Use of Sodium Thiosulfate as an Otoprotectant in Patients With Cancer Treated With Platinum Compounds: A Review of the Literature.

PURPOSE: Hearing loss occurs in 50%-70% of children treated with cisplatin. Scientific efforts have led to the recent approval of a pediatric formula of intravenous sodium thiosulfate (STS) for otoprotection by the US Food and Drug Administration, the European Medicines Agency, and the Medicines and Health Regulatory Authority in the United Kingdom. To inform stakeholders regarding the clinical utility of STS, the current review summarizes available literature on the efficacy, pharmacokinetics (PK), and safety of systemic STS to minimize cisplatin-induced hearing loss (CIHL). DESIGN: A comprehensive narrative review is presented. RESULTS: Thirty-one articles were summarized. Overall, systemic STS effectively reduces CIHL in the preclinical and controlled clinical study settings, in both adults and children with cancer. The extent of CIHL reduction depends on the timing and dosing of STS in relation to cisplatin. Both preclinical and clinical data suggest that systemic STS may affect plasma platinum levels, but studies are inconclusive. Delayed systemic administration of STS, at 6 hours after the cisplatin infusion, does not affect cisplatin-induced inhibition of tumor growth or cellular cytotoxicity in the preclinical setting, nor affect cisplatin efficacy and survival in children with localized disease in the clinical setting. CONCLUSION: Systemic administration of STS effectively reduces the development and degree of CIHL in both the preclinical and clinical settings. More studies are needed on the PK of STS and cisplatin drug combinations, the efficacy and safety of STS in patients with disseminated disease, and the ability of STS to prevent further deterioration of pre-established hearing loss.

Success of small-dose fractionated sodium thiosulfate in the treatment of calciphylaxis in a peritoneal dialysis patient.

BACKGROUND: Calciphylaxis, or calcific uremic arteriolopathy (CUA), is a rare, fatal disorder of microvascular calcification and thrombosis that typically affects patients with end-stage renal disease (ESRD) receiving long-term dialysis. Fewer reports describe calciphylaxis in peritoneal dialysis patients than hemodialysis patients as per a literature review. To date, there are no clear guidelines for CUA diagnosis and treatment. While sodium thiosulfate (STS) has been increasingly used for treatment in recent years, there have also been reports of severe side effects. There is no uniform standard for its usage and dosage, especially for peritoneal dialysis patients. CASE PRESENTATION: We present a case of a 40-year-old Chinese male patient with ESRD on peritoneal dialysis who developed calciphylaxis with severe painful cutaneous ulcers on the fingers and toes that were managed successfully for 6 months with comprehensive treatment composed mainly of small-dose fractionated sodium thiosulfate. CONCLUSIONS: Our experience suggests that the treatment of calciphylaxis requires timely and multi-angle intervention. Treatment with small-dose fractionated sodium thiosulfate has proven effective and tolerated in this patient.

Sodium thiosulfate-supplemented UW solution protects renal grafts against prolonged cold ischemia-reperfusion injury in a murine model of syngeneic kidney transplantation.

INTRODUCTION: Cold ischemia-reperfusion injury (IRI) is an inevitable event that increases post-transplant complications. We have previously demonstrated that supplementation of University of Wisconsin (UW) solution with non-FDA-approved hydrogen sulfide (H2S) donor molecules minimizes cold IRI and improves renal graft function after transplantation. The present study investigates whether an FDA-approved H2S donor molecule, sodium thiosulfate (STS), will have the same or superior effect in a clinically relevant rat model of syngeneic orthotopic kidney transplantation. METHOD: Thirty Lewis rats underwent bilateral nephrectomy followed by syngeneic orthotopic transplantation of the left kidney after 24-hour preservation in either UW or UW+STS solution at 4 °C. Rats were monitored to post-transplant day 14 and sacrificed to assess renal function (urine output, serum creatinine and blood urea nitrogen). Kidney sections were stained with H&E, TUNEL, CD68, and myeloperoxidase (MPO) to detect acute tubular necrosis (ATN), apoptosis, macrophage infiltration, and neutrophil infiltration. RESULT: UW+STS grafts showed significantly improved graft function immediately after transplantation, with improved recipient survival compared to UW grafts (p < 0.05). Histopathological examination revealed significantly reduced ATN, apoptosis, macrophage and neutrophil infiltration and downregulation of pro-inflammatory and pro-apoptotic genes in UW+STS grafts compared to UW grafts (p < 0.05). CONCLUSION: We show for the first time that preservation of renal grafts in STS-supplemented UW solution protects against prolonged cold IRI by suppressing apoptotic and inflammatory pathways, and thereby improving graft function and prolonging recipient survival. This could represent a novel clinically applicable therapeutic strategy to minimize the detrimental clinical outcome of prolonged cold IRI in kidney transplantation.

Inhibition of PI3K/mTOR/KATP channel blunts sodium thiosulphate preconditioning mediated cardioprotection against ischemia-reperfusion injury.

Recent studies have shown that pre and postconditioning the heart with sodium thiosulfate (STS) attenuate ischemia-reperfusion (IR) injury. However, the underlying mechanism involved in the cardioprotective signaling pathway is not fully explored. This study examined the existing link of STS mediated protection (as pre and post-conditioning agents) with PI3K, mTOR, and mPTP signaling pathways using its respective inhibitors. STS was administered to the isolated perfused rat heart through Kreb's Heinselit buffer before ischemia (precondition: SIPC) and reperfusion (postcondition: SPOC) in the presence and absence of the PI3K, mTOR, and mPTP signaling pathway inhibitors (wortmannin, rapamycin, and glibenclamide respectively). SIPC failed to improve the IR injury-induced altered cardiac hemodynamics, increased infarct size, and the release of cardiac injury markers in the presence of these inhibitors. On the other hand, the SPOC protocol effectively rendered the cardioprotection even in the PI3K/mTOR/KATP inhibitors presence. Interestingly, the SIPC's identified mode of action viz reduction in oxidative stress and the preservation of mitochondrial function were lost in the inhibitors' presence. Based on the above results, we conclude that the underlying mechanism of SIPC mediated cardioprotection works via the PI3K/mTOR/KATP signaling pathway axis activation.

Efficacy of oral administration of sodium thiosulfate in a large, swine model of oral cyanide toxicity.

INTRODUCTION: Cyanide is a deadly poison, particularly with oral exposure where larger doses can occur before symptoms develop. Prior studies and multiple governmentagencies highlight oral cyanide as an agent with the potential for use in a terrorist attack. Currently, there are no FDA approved antidotes specific to oralcyanide. An oral countermeasure that can neutralize and prevent absorption of cyanide from the GI tract after oral exposure is needed. Our objective was toevaluate the efficacy of oral sodium thiosulfate on survival and clinical outcomes in a large, swine model of severe cyanide toxicity. METHODS: Swine (45-55kg) were instrumented, sedated, and stabilized. Potassium cyanide (8 mg/kg KCN) in saline was delivered as a one-time bolus via an orogastric tube. Three minutes after cyanide, animals randomized to the treatment group received sodium thiosulfate (510 mg/kg, 3.25 M solution) via orogastric tube. Our primary outcome was survival at 60 minutes after exposure. We compared survival between groups by log-rank, Mantel-Cox analysis and trended labs and vital signs. RESULTS: At baseline and time of treatment all animals had similar weights, vital signs, and laboratory values. Survival at 60 min was 100% in treated animals compared to 0% in the control group (p=0.0027). Animals in the control group became apneic and subsequently died by 35.0 min (20.2,48.5) after cyanide exposure. Mean arterial pressure was significantly higher in the treatment group compared to controls (p=0.008). Blood lactate (p=0.02) and oxygen saturation (p=0.02) were also significantly different between treatment and control groups at study end. CONCLUSION: Oral administration of sodium thiosulfate improved survival, blood pressure, respirations, and blood lactate concentrations in a large animal model of acute oral cyanide toxicity.

Familial hyperphosphatemic tumoral calcinosis in an unusual and usual sites and dramatic improvement with the treatment of acetazolamide, sevelamer and topical sodium thiosulfate.

OBJECTIVES: Familial hyperphosphatemic tumoral calcinosis is a rare disorder characterized by hyperphosphatemia with recurrent ectopic periarticular calcifications, in addition to other visceral and vascular manifestations, without any inflammatory or neoplastic disorder. The available treatment strategies are limited. Here we report an eight year old female patient with recurrent lesions under the chin, and bilateral hips which are painful and improving of the size of the lesions and hyperphosphatemia. CASE PRESENTATION: The patient was started to the treatment with peroral acetazolamide however the lesion did not regress but a new lesion appeared then we added sevelamer and topical sodium thiosulfate treatment for three months. After the three months of the combination treatment the lesions, there were no pain, no hyperphospahtemia regression/disappearance of the lesions. CONCLUSIONS: This combination treatment or topical sodium thiosulfate use only may be a novel treatment strategy for the patients prospective controlled trials are needed.

Identification of sulfur components enhancing the anti-Candida effect of Lactobacillus rhamnosus Lcr35.

GYNOPHILUS (Lcr REGENERANS) is a live biotherapeutic product (LBP) aimed at restoring the vaginal microbiome and contains the live biotherapeutic microorganism Lactobacillus rhamnosus Lcr35. In this study, the LBP formulation and manufacturing process significantly enhanced the anti-Candida activity of L. rhamnosus Lcr35, with a complete loss of viability of the yeast after 48 h of coincubation. Sodium thiosulfate (STS), one excipient of the product, was used as a potentiator of the anti-Candida spp. activity of Lactobacilli. This contact-independent phenomenon induced fungal cell disturbances, as observed by electron microscopy observations. Nonverbal sensory experiments showed clear odor dissimilarities between cocultures of L. rhamnosus Lcr35 and C. albicans in the presence and absence of STS, suggesting an impact of odor-active metabolites. A volatolomic approach allowed the identification of six odor-active compounds, including one sulfur compound that was identified as S-methyl thioacetate (MTA). MTA was associated with the antifungal effect of Lcr35, and its functional link was established in vitro. We show for the first time that the LBP GYNOPHILUS, which is a highly active product in the reduction of vulvovaginal candidiasis, requires the presence of a sulfur compound to fully achieve its antifungal effect.

Safety and Tolerability of Sodium Thiosulfate in Patients with an Acute Coronary Syndrome Undergoing Coronary Angiography: A Dose-Escalation Safety Pilot Study (SAFE-ACS).

BACKGROUND: In animal studies, hydrogen sulfide (H2S) has been shown to protect the heart from ischemia-reperfusion injury. This study evaluates the safety and tolerability of the H2S donor sodium thiosulfate (STS) in patients with acute coronary syndrome (ACS). METHODS: Eighteen patients, undergoing coronary angiography for ACS, received STS intravenously immediately after arrival at the catheterization laboratory according to a "3 + 3 dose-escalation design" with fixed dosing endpoint (0, 2.5, 5, 10, 12.5, and 15 grams). This first dose STS was combined with verapamil and nitroglycerin required for transradial procedures. A second dose STS was administered 6 hours later. Primary endpoint was dose-limiting toxicity, defined as significant hemodynamic instability or death up to 24 hours or before discharge from the coronary care unit. Secondary outcomes included the occurrence of anaphylaxis, nausea, vomiting, and systolic blood pressure (SBP) course. RESULTS: Sixteen patients received two dosages of STS and two patients one dosage. None of the patients reached the primary endpoint, nor experienced a serious adverse event. We observed a clinically well-tolerated decline in SBP 1 hour after administration of the first STS dose and concomitant verapamil/nitroglycerin. SBP for all patients together reduced 16.8 (8.1-25.5) mmHg (P = 0.0008). No significant decline in SBP occurred after the second dose. Mild nausea was observed in one patient. CONCLUSION: This is the first report on sodium thiosulfate administration in patients with acute coronary syndromes. Our data suggest that sodium thiosulfate was well tolerated in this setting. The potential benefit of this intervention has to be examined in larger studies.

Therapeutic effect of intravenous sodium thiosulfate for uremic pruritus in hemodialysis patients.

OBJECTIVES: This study aimed to compare the efficacy of intravenous sodium thiosulfate (IV STS) with that of loratadine in the treatment of uremic pruritus in hemodialysis (HD) patients. METHODS: This retrospective study included 44 HD patients with pruritus aged over 18 years between June 2018 and January 2020 at the Aerospace Center Hospital of China. Twenty-four HD patients received 3.2 g IV STS treatment three times per week at the end of each HD session for 8 weeks. Twenty HD patients received loratadine (10 mg/day) for 8 weeks. Pruritus intensity was measured using a visual analog scale (VAS) and the detailed pruritus score (DPS) at three time points. The safety of STS was evaluated according to adverse event symptoms and biological variable changes. RESULTS: There was no significant difference between the STS and loratadine groups in age, sex, characteristics of pruritus, or other clinical variables before treatment. After 8 weeks of treatment, the VAS score (7.07 ± 2.56 and 2.67 ± 2.01) and DPS (30.72 ± 4.81 and 8.04 ± 2.86) decreased significantly in the STS group (p < 0.05). The mean decrease in VAS score (6.89 ± 1.98 and 6.34 ± 2.35) and DPS (28.90 ± 3.24 and 26.92 ± 2.41) in the loratadine group was not statistically significant (p > 0.05). There were no morbidities or mortalities associated with the use of either drug. All biological variables remained stable after therapy. CONCLUSIONS: STS can improve uremic pruritus in HD patients. However, literature on the subject remains lacking. Close monitoring for adverse effects is advised.

Pathological evaluation of radiotherapy and concomitant intraarterial cisplatin for maxillary sinus cancer.

OBJECTIVE: Since 2010, we have mainly performed surgical treatment following radiotherapy and concomitant intraarterial cisplatin (RADPLAT) for locally advanced maxillary sinus cancer (MSC). The present study investigated treatment results and pathological evaluations following RADPLAT for MSC. METHODS: Pathological response to RADPLAT was evaluated using surgical specimens. Pathological response was graded in accordance with the classification method that Shimosato reported in 1964, as grade V (no tumor cells remain in any of section), grade IV, III, II, I, and 0. Five-year overall and disease-specific survival rates were estimated using Kaplan-Meier methods. Univariate analyses of correlations between recurrence of MSC and other clinicopathological parameters were evaluated using the chi-square or Fisher's exact tests. RESULT: 19 patients were enrolled in this study, 5 patients showed T3 disease and 14 had T4 disease. One patient demonstrated local recurrence and 3 patients experienced distant metastasis. The 5-year overall survival rate was 67.1% (T3, 50.0%; T4, 69.6%), and the 5-year disease-specific survival rate was 81.9% (T3, 100%; T4, 76.0%). Histological response was categorized as grade V in 9 cases. No significant risk factors for residual cancer were identified. CONCLUSION: Our study suggested that RADPLAT not only has a low risk of side effects, but also could represent an effective procedure for locally advanced MSC by pathological evaluation. Increasing the therapeutic intensity of RADPLAT might provide an effective modality to avoid highly invasive surgery.

Calciphylaxis in a Patient on Home Hemodialysis.

Calciphylaxis is a rare and severe complication characterized by calcification of arterioles and capillaries in the dermis and subcutaneous adipose tissue that leads to ischemia, necrosis, and painful skin lesions in patients with end-stage renal disease (ESRD). It is also known as calcific uremic arteriolopathy. Calciphylaxis occurs most commonly with the ESRD with skin ulceration as a predominant presenting feature. Calcium-phosphorus dysregulation in dialysis patients are traditionally considered as a risk factor for the development of calciphylaxis. The involvement of an integrated interdisciplinary and multifaceted approach is key to the success of the calciphylaxis treatment. We present a case of a 51-year-old female with ESRD on home hemodialysis who developed calciphylaxis, which was successfully managed with increasing dialysis prescription, diligent wound care, and sodium thiosulfate infusion. Management of calciphylaxis in a patient receiving home hemodialysis has never been reported as per the review of the literature. Calciphylaxis is a sporadic disease, frequently encountered in the patients undergoing hemodialysis and carries a very grave prognosis. Current treatment is rarely effective, so preventive strategies play an important role by modifying the risk factors that promote the development of calciphylaxis.

Phase 1 study to evaluate safety, tolerability and pharmacokinetics of a novel intra-tympanic administered thiosulfate to prevent cisplatin-induced hearing loss in cancer patients.

Cisplatin is a widely used chemotherapy for the treatment of certain solid tumors. Ototoxicity and subsequent permanent hearing loss remain a serious dose-limiting side effect associated with cisplatin treatment. To date, no therapies have been approved to prevent or treat cisplatin-induced hearing loss (CIHL). Sodium thiosulfate effectively inactivates cisplatin through covalent binding and may provide protection against cisplatin-induced ototoxicity. DB-020 is being developed as a novel formulation of sodium thiosulfate pentahydrate in 1% sodium hyaluronate for intratympanic injection (IT), enabling the delivery of high concentrations of thiosulfate into the cochlea prior to cisplatin administration. In the DB-020-002 phase 1a single-ascending dose study, healthy volunteers were enrolled into 5 cohorts to receive different doses of DB-020 via IT injection. Cohorts 1-4 received unilateral injections while Cohort 5 received bilateral injections. Plasma thiosulfate pharmacokinetics was measured, and safety and audiometric data were collected throughout the study. This study has demonstrated that intratympanic administration of DB-020 results in nominal systemic increases in thiosulfate levels, hence it should not compromise cisplatin anti-tumor efficacy. Furthermore, DB-020 was safe and well tolerated with most adverse events reported as transient, of mild-to-moderate severity and related to the IT administration procedure. These results support the design and execution of the ongoing proof-of-concept study, DB-020-002, to assess otoprotection using DB-020 in cancer patients receiving cisplatin without negatively impacting cisplatin anti-tumor efficacy.

Treatment of calcinosis cutis in systemic sclerosis and dermatomyositis: A review of the literature.

BACKGROUND: We have limited data on the treatment of calcinosis cutis associated with systemic sclerosis and dermatomyositis. OBJECTIVE: To assess the efficacy and tolerance of available treatments for calcinosis cutis based on previously published studies. METHODS: We performed a systematic review of studies published in Medline, Embase, and the Cochrane library during 1980-July 2018. The strength of clinical data was graded according to the modified Oxford Centre for Evidence-Based Medicine levels of evidence. RESULTS: In all, 30 studies (288 patients) were included. Eleven therapeutic classes, surgery, and physical treatments were identified as potential treatment options for calcinosis cutis. On the basis of results of a small randomized controlled trial and 4 retrospective studies, low-dose warfarin should not be used for calcinosis cutis (level IB evidence). The results of several studies suggest diltiazem and bisphosphonates might be useful treatment options (level IV). Considering biologic therapies, rituximab has shown promising results in treating both dermatomyositis and systemic sclerosis, whereas tumor necrosis factor inhibitors might be useful for treating juvenile dermatomyositis (level IV). Intralesional sodium thiosulfate might be a promising alternative (level IV). LIMITATIONS: Few included studies had a high level of evidence. CONCLUSION: This study highlights the efficacy and tolerance profiles of available treatments for calcinosis cutis, with a focus on level of evidence.

Tolerance and effect of sodium thiosulfate in calcific tendinitis of the rotator cuff.

BACKGROUND: Calcific tendinitis of the rotator cuff is one of the most common causes of shoulder pain. Ultrasound-guided percutaneous lavage of calcific tendinopathy is performed when conservative treatments have failed. Sodium thiosulfate (STS) has recently been used with success in the treatment of tumoral calcinosis. The goal of this phase II study was to assess the tolerance and the feasibility of STS lavage of calcific tendinopathy. METHODS: We included patient with type hard calcifications. Patients were treated with puncture and lavage followed by injection of STS in the calcification. VAS pain at rest and during activities, ultrasound, and X-ray were evaluated at 1 week and 1 and 3 months. RESULTS: Seventeen patients were included. Baseline VAS at rest and during daily activities was a mean 40.2 ± 25.9 and 65.5 ± 21.6 respectively. All patients underwent the entire procedure with no adverse event. Calcium backflow could be obtained in 15 patients (88.2%). Five patients (30%) had more than 50% decrease of their calcific deposit size at 1 month and 8 (47%) patients at 3 months. VAS pain during activities and at rest decreased significantly at 3 months (p = 0.0004; p = 0.001). Efficacy would be demonstrated if 60% of the patients had more than 50% decrease size of their calcification CONCLUSION: Overall, STS was well tolerated with no side effect occurring during the procedure and the follow-up. However, no significant effect on calcium disappearance could be demonstrated compared with what is expected without STS. New studies using larger volume and repeated injections of STS are now needed. CLINICAL TRIAL REGISTRATION NUMBER: NCT02538939Key Points• Lavage of calcific tendinopathy of the rotator cuff with sodium thiosulfate is feasible• No adverse events have been observed after or in the 3 months after the procedure• We could not demonstrate that sodium thiosulfate increases the chance of calcium disappearance• New studies using larger volume and repeated injections of STS are needed to further explore the interest of sodium thiosulfate in the treatment of calcific tendinopathy.

Effects of sodium thiosulfate (Na2S2O3) during resuscitation from hemorrhagic shock in swine with preexisting atherosclerosis.

Controversial data are available on hydrogen sulfide (H2S) during hemorrhage and resuscitation, depending on timing, dosing, mode of application, and the H2S donor used. Sodium thiosulfate (Na2S2O3) is a recognized drug devoid of major side effects, which attenuated murine acute lung injury and cerebral ischemia/reperfusion injury. Therefore, we tested the hypothesis whether Na2S2O3 would mitigate organ dysfunction in porcine hemorrhage-and-resuscitation. We studied animals with pre-existing coronary artery disease because of the reduced coronary arterial expression of the H2S producing enzyme cystathionine-γ-lyase (CSE) in this prospective, randomized, controlled, blinded experimental study. 20 anesthetized and instrumented pigs underwent 3 h of hemorrhage (removal of 30 % of the blood volume and subsequent titration of mean arterial pressure to 40 mmHg). Resuscitation (72 h) comprised re-transfusion of shed blood, crystalloids, and continuous i.v. norepinephrine. Animals randomly received vehicle or Na2S2O3 (0.1 g·kg-1 h-1) for 24 h. Before, at the end of and every 24 h after shock, hemodynamics, metabolism, blood gases, lung, heart, kidney, and liver function and injury were evaluated together with cytokines and parameters of oxidative and nitrosative stress. Immediate post mortem lung, kidney, heart, and liver specimen were analyzed for marker proteins of inflammation and oxidative and nitrosative stress and mitochondrial respiratory activity in the heart, kidney, and liver. Immuno-histochemical analysis comprised lung extra-vascular albumin accumulation, nitrotyrosine formation, and CSE and glucocorticoid receptor (GCR) expression. Na2S2O3 significantly attenuated shock-induced impairment of lung mechanics and gas exchange (plateau and positive end-expiratory pressure at 72 h p = 0.0006/p = 0.0264; Horovitz index at 48 h p = 0.0261), which coincided with a higher tissue GCR expression (p = 0.0415). During resuscitation from hemorrhagic shock Na2S2O3 attenuated shock-induced acute lung injury in co-morbid swine, most likely due to a GCR expression related mechanism.

Adequate nephroprotection reduces renal complications after hyperthermic intrathoracic chemotherapy.

BACKGROUND AND OBJECTIVES: Hyperthermic intrathoracic chemotherapy (HITOC) is used for the treatment of malignant pleural tumors. Although HITOC proved to be safe, postoperative renal failure due to nephrotoxicity of intrapleural cisplatin remains a concern. METHODS: This single-center study was performed retrospectively in patients who underwent pleural tumor resection and HITOC between September 2008 and December 2018. RESULTS: A total of 84 patients (female n = 33; 39.3%) with malignant pleural tumors underwent surgical cytoreduction with subsequent HITOC (60 minutes; 42°C). During the study period, we gradually increased the dosage of cisplatin (100-150 mg/m2 BSA n = 36; 175 mg/m2 BSA n = 2) and finally added doxorubicin (cisplatin 175 mg/m2 BSA/doxorubicin 65 mg; n = 46). All patients had perioperative fluid balancing. The last 54 (64.3%) patients also received perioperative cytoprotection. Overall 29 patients (34.5%) experienced renal insufficiency. Despite higher cisplatin concentrations, patients with cytoprotection showed significantly lower postoperative serum creatinine levels after 1 week (P = .006) and at discharge (P = .020). Also, they showed less intermediate and severe renal insufficiencies (5.6% vs 13.3%). CONCLUSIONS: Adequate perioperative fluid management and cytoprotection seem to be effective in protecting renal function. This allows the administration of higher intracavitary cisplatin doses without raising the rate of renal insufficiencies.