The second is a digit transposition of it, and it carries a correctly recomputed check digit, which is why it passes validation and survives in circulation. Both strings are in use, and a document quoting the second will not match a database keyed to the first. The hydrochloride salt is a separate record, CID 656664, formula C17H21ClN2O2, molecular weight 320.8, and it is the salt rather than the free base that appears on marketed-product documentation.

No FDA record exists for this molecule as an active ingredient. A query of the openFDA Drugs@FDA index for tropisetron returns no match, and the only two United States product labels that name it at all are versions of the panobinostat label, which lists tropisetron among anti-emetic drugs with known QT-prolonging risk. That is a regulatory statement made inside a document about a different medicine. The one compound-specific electrocardiographic study located, in 55 cancer patients given a 5 mg intravenous bolus, found no significant change in the corrected QT interval (PMID 18239945), and no thorough QT study to the ICH E14 design was found. Koike and colleagues described the compound in 2005 as already approved for clinical use outside the United States (PMID 15927799). The Irish medicines regulator holds a withdrawn authorisation for a tropisetron hydrochloride product, licence status withdrawn on 30 November 2000, no reason stated. No current national authorisation was retrieved for this page.

Two receptors, and a number that was remeasured

Macor and colleagues reported in 2001 that this 5-HT3 antagonist was a potent and selective partial agonist at alpha7 nicotinic receptors, and that two other 5-HT3 antagonists, ondansetron and LY-278,584, lacked high affinity there. The abstract states no figures. ChEMBL's curation of that same paper records the values sitting in its tables: an alpha7 binding constant of 6.9 nM, an alpha7 EC50 of 1300 nM with a maximal response of 36 percent of the acetylcholine response, a 5-HT3 binding constant of 5.3 nM, and binding constants of 55 micromolar at alpha4beta2, 16 micromolar at alpha3 and 27 micromolar at the muscle-type receptor.

Potency figures do not agree between laboratories. Callahan and colleagues in 2017, recording from human receptors expressed in Xenopus oocytes, put the alpha7 EC50 near 2.4 micromolar and the alpha7beta2 EC50 near 1.5 micromolar, roughly twice the Macor value (PMID 28259598). ChEMBL's curation of Papke 2004 records an alpha7 EC50 of 10 nM with a maximum response of 38 percent, two orders of magnitude away from either, and that entry could not be checked against the paper (PMID 15050614). Reading Papke 2005 directly, Ruepp and colleagues give that paper's alpha7 EC50 as 0.6 micromolar, which sits with the micromolar figures rather than the nanomolar one. Papke and colleagues in 2005 also took the molecule apart and found bare tropane and tropinone had alpha7 activity comparable to the intact compound, tropinone more efficacious and a hundredfold less potent.

The selectivity ratio was disputed, and then remeasured. Ruepp and colleagues in 2017 could detect no saturable binding of tritiated tropisetron at alpha7 receptors at all, and determined its affinity instead by competition against tritiated epibatidine, which bound with a dissociation constant of 8.81 nM across five experiments. That gave an alpha7 binding constant of 1.58 micromolar, standard error 0.84, across three experiments, against a paired 5-HT3 binding constant of 0.72 nM, a pKi of 9.15, across eight. The ratio between them is greater than a thousandfold. The paper set its figure against Macor's 6.9 nM explicitly, arguing that a micromolar affinity is what a low-potency agonist should show and that Macor's own EC50 of 1.3 micromolar points the same way. Secondary pages still reproduce the 2001 pair without the remeasurement.

Auditory gating and the schizophrenia programme

DBA/2 mice supplied the starting point. Hashimoto and colleagues reported in 2005 that 1 mg/kg intraperitoneal tropisetron changed the deficient inhibitory processing of the P20-N40 auditory evoked potential in that strain, that co-administration of methyllycaconitine at 3 mg/kg blocked the change, and that methyllycaconitine alone did nothing. Sample sizes are not stated in the retrieved report. The rodent P20-N40 potential is treated in this literature as the analogue of the human P50 evoked potential, and the whole clinical programme that followed was built on that translation.

Human work began as an open-label single-dose observation reported by Koike and colleagues in 2005 (PMID 15927799), and moved to a randomised design. Shiina and colleagues in 2010 enrolled 40 patients with chronic schizophrenia taking risperidone at 2 to 6 mg per day and assigned them to 10 mg per day of tropisetron or placebo for eight weeks; 33 completed. P50 measures changed in the tropisetron arm and not in the placebo arm, in the whole group and again in the non-smoker subgroup, and the Cambridge battery rapid visual information processing score changed among non-smokers. Quality of Life Scale scores changed in all patients but not in non-smokers. Positive and Negative Syndrome Scale total and subscale scores did not change in either arm.

Zhang and colleagues in 2012 randomised 40 non-smoking patients with P50 ratios above 0.5, stabilised on risperidone at 3 to 6 mg per day, to placebo or 5, 10 or 20 mg per day for ten days, and reported that neuropsychological battery scores rose in all three active arms, that P50 measures changed, and that two participants in the 20 mg arm withdrew because of adverse effects. Xia and colleagues in 2020 reported a trial with the same size, the same four arms, the same inclusion criteria and overlapping authorship including the same senior author, measured after one day. Whether the two reports describe the same 40 participants at two timepoints is not stated in either.

The phase 3 result that exists only in the registry

NCT00435370, sponsored by Baylor College of Medicine, ran from November 2006 to August 2011 at two sites, one in Houston and one in Beijing, and tested tropisetron at 10 mg per day added to risperidone at 6 mg per day against placebo added to risperidone. One hundred and seventy-nine participants were randomised, 90 to tropisetron and 89 to placebo, and 68 and 69 respectively completed. A single primary outcome was registered: the Measurement and Treatment Research to Improve Cognition in Schizophrenia composite at the end of twelve weeks, normalised to a mean of 100 and a standard deviation of 10, with higher scores indicating better performance.

The posted result is 96 with a standard deviation of 16 on tropisetron and 95 with a standard deviation of 15 on placebo, and the posted analysis gives a p value of less than 0.05. One point of separation, on a composite whose own posted dispersion is fifteen times that. Adverse events posted at the five percent threshold amount to 8 of 90 against 6 of 89 in a single undifferentiated category, with no serious events posted. No dedicated publication of that twelve-week outcome was located. The two papers the registry links to the record are the 40-participant ten-day report and a 2023 functional imaging paper about risperidone response.

What the compound class did in aggregate

Lewis and colleagues in 2017 pooled every randomised placebo-controlled trial of compounds with alpha7 nicotinic activity for cognitive dysfunction in schizophrenia and Alzheimer's disease: 18 studies, 2,670 participants, eight compounds. Effects on overall cognition and on each of eight cognitive subdomains ranged from a standardised effect of minus 0.077 to 0.12 with all doses included, and none reached statistical significance. The same review pooled 29 rodent studies of the same agonists and found standardised effects between minus 1.18 and minus 0.73. The authors framed the gap between the two as a translational problem rather than a dosing one.

Recio-Barbero and colleagues in 2021 narrowed the question to adjunctive treatment in schizophrenia and included 13 studies (PMID 33889097). Four randomised trials covering 414 participants showed no difference on any cognitive domain assessed. Nine trials covering 978 participants produced a small effect on negative symptoms, a standardised mean difference of minus 0.28 with a 95 percent confidence interval of minus 0.56 to minus 0.00 and a p value of 0.05, which the reviewers graded as low-confidence evidence. Their stated conclusion was that current evidence is too weak to treat this receptor class as an effective add-on.

One signal recurs across the reviews, and it is narrower than the claims built on it. Tsitsipa and colleagues in 2022 reviewed 11 human studies of 5-HT3 antagonists and sensory processing and counted their results rather than pooling them: five reported improved sensory gating in patients with schizophrenia, with tropisetron also associated with improved sustained visual attention in non-smoking patients. That review ran a narrative synthesis and no meta-analysis, so its count carries none of the quantitative weight of the two pooled analyses above. Effects on other sensory processing measures were inconsistent, and the reviewers attributed that to small study numbers, methodological heterogeneity and concomitant medication. Gating is a physiological measurement, not a clinical endpoint, and the review said as much.

Fibromyalgia: one large trial, then nothing

Farber and colleagues published the largest randomised trial of this molecule outside oncology in 2000, on behalf of the German Fibromyalgia Study Group. Four hundred and eighteen patients meeting American College of Rheumatology criteria were assigned to placebo or to 5, 10 or 15 mg once daily for ten days in a multicentre, double-blind, parallel-group design. The response rate was 39.2 percent on 5 mg against 26.2 percent on placebo, p equal to 0.033. Absolute pain-score reduction was minus 13.5 percent at 5 mg, minus 13.0 percent at 10 mg and minus 6.3 percent on placebo. The 15 mg arm performed like placebo, and the authors described the dose-response as bell-shaped.

Nothing has confirmed that trial. A ClinicalTrials.gov search across tropisetron and fibromyalgia returns zero registered studies. The reports published alongside Farber in the same 2000 supplement of the Scandinavian Journal of Rheumatology were open-label or uncontrolled: a 28-day study in 30 women reporting a mean visual analogue reduction of 59.7 percent by day 28 with no comparator (Haus 2000, PMID 11028833), and an uncontrolled report of intravenous administration by Muller and Stratz, which states no sample size in its abstract and closes by asking for randomised placebo-controlled confirmation (PMID 11028834). Calandre and colleagues, updating the pharmacotherapy of fibromyalgia in 2015, listed tropisetron among drugs with at least one positive clinical trial and not among the drugs of choice (PMID 26001183). No later controlled trial was located.

Metabolism, and the paracetamol dispute

Fischer and colleagues gave 12 healthy male volunteers a single oral dose of 20 or 100 mg of carbon-14 labelled tropisetron in 1992 and collected plasma, urine and faeces for 120 hours. Absorption was rapid and complete, but bioavailability was estimated at 66 percent for the 100 mg dose and 52 percent for the 20 mg dose, which the authors attributed to saturable first-pass metabolism. Terminal half-life of the parent compound averaged 6 to 7 hours. That is the only human half-life on this page resting on a pharmacokinetic study. A figure of 11.1 hours circulates widely; it traces to one unattributed background sentence in a 1993 antiemetic dose-ranging report that measured no pharmacokinetics, and it is recorded below rather than quoted here as a measurement.

Firkusny and colleagues characterised the enzymes in microsomes from eight human livers, seven from extensive metabolisers and one from a poor metaboliser of CYP2D6 (PMID 7598739). The high-affinity 5- and 6-hydroxylation component was CYP2D6 and was absent from the poor-metaboliser liver; a low-affinity component present in both was CYP3A4. Kaiser and colleagues then genotyped 270 patients on their first day of chemotherapy: genetically defined poor metabolisers carried higher tropisetron serum concentrations in a 42-patient subgroup, and genetically defined ultrarapid metabolisers vomited more within the first four hours and again from five to twenty-four hours, with the difference more pronounced for tropisetron than for ondansetron.

The paracetamol interaction has not resolved. Pickering and colleagues in 2006 gave 26 rapid metabolisers 1 g of oral paracetamol with intravenous tropisetron, granisetron or saline in a crossover design and reported that the analgesic effect of paracetamol was completely inhibited by both antagonists, with paracetamol concentrations unchanged (PMID 16580905). Bandschapp and colleagues in 2011 found in 16 volunteers that each drug alone reduced pain ratings against saline while the combination did not (PMID 21420788). Tiippana and colleagues ran two crossover studies of 18 healthy men each and found paracetamol produced no measurable analgesia in their tests, so no conclusion about the interaction could be drawn, and tropisetron appeared to amplify rather than block (PMID 22905891). A trial in 36 post-operative patients found the between-group difference not significant (PMID 21395680).

What is not known

The longest randomised human exposure located is the twelve weeks of NCT00435370, and that trial's primary outcome exists only as a registry posting rather than a peer-reviewed report, so the largest and longest dataset in the alpha7 hypothesis for this compound has never been through review. No trial has tested it for cognition in people without a psychiatric diagnosis. ClinicalTrials.gov returns zero registered studies for tropisetron in fibromyalgia and zero in Alzheimer's disease, so the 418-patient German trial of 2000 has stood unconfirmed for twenty-six years and the animal work in dementia models has never been carried into a registered human study. Two registered trials that would add substantially to the record have gone quiet: NCT04027751, a 1,508-participant trial of intravenous tropisetron for emergence delirium with an estimated completion of March 2022, and NCT04195204, a 72-participant pilot in postoperative cognitive dysfunction, both listed as status unknown with no results posted and no publication located. Sample sizes are absent from most of the animal reports, including the mouse gating study that set the programme's direction. The compound's affinity at alpha7 is not settled: two peer-reviewed measurements differ by more than two orders of magnitude, and only one of them was made by competition binding against a radioligand that could be detected at that receptor. Only one published pharmacokinetic study in humans was located, and it used a single oral dose in twelve healthy men. On cardiac risk, a United States label for a different medicine names tropisetron among anti-emetics with known QT-prolonging risk, but the one compound-specific electrocardiographic study located, in 55 cancer patients given a 5 mg intravenous bolus, found no significant change in the corrected QT interval; no thorough QT study to the ICH E14 design was located, and the class attribution has not been reproduced as a compound-specific measurement. No published data on use in pregnancy, in lactation, in adolescents or in people over 75 for any indication other than antiemesis were located. Tropisetron is not an approved medicine in the United States, no currently active authorisation in any jurisdiction was retrieved for this page, and material obtained outside a pharmacy in a jurisdiction where it is registered has not been subject to the identity, purity or sterility controls that apply to medicinal supply.

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