Mesalamine

Limits on what this shows

• Key null / negative: Salicylic acid uncoupling data exist but come from tobacco cells and isolated tobacco mitochondria, 5-ASA was not tested, and the source fails the cohort test [20].
• At-risk subgroups: None established. Higher systemic exposure occurs in older patients (about 2-fold Cmax) [1], but no mitochondrial outcome has been linked to it.

Regulatory

No mitochondrial statement in the extracted label [1].

Population evidence

No human data located. Tier B: isolated rat heart mitochondria (male Wistar rats) exposed to 0, 10, 25, 50, 100 µM mesalazine showed concentration-dependent succinate dehydrogenase inhibition, increased ROS, membrane potential collapse, swelling, and cytochrome c release [4]. Tier B, opposite direction: in DSS-colitis C57BL/6J mice, 5-ASA "reestablished mitochondrial bioenergetics in the colonic epithelium" in a PPAR-gamma-dependent manner [5].

Mechanism

Named in vitro (SDH inhibition, ROS, permeability transition markers) [4]; in vivo protective route via epithelial PPAR-gamma [5]. Clinical relevance of the micromolar in vitro range was not established here.

Counter-evidence held on record

Counter-evidence on record The colonic-epithelium result [5] runs the opposite way and is the tissue where the drug acts. The heart-mitochondria study used isolated organelles from a non-target organ. Framing caution Not a human mitochondrial toxicity finding and not a basis for CoQ10 or other supplement advice.

Limits on what this shows

• Key null / negative: The one human study read shows lipid peroxide falling with treatment, the reverse of an oxidant-stress finding, but it cannot separate drug effect from disease remission [9].
• At-risk subgroups: None identified. Active IBD is itself associated with lower superoxide dismutase activity (35 IBD patients vs. 30 controls, p<0.05; medication not analyzed) [10], a disease-intrinsic confounder.

Regulatory

The extracted label contains no oxidative-stress or antioxidant statement [1].

Population evidence

Human data are limited to a 1990 study of IBD patients taking sulfasalazine versus rheumatoid arthritis controls, 5-week treatment, in which rectal biopsy lipid peroxide levels normalized alongside clinical improvement; sample size was not stated in the extract [9]. Mesalamine itself was not given, so this is a labeled prodrug-moiety extrapolation (see Class extrapolation below). Pro-oxidant data are in vitro: isolated rat heart mitochondria exposed to 10 to 100 µM mesalazine showed concentration- and time-dependent ROS formation [4]; 5-ASA with Fe3+ at 20 µM each (maximal at 1:1) generated hydroxyl radical and lipid peroxidation in solution [6]; mesalamine, a 4-aminophenol derivative, drove copper- or iron-dependent ROS in permeabilized yeast cells [7].

Mechanism

Named, bidirectional: reactive-oxygen scavenging by the aminophenol ring (intended anti-inflammatory action) versus metal-reducing redox cycling (Fe3+ to Fe2+, Cu reduction) in vitro [6][7].

Class extrapolation

Yes, partial. Source [9] used sulfasalazine, whose 5-ASA moiety is mesalamine; mesalamine was not in the cohort. Cohort test: passes only for a yellow context flag about intended pharmacology, never as a deficiency claim.

Counter-evidence held on record

Counter-evidence on record The scavenging effect is the drug's intended mechanism and is excluded from deficiency grading under Hard Rule 2. In vitro pro-oxidant effects used micromolar concentrations in cell-free or isolated-organelle systems whose relation to tissue exposure was not established in this review. Framing caution Do not present as an antioxidant deficiency or as a reason to add antioxidant supplements. No dose or supplement is supported.

Limits on what this shows

• At-risk subgroups: Active IBD, children (about 70% anemia prevalence per [14]); these are disease groups, not drug-attributable groups.

Regulatory

No iron statement in the extracted label [1].

Population evidence

No iron-status study stratified by mesalamine located. Tier B in vitro: "5-ASA was very effective at chelating ferric iron (Fe3+), and it rapidly reduced Fe3+ to the ferrous form (Fe2+)," with lipid peroxidation of polyunsaturated fatty acids [6]. Iron-dependent ROS also shown for aminophenols including mesalamine in permeabilized yeast [7].

Mechanism

Named (chelation and reduction of Fe3+) but demonstrated only in solution; chelation in a test tube does not show reduced intestinal absorption.

Disease-intrinsic causes

The ECCO consensus attributes iron deficiency in IBD to continuous blood loss from ulcerated bowel, reduced intake, impaired uptake, and inflammation-driven hepcidin (functional iron deficiency); anemia affects about two-thirds of patients at diagnosis and about 30% to 40% in follow-up [14]. This must not be attributed to mesalamine (Hard Rule 2, confounding by indication).

Counter-evidence held on record

Counter-evidence on record The label lists no iron interaction and no separation interval, and none is supported here [1]. Source [14] lists hemolysis or aplasia as minor drug-related contributors but is a narrative consensus without drug-level stratification. Framing caution Do not tell patients mesalamine causes iron deficiency. Iron decisions belong to the IBD care team; this dossier recommends no iron dose.

Limits on what this shows

• Key null / negative: In 35 active IBD patients and 30 controls, serum copper did not differ significantly, while zinc was lower [10]. In 98 Crohn's and 56 ulcerative colitis patients, copper insufficiency was 20.4% and 7.1% and serum copper correlated positively with CRP and fecal calprotectin; 5-ASA was listed as a current medication in 2% of Crohn's and 30.4% of UC patients but was not analyzed against copper [11].
• At-risk subgroups: None attributable to the drug. Copper shifts in IBD track inflammation [11].

Regulatory

No copper statement in the extracted label [1].

Population evidence

No human copper study stratified by mesalamine located. Tier B in vitro: aminophenols including mesalamine reduce copper ions and sustain ROS production in permeabilized yeast cells [7]. A 2010 Toxicology paper reports oxidative DNA damage by mesalamine in the presence of copper, framed as a possible anticancer mechanism [8]; only the record title and bibliographic data could be read, not the abstract.

Mechanism

Named (Cu reduction and redox cycling) [7]. No mechanism for copper loss, malabsorption, or retention was found.

Counter-evidence held on record

Counter-evidence on record Both IBD cohorts show copper variation tied to disease activity, and neither examined the drug [10][11]. The redox interaction is not depletion or excess. Framing caution Kept separate from Iron. Not a copper deficiency or excess claim; no copper supplementation is supported.

Limits on what this shows

• Key null / negative: No alpha-diversity difference in the larger exploration cohort [12].
• At-risk subgroups: None defined. Untreated and treated patients likely differ in disease severity (confounding by indication); no microbiome-derived nutrient (for example vitamin K or B vitamin synthesis) was measured.

Regulatory

No microbiome statement in the extracted label [1].

Population evidence

Cross-sectional, 16S rDNA of mucosal samples: 57 ulcerative colitis patients (20 untreated, 37 on 5-ASA for at least 1 month) plus a 10-patient validation cohort. Alpha diversity did not differ in the exploration cohort and was decreased with 5-ASA in the validation cohort; treated patients had higher Firmicutes, lower Proteobacteria, and decreased Escherichia-Shigella [12]. Tier B, mouse: 5-ASA blunted dysbiotic E. coli expansion in DSS colitis via epithelial PPAR-gamma, restored epithelial hypoxia, and reduced oxygen available to bacteria [5].

Mechanism

Named in mice (host epithelial metabolism limiting aerobic bacterial growth) [5]; not established in humans.

Counter-evidence held on record

Counter-evidence on record The direction reported (less Proteobacteria and Escherichia-Shigella) is toward a less dysbiotic profile, consistent with the drug's anti-inflammatory effect, not a harm signal [12][5]. Framing caution Reverse-direction or neutral finding. Do not suggest probiotics or other supplements on this basis.

Limits on what this shows

• Key null / negative: No hemolytic events in 78 G6PD-deficient patients [13]. No study located measured hemoglobin or hematocrit change attributable to mesalamine against an untreated IBD comparator.
• At-risk subgroups: Age 65 or older, combination with thiopurines, pre-existing blood disease [1]. Anemia in IBD is common and disease-driven (see Iron) [14].

Regulatory

Postmarketing reports of agranulocytosis and aplastic anemia; higher incidence of blood dyscrasias (agranulocytosis, neutropenia, pancytopenia) in patients aged 65 or older; azathioprine or 6-mercaptopurine co-therapy may increase blood-disorder risk [1].

Population evidence

Retrospective-prospective multicenter study with ex vivo work in 78 G6PD-deficient IBD patients on mesalamine (30 enrolled prospectively): no hospitalization for hemolysis, no significant difference in chronic hemolysis markers up to 4500 mg/day; ex vivo methemoglobin release only above 2.5 mg/mL, a concentration reported as never reached clinically [13].

Mechanism

Idiosyncratic marrow or hemolytic reaction; no nutrient mechanism named. The local epithelial oxygen-consumption effect in mice [5] is intended pharmacology at the target and is not hemoglobin, red-cell mass, or tissue oxygen delivery.

Class extrapolation

Source [14] groups "sulphasalazine or 5-aminosalicylic acid" as related to a minor degree of hemolysis or aplasia without drug-level stratification; treated as Tier C context only.

Counter-evidence held on record

Counter-evidence on record Anemia in a patient with IBD is not an iron-deficiency or oxygen-delivery finding attributable to the drug (Hard Rule 2). Mesalamine toxicity is handled through CBC monitoring, not nutrient repletion. Framing caution Kept separate from ATP production. Recorded as an outcome entry; no nutrient or supplement action is implied.

Limits on what this shows

• Key null / negative: No clinical study of fatigue or energy output attributable to mesalamine was read; a 2016 listing titled "Conventional treatment regimens for ulcerative colitis alleviate fatigue" appeared in search listings but was not opened and is not relied on.
• At-risk subgroups: None defined.

Regulatory

No energy-metabolism statement in the extracted label [1].

Population evidence

Tier B, DSS-colitis mice: 5-ASA treatment restored ATP levels and pyruvate dehydrogenase activity in colonic epithelium and increased epithelial oxygen consumption [5]. The isolated heart-mitochondria study measured SDH activity, ROS, membrane potential, swelling, and cytochrome c release; ATP was not among the outcomes listed in the extract [4].

Mechanism

Restoration via PPAR-gamma signaling [5]; a possible inhibitory route via SDH inhibition in vitro [4] is unconfirmed for ATP output.

Counter-evidence held on record

Counter-evidence on record The ATP signal is protective at the drug's target tissue and reflects resolution of inflammation, so it is not a nutrient effect. Framing caution Kept separate from Mitochondrial burden and Oxygen delivery/utilization; shared sources are disclosed in the Overlap map. Fatigue in IBD is not an ATP finding for this drug and no supplement is supported.