Advances in the clinical applications of sodium thiosulphate

Abstract

Background

Sodium thiosulphate (STS) is a clinically approved pharmaceutical agent known for its antioxidant and sulphide-releasing properties. Currently, it is commonly employed in the detoxification treatment of various chemical intoxications, including cyanide, arsenic, and lead poisoning. In recent years, research into the clinical applications of STS has advanced rapidly, resulting in numerous significant breakthroughs. However, awareness and adoption of these developments remain limited among clinical practitioners.

Discussion

In addition to its research progress in the treatment of cyanide poisoning, STS has also demonstrated protective effects against chemotherapeutic drug-induced ototoxicity and nephrotoxicity, as well as in conditions such as vascular calcification and uraemic pruritus. Furthermore, STS has been shown to exert protective effects on multiple organs, including the heart, brain, and kidneys, by mitigating ischaemia-reperfusion injury. There is also evidence suggesting that STS may offer protection in diseases such as preeclampsia and hypertensive renal injury. However, these studies exhibit considerable variability in terms of STS administration strategies.

Conclusions

This paper provides a comprehensive review of current preclinical and clinical studies on STS, with the aim of highlighting its potential therapeutic applications in chemical intoxications, cancer treatment, vascular calcification, uraemic pruritus, and other related pathological conditions. Owing to its multiple biological protective effects and a favourable safety profile, STS is anticipated to receive growing recognition among the medical community, which may pave the way for the exploration of novel clinical indications and contribute meaningfully to public health.

Graphical abstract

1. Introduction

Sodium thiosulphate (STS, Na₂S₂O₃), an inorganic salt, exhibits high solubility in water. Its chemical structure comprises two sodium ions and one thiosulphate ion. In the STS molecule, the two sulphur atoms are connected via a covalent bond, endowing it with strong reducibility [1]. STS has a molecular weight of 158.11 g/mol and typically exists as a white to off-white crystalline solid (Na₂S₂O₃·5H₂O). It is an odourless, low-toxicity, and stable hydrogen sulphide (H₂S) donor [2]. The half-life of STS ranges from 1 to 2 h, and it generally takes 4 to 6 h for complete metabolism and excretion. The specific time varies according to renal function and dosage. It possesses properties such as anti-oxidation, anti-inflammation, and vasodilation [3–5]. Currently, it is predominantly used in clinical practice as an antidote for cyanide poisoning [6,7]. Accumulating scientific evidence has demonstrated that STS exerts therapeutic effects in the treatment of various conditions, including vascular calcification (VC), uraemic pruritus (UP), cisplatin-induced organ toxicity, and ischaemia-reperfusion (IR) injury [8–14]. However, its potential in these emerging therapeutic areas remains underappreciated among clinicians. Considering the low cost, high safety of STS, and its promising therapeutic potential demonstrated in recent clinical studies of various diseases, we believe that it is an appropriate time to summarize recent advances in the clinical application of STS, with the objective of raising awareness within the medical community and supporting the development and optimization of treatment strategies.

2. The biological characteristics of STS

2.1. Metabolism and transformation of thiosulphate in the body

Thiosulphate serves as the primary metabolite of H₂S. Within the mitochondrial matrix, there exist mitochondrial enzymes, including sulphide quinone oxidoreductase (SQR), persulphide dioxygenase (PDO), rhodanese, and sulphite oxidase (SO). Under the influence of these mitochondrial enzymes, H₂S undergoes an oxidation reaction, sequentially yielding persulphide, sulphite (SO₃^2–), thiosulphate (S₂O₃^2–), and sulphate (SO₄^2–) [15] (as depicted in Figure 1). In a hypoxic condition, thiosulphate can be reconverted to H₂S under the action of 3-mercaptopyruvate sulphurtransferase (MST) and rhodanese. A small quantity of H₂S can stimulate mitochondrial respiration. STS directly exerts cell-regulatory effects by activating or inhibiting enzymes and modifying protein activity [16]. Additionally, thiosulphate itself functions as an effective antioxidant, capable of exerting biological effects by generating H₂S and suppressing the NF-κB inflammatory pathway [17].

Figure 1.

Metabolic transformation of thiosulphate in the body. In the cytoplasm, both CSE and CBS facilitate the release of H₂S from L-cysteine and cystathionine, while MST promotes the generation of endogenous H₂S from 3-mercaptopyruvate. SQR oxidizes H₂S to generate hydropersulphides (-SSH) and transforms GSH into GSSH. PDO within the mitochondrial matrix oxidizes hydropersulphides to yield sulphite (SO₃^2–). Rhd transfers the sulphur from glutathione persulphide to sulphite, resulting in the formation of thiosulphate (S₂O₃^2–). Sulphite can be oxidized by sulphite oxidase (SO) to produce sulphate (SO₄^2–), which is subsequently excreted from the body via urine. Abbreviations: ATP: adenosine triphosphate; ADP: adenosine diphosphate; CBS: cystathionine-β-synthase; CSE: cystathionine γ-lyase; CoQ: coenzyme Q; Cytc: cytochrome c; FAD: Flavin adenine dinucleotide; FADH₂: Flavin adenine dinucleotide reduced form; GSH: glutathione; GSSH: glutathione persulphide; MST: 3-mercaptopyruvate-sulphurtransferase; NAD⁺: Nicotinamide Adenine Dinucleotide oxidized form; NADH: Nicotinamide Adenine Dinucleotide; PDO: persulphide dioxygenase; Rhd: rhodanese; SQR: sulphide quinone oxidoreductase.

2.2. The main mechanisms of action of STS in treating diseases

STS is capable of treating a wide range of diseases, and its main mechanisms of action can be summarized into the following four aspects [18] (as shown in Figure 2):

Figure 2.

The mechanism of action of STS in treating various diseases. STS binds to calcium, cyanide, and cisplatin, and the resulting complexes are excreted in the urine. STS exerts an anti-apoptotic effect by inhibiting the activities of JNK and caspase-3. Under the catalysis of Rhd, STS generates H₂S and NO, which activate the arginine/cAMP and NO/cGMP signalling pathways, along with the downstream SIRT3/PGC-1α signalling pathway. This enhances the activities of mitochondrial electron transport chain complex enzymes (I–IV), thereby exerting antioxidant and vasodilatory effects. In addition, STS also enhances the phosphorylation of AKT, activates the Nrf2 signalling pathway, promotes the production of GSH, scavenges ROS, and exerts an antioxidant effect. Abbreviations: AKT: protein kinase B; cAMP: cyclic adenosine monophosphate; CBS: cystathionine-β-synthase; CSE: cystathionine γ-lyase; cGMP: cyclic guanosine monophosphate; GSH: glutathione; IR: ischaemia-reperfusion; JNK: c-Jun N-terminal kinase; NO: nitric oxide; Nrf2: nuclear factor erythroid-related factor 2; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-α; Rhd: rhodanese; ROS: reactive oxygen species; SIRT3: sirtuin 3; STS: sodium thiosulphate.

1. Chelation: STS can increase the solubility of calcium by 100,000 times [19], forming calcium thiosulphate and facilitating the excretion of calcium from the body via urine [20,21]. STS can also combine with cyanide and cisplatin to form non-toxic complexes that are excreted through urine, thereby reducing their toxicity to various organs.

2. Antioxidant effect: STS can generate H₂S, activate the arginine/cyclic adenosine monophosphate (cAMP) and nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signalling pathways, and subsequently activate the downstream SIRT3/PGC-1α signalling pathway. This activation enhances the activity of mitochondrial electron transport chain complex enzymes (I–IV) and safeguards the integrity and function of the mitochondrial structure [22,23]. In addition, STS can enhance the phosphorylation of protein kinase B (AKT), activate the nuclear factor erythroid-related factor 2 (Nrf2) signalling pathway, stimulate the production of glutathione (GSH), scavenge reactive oxygen species (ROS), and exert an antioxidant stress effect [8].

3. Anti-apoptotic effect: STS inhibits cell apoptosis by suppressing the activity of cysteine aspartate protease-3 (caspase-3) and c-Jun N-terminal kinase (JNK) [8,24].

4. Vasodilation, anti-inflammation, and analgesic effects: The arginine/cAMP and NO/cGMP signalling pathways activated by STS are among the most prevalent vasodilatory pathways [22]. Moreover, STS promotes the production of H₂S and nitric oxide [25,26], which can reduce the release of inflammatory cytokines (TNF-α, IL-1β, IL-6), mitigate vascular endothelial damage, and dilate blood vessels to enhance tissue perfusion [27,28].

3. Medication strategies and efficacy of STS

At present, STS has been found to exert varying degrees of therapeutic effects or potential therapeutic roles in a variety of diseases. However, there remains a lack of clear and unified guidelines regarding its dosage, duration of administration, and route of administration. Currently, it is widely recognized that the usage and dosage recommendations in the package insert of STS (PedMark), which is produced by Fennec Pharmaceuticals and approved for marketing by the Food and Drug Administration (FDA), are as follows: When the actual body weight is within the range of 5–10 kg, the dosage is 15 g/m²; when the actual body weight exceeds 10 kg, the dosage is 20 g/m². After calculating the required dose, withdraw it into a syringe or transfer it to an empty infusion bag and use it promptly. The intravenous infusion should be completed within 15 min. Generally, the bioavailability and gastrointestinal tolerance of oral STS are low and unstable [29,30]. In clinical practice, STS is often diluted with 5% dextrose solution or 0.9% normal saline before intravenous infusion. Current medication strategies for STS differ depending on the disease being treated. Below, we will summarize the major clinical applications and progress regarding STS therapy.

3.1. STS in the treatment of VC

VC is a pathological condition characterized by the deposition of calcium salts in the vascular wall, resulting in vessel stiffness, reduced compliance, and impaired structural and functional integrity. It represents a common form of ectopic calcification and is frequently observed in patients with end-stage chronic kidney disease, diabetes, and other metabolic disorders [31–35]. This condition can cause damage to both the intima and media layers of blood vessels, potentially resulting in vessel rupture, thrombus formation, localized ischaemia or haemorrhage, and a systemic hypercoagulable state. These complications may lead to severe clinical outcomes, such as disability or mortality [36–38]. Currently, no universally accepted treatment guidelines or standardized therapeutic approaches exist for VC. Clinical management primarily aims to slow disease progression and manage associated complications [39].

To date, multiple clinical studies, including prospective randomized controlled trials (RCTs), have confirmed the feasibility and efficacy of STS in the treatment of VC [40–44]. We have compiled the currently published relevant studies [45–49], as summarized in Table 1.

Table 1.

Characteristics of five clinical trials evaluating STS in the treatment of VC.

Study ID and country	Study design	Population	No. of participants (T:C)	Age (T versus C) (mean ± SD, years)	Gender (T versus C)	Dialysis vintage (T versus C)	STS treatment	Control treatment and duration	Adverse STS reactions	Outcome measurements	Results
Bian et al. [45] China	RCT	HD patients without Diabetes, severe infection, hypercalcemia, or iPTH <150 pg/mL	25:25	52.1 ± 20.8 versus 52.5 ± 19.4	12 M, 13 F versus 12M, 13 F	29 (4–101)a mo versus 30 (3–107)a mo	0.18 g/kg dissolved in 100 mL normal saline three times a week	Usual care; 6 mo	No adverse STS reactions were reported	Agatston score	STS obviously reduces the high level of Agatston score
Djuric et al. [46] Serbia	RCT	ESRD on HD with AACS ≥100	30:30	63.8 ± 13.2 versus 64.1 ± 9.7	17 M, 13 F versus 21 M, 9 F	104.4 ± 80.5b mo versus 103.7 ± 75.1b mo	25 g/1.73 m2 dissolved in 100 mL saline i.v. during the last 15 min of every HD session	100 mL of 0.9% saline; 6 mo	No adverse STS reactions were reported	Agatston score; CVS; PWV	STS can reduce the Agatston score, CVS, PWV
Liu et al. [47] China	RCT	HD patients	22:22	52.8 ± 17.2 versus 58.9 ± 9.6	12 M, 10 F versus 12M, 10 F	5.0 ± 3.0b ye versus 5.3 ± 3.3b ye	0.18 g/kg dissolved in 100 mL saline i.v. three times a week during the last 1 h of every HD session	Usual care; 3 mo	Anorexia (4.5%), transient hypotension (4.5%) and gastrointestinal symptoms (9.1%)	Levels of the VC factors	STS can reduce the VC factors and delay the progress of VC
Saengpanit et al. [48] Thailand	RCT	ESRD on HD with CAVI ≥8	24:26	50.4 ± 9.5 versus 54.4 ± 10.7	12 M, 12 F versus 16M, 10 F	69 (38–110)c mo versus 55 (30–101)c mo	12.5g during the last hour of HD twice a week	Usual care; 6 mo	Transient hypotension (8.3%), flushing (8.3%) and anorexia (12.5%)	CAC score; PWV;CAVI; biochemical parameters	STS significantly reduce the AS, which prevents and delays VC
Yang et al. [49] China	Non- randomized trail	Calciphylaxis patients with CKD or ESRD	31:31	51.1 ± 14.8 versus 51.1 ± 14.8	22 M, 9 F versus 22M, 9 F	74 (48–120)c mo versus 74(48–120)c mo	an initial dose of 5 g increased by 1 g per day to 10 g as a maintenance dose, i.v. once a day for 3 weeks, followed by a 2-week drug-free period before the next course	Usual care; until the symptoms were effectively relieved	Infection (9.68%), multi-complications (12.90%) and nausea /vomiting (16.13%)	Clinical improvement; survival rate; adverse events	The optimized STS regimen can safely treat VC and get clinical improvement

^a Median (P2.5–P97.5).

^b Mean ± SD.

^c Median (IQR1–IQR3).

Abbreviations: AACS: abdominal aortic calcification score; AS: arterial stiffness; C: control group; CAC: coronary artery calcification; CAVI: cardio-ankle vascular index; CKD: chronic kidney disease; CVS: calcium volume score; ESRD: end-stage renal disease; F: female; HD: hemodialysis; ID: identity; i.v.: intravenous; M: male; mo: months; PWV: pulse wave velocity; RCT: randomized controlled trial; STS: sodium thiosulphate; T: treatment group; VC: vascular calcification; we: weeks; and ye: years.

In addition, a case report presented a case of skin ulcer in a 40-year-old male patient with end-stage renal disease (ESRD) undergoing peritoneal dialysis who was treated with a low dose of STS [50]. Upon admission to the hospital, the patient exhibited focal skin necrosis of the fingers and toes, organization of small arterial thrombi, and extensive calcification of the extremities. The patient underwent a total of 5 courses of STS combined with conventional peritoneal dialysis treatment, with an interval of 1 month between each course. In the first course, 3.2 g of STS was diluted in 50 mL of normal saline and continuously infused via an intravenous pump over 2 h. In the second and third courses, the dosage of STS was increased to 6.4 g, while the rest of the treatment regimen remained unchanged. The patient experienced nausea and vomiting only during the third course, which resolved after discontinuation of the drug. Therefore, the dosage of STS was reduced to 3.2 g in the fourth and fifth courses. After 6 months (5 courses) of comprehensive treatment, the patient’s skin wound healed, and the pain was significantly alleviated. Nine months after the completion of the treatment, the patient had not developed new skin ulcers.

It can be observed that although the STS administration protocols vary across studies, they consistently demonstrate therapeutic benefits and a relatively favourable safety profile [51–53]. Among these, a more commonly recommended regimen involves dissolving 0.18 g/kg or 25 g/1.73 m² of STS in 100 mL of normal saline and administering it via intravenous infusion during the final 15 min of each haemodialysis session, 2–3 times per week, for a total duration of 6 months.

Based on current evidence, we believe that STS is effective and safe for the treatment of VC and merits broader clinical application. It is anticipated that STS may be incorporated into VC management guidelines across various countries and regions in the near future. As of November 2025, a search for ‘sodium thiosulphate’ on clinicaltrials.gov reveals 16 clinical studies regarding the treatment of VC with STS. We eagerly await the results of these studies, which are expected to help in exploring more precise and personalized treatment strategies for VC patients across different ages, weights, ethnicities, and comorbidities in the future.

In addition, the specific mechanism by which STS treats VC remains unclear. Currently, the more widely recognized view is that STS can treat VC through multiple effects, including calcium chelation, anti-oxidative stress, reduction of vascular endothelial damage, and vasodilation [54] (as shown in Figure 2). In the future, research on the relevant mechanisms is also a direction that warrants continuous exploration [55].

3.2. STS in the treatment of up

UP, also known as chronic kidney disease-associated pruritus (CKD-aP), is one of the most prevalent dermatological complications among patients undergoing haemodialysis [56–59]. It is primarily characterized by recurrent episodes of generalized or localized itching, commonly affecting areas such as the back, limbs, and chest. Typically, no significant rash is present; however, the intensity of the itching can be severe, often worsening at night and proving resistant to treatment [60,61]. Consequently, UP significantly impairs patients’ sleep quality [62,63] and overall quality of life [64–66]. Systemic itching episodes occur in 20–50% of patients and have been identified as an independent risk factor for mortality in individuals with chronic kidney disease [67–69].

To date, we have conducted a search for publicly published clinical studies on the use of STS in the treatment of UP in PubMed, Embase, and Cochrane Library databases, and retrieved only one research article. In this study, haemodialysis patients with UP were randomly assigned to either an experimental or a control group. Both groups underwent haemodialysis three times per week. The control group received loratadine at a daily dose of 10 mg, whereas the experimental group was administered an intravenous infusion of 3.2 g of STS dissolved in 20 mL of normal saline, given 5 min before the end of each dialysis session. After 8 weeks of treatment, both groups exhibited improvements in UP symptoms to varying degrees, with the experimental group showing a significantly greater reduction in itching than the control group [70]. In addition, following a comprehensive search of Chinese databases, Xu et al. conducted a systematic review and meta-analysis of eight clinical studies published in Chinese journals that evaluated the efficacy and safety of STS in treating UP. This meta-analysis suggested that, when compared with the control group, the visual analogue scale score of the treatment group was significantly decreased (weighted mean difference = −5.023; 95% CI: −6.137 to −3.909; p < 0.001). STS could significantly relieve UP symptoms without remarkable adverse reactions [OR (odds ratio) = 8.187; 95% CI (confidence interval): 4.648 to 14.422; p < 0.001], and the difference was statistically significant [11].

It is important to note that the samples in the aforementioned studies were all from the Chinese population, and no relevant studies on other regions or populations were retrieved. In fact, current global research on the treatment of UP primarily focuses on several new drugs, such as opioid-based therapies (e.g. difelikefalin, naltrexone, nalbuphine) and monoclonal antibody drugs (e.g. dupilumab) [71,72]. However, these new drugs are relatively costly, and there may be unknown side effects due to their short market presence. In contrast, we contend that STS has unique advantages. We anticipate that large-scale, multi-centre RCTs will be conducted globally in the future to further elucidate the value of STS in the treatment of UP.

Overall, although a limited number of clinical studies have indicated potential benefits of STS for patients with UP, the current evidence remains insufficient. Moreover, the specific mechanism by which STS treats UP is also unclear. At present, the more widely accepted view is that STS can treat UP through effects such as calcium chelation, anti-oxidative stress, and vasodilation [54,73] (as shown in Figure 2). Therefore, both preclinical and clinical studies are necessary to further investigate this topic.

3.3. STS in the treatment of cisplatin-induced organ damage

Cisplatin is the most widely used platinum-based anticancer drug, characterized by a broad anticancer spectrum, effectiveness against hypoxic cells, and potent therapeutic efficacy. It holds a pivotal role in the field of cancer treatment. However, its toxicity to normal tissues and organs remains a significant clinical challenge, particularly in the form of severe ototoxicity and nephrotoxicity [74–76]. Encouragingly, recent collaborative research efforts worldwide have identified the protective potential of STS against cisplatin-induced organ damage [77]. This is because STS can undergo a covalent reaction with cisplatin, and the resultant complex exhibits no nephrotoxicity, ototoxicity, or cytotoxicity [78,79]. Pharmacokinetic analysis indicates that STS is highly concentrated in urine, where it neutralizes cisplatin, yet it scarcely binds to cisplatin in plasma. Meanwhile, STS can enhance the total exposure of cisplatin in plasma without influencing the therapeutic activity, elimination rate constant, volume of distribution, or total clearance rate of cisplatin [78]. Currently, there is emerging clinical evidence supporting the efficacy of STS in mitigating cisplatin-induced ototoxicity and nephrotoxicity [80,81]. The mechanisms through which STS inhibits the side effects induced by cisplatin primarily encompass three aspects (as depicted in Figure 2): (1) STS can directly bind to cisplatin to form a non-toxic complex, which is subsequently excreted via urine; (2) STS can generate H₂S, thereby activating the arginine/cAMP and NO/cGMP signalling pathways and their downstream mechanisms [22]; and (3) STS exerts an anti-apoptotic effect [82].

Nevertheless, awareness among clinicians regarding this protective strategy remains limited. In light of this, we provide a summary of the relevant findings to raise awareness and promote further consideration among professionals in the field.

3.3.1. STS in the treatment of cisplatin-induced ototoxicity

On 20 September 2022, the FDA approved the marketing application for STS injection (Pedmark) submitted by Fennec Pharmaceuticals. It is indicated for the reduction of cisplatin-induced hearing loss in children aged 1 month and older with locally non-metastatic solid tumours, marking it as the first approved agent in this therapeutic area [83–85]. This approval was based on data from two multi-centre, open-label, randomized Phase III clinical trials [86,87], which evaluated the efficacy and safety of STS in paediatric patients undergoing cisplatin therapy [88]. The results of these two studies indicate that STS can reduce the incidence of hearing loss by 48% (RR = 0.52; 95% CI: 0.33–0.81; p = 0.002) [86], and STS can also lower the incidence of hearing loss (OR = 0.31; 95% CI: 0.13–0.73; p = 0.0036) [87]. In addition, analyses of these studies demonstrated that STS significantly reduces the risk of hearing impairment in this patient population [89–91]. Overall, the drug exhibits favourable safety and tolerability profiles. The most commonly reported adverse reactions (≥25%) included vomiting, nausea, decreased haemoglobin levels, hyponatremia, and hypokalaemia. The key findings from these clinical trials are summarized in Table 2 [86,87,92]. As of November 2025, no other relevant and publicly available clinical research results were retrieved from PubMed, Embase, and Cochrane Library databases. Subsequently, by using ‘sodium thiosulphate’ as the search term, 12 relevant clinical studies regarding the use of STS in treating cisplatin-induced ototoxicity were identified on clinicaltrials.gov. It is anticipated that in the near future, with the release of the results of these ongoing clinical studies, more effective treatment strategies for STS in treating cisplatin-induced ototoxicity can be developed.

Table 2.

Characteristics of two clinical trials evaluating STS in the treatment of cisplatin-induced ototoxicity.

Study ID and country	Study design	Population	No. of participants (T versus C)	Age (months) (T versus C)	Gender (T versus C)	STS treatment	Control treatment and duration	Adverse STS reactions	Outcome measurements	Results
Brock et al. [86] England et al.	RCT	Standard-risk hepatoblastoma children	57:52	13.4(3.0–70.2)a versus 12.8(1.2–98.6)a	29M, 28 F versus 30M, 22 F	20 g/m2 in a 15-min intravenously 6 h after cisplatin was stopped	80 mg/m2 Cisplatin i.v. for 6 h; 6 we	Anaemia (1.8%); nausea and vomiting (1.8%); tumour progression (3.5%); infections (3.5%); neutropenia (3.5%).	Incidence of hearing loss	STS reduces the 48% incidence of hearing loss. (RR = 0.52; 95% CI:0.33 ∼ 0.81; p = 0.002)
Freyer et al. [87] America; Canada	RCT	Eligible participants with newly diagnosed cancer and normal audiometry	61:64	1–18b versus 1–18b	35M, 26 F versus 41M, 23 F	16 g/m² over 15 min intravenously 6 h after cisplatin dose completed	Specified by each participant’s cancer treatment plan; 4 we	Neutropenia (66.1%), hypokalaemia (17.0%), decreased neutrophil count (13.4%), but none of the serious adverse events were considered probably or definitely related to STS.	Incidence of hearing loss	STS can reduce the incidence of hearing loss. (OR = 0.31; 95% CI:0.13 ∼ 0.73; p = 0.0036)
Duinkerken et al. [92] Netherlands	RCT	Lung or head and neck (HNSCC) cancer with high-dose cisplatin (75 mg/m2)	6:6	60 (46–67)a versus 59 (46–63)a	5M, 1 F versus 3M, 3 F	0.1M STS gel on one side and placebo gel on the other side was transtympanically applied to the middle ear 3 h before cisplatin administration	STS gel was injected directly through the posterior part of the eardrum; 5 years	No grade ≥ 2 or serious adverse events related to STS injections were observed.	Hearing threshold	Transtympanic STS CIHL was reduced by 18.4 dB (p = 0.068).

^a Median (range).

^b Range.

Abbreviations: C: control group; F: female; ID: identity; i.v.: intravenous; M: male; RCT: randomized controlled trial; STS: sodium thiosulphate; T: treatment group; we: weeks; RR: relative risk; CI: confidence interval; P: p-values; and OR: odds ratio.

3.3.2. STS treatment for cisplatin-induced nephrotoxic injury

Cisplatin is primarily metabolized by the kidneys, and cisplatin-induced acute kidney injury (AKI) represents one of the most common and severe toxic side effects [93–97]. As a result, AKI has become a critical limiting factor in the clinical application of anticancer chemotherapeutic agents. Therefore, the development of effective antidotes and adjuvant strategies to prevent and manage chemotherapy-induced organ toxicity is essential for improving cancer treatment outcomes in the future [98–100]. Earlier studies have suggested that STS may exert a protective effect against cisplatin-induced AKI [101–103]. Three publicly available clinical studies [78,104,105] have provided preliminary support for this hypothesis, which we have summarized and presented in Table 3. Based on the current evidence, we believe that STS holds promising potential in mitigating the nephrotoxic effects of platinum-based chemotherapeutic agents. As of November 2025, no relevant clinical studies regarding the existing achievements were retrieved from PubMed, Embase, and Cochrane Library databases. When using ‘sodium thiosulphate’ as the search term, two relevant clinical studies on the treatment of cisplatin-induced nephrotoxicity with STS can be found on clinicaltrials.gov. It is expected that in the future, more high-quality clinical investigations will refine its therapeutic application and optimize treatment protocols.

Table 3.

Characteristics of two clinical trials evaluating STS in the treatment of cisplatin-induced nephrotoxicity.

Study ID and country	Study design	Population	No. of participants (T versus C)	Age (years) (T versus C)	Gender (T versus C)	STS treatment	Control treatment and duration	Adverse STS reactions	Outcome measurements	Results
Pfeifle et al. [78] France	Non-randomized trail	Received and failed to respond to prior radiation and/ or chemotherapy.	4:8	N/A	N/A	3.3 g/ m2 i.v. over the first hour, 6.6 g/m2 during the second and third hours, and the requisite dose of cisplatin were infused simultaneously through separate i.v. sites every 3 weeks	The experimental group received a total of 3 treatments, while the control group received 2 treatments	No adverse STS reactions were reported	Renal function	STS can provide significant protection for the kidneys and double the total exposure to cisplatin.
Kurreck et al. [104] Germany	Non-randomized trail	Underwent CRS in combination with HIPEC including cisplatin	46:192	59 (23–77)a versus 57 (19–83)a	19M, 27 F versus 86M, 106 F	9 g/m2 i.v. before HIPEC, 12 g/m2 i.v. over 6 h following HIPEC	Usual care; once prior to chemotherapy and once following its completion	No adverse STS reactions were reported	Incidence of AKI; clinical outcome parameters; renal function	STS reduces the incidence (6.5% vs. 30.7%; p = 0.001) and severity of AKI (p = 0.009), STS can protect renal function (OR = 0.089, p = 0.001).
Laplace et al. [105] France	RCT	Underwent CRS in combination with HIPEC including cisplatin	38:35	60.5 ± 11.7b versus 64.5 ± 11.9b	5M, 33 F versus 4M, 31 F	9 g/m2 i.v. in 20 min at the same time of the start of the HIPEC, 12 g/m2 i.v. for 6 h the end of the HIPEC	Usual care; 6 mo	No adverse STS reactions were reported	Incidence of AKI; chronic renal injury rate	STS reduces the rate of post-operative AKI to zero (p < 0.05).

^a Median (range).

^b Mean ± SD.

Abbreviations: AKI: acute kidney injury; C: control group; CRS: cytoreductive surgery; F: female; HIPEC: hyperthermic intraperitoneal chemotherapy; ID: identity; i.v.: intravenous; M: male; mo: months; N/A, not applicable; RCT: randomized controlled trial; STS: sodium thiosulphate; and T: treatment group.

3.4. STS in the treatment of cyanide poisoning

Cyanide can be found in certain natural plants, but building fires represent the most common source of cyanide exposure [106,107]. It is released during the incomplete combustion of natural fibres and synthetic materials, such as polyurethane and nylon, at high temperatures. Upon inhalation, gaseous cyanide is rapidly absorbed and reacts within the body [108,109]. The clinical manifestations of severe cyanide poisoning include nausea, vomiting, weakness, ataxia, as well as elevated blood pressure, respiratory rate, and heart rate. The condition may progress to seizures, cardiovascular and respiratory depression, and ultimately death [110–112].

In the 1930s, STS was initially employed in combination with sodium nitrite for the treatment of cyanide poisoning, yielding remarkable therapeutic outcomes [113]. Its mode of action is as follows: As a sulphur donor, under the catalysis of rhodanese, STS can transform cyanide into non-toxic thiocyanate, which is subsequently excreted via urine [114] (as depicted in Figure 2). Since then, the efficacy of STS in treating cyanide poisoning has drawn attention and spurred subsequent drug research and development. For instance, in the United States, there exists a standard cyanide antidote kit: first, 10 mL of sodium nitrite is administered intravenously, followed promptly by 50 mL of STS intravenously [115].

In August 2011, Nithiodote, an antidote for acute cyanide poisoning developed by the Hope Pharmaceutical Company, was officially approved for marketing in the United States. Nithiodote is a combination product containing both sodium nitrite injection and STS injection. It was the first drug approved by the FDA that includes either sodium nitrite or STS as active ingredients [116]. This approval further solidifies the clinical status of STS in the first-aid treatment of cyanide poisoning. The 2023 updated ‘American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care’ further elevates its clinical value. The guidelines explicitly state that if cyanide poisoning is suspected, there is no need to wait for the results of confirmatory tests. Instead, treatment should be promptly initiated with hydroxocobalamin (preferred) or a combination of sodium nitrite and STS [117].

Given the disease characteristics of cyanide poisoning, it is extremely challenging to conduct clinical trials. To optimize the treatment strategies for cyanide poisoning, the current primary progress lies in preclinical studies. These studies have revealed that the mortality rate of experimental animals with untreated cyanide poisoning can reach up to 100%. Nevertheless, after treatment with STS via gastric tube or intravenous injection, the survival rate of cyanide-poisoned animals can be significantly improved, and the mortality rate can be reduced to 0% [118,119].

In addition, several publicly reported cases are worthy of reference for clinicians:

1. Shively et al. reported a case of a 33-year-old woman who deliberately ingested 20 g of amygdalin and suffered from severe cyanide poisoning. The patient was treated with hydroxocobalamin and STS and recovered. Five hours after ingestion of amygdalin, the patient presented with agitated delirium, metabolic acidosis, hyperlactatemia, and prolonged QTc. Initially, the patient was treated with an intravenous infusion of 5 g of hydroxocobalamin and 25 g of STS, and the symptoms were relieved. However, 12 h later, hypotension, acidosis, elevated lactate, and prolonged QTc recurred. After repeated antidote treatment (an intravenous drip of 10 g of hydroxocobalamin plus 25 g of STS), the patient’s condition stabilized, and she was finally discharged from the hospital after full recovery [120].

2. De Capitani et al. reported a case of a lactating mother who recovered after being treated with STS following the ingestion of acetonitrile (a type of cyanide). More than 20 h after the patient ingested approximately 157 g of acetonitrile, symptoms such as lethargy, hypotension, and tachycardia occurred. The patient was given an intravenous infusion of 12.5 g of STS over 1 h, once every 24 h. The patient’s symptoms disappeared the next day, and the patient was discharged after a 4-day consecutive treatment [121].

These animal studies and case reports have confirmed that STS significantly improves survival rates in cases of acute cyanide poisoning. However, due to the rapid progression and high mortality associated with this condition, as well as the high demands on medical personnel and equipment, clinical management remains challenging. Therefore, it may take considerable time before STS-based regimens can be effectively optimized for the treatment of acute cyanide poisoning.

3.5. Treatment of other diseases with STS

3.5.1. STS in the treatment of IR injury in different organs

Currently, the research progress on IR injury predominantly centres on preclinical studies. These preclinical investigations have revealed that pretreating with STS (e.g. via oral administration or intraperitoneal injection) prior to IR injury can mitigate oxidative stress, enhance mitochondrial function, and alleviate organ IR injury [122,123]. Immersing the donor organ in an STS solution before kidney transplantation can notably reduce the apoptosis of renal epithelial cells post-transplantation and improve the function of the transplanted kidney [124]. STS safeguards the structural integrity and activity of mitochondria and treats organ IR injury by inhibiting calcium overload, oxidative stress, and cell apoptosis (as depicted in Figure 2) [125,126].

As of November 2025, no relevant clinical research findings have been retrieved from PubMed, Embase, and Cochrane Library databases. When using ‘sodium thiosulphate’ as the search term, three clinical studies associated with IR injury can be found on clinicaltrials.gov. One of these studies focuses on the protective effect of STS on cardiac function in patients with ST-segment elevation myocardial infarction. This study completed the recruitment of 380 patients in March 2021, and the results of the primary endpoint analysis were anticipated to be announced in the first quarter of 2022 [127]; however, no relevant results have been made public thus far. The other two studies focus on the application value of STS in ESRD and kidney transplantation, but the specific research progress remains unknown at present. It is anticipated that in the near future, with the disclosure of the results of these clinical studies, valuable recommendations can be provided to clinicians in managing organ IR injury.

3.5.2. Other ongoing clinical trials of STS

In addition to the 33 STS-related clinical trials registered on ClinicalTrials.gov as previously mentioned, there are an additional 48 ongoing clinical trials regarding STS. These trials primarily focus on a diverse range of diseases, including various tumours (lymphoma, mesothelioma, gastric cancer, head and neck cancer, adrenocortical carcinoma, etc.), acute coronary syndrome, dental diseases, and urinary calculi. However, considering the limited relevant information available, we will have to wait for the release of subsequent research results to further evaluate the application value of STS in these diseases.

3.5.3. STS in the treatment of preeclampsia and hypertensive renal injury

Although there are currently no publicly published or ongoing clinical studies on the use of STS in treating preeclampsia and hypertensive renal injury, given the high incidence of these two diseases, the suboptimal current clinical treatment options, and the excellent performance of STS in preclinical studies for both diseases, we believe that STS has therapeutic potential for treating these conditions and warrants in-depth exploration. Therefore, we would like to specifically present the results of relevant preclinical studies here: One study found that the blood pressure of female mice treated with oral STS decreased, compared with the non-intervention control group. This reduction in blood pressure may contribute to alleviating the symptoms of preeclampsia and potentially enhancing foetal outcomes [128]. Another study showed that, compared with the non-special-treatment control group, the blood pressure and proteinuria levels in rats treated with oral or intraperitoneal injection of STS were significantly reduced, and that STS can alleviate hypertension and prevent glomerulosclerosis [129]. Subsequent studies further revealed that STS can improve hypertensive nephropathy and renal oxidative damage through its antioxidant properties [130,131]. We hope that our work will have a positive impact on the implementation of clinical studies on STS for these two conditions.

4. Adverse reactions of STS and countermeasures

The adverse reactions of STS mainly include gastrointestinal symptoms (e.g. nausea, vomiting), hypersensitivity, metabolic acidosis, hyperkalaemia, hypernatremia, transient hypotension or hypertension, muscle cramps, and skin disorders. In some patients, less common adverse effects such as delirium, generalized weakness, arrhythmia (including QTc prolongation), disturbances in calcium and phosphorus homeostasis, and bone toxicity may also occur.

The following suggestions are provided for managing the adverse reactions of STS: (1) In the event of gastrointestinal reactions such as nausea and vomiting, STS should be promptly discontinued, and symptomatic and supportive treatment should be administered. An anti-emetic should be taken prior to the next dose. (2) If an allergic reaction occurs, STS should be immediately discontinued, and symptomatic and supportive treatment should be provided. An antihistamine or glucocorticoid should be taken before subsequent use. (3) The patient’s blood pressure, electrocardiogram, and serum sodium and potassium levels should be monitored both at rest and during clinical treatment. If drug-related adverse reactions (such as electrolyte imbalance, blood pressure fluctuation, arrhythmia, etc.) are detected, STS should be immediately discontinued, and symptomatic and supportive treatment should be administered. Close monitoring of the patient’s condition is essential, and consultation with cardiology or neurology specialists should be considered when necessary. Additionally, STS should not be mixed with other injectable medications to avoid potential drug interactions that may exacerbate adverse effects [132].

Song et al. suggested that STS-induced metabolic acidosis may be alleviated through the use of bicarbonate dialysate [133]. The finding raises an important question: could this strategy also be effective in managing other adverse reactions associated with STS administration? This presents a promising avenue for future research. Indeed, for diverse disease conditions and patient populations, the development of more precise therapeutic protocols – such as optimizing dosage and administration frequency to better balance efficacy with safety – is likely to enhance the overall tolerability of STS. However, realizing these advancements will require high-quality, multi-centre, large-scale clinical trials to generate robust and generalizable evidence [134–138].

Overall, STS demonstrates a relatively favourable safety profile, with a low incidence of severe adverse reactions, supporting its continued clinical application and potential for broader use.

5. Future outlook for the clinical applications of STS

Despite years of basic and clinical research on STS, significant knowledge gaps and controversies still remain. For example, when STS exerts its biological effects, it is still unclear whether STS itself is the dominant factor or whether it acts via H₂S mediation. Some studies suggest that STS protects organs from IR injury by promoting the production of H₂S [139]. However, a study by Ravindran et al. showed that the H₂S content in rat tissues did not increase after the administration of STS [8]. This suggests that STS itself has a strong antioxidant effect and may also play a key role in the treatment process [140]. Besides, numerous clinical studies have shown that STS can effectively alleviate cisplatin-induced ototoxicity. Nevertheless, a study by Rolland et al. indicated that, statistically, the use of STS gel did not reduce cisplatin-induced hearing loss [141]. This disparity might be related to the premature termination of Rolland et al.’s study due to insufficient funding. In conclusion, the efficacy of STS in treating certain diseases has not been verified, the specific mechanism of its action has not been fully clarified, and there is a lack of clear medication guidelines. In the future, more high-quality studies with rigorous designs, sufficient sample sizes, and clear mechanism-oriented approaches are required to explore its efficacy, safety, and mechanism of action, identify the applicable population, optimize the dosing regimen, and expand its application prospects in the treatment of other diseases.

The medication costs associated with STS also merit discussion. For example, in China, an adult weighing 60 kg spends approximately $50 per use of STS (after exchange-rate conversion). With three doses per week, the monthly cost is around $600. Considering the efficacy and safety of STS in disease treatment as previously mentioned, we believe that STS has a relatively high price-to-performance advantage. Of course, Pedmark is more expensive. However, compared to STS from other manufacturers, Pedmark has more reliable effects and higher safety. It’s important to note, though, that real-world long-term data on the cost-effectiveness of Pedmark after market entry remain limited. As such, future economic evaluations – such as cost-utility or budget impact analyses – would be valuable, offering deeper insights into the drug’s sustainability and supporting informed decision-making for patients and policymakers alike.

In addition, we firmly believe that enhancing the medical professionals and patients’ understanding of the awareness and recognition of STS should be an integral part of future work. We hereby propose the following measures: (1) Conduct multi-centre clinical studies in collaboration with hospitals across different regions worldwide, focusing on patient groups with distinct characteristics, and assess the efficacy and safety of STS in diverse populations with the same disease or across different diseases. This approach will enable a more scientific promotion of the clinical indications of STS. (2) Extensively organize global academic lectures related to STS, particularly in regions with relatively underdeveloped medical services and economies, to deepen the understanding of STS among medical staff and patients with relevant diseases through the sharing of clinical cases. (3) It is recommended that STS manufacturers introduce preferential policies to facilitate the broader application of STS in clinical practice. (4) Experts in relevant fields should collaborate to promote the formulation and implementation of medication guidelines related to STS. It is anticipated that the collaborative efforts of multiple stakeholders, including healthcare professionals and enterprises, will contribute to the positive advancement of the clinical application of STS.

6. Conclusion

Currently, STS has demonstrated promising outcomes in clinical research on chemical intoxications, VC, UP, and organ damage induced by cisplatin-based chemotherapy. It is anticipated that STS will emerge as a key therapeutic strategy for managing these conditions. Moreover, studies have also reported the therapeutic potential of STS in various other diseases, including pregnancy-induced preeclampsia, renovascular hypertension, and organ IR injury. These findings warrant further investigation into the therapeutic applications of STS (Graphical Abstract). Nevertheless, the precise mechanisms underlying the therapeutic effects of STS in these diseases remain incompletely understood. Further research into its molecular and cellular mechanisms is warranted to provide insights that could guide future drug optimization or the development of novel therapeutic agents. In summary, given its broad biological protective properties and favourable safety profile, STS is poised to garner increasing attention from the medical community. It holds promise for expanded clinical applications in the future, thereby contributing significantly to public health.

Funding Statement

The present study is supported by the National Natural Science Foundation of China (No. 82260150).

Disclosure statement

The authors declare that they have no competing interests.

Data Availability statement

Data sharing is not applicable to this article as no data were created or analyzed in this study.