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.

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.

Severe anion gap acidosis associated with intravenous sodium thiosulfate administration.

INTRODUCTION: Severe anion gap (AG) acidosis associated with intravenous sodium thiosulfate (STS) administration has not been previously described in nondialysis chronic kidney disease (CKD) patients. CASE REPORT: We present a CKD patient with a baseline creatinine 1.8 mg/dL (eGFR 28 ml/min/1.73 m²) who developed sustained and life-threatening AG acidosis associated with intravenous STS treatment for calciphylaxis. DISCUSSION: Although marketed as a safe drug, STS can cause life-threatening acidosis as illustrated in this case. STS-induced AG acidosis should be considered in the differential diagnosis of severe acidosis in patients receiving STS. Dosage adjustment and close follow-up of patients' acid-base status after STS initiation is necessary.

Sodium thiosulfate pharmacokinetics in hemodialysis patients and healthy volunteers.

BACKGROUND AND OBJECTIVES: Vascular calcification is a major cause of morbidity and mortality in dialysis patients. Human and animal studies indicate that sodium thiosulfate (STS) may prevent the progression of vascular calcifications. The pharmacokinetics of STS in hemodialysis patients has not been investigated yet. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: STS was given intravenously to 10 hemodialysis patients on- and off-hemodialysis. Additionally, STS was applied to 9 healthy volunteers once intravenously and once orally. Thiosulfate concentrations were measured by using a specific and sensitive HPLC method. RESULTS: In volunteers and patients, mean endogenous thiosulfate baseline concentrations were 5.5 ± 1.82 versus 7.1 ± 2.7 µmol/L. Renal clearance was high in volunteers (1.86 ± 0.45 ml/min per kg) and reflected GFR. Nonrenal clearance was slightly, but not significantly, higher in volunteers (2.25 ± 0.32 ml/min per kg) than in anuric patients (2.04 ± 0.72 ml/min per kg). Hemodialysis clearance of STS was 2.62 ± 1.01 ml/min per kg. On the basis of the nonrenal clearance and the thiosulfate steady-state serum concentrations, a mean endogenous thiosulfate generation rate of 14.6 nmol/min per kg was calculated in patients. After oral application, only 4% of STS was recovered in urine of volunteers, reflecting a low bioavailability of 7.6% (0.8% to 26%). CONCLUSIONS: Given the low and variable bioavailability of oral STS, only intravenous STS should be prescribed today. The biologic relevance of the high hemodialysis clearance for the optimal time point of STS dosing awaits clarification of the mechanisms of action of STS.

Simulation-based sodium thiosulfate dosing strategies for the treatment of calciphylaxis.

BACKGROUND AND OBJECTIVES: Calciphylaxis remains a poorly understood life-threatening disorder with limited therapeutic options. Sodium thiosulfate (STS) has reported efficacy, thought to be because solubilizing calcium deposits promote clearance by hemodialysis (HD). Lack of rigorous pharmacokinetic studies makes it problematic for determining proper STS dosing given the expanding range of dialysis prescriptions and intensities. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The purpose of this study was to determine the dosing strategies for STS during different dialysis regimens. Given reported successes using an empiric 25 g, intravenous, 3 times per week after HD, simulations were performed to predict dosing guidelines for alternative, more or less intense dialysis to produce equivalent area under the curve drug exposure. The modeled prescriptions varied HD time from 12 to 40 h/wk over three to six sessions (Q(b) 200 to 400 ml/min, Q(d) 500 to 800 ml/min), and continuous venovenous hemodialysis at low flow rates (Q(b) 100 to 200 ml/min, Q(d) 35 to 50 ml/min), using high-flux polysulfone hemofilters. RESULTS: Simulations showed a marked variation in STS doses depending on HD frequency and duration. Blood and dialysate flows have a less prominent effect. Assuming no residual renal function, HD prescription permutations caused the dose to vary from 72 to 245 g/wk (70-kg adult), and the simulations provide specific guidelines for clinicians. CONCLUSIONS: Based on the success reported for one STS dosing regimen and assuming area under the curve exposure of STS is proportional to its effect, pharmacokinetic simulations can be used to calculate the dose for alternative, higher or lower intensity dialysis regimens. These strategies are imperative to assure adequate treatment for this mortal disease, as well as to avoid toxicity from excess dosing.

High concentrations of thiosulfate in scala tympani perilymph after systemic administration in the guinea pig.

CONCLUSION: High concentrations of the antioxidant thiosulfate reach scala tympani perilymph after i.v. administration in the guinea pig. Thiosulfate concentrations in perilymph remain elevated longer than in blood. This warrants further studies on the possibility of obtaining otoprotection by thiosulfate administration several hours before that of cisplatin without compromising the anticancer effect caused by cisplatin inactivation in the blood compartment. OBJECTIVE: Thiosulfate may reduce cisplatin-induced ototoxicity, presumably by oxidative stress relief and formation of inactivate platinum complexes. This study aimed to explore to what extent thiosulfate reaches scala tympani perilymph after systemic administration in the guinea pig. MATERIALS AND METHODS: Scala tympani perilymph (1 microl) was aspirated from the basal turn of each cochlea up to 3 h after thiosulfate administration (103 mg/kg b.w., i.v.). Blood samples were also taken. Thiosulfate was quantified by HPLC and fluorescence detection. RESULTS: Substantial thiosulfate concentrations were found in perilymph. The area under the concentration-time curve for thiosulfate in perilymph and blood was 3100 microMxmin and 6300 microMxmin, respectively. The highest thiosulfate concentrations in perilymph were found at the first sampling at about 10 min. Due to a more rapid elimination from blood, perilymph concentrations exceeded those of blood towards the end of the experiment.

Sodium thiosulfate administered six hours after cisplatin does not compromise antineuroblastoma activity.

PURPOSE: We determined if the potentially otoprotective agent sodium thiosulfate (STS) could be given 6 h after cisplatin without diminishing the antineuroblastoma activity of cisplatin in human neuroblastoma cell lines in vitro (including cisplatin-resistant cell lines) and in neuroblastoma xenografts in vivo. EXPERIMENTAL DESIGN: We determined the antineuroblastoma activity of cisplatin with or without the addition of STS at 0 or 6 h after cisplatin in six neuroblastoma cell lines, both in standard cell culture conditions (20% O(2)) and in physiologic hypoxia (2% O(2)). Drug cytotoxicity was measured using the DIMSCAN fluorescence/digital imaging microscopy assay. In vivo studies of cisplatin combined with STS used a human neuroblastoma subcutaneous xenograft model (SMS-SAN) in athymic nu/nu mice. RESULTS: A significant protection against cisplatin cytotoxicity was seen when the neuroblastoma cells were exposed to cisplatin directly combined with STS. However, when cisplatin was given first and STS exposure occurred 6 h later, no effect on cisplatin cytotoxicity was observed. In a subcutaneous neuroblastoma xenograft model in nu/nu mice, mice receiving cisplatin alone or cisplatin + STS at 6 h had significantly better progression-free survival rates (P < 0.03) compared with controls or mice treated with cisplatin + STS concurrently. There was no statistically significant difference in outcomes between mice treated with cisplatin alone and the group treated with cisplatin followed by STS 6 h later (P = 0.9). CONCLUSION: These preclinical data suggest that the use of STS 6 h after cisplatin for otoprotection is unlikely to compromise the antineuroblastoma activity of cisplatin.

Kinetics of Cisplatin and its monohydrated complex with sulfur-containing compounds designed for local otoprotective administration.

The anticancer drug cisplatin can cause permanent inner ear damage. We have determined the second-order degradation rate constant, k(Nu), of cisplatin and its more toxic monohydrated complex (MHC) in the presence of each of the sulfur-containing nucleophiles N-acetyl-l-cysteine, l-cysteine methyl ester, 1,3-dimethyl-2-thiourea, d-methionine, and thiosulfate, compounds that are under evaluation for local administration to prevent cisplatin-induced ototoxicity. MHC was isolated from a hydrolysis solution of cisplatin using liquid chromatography (LC). The degradations were evaluated by measuring the disappearance of MHC and cisplatin at 37 degrees C and pH 7.4 in the presence of each of the nucleophiles using LC and photometric detection. The k(Nu) of MHC and of cisplatin was 0.044 M(-1)sec(-1) and 0.012 M(-1)sec(-1) with N-acetyl-l-cysteine, 0.24 M(-1)sec(-1) and 0.067 M(-1)sec(-1) with l-cysteine methyl ester, 0.16 M(-1)sec(-1) and 0.074 M(-1)sec(-1) with 1,3-dimethyl-2-thiourea, 0.070 M(-1)sec(-1) and 0.069 M(-1)sec(-1) with d-methionine, and 3.9 M(-1)sec(-1) and 0.091 M(-1)sec(-1) with thiosulfate, respectively. Our results suggest that thiosulfate, as being the strongest nucleophile, is a promising candidate for local application in order to reduce the inner ear content of MHC and cisplatin. However, otoprotection is a multifactorial event, and it remains to be established how important nucleophilicity is for the effectiveness of the protecting agent.

Toxicity profile of delayed high dose sodium thiosulfate in children treated with carboplatin in conjunction with blood-brain-barrier disruption.

PURPOSE: To assess the safety of delayed high dose intravenous (i.v.) sodium thiosulfate (STS) in a case series of 12 children with malignant brain tumors who were treated with intraarterial (i.a.) carboplatin in conjunction with blood-brain-barrier disruption (BBBD). METHODS: Twelve children ages 17 months-12 years underwent a total of 132 BBBD chemotherapy treatments and also received delayed high dose STS (i.v.). Dose 1 of STS (10-16 g/m(2)) was administered 2 or 4 hr after carboplatin, and a second STS dose was administered 4 hr after dose 1 if the child had impaired baseline hearing. Toxicity data were graded in accordance with the National Cancer Institute Common Toxicity Criteria (Version 2). Audiologic monitoring to evaluate the otoprotective potential of STS was performed on 11 children. Ototoxicity was defined in accordance with the American Speech-Language-Hearing Association (ASHA) criteria. Baseline and end of treatment hearing status were graded using Brock's criteria. RESULTS: Nausea and vomiting were well controlled with anti-emetics administered approximately 30 min prior to STS infusion. Analogous to results in adult patients, there was mild transient hypernatremia and a trend for improved protection from ototoxicity in children who received STS delayed to 4 hr post-treatment versus 2 hr. Tumor responses were seen in heavily pre-treated patients with relatively chemo-resistant tumors, suggesting that STS did not protect the tumor from platinum cytotoxicity. CONCLUSION: High dose STS is well tolerated in children under 12 years of age. Further studies of STS in children are warranted to assess otoprotection and the impact of STS on platinum mediated efficacy.

Quantification of sodium thiosulphate protection on cisplatin-induced toxicities.

OBJECTIVE: To quantify the amount of protection from cisplatin (CDDP)-induced mortality and toxicity provided by sodium thiosulphate (STS). DESIGN: Prospective controlled animal study. SETTING: Animal research facility. METHOD: Nephrotoxicity, myelotoxicity, and auditory/neurotoxicity were studied in guinea pigs. Total CDDP doses of 15, 21, 25, 35, and 45 mg/kg were administered to animals in groups of five. In some groups, STS (8000 mg/kg) was given. Animals underwent bloodwork and auditory brainstem response (ABR) testing to estimate toxicity before and 1 month after treatment. MAIN OUTCOME MEASURES: Blood urea nitrogen, creatinine, and white blood cell count were used to assess renal and myelotoxicity. Hearing was assessed with ABR thresholds to click stimuli. Survival was an overall measure of toxicity. RESULTS: Forty guinea pigs in six treatment groups were studied. Animals given 21 mg/kg CDDP all died within 1 month and showed evidence of severe toxicity. Eighty percent of subjects treated with CDDP 15 mg/kg survived and showed evidence of nephrotoxicity and ototoxicity. Subjects treated with STS and CDDP showed survival comparable to the control group treated with CDDP 15 mg/kg. Under STS protection, CDDP was tolerated in doses three times the toxic dose without protection. Without STS, the maximum dose of CDDP tolerated for a month was 15 mg/kg. CONCLUSIONS: STS protects against mortality owing to CDDP by reducing toxicity. Under STS protection, the maximum tolerated dose of CDDP is greatly increased in guinea pigs.

The physiological effects of a biologically incorporated silver diet on rainbow trout (Oncorhynchus mykiss).

Silver was biologically incorporated into a diet by exposing rainbow trout for 7 days to 100 mg/l of waterborne silver as silver thiosulphate. These fish were processed into a fine powder (trout meal) and pelleted to form a nutritionally balanced feed which was then fed to juvenile rainbow trout (Oncorhynchus mykiss). Fish were fed either a diet containing 3.1 microg/g biologically incorporated silver (an environmentally relevant concentration), or one of three control diets containing approximately 0.05 microg/g Ag for 128 days. All dietary treatments were fed to satiation once daily. Dietary silver did not significantly affect mortality, growth, food consumption, or food conversion efficiency. Furthermore, ion regulation (plasma Na(+) levels and Na(+) influx rates), hematological parameters (hematocrit, plasma protein, hemoglobin levels), plasma glucose, metabolism (oxygen consumption, ammonia and urea excretion rates) and intestinal Na/K-ATPase and amylase activities were all unaffected. Based on the physiological parameters investigated here, this dietary silver exposure appeared to be physiologically benign to rainbow trout. However, silver concentrations in the livers of the silver-fed fish were significantly elevated at day 16, and reached a steady-state level of approximately 20 microg/g Ag by day 36. The concentration specific accumulation rate in the livers of fish fed biologically incorporated silver was about 4.6 orders of magnitude greater than when fed dietary silver sulfide, indicating much greater bioavailability. Despite this increase, hepatic metallothionein concentrations remained unchanged, in contrast to waterborne exposures, indicating that bioaccumulated silver behaves differently depending on whether it is taken up from the diet or from the water. Apart from a significant reduction in hepatic Cu at day 16, liver concentrations of Cu and Zn were not affected by dietary silver. Silver concentrations were also significantly elevated (relative to control fish) in the kidneys of the silver-treated fish on days 88 and 126, and in the gills and plasma at day 126.

Effect of sodium thiosulfate on cisplatin removal with complete hepatic venous isolation and extracorporeal charcoal hemoperfusion: a pharmacokinetic evaluation.

BACKGROUND: Complete hepatic venous isolation and extracorporeal charcoal hemoperfusion (HVI.CHP) can limit systemic exposure to high-dose chemotherapeutic agents when given by hepatic arterial infusion (HAI). The purpose of this study was to determine if the concomitant use of sodium thiosulfate (STS) could further expand the advantages of pharmacologic delivery of HVI.CHP for cisplatin (CDDP) during HAI chemotherapy. METHODS: CDDP (4mg/kg) was administered over 20 minutes via HAI under conditions of HVI.CHP in 14 mongrel dogs. HVI.CHP was performed for 30 minutes after initiation of HAI. During CDDP infusion, 7 dogs each received 400 mg/kg STS (a 100-fold molar ratio to CDDP) over 20 minutes via the prefilter (STS group) circuit line, while the remaining 7 dogs (controls) received no STS. Blood samples were taken serially from the prefilter circuit line (hepatic venous blood), postfilter line, and the left carotid artery (systemic blood). The free and total CDDP concentrations in these samples were determined by flameless atomic absorption spectrophotometry. RESULTS: During 20 minutes HAI of CDDP, the mean CDDP extraction ratios (ER) by CHP filter were always higher in the STS group than in the control group, regardless of the form (free or total) of CDDP. The differences between the STS and control groups in the extraction ratios of free and total CDDP were significant at all time points measured (P < .05). Consequently, systemic exposure to CDDP, as assessed by area under the time-concentration curve of total CDDP, was significantly lower in the STS group than in the control group (P < .05). CONCLUSIONS: These results indicated that concomitant STS infusion could further increase the effect of HVI.CHP on CDDP removal after HAI.

Isomeric effects on thiosulfate transformation and detoxification of 1,3-dichloropropene.

The fumigant 1,3-dichloropropene (1,3-D) is one of the most heavily used pesticides but also a suspected carcinogen. Previous research has shown that 1,3-D was rapidly transformed and detoxified by ammonium thiosulfate (ATS), a sulfur and nitrogen fertilizer. As common formulations contain cis and trans isomers at roughly equivalent ratios, this study was conducted to understand isomeric differences in thiosulfate transformation and detoxification of 1,3-D. Under the same conditions, reaction of cis-1,3-D with thiosulfate was more than three times faster than trans-1,3-D, which was correlated with a lower reaction activation energy for the cis isomer. The trans isomer was considerably more toxic to the luminescent bacteria Vibrio fisheri than the cis isomer, but the toxicity was reduced by 14 times after thiosulfate transformation. Mutagenic activity to strains of Salmonella typhimurium was observed for trans-1,3-D but was not detected after thiosulfate transformation. These results suggest that thiosulfate transformation detoxifies 1,3-D primarily by deactivating the trans isomer, and the reaction is toxicologically beneficial, as it negates the potential harmful effects of 1,3-D to the environment and human health.

The lack of transplacental movement of the cyanide antidote thiosulfate in gravid ewes.

UNLABELLED: A previous study reported that the co-infusion of IV sodium thiosulfate (STS) with sodium nitroprusside (SNP) to near-term gravid ewes prevented both maternal and fetal cyanide toxicity. We questioned whether maternally administered STS crossed the ovine placenta to enhance fetal transulfuration of cyanide, or whether the fetus was dependent on maternal detoxification of cyanide after diffusion of cyanide into the maternal circulation. Ten anesthetized, near-term gravid ewes underwent hysterotomies with delivery of fetal heads for venous catheterization. Five control ewes received IV isotonic sodium chloride solution, whereas five experimental ewes received IV STS (50 mg/kg over 15 min). Serial plasma thiosulfate concentrations in ewes and fetuses were measured over 135 min. Areas under the time-plasma thiosulfate concentration curves were calculated for experimental and control ewes at 2758+/-197 and 508+/-74 min x mg(-1) x L(-1), respectively (P < 0.008). Mean areas under the curve for experimental and control fetuses were 236+/-34 and 265+/-23 min x mg(-1) x L(-1), respectively (P > 0.5). Maternally administered STS may prevent fetal cyanide poisoning from SNP administration without relying on STS crossing the placenta into the fetal circulation. Fetal cyanide may cross down a concentration gradient from fetal to maternal circulation, to be transulfurated to thiocyanate in maternal tissues. IMPLICATIONS: We evaluated the mechanism of action of sodium thiosulfide (STS) in sodium nitroprusside-induced cyanide toxicity in the ewe. Fetal cyanide poisoning is alleviated by maternal administration of STS, although this cyanide antidote apparently does not cross the placenta.

First evidence of otoprotection against carboplatin-induced hearing loss with a two-compartment system in patients with central nervous system malignancy using sodium thiosulfate.

Sodium thiosulfate (STS) provides protection against carboplatin-induced ototoxicity in an animal model. The purpose of this study was to determine the STS dose required for otoprotection, in patients with malignant brain tumors treated with carboplatin in conjunction with osmotic blood-brain barrier disruption. Twenty-nine patients received STS intravenously 2 hr after carboplatin. Doses were escalated from 4 g/m2 to 8, 12, 16 and 20 g/m2 on consecutive months. Audiologic assessment was performed at baseline and monthly. The audiograms were compared with those of 19 similarly treated historical control patients who did not receive STS. The incidence of ototoxicity in the historical control group of patients was 79% (15/19). This group had an average loss of 20.8 +/- 5.9 dB (n = 19) at 8 kHz after one treatment with carboplatin, whereas the STS treatment group lost only 3.7 +/- 2 dB (n = 15) after one treatment. This difference was statistically significant as assessed by Student's t test (P < .05). Furthermore, patients in the STS treatment group with excellent base-line hearing showed little change in hearing thresholds at 8 kHz after the second treatment (8.0 +/- 8.3 dB) (n = 5) compared with the historical control patients with excellent base-line hearing, (40.5 +/- 8.6 dB) (n = 11). Our data support that doses of 16 or 20 g/m2 of STS decrease carboplatin-induced hearing loss without central nervous system entry. Clinical demonstration of an otoprotective effect with a two-compartment system to prevent drug-induced hearing loss, while preserving central nervous system cytotoxicity, has not been reported previously.

[Antioxidant therapy of vision organ disorders in the Chernobyl accident liquidators]. / Antioksidantnaia terapiia patologicheskikh izmenenii organa zreniia u likvidatorov avarii na Chernobyl'skoi AES.

Antioxidant complex including flacumine, glutamic acid, and sodium thiosulfate was used to treat pathological changes in the organ of vision in the liquidators of the Chernobyl accident. The treatment stabilized vision acuity and improved some hormonal and immunological parameters of the blood. Hence, this therapeutic complex can be used for the prevention and treatment of ocular abnormalities in subjects exposed to radionuclides.

Experimental and clinical studies on the intraperitoneal administration of cis-diamminedichloroplatinum (II) for peritoneal carcinomatosis caused by gastric cancers.

The effectiveness of the intraperitoneal administration of cis-diamminedichloroplatinum (II) (DDP) on peritoneal carcinomatosis caused by gastric cancers was evaluated. Seventeen patients were treated with one of three protocols, consisting of the intraperitoneal injection (ip) of DDP at doses of 70 and 110 mg/m2, with or without sodium thiosulfate (STS) rescue. The area under the curve (AUC) of DDP for sufficient anticancer activities against cultured human cell lines in vitro was estimated at 240 micrograms h/ml, which was equivalent to the AUC gained by 110 mg/m2 ip DDP in the clinical studies. The cytotoxic activity of DDP was reduced by approximately 50% with 100-fold STS in the AUC in the experimental studies. However, this was achieved only in urine, and not in either the peritoneal cavity or in plasma in the clinical studies. Three cases of a partial response against peritoneal carcinomatosis were seen from a total of four evaluable cases treated with 110 mg/m2 DDP, and no renal toxicities were observed in those treated with the STS rescue. The results of this study led us to conclude that high-dose ip DDP treatment combined with the STS rescue would be useful chemotherapy against peritoneal carcinomatosis caused by gastric cancers.

The antidotal action of sodium nitrite and sodium thiosulfate against cyanide poisoning.

The combination of sodium thiosulfate and sodium nitrite has been used in the United States since the 1930s as the primary antidote for cyanide intoxication. Although this combination was shown to exhibit much greater efficacy than either ingredient alone, the two compounds could not be used prophylactically because each exhibits a number of side effects. This review discusses the pharmacodynamics, pharmacokinetics, and toxicology of the individual agents, and their combination.

Rhodanese and sodium thiosulfate encapsulated in mouse carrier erythrocytes. II. In vivo survivability and alterations in physiologic and morphologic characteristics.

Biodegradable drug carrier mechanisms were employed in drug antagonism studies. Prior studies indicated that erythrocytes containing encapsulated rhodanese and sodium thiosulfate metabolized cyanide to thiocyanate in vitro. Studies were conducted to investigate the properties of these sulfurtransferase-loaded red blood cells in vivo by administering the carrier red blood cells intravenously. Approximately 40 to 50% of the cells were eliminated within the first few hours while the remaining loaded erythrocytes persisted in the circulation. The present studies were initiated to investigate the characteristics of the disposition of the loaded erythrocytes and to examine differences in the properties between carrier and noncarrier erythrocytes. Also, the disposition and viability of the erythrocytes in vivo were studied with relation to various biochemical, physiological, and morphological properties. These studies indicated that the carrier erythrocytes had a smaller cell volume and were more susceptible to hemolysis than normal erythrocytes. Morphologic studies by electron microscopy indicated that extensive morphologic changes occurred during the procedures after hypotonic dialysis, isotonicity adjustment, and resealing were completed. Differences were noted between those cells that were only resealed and those cells that were also subjected to annealing. The morphologic characteristics of most of the cells were restored to the "normal" morphologic appearance only after annealing. Annealed erythrocytes' in vivo survivability was correlated with the physical properties of these cells.

[The diminishing oocyte toxicity following intraperitoneal infusion of cisplatin (CDDP) combined with subcutaneous injection of sodium thiosulfate (STS) in syngeneic young mice].

Small oocytes in 6-week-old C57BL/6 mice were destroyed in a dose-dependent fashion following intraperitoneal infusion of CDDP. ED65, the effective dose of which theoretically produced 65% destruction of small oocytes according to Probit analysis, was determined as 0.2mg/mouse. In this study, the oocyte toxicity induced with intraperitoneal treatment with CDDP (0.2mg) was offset by subcutaneous treatment with STS (40mg, 400 x molar ratio compared to that of CDDP). STS was subcutaneously injected into the back skin of mice at 60, 30, 15 minutes before, at the same time or at 15, 30, 60 minutes after the CDDP injection. STS markedly diminished the oocyte toxicity and reduced oocyte destruction about 45% when it was injected at 30, 15 minutes before or at the same time as CDDP infusion. On the other hand STS failed to reduce oocyte destruction when it was injected 15, 30 or 60 minutes later. STS might neutralize CDDP in the circulating blood to decrease the amount of active CDDP, but STS might not have any effect on CDDP once it is incorporated and conjugated with the DNA in the oocytes.