Alosetron

Limits on what this shows

• Null findings: None located for alosetron. The label's nonclinical section reports no carcinogenicity or genotoxicity [1], which is not a mitochondrial measure.
• At-risk subgroups: Not defined.

Regulatory status

No mitochondrial statement in the label extraction [1].

Population evidence

None in people. Rao 2023 [13] (in vitro; HEK293T cells and isolated mitochondria): serotonin 30 uM; ondansetron 3 nM was the only antagonist tested. Mitochondria from cells expressing 5-HT3A, 5-HT3E or both showed a serotonin-evoked membrane-potential fluorescence signal and a rise in oxygen consumption, and ondansetron pre-treatment suppressed both. Granisetron, tropisetron and palonosetron were discussed but not tested. Tier C for alosetron. No alosetron-named mitochondrial study was found.

Mechanism

Proposed receptor-level mechanism (5-HT3 subunits on the mitochondrial membrane) in the ondansetron work. Whether alosetron reaches or acts on mitochondrial receptors is unknown. Alosetron is a potent 5-HT3 antagonist by label indication, so the extrapolation is mechanistically plausible but untested. Structural similarity to ondansetron was not verified from an opened source.

Class cohort test

CLASS EXTRAPOLATION. Cohort: ondansetron only; alosetron was NOT in the cohort. Capped at yellow. Borrowing is limited to the receptor-blockade concept; nothing is borrowed from granisetron or sepsis-model ondansetron papers, which were not opened here.

Counter-evidence held on record

Counter-evidence The cited result is blockade of a serotonin-stimulated response in a transfected-cell system, not injury or reduced baseline function. Concentration relevance to alosetron plasma levels (peak about 5 to 9 ng/mL [1]) was not assessed. Framing caution Theoretical only. Do not tell readers alosetron damages mitochondria and do not recommend mitochondrial or antioxidant supplements from this entry.

Limits on what this shows

• Null findings: No direct redox marker (malondialdehyde, glutathione, SOD, total antioxidant capacity) was seen for alosetron. No human oxidative stress study was found.
• At-risk subgroups: Not applicable.

Regulatory status

No oxidative stress or antioxidant statement in the label extraction [1].

Population evidence

None in people. Motavallian 2019 [10]: male Wistar rats, TNBS (50 mg/kg) colitis; alosetron 1 mg/kg intraperitoneally for 6 days, compared with dexamethasone, the 5-HT3 agonist mCPBG and the combination. Alosetron improved colonic damage and lowered inflammatory markers (myeloperoxidase activity and cytokines), and mCPBG antagonized the effect, which the authors read as 5-HT3 mediation. Tier B, alosetron-named. Abstract level only (reconstructed from an OpenAlex record); PMC returned bot verification and the DOI returned HTTP 402, so group sizes and any other markers in the full text were not seen.

Mechanism

5-HT3 receptor blockade lowering mucosal inflammation in the model. Myeloperoxidase is a neutrophil enzyme used as an inflammation and neutrophil-infiltration marker; it is not malondialdehyde, glutathione or antioxidant capacity.

Counter-evidence held on record

Counter-evidence Intraperitoneal dosing in a chemically induced colitis model is far from oral dosing in IBS-D (the label contraindicates ulcerative colitis, Crohn's disease and diverticulitis [1]). Protective rodent findings do not show a human antioxidant effect. Framing caution Reverse-direction and preclinical. Do not market alosetron as antioxidant or anti-inflammatory, and do not use this entry to suggest antioxidant supplementation.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C source supports even a yellow grade, and no circulating consumer claim of alosetron copper effects was found to rebut. This is a disclosed gap, not a finding of safety. Kept independent of Iron (Hard Rule 7). Re-check when PubMed access is restored.

What was searched

Label extraction (no copper content) [1]; Drugs.com food and supplement interaction pages for alosetron (none for copper) [16][17]; Crossref query "alosetron copper OR ceruloplasmin OR zinc" (15 results, none mentioning alosetron) [20]; Crossref title index for alosetron, 200 of 243 records listed, none about trace minerals by title [19]. A specific alosetron copper-depletion page does not exist at the Antidote Research URL tried (HTTP 404).

Channel outcomes

PubMed listing pages (alosetron with microbiota, hemoglobin or iron, mitochondria or oxidative or ATP): HTTP 429, with the fetch tool asking not to retry. Europe PMC REST and OpenAlex search: HTTP 429. Web search: budget exhausted. A PubMed copper query specific to alosetron was therefore not completed. Mixed result: clean zero on the channels that worked, tooling-limited on PubMed.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C source on alosetron and iron, and no circulating claim to rebut. This is a disclosed gap, not a finding of safety. Anemia would be an outcome, not iron deficiency (Hard Rule 2); see Overlap map for the link to the oxygen-delivery entry.

What was searched

Label extraction: no iron statement; the labeled "hemorrhage" and ischemic colitis bleeding signs are handled under Oxygen delivery/utilization [1]; Drugs.com food and supplement pages (no iron interaction listed) [16][17]; RxList label rewrite (no iron or anemia mention beyond the rare hemoglobin wording) [18]; Crossref query "alosetron anemia OR hemoglobin OR iron deficiency OR hematologic" returned 25 iron-deficiency-anemia records, none naming alosetron [20]; Crossref title index [19].

Channel outcomes

PubMed and Europe PMC searches rate-limited (HTTP 429) as above; web search exhausted. Crossref matches on title and metadata, not abstract text, so an abstract-only mention would be missed. Mixed result: clean zero on working channels, tooling-limited otherwise.

Limits on what this shows

• Null findings: None located. No alosetron-named microbiome, 16S, dysbiosis or C. difficile study was found in Crossref title searches [19][20]; PubMed and Europe PMC searches were rate-limited.
• At-risk subgroups: Not defined. Confounding by indication is presumed: IBS-D and prior failed therapies are the treated population [1].

Regulatory status

No microbiome statement in the label extraction. Label pharmacodynamics: colonic transit time increased (alosetron 2 mg twice daily, 8 days), constipation 29% versus 6% placebo [1].

Population evidence

None in people. Feng 2019 [14]: rats, six groups of n=6, ondansetron 1.3 mg/kg by gavage, including an ondansetron-alone control arm. The authors state that ondansetron, [6]-gingerol and cisplatin could increase Bacteroidetes and decrease Firmicutes (a pooled statement; the extraction did not give a per-arm breakdown or diversity direction). Tier C for alosetron.

Mechanism

Not established for alosetron. A transit-slowing drug could plausibly alter community composition, but no opened source tests that for alosetron, and the link is an inference, not a finding.

Class cohort test

CLASS EXTRAPOLATION. Cohort: ondansetron in rats; alosetron was NOT in the cohort. Capped at yellow. No granisetron or other 5-HT3 antagonist microbiome paper was borrowed.

Counter-evidence held on record

Counter-evidence Animal data on a different molecule, with pooled wording. Phylum-level ratios carry no established clinical meaning here. Framing caution Do not tell readers alosetron disrupts the microbiome and do not recommend probiotics from this entry. A monitoring prompt about new bowel-pattern changes belongs to the label's ischemic colitis and constipation warnings, not to this entry.

Limits on what this shows

• Null findings: Colonic blood flow unchanged and 7-day oral dosing without hemodynamic change in rats [9]; no ischemic colitis in the 48-week trial [8]; hemoglobin and red-cell indices were not reported in any abstract opened. The rare hemoglobin and red cell wording is unquantified and could reflect bleeding events or unrelated laboratory events; the label does not say.
• At-risk subgroups: Label contraindications (prior ischemic colitis, impaired intestinal circulation, hypercoagulable state, constipation history) and older adults, who have about 40% higher exposure and may be at greater risk for constipation complications [1].

Regulatory status

Boxed warning: ischemic colitis and serious complications of constipation "have resulted in hospitalization, and rarely, blood transfusion, surgery, and death." Section 6.1 (blood and lymphatic): "Rare: Quantitative red cell or hemoglobin defects, and hemorrhage," with no incidence given. Section 5.2: discontinue for rectal bleeding, bloody diarrhea or new or worsening abdominal pain. Postmarketing: small bowel mesenteric ischemia. Contraindications include impaired intestinal circulation, thrombophlebitis and hypercoagulable state [1]. The first label extraction missed the 6.1 sentence; a targeted second extraction returned it, and a Tier D rewrite repeats it [18]. Label text was not read directly.

Population evidence

Label: cumulative ischemic colitis incidence in women in IBS trials 0.2% (2 per 1,000) through 3 months and 0.3% (3 per 1,000) through 6 months; serious complications of constipation about 0.1% [1]. Tong 2013 [6]: postmarketing under the risk management program, 20 November 2002 to 31 December 2011, 29 adjudicated probable or possible ischemic colitis cases and 7 constipation complications; cumulative ischemic colitis 1.03 and constipation complications 0.25 per 1,000 patient-years. Chey 2004 [8]: 48-week randomized trial, alosetron 1 mg twice daily n=351 versus placebo n=363; neither ischemic colitis nor serious bowel motor adverse events were reported. Miller 2003 [7]: UnitedHealthcare claims cohort, 3,631 alosetron users and 2,480 IBS comparators, follow-up about 5 months; the authors state that early market withdrawal limited the size and duration of follow-up. Abstract-level reads only; the reconstructed Miller abstract was garbled, so none of its rate figures are used.

Mechanism

Not established. Gallo-Torres 2006 [4] (authors include FDA staff) states that analyses of trial and postmarketing data established a causal link to ischemic colitis and constipation complications while the underlying mechanism remains unclear. In anesthetized rats [9], intravenous alosetron reduced mesenteric vascular conductance by 15% to 20% (also seen with intraduodenal alosetron and with cilansetron); 7 days of peroral treatment did not change mesenteric hemodynamics; colonic blood flow was not altered. This is Tier B, alosetron-named, and does not demonstrate a human mechanism.

Cohort test

Alosetron is named and was in the cohort in every source cited here [1][6][7][8][9]. No class borrowing was used. Granisetron and ondansetron data were not borrowed.

Counter-evidence held on record

Counter-evidence and confounding Ischemic colitis occurs without the drug and in IBS generally; the claims-database comparison [7] is described by its authors as limited by early market withdrawal, and its garbled reconstructed abstract was not relied on for any rate. A drug-caused bleed could lower hemoglobin and iron indirectly, but no source quantified that pathway. Framing caution This is a mechanism clarification, not a nutrient-style finding. Tissue ischemia and rare hemoglobin defects are the drug's own toxicity (Hard Rule 2); anemia is an outcome, not iron deficiency. Do not present it as a deficiency or recommend iron or any supplement from this entry. Bleeding symptoms call for stopping the drug and medical review per the label.

Limits on what this shows

• Null findings: No alosetron ATP, oxidative phosphorylation or membrane-potential result was located (see searches under Sources). The label reports no energy-related adverse reaction beyond the gastrointestinal events [1].
• At-risk subgroups: Not defined.

Regulatory status

Not mentioned in the label extraction [1].

Population evidence

None in people and none alosetron-named. Rao 2023 [13]: oxygen consumption rate was measured, ATP and ROS were not. Ondansetron suppressed the serotonin-induced rise in oxygen consumption. The respiration surrogate is the reason this is yellow and not ungraded; it is the same evidence as the Mitochondrial burden entry, not a second line (see Overlap map).

Mechanism

Hypothesized only: respiration modulated through mitochondrial 5-HT3 receptors. No ATP output change was shown even for ondansetron.

Class cohort test

CLASS EXTRAPOLATION. Cohort: ondansetron only; alosetron was NOT in the cohort. Capped at yellow.

Counter-evidence held on record

Counter-evidence Oxygen consumption is not ATP synthesis. Fatigue-type complaints in IBS-D populations are indication-linked and were not tied to the drug in any source read. Framing caution Theoretical only. Do not present as a "low energy" effect of alosetron, and do not recommend an energy-support supplement from this entry.