Dapsone

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C source was opened to support even a yellow grade, and no circulating consumer claim of dapsone mitochondrial damage was found to rebut. This is a disclosed gap, not a finding of safety. Re-check when PubMed and Europe PMC access is available.

What was searched

Crossref title search for "dapsone oxidative stress mitochondria": 15 records returned, none with dapsone in the title (all generic mitochondria and oxidative stress papers). Further Crossref title searches phrased around "dapsone mitochondrial", "dapsone mitochondria respiration", "dapsone mitochondrial membrane potential ATP" and "dapsone mitochondrial toxicity" were rate-limited (429) or returned fetch errors. One web search was refused because the shared search budget was exhausted. PubMed listing pages returned 429 and the tool asked not to retry them. Repair pass: WebSearch retried for "dapsone mitochondria hydroxylamine mitochondrial function respiration" and refused again (budget used up). Crossref bibliographic search "dapsone hydroxylamine mitochondrial toxicity" completed (20 records, all dapsone or hydroxylamine records on methemoglobin, hemolysis, procoagulant red cells, cytotoxicity and neutrophil chemotaxis; no title mentioning mitochondria). Crossref search "dapsone mitochondrial membrane potential ATP cells" completed (20 records, all generic mitochondrial papers, none naming dapsone). Europe PMC REST search (dapsone with copper terms) was refused by the proxy (429) twice. One caveat: Crossref returns titles only, so a mitochondrial finding inside the abstract of a dapsone paper would not be visible.

Channel outcomes

Label [1]: no mitochondrial content in the sections retrieved. OpenAlex list and search endpoints returned fetch errors; single-DOI lookups worked but only for records already identified. Repair pass: three completed Crossref searches with no mitochondrial dapsone title, plus the red-cell chapter on dapsone hydroxylamine [16] (see Sources) whose full text could not be read. Red cells have no mitochondria, so the hydroxylamine red-cell work in [8] is not mitochondrial evidence. Partly tooling-limited (no PubMed, Europe PMC or web search), but no lead was found.

Limits on what this shows

• Null findings: No change in lipid peroxidation, nitric oxide, SOD or total antioxidant capacity, and glutathione rose [7].

Regulatory status

The label describes Heinz body formation and hemolysis but no antioxidant-nutrient effect [1].

Population evidence

Clinical oxidative stress during leprosy multidrug therapy [7]: 23 leprosy patients (dapsone, clofazimine, rifampicin) and 20 healthy people in the Brazilian Amazon, sampled before treatment and through month 3. Methemoglobin and Heinz body counts rose significantly after the third supervised dose; catalase activity fell significantly; glutathione content rose; lipid peroxidation, nitric oxide, superoxide dismutase and total antioxidant capacity did not change significantly. Plasma dapsone was 0.518 +/- 0.029 ug/mL (multibacillary) and 0.662 +/- 0.123 ug/mL (paucibacillary). Read as an OpenAlex abstract paraphrased by a summarizing fetch tool; p-values, correlations with dapsone level and full text were not retrieved. Dapsone is in the cohort only as one component of a three-drug regimen. In vitro, the hydroxylamine metabolite triggered band 3 aggregation and antibody binding in human red cells [8].

Mechanism

Present: the N-hydroxylated metabolite is the species linked to methemoglobin formation and red-cell damage [7][8]; the authors of [7] also examined redox mechanisms of the metabolite and modeled dapsone binding to CYP2C19, which is not interpreted here. A 1995 report on the metabolite and red-cell sulfhydryl status was seen as a title only (abstract not available) and is not used [13].

Class cohort test

Not a class extrapolation. Dapsone was in the cohort [7], but with rifampicin and clofazimine, so attribution to dapsone alone is not established. No other-class borrowing was used.

Counter-evidence held on record

Counter-evidence The only human marker study is mixed and confounded by two co-drugs and by leprosy itself. A Tier D page states dapsone inhibits myeloperoxidase [10], an anti-inflammatory enzyme effect that was not verified in a primary source here. Framing caution Redox injury is a drug toxicity mechanism, not an antioxidant-vitamin deficiency. Do not use this entry to recommend antioxidant supplements; see the vitamin E entry for the one trial.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C source opened and no circulating copper claim for dapsone found. Disclosed gap, not reassurance. Kept independent of the Iron entry (Hard Rule 7). Re-check recommended.

What was searched

The label text [1] has no copper statement. A copper-specific Crossref title search could not be completed in this review because of rate limiting (429); no copper phrasing was returned by any other opened record. Web search was unavailable. Repair pass, completed Crossref searches: "dapsone copper ceruloplasmin" (15 records, all generic copper and ceruloplasmin papers, none naming dapsone); "dapsone serum copper" run as a title search (15 records, all titled only "Dapsone", i.e. drug monograph digests with no copper content in the title); "leprosy serum copper zinc ceruloplasmin" (15 generic trace element papers, none about leprosy); "dapsone copper zinc trace elements leprosy serum" (20 records, none about dapsone or leprosy); "leprosy patients serum copper zinc" (20 records, two about leprosy: a 1993 serum lactoferrin study in lepromatous leprosy and a 2021 serum zinc study in leprosy patients, DOI 10.9734/bpi/nfmmr/v1/11351d; neither was opened, neither is a copper study, and neither isolates dapsone). A PubMed "dapsone copper" listing and a PubChem pug_view fetch were refused (429); the OpenAlex search endpoint returned a fetch error; WebSearch was refused (budget used up).

Channel outcomes

Searched across five completed Crossref queries with several phrasings (copper, ceruloplasmin, trace elements, leprosy), none returning a dapsone and copper record. Because Crossref gives titles only and PubMed, Europe PMC and web search were blocked, this remains partly tooling-limited, but it is no longer an unsearched entry: no title-level lead exists in the channel that did work.

Limits on what this shows

• Why no grade: Dual condition met: no opened Tier B or C source supports even yellow, and no circulating iron claim for dapsone was found. The hemoglobin fall is covered in the Oxygen delivery entry and is not re-counted here. Not reassurance. Kept independent of Copper (Hard Rule 7).

What was searched

Crossref title search "dapsone iron deficiency anaemia": 15 records returned, none with dapsone in the title. A Reactions Weekly record titled "Dapsone/ferrous oxalate" (2011) appeared in a Crossref listing; OpenAlex held no abstract and the Springer page fetched for its DOI showed an unrelated daptomycin case, so the content was not opened and is not used [15]. The Naik and Byrd cohorts report hemoglobin but not ferritin or iron indices [3][4]. A plain "dapsone iron" title search was rate-limited. Repair pass: the Crossref search "dapsone iron ferritin anemia" completed (20 records); the only dapsone records were "Hemolysis and Anemia Induced by Dapsone Hydroxylamine" (2012, IntechOpen chapter by Dona, Ragazzi, Clari and Bordin, DOI 10.5772/30462) and a 2024 preprint "Dapsone-Induced Heinz Body Hemolytic Anemia" (DOI 10.22541/au.172678249.96489126/v1). The chapter page on IntechOpen was opened but showed only the title and metadata, with no iron, ferritin or other nutrient text and no mechanism text (the body is in a PDF that was not retrieved) [16]. The preprint was not opened. An earlier "dapsone iron deficiency anaemia" search also returned nothing dapsone-titled. A second phrasing, "dapsone ferritin serum iron anaemia leprosy", hit a fetch error.

Channel outcomes

Mixed: two completed title searches without an iron-and-dapsone study, an unopened interaction record [15], and two unopened hemolysis records; web search and PubMed were unavailable. Tooling-limited, with the interaction record and the hemolysis chapter full text as the leads to re-check.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C source and no circulating claim found. A leprosy multidrug microbiome study, had one been found, would be regimen-confounded and capped at yellow. Not reassurance.

What was searched

Crossref title search "dapsone gut microbiota OR microbiome OR intestinal flora": 15 records, none dapsone-related. Crossref title search "gut microbiome leprosy patients multidrug therapy dapsone rifampicin": returned dapsone-leprosy papers (pharmacokinetics, adverse reactions, an oxidative stress study) but no microbiome study. The label text retrieved [1] did not report a microbiome or C. difficile statement, though the request did not ask for it specifically. Repair pass: Crossref bibliographic search "leprosy gut microbiota multidrug therapy" completed (20 records, all Leprosy Review articles on multidrug therapy outcomes, none on microbiota); "gut microbiome leprosy patients 16S rRNA" completed (20 records, generic 16S gut microbiome papers in insects, eels, dogs and humans, none on leprosy); title search "gut microbiota leprosy" completed (20 generic gut microbiota titles, none on leprosy). A title search "leprosy microbiome" hit a fetch error. WebSearch for "leprosy multidrug therapy gut microbiome dapsone 16S" was refused (budget used up).

Channel outcomes

Five completed title-level searches, none with a leprosy or dapsone microbiome study; PubMed, Europe PMC and web search unavailable. Plausibly a true gap for this drug, but unconfirmed because Crossref ranking is noisy and shows no abstracts.

Limits on what this shows

• Null findings: None found for the hemoglobin fall itself. A human trial of vitamin E in 16 dapsone patients showed no significant hemoglobin, reticulocyte or haptoglobin change from the vitamin, so the fall was not reversed by it [6]. In the malaria trial the comparator regimen (amodiaquine plus sulfadoxine-pyrimethamine) also dropped hematocrit by 1.3% per day regardless of G6PD status, so some of that trial's decline is attributable to malaria and the comparator, not only dapsone [5].
• At-risk subgroups: G6PD deficiency and methemoglobin reductase deficiency [1][5]; older age and higher daily dose [3]; pre-existing anemia, malnutrition, malaria or intestinal parasitism (the Byrd and Gelber authors flag these as compromising baseline hemoglobin) [3]; severe cardiopulmonary disease [1]; neonates via breast milk [1].

Regulatory status

Label [1]: "Dose-related hemolysis is the most common adverse effect"; nearly all patients show a loss of 1 to 2 g of hemoglobin, a reticulocyte rise of 2 to 12%, shortened red-cell lifespan and elevated methemoglobin; G6PD-deficient patients respond more strongly. Severe anemia should be treated before starting; frequent complete blood counts are advised (the FDA Dermatology Advisory Committee suggestion quoted in the label is weekly for the first month, monthly for six months, then semi-annually). Hemolysis and methemoglobin may be poorly tolerated in severe cardiopulmonary disease.

Population evidence

(a) Byrd and Gelber 1991 [3]: retrospective analysis of 100 leprosy patients starting daily dapsone (generally 100 mg/day); mean hemoglobin fell from 14.25 +/- 1.27 to a nadir of 12.31 +/- 1.61 g/dL (P below 0.001); 83% fell by 1 g/dL or more and 16% by 3 g/dL or more; larger fall with older age (P 0.004 or lower) and with higher daily dose (P below 0.001). (b) Naik 2024 [4]: retrospective hospital series, 36 leprosy patients on multidrug therapy; 83.3% had a hemoglobin fall; mean 13.05 +/- 1.8 to 11.8 +/- 1.9 g/dL (P below 0.05); dapsone was stopped in 33.3% and 25% met the authors' definition of confirmed dapsone hemolysis. (c) Secondary analysis of an open-label randomized trial in 702 children with uncomplicated P. falciparum malaria [5] (those followed for 28 days were genotyped for G6PD A-): in the arm given chlorproguanil-dapsone plus artesunate (dapsone is a fixed-combination component), hematocrit fell 1.94% per day (95% CI 1.54 to 2.33) in G6PD A- deficient children versus 1.05% per day (95% CI 0.95 to 1.15) in G6PD-normal children over the first 4 days; severe anemia relative risk 10.2 (95% CI 1.8 to 59.3) for G6PD-deficient children given that regimen (the comparator group was not stated in the summary read; it is presumably G6PD-normal children). Sample sizes by genotype were not retrieved. An audit of dapsone-associated methemoglobinemia in renal transplant recipients exists but its abstract was unavailable and it is not used [14]. Abstracts were read through OpenAlex reconstructions and a summarizing fetch tool; full texts were not opened.

Mechanism

Present and named. The N-hydroxylated metabolite (dapsone hydroxylamine), not the parent sulfone, altered red-cell membrane band 3 (tyrosine phosphorylation, aggregation) and increased autologous IgG binding in red cells from healthy donors, and the same changes appeared in red cells from two patients on dapsone, which may shorten red-cell lifespan [8]. The same metabolite drives methemoglobin formation [1][7][8].

Hard Rule 2 justification for orange

This entry is graded above yellow on purpose and against the usual caution that a drug toxicity outcome should not exceed yellow unless a nutrient is measured. The justification: the Oxygen delivery/utilization category is defined by hemoglobin, hematocrit, red-cell mass and functional hemoglobin, and those variables were measured directly (hemoglobin in [3][4]; hematocrit in [5]; methemoglobin and hemolysis markers in [1]). The entry makes no iron, folate or B12 deficiency claim and no supplementation claim; anemia is explicitly not filed as a nutrient deficiency; iron, folate and B12 are separate entries. Orange (bounded) rather than red because the exposure is conditional on dose, G6PD status and age, no nutrient is measured, and the multidrug and combination cohorts [4][5] do not isolate dapsone. This matches how other drug-toxicity oxygen-delivery entries in this series have been handled.

Counter-evidence held on record

Counter-evidence and confounding Cohort [4] used multidrug therapy (rifampicin and clofazimine accompany dapsone), [5] used a fixed dapsone combination with artesunate in children with acute malaria (malaria itself lowers hemoglobin), and [3] and [4] are retrospective with no unexposed comparator, so baseline-to-nadir change is the exposure contrast. A Tier D page states hemolysis occurs in about 20% of patients [10]; that figure is not reconciled here with the 83% hemoglobin-fall rates and may refer to clinically overt hemolysis under a stricter definition. Framing caution This is a drug toxicity monitoring signal, not an iron, folate or B12 deficiency and not a reason to supplement anything. Anemia is an outcome (Hard Rule 2). Do not infer an oxygen-carrying nutrient gap from this entry.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence and no circulating "low energy" claim for dapsone found. Not a finding of safety. Kept independent of Mitochondrial burden and Oxygen delivery/utilization (Hard Rule 7); the reduced oxygen-carrying capacity from methemoglobin is a separate, graded entry and is not converted into an ATP claim here.

What was searched

The same Crossref title searches as Mitochondrial burden, including the ATP and membrane potential phrasing (rate-limited). No ATP, respiration or oxidative phosphorylation study of dapsone was found in any opened source. Repair pass: the Crossref search "dapsone mitochondrial membrane potential ATP cells" completed and returned 20 generic ATP and membrane potential papers, none naming dapsone; WebSearch was refused again (budget used up).

Channel outcomes

As above: two completed title searches in the repair pass with no dapsone-titled ATP hit, on top of the earlier partial searches. Mostly tooling-limited (title-only search, no abstract search), with no lead found.