从解毒剂到多模式辅助药物：犬和猫N-乙酰半胱氨酸的系统综述。

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【Abstract】 INTRODUCTION: N-acetylcysteine (NAC) is used in small-animal medicine as an antidote, mucolytic, thiol donor, and cytoprotective adjunct, yet its evidentiary basis varies markedly among indications and between dogs and cats. We systematically evaluated species-specific pharmacokinetic, clinical, experimental, and in vitro evidence to distinguish established uses from extrapolated practice. METHODS: A 104-record legacy evidence library was re-screened, and an update search of PubMed/MEDLINE, Europe PMC, Crossref-resolved publisher records, Google Scholar, selected Hungarian databases and journal archives, and backward/forward citations was completed through 1 August 2026. Eligible reports evaluated NAC in dogs or cats in vivo, or in canine- or feline-derived tissues, cells, or clinical isolates. Risk of bias was appraised with design-specific tools, and findings were synthesized narratively because interventions, models, doses, and outcomes were too heterogeneous for meta-analysis. RESULTS: Seventy-one reports were included in the qualitative synthesis. The strongest evidence supported early NAC administration for feline and canine acetaminophen toxicosis. Controlled or clinically direct evidence also supported redox restoration in hospitalized dogs, adjunctive treatment of canine parvoviral enteritis, short-course intravenous treatment in cats with acute-on-chronic kidney disease and selected topical ophthalmic applications. Antibacterial and antibiofilm activity against canine otitis and infectious-keratitis pathogens was reproducible in vitro, and a small clinical study supported multicomponent topical therapy for superficial pyoderma; however, NAC-specific effects and antimicrobial interactions remained formulation dependent. Experimental cardiopulmonary, renal, hepatic, and diabetic-organ-protection studies yielded biologically coherent but clinically immature signals. Conversely, perioperative neuroprotection, doxorubicin cardioprotection, and nebulized treatment of feline asthma were neutral or unfavorable. Conventional aqueous NAC pharmacokinetics remain undefined in dogs, and many widely quoted dosing schedules originate from expert synthesis rather than dose-ranging trials. DISCUSSION: NAC is therefore best regarded as an evidence-supported antidote and a context-dependent adjunct, not a generic antioxidant therapy. Future studies should prioritize canine pharmacokinetics, standardized formulations, clinically meaningful outcomes, and prospective validation of topical antimicrobial and renal indications. 【Introduction】 N-acetylcysteine (NAC) occupies an unusual position in companion-animal therapeutics. It is simultaneously an established antidote, a classical mucolytic, a precursor of reduced glutathione (GSH), a reactive-thiol compound, and an increasingly investigated antimicrobial and organ-protective adjunct. This pharmacological breadth is attractive in diseases characterized by oxidative injury, viscous secretions, electrophilic metabolites, microvascular dysfunction, or biofilm formation. It also creates a recurrent interpretive problem: mechanistic plausibility is often treated as if it were equivalent to clinical efficacy. The core chemistry is well-described. NAC is an N-acetylated cysteine derivative whose free sulfhydryl group can participate in nucleophilic reactions and disulfide exchange. After deacetylation, the released cysteine can support GSH synthesis when cysteine availability becomes rate limiting. Direct reaction kinetics are favorable for selected oxidants and electrophiles, but comparatively slow for hydrogen peroxide and superoxide under physiological conditions; much of the antioxidant effect is therefore indirect and dependent on cellular uptake, deacetylation, substrate limitation, and an intact glutathione system (–). NAC may additionally modulate redox-sensitive inflammatory pathways and alter extracellular matrices through thiol-disulfide chemistry (, ). These mechanisms are clinically relevant in dogs and cats, but the two species cannot be treated as interchangeable. Cats have restricted glucuronidation capacity and are exceptionally vulnerable to acetaminophen-induced methaemoglobinaemia and oxidative erythrocyte injury (, ). They also respond adversely to direct airway exposure: nebulized NAC increased airway resistance in an experimental feline asthma model (). Conversely, the only controlled pharmacokinetic study of conventional aqueous NAC in a companion species was performed in cats, whereas conventional-formulation canine pharmacokinetics remain undefined (, ). The evidence base has expanded beyond antidotal use. Recent studies have examined NAC in canine parvoviral enteritis, babesiosis and pancytopenia, feline chronic kidney disease, canine otitis, infectious keratitis, critical illness, and several induced disease models. At the same time, a 2026 narrative review summarized canine and feline pharmacokinetics and therapeutic effects, emphasizing the need for species-specific interpretation (). A further synthesis is justified only if it moves beyond catalog-style description. The present review therefore uses explicit eligibility criteria, design-specific quality appraisal, and an evidence-maturity framework to answer three questions: (i) which canine and feline indications are supported by direct clinical evidence; (ii) which dosing practices are experimentally supported, consensus-derived, or extrapolated; and (iii) where do negative findings, species differences, and translational limitations constrain use? 【Materials and methods】 This systematic review was designed and reported in accordance with PRISMA 2020 and PRISMA-S; narrative synthesis followed the SWiM framework (–). No meta-analysis was planned because the anticipated evidence encompassed pharmacokinetic crossover studies, controlled clinical trials, observational reports, induced-disease animal experiments, and in vitro assays with non-comparable outcomes. The review protocol was developed before the update search but was not prospectively registered because the systematic review evolved from a pre-existing topic-curated evidence library rather than being initiated de novo as a prospectively registered review. The absence of prospective registration is acknowledged as a methodological limitation because it reduces the external verifiability of pre-specified review decisions. The completed search strategies are provided in . 【Review question and eligibility criteria】 The review question was structured using an expanded PICOS framework (). The population comprised dogs and cats, as well as canine- or feline-derived tissues, primary cells, cell lines, secretions, and clinical microbial isolates. The intervention was NAC, acetylcysteine, or N-acetyl-L-cysteine administered alone or in a defined combination. Comparators included placebo, vehicle, no treatment, baseline, standard care, or an active comparator; uncontrolled safety reports and case series were retained when they supplied otherwise unavailable clinical information. Outcomes included pharmacokinetic variables, antioxidant and inflammatory biomarkers, clinical efficacy, organ function, microbiological activity, biofilm endpoints, adverse events, and drug interactions. Pre-specified PICOS eligibility framework. Eligible designs were randomized or non-randomized clinical studies, cohort or retrospective studies, case series and case reports, experimental in vivo studies, species-specific pharmacokinetic or pharmacodynamic studies, and in vitro or ex vivo experiments using canine or feline material. English- and Hungarian-language full-text publications from database inception through 1 August 2026 were eligible; publications available only in other languages were not included in the primary evidence synthesis. Human, rodent, and livestock studies were excluded from the primary evidence synthesis; selected non-veterinary mechanistic sources were retained only to explain chemistry or reporting methods and were clearly separated from the included evidence. Conference abstracts without adequate methods, commercial material, editorials without original data, and studies that merely mentioned NAC were excluded. The pre-specified eligibility framework is summarized in . 【Information sources and search strategy】 The evidence base was assembled in two stages. First, the 104-record legacy library underlying the source manuscript was re-screened in full. This library had originally been developed from PubMed- and Crossref-indexed literature using combinations of the core drug terms (“N-acetylcysteine,” “acetylcysteine,” or “NAC”) with species terms (“dog,” “canine,” “cat,” “feline,” “small animal,” or “veterinary”) and indication- or mechanism-related terms, including “hepatotoxicity,” “otitis externa,” “pancreatitis,” “spinal cord,” “asthma,” “cardioprotection,” “oxidative stress,” and “glutathione.” Although complete database-specific yields and search histories were not retained for the legacy library, its coverage was strengthened by full-text re-screening of all 104 records and by a deliberately broader update search. The update search included PubMed/MEDLINE and Europe PMC records, Crossref-resolved publisher pages, Google Scholar, and journal/publisher websites. The principal update concept block was (“N-acetylcysteine” OR acetylcysteine OR “N-acetyl-L-cysteine” OR NAC) AND (dog OR dogs OR canine OR canines OR beagle OR beagles OR cat OR cats OR feline OR felines OR “small animal” OR “small animals” OR “companion animal” OR “companion animals”). Hungarian-language retrieval used MTMT, MATARKA, HuVetA, the online archive of Magyar Állatorvosok Lapja, and the Acta Veterinaria Hungarica archive with (N-acetilcisztein OR acetilcisztein OR NAC) AND (kutya OR macska). Reference lists of included studies and relevant reviews were examined manually, and forward citation searching was used for sentinel pharmacokinetic, toxicological, and clinical studies. Thus, the update search, journal-specific retrieval, and bidirectional citation chasing were used both to identify recent studies and to detect potentially relevant reports absent from the legacy library. The complete reproducible concept strings and source-specific adaptations used for the update are provided in . The initial manuscript library contained 104 records. Twelve additional NAC-specific records not represented in that library were identified during the update and citation search. All 12 additional records met the pre-specified eligibility criteria and were retained in the qualitative synthesis; consequently, the 45 full-text exclusions arose from the 104-record legacy library. All 116 records were assessed at full text because the legacy library had already been topic-curated. Database-of-origin metadata were not recoverable for every legacy record; consequently, the PRISMA diagram reports the auditable consolidated-library workflow rather than retrospective per-database yields. This limitation is considered explicitly in the Discussion and . 【Study selection, data extraction, and synthesis】 All candidate reports were reassessed against the pre-specified criteria at full text. Full-text eligibility assessment and data extraction were performed by ZTT and subsequently verified by MN-T. Evidence-maturity assignments were additionally reviewed by NKT and AK. Any discrepancies in eligibility, extracted data, or evidence classification were resolved by discussion and consensus among the reviewing authors. For each included report, data were extracted into a standardized evidence table covering species, design, population or experimental model, sample size where reported, NAC formulation, route, dose or concentration, comparator, follow-up, principal outcomes, adverse events, and study limitations. The primary synthesis unit was the report. Evidence was grouped by clinical domain and proximity to practice: direct clinical evidence from spontaneous disease, controlled experimental in vivo evidence, and in vitro or ex vivo evidence; these evidence settings are displayed separately in to prevent publication counts from being interpreted as equivalent levels of clinical support. Dosing statements were assigned a provenance label—trial-tested, experimentally tested, consensus-derived, or extrapolated—rather than being presented as uniformly validated recommendations. Given the non-comparable interventions and endpoints, results were synthesized narratively and displayed as an evidence-maturity map; no quantitative pooling was undertaken. Evidence setting, maturity, and clinical interpretation by indication. Evidence setting distinguishes studies in animals with spontaneous clinical disease from experimental in vivo models and in vitro or ex vivo evidence. The 71 reports meeting the pre-specified eligibility criteria constituted the primary evidence dataset of the systematic review. The manuscript reference list contains 101 citations in total because it additionally includes 30 methodological, mechanistic, review, and contextual sources used to support the review framework and interpretation; these sources were not counted as studies included in the qualitative synthesis. 【Risk of bias and evidence maturity】 Randomized clinical studies were evaluated for sequence generation, allocation, blinding, incomplete outcome data, selective reporting, and other bias. Non-randomized intervention studies were considered with ROBINS-I principles (); case reports and case series were assessed for diagnostic clarity, intervention description, follow-up, and alternative explanations. Experimental animal studies were appraised using the SYRCLE domains (). In vitro and ex vivo studies were assessed using an adapted reliability framework derived from ToxRTool, emphasizing model identity, replicate structure, vehicle controls, concentration verification, endpoint validity, and completeness of reporting (). Because study designs were heterogeneous, no single pooled certainty score was assigned. Instead, each indication was classified using a review-specific evidence-maturity framework as established (replicated, species-specific clinical or antidotal evidence); supported (controlled clinical evidence or convergent direct evidence, but with remaining replication or translational limitations); preliminary (small, uncontrolled, mixed, or otherwise limited direct clinical evidence); experimental (predominantly induced-disease or in vitro evidence); or unsupported as tested (controlled evidence showing no meaningful benefit or clinically relevant harm). Direction of effect was categorized as favorable, mixed/context-dependent, neutral, or unfavorable. These evidence-maturity categories were descriptive and review-specific and were not intended to represent formal GRADE certainty-of-evidence ratings. 【Results】 The auditable evidence library comprised 116 unique records: 104 legacy records and 12 additional NAC-specific reports identified during the update. Because the source library was already topic-curated, all 116 reports underwent full-text eligibility assessment. Of the 104 legacy records, 59 met the eligibility criteria and 45 were excluded, most commonly because they were reviews or background mechanistic papers without original canine/feline NAC data, evaluated no direct NAC exposure, or used no eligible canine/feline model. All 12 additional records identified during the update met the eligibility criteria. Accordingly, the final qualitative synthesis comprised 71 reports: 59 from the legacy library and 12 newly identified reports (). The newly identified reports broadened the evidence base across clinical or translational, controlled experimental, and in vitro or ex vivo study designs. These 71 reports represent the included primary evidence base and should be distinguished from the complete manuscript bibliography, which also contains methodological and contextual references that were not eligible for inclusion as primary studies. The evidence was dominated by dog-only studies; feline clinical evidence remained concentrated in acetaminophen toxicosis, pharmacokinetics, airway safety, and acute-on-chronic kidney disease. Publication dates ranged from 1980 to 2026. PRISMA 2020 flow diagram for evidence-library consolidation, full-text reassessment, eligibility assessment, and inclusion. The auditable evidence library comprised 104 legacy records and 12 additional records identified during the update search. Of the 104 legacy reports, 59 met the eligibility criteria and 45 were excluded; all 12 additional reports identified during the update met the eligibility criteria, yielding 71 reports in the final qualitative synthesis. PRISMA counts refer exclusively to reports evaluated for inclusion in the primary evidence synthesis and should not be equated with the 101 citations contained in the complete manuscript bibliography, which additionally includes methodological, mechanistic, review, and contextual sources. Because database-of-origin metadata were unavailable for some legacy records, the diagram reports consolidated rather than retrospective per-database yields. The evidence landscape was highly asymmetric (; ). Acetaminophen toxicosis had the strongest species-specific foundation. Several newer indications—parvoviral enteritis, feline acute-on-chronic kidney disease, canine babesiosis, and local antimicrobial applications—were supported by direct but limited studies. Cardiovascular, renal ischemia-reperfusion, hepatic, neurological, and diabetic-organ-protection literatures were dominated by purpose-bred canine models rather than spontaneous disease. Evidence landscape by direct clinical relevance, maturity, and direction of effect. Bubble area reflects the number of included reports assigned to each mapped domain. Position reflects the overall evidence classification rather than a quantitative meta-analytic effect estimate. The experimental diabetes domain comprises 10 publications arising from a closely related experimental platform and should not be interpreted as representing 10 independent evidence streams. All 71 primary reports constituting the qualitative evidence base are individually identified in , with their study characteristics and evidence domain; the corresponding design-specific appraisal is provided in . The complete report-level exclusion list and the primary reason assigned to each excluded report are provided in . 【Pharmacokinetics and disposition】 The only crossover pharmacokinetic study of conventional aqueous NAC in companion animals enrolled six healthy cats given 100 mg/kg orally and intravenously. Mean oral bioavailability was 19.3%, and elimination was rapid after both routes, with mean terminal half-lives of approximately 0.78 h intravenously and 1.34 h orally (). These data support the intuitive need for higher oral doses or repeated administration, but they do not establish therapeutic exposure targets for any disease. No equivalent study of standard aqueous NAC was identified in dogs. A beagle study characterized liposomal formulations containing NAC or tocopherols after intravenous administration, primarily for formulation safety and disposition; its vehicle, formulation, and purpose limit direct translation to routine aqueous products (). This absence is consequential: many canine schedules are repeated in formularies and reviews, yet their dosing interval has not been anchored to conventional-formulation canine exposure-response data. NAC circulates as reduced free drug, disulfides, mixed disulfides, and protein-bound forms. Rapid deacetylation supplies cysteine, while oxidation, incorporation into thiol pools, and renal elimination contribute to clearance. Human pharmacokinetic work remains useful for chemical interpretation, but it should not be used to assign precise canine bioavailability or half-life values (–). Route of administration should therefore be interpreted together with the limited species-specific pharmacokinetic evidence. In cats, oral administration of conventional aqueous NAC results in relatively low systemic bioavailability (19.3%) and a short terminal half-life (approximately 1.34 h), whereas intravenous administration provides immediate systemic exposure with a terminal half-life of approximately 0.78 h (). These findings demonstrate substantial route-dependent differences in exposure but do not establish disease-specific target concentrations or optimal dosing intervals. When i