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[Modulation of endotoxin-induced respiratory splash of granulocytes and monocytes in patients with Familial Mediterranean Fever by iodine-lithium-alpha-dextrin and sodium thiosulfate].

The effect of an endotoxin--E. coli liposaccharide (LPS) of serotype 026:B6--on the respiratory splash (RS) of neutrophils and monocytes in peripheral blood of patients with Familial Mediterranean Fever (FMF) was studied. It is shown that FMF patients have a periodic increase (during an attack) and a decrease (in the period of remission) in endotoxin-induced RS of neutrophils and monocytes. LPS stimulates chemotoxis-induced RS of neutrophils and monocytes in patients both in the period of remission and during the attack equally effectively. Iodine-lithium-alpha-dextrin and sodium thiosulfate have a marked anti-endotoxic effect which manifests with quick neutralization of endotoxin activity on RS of monocytes and neutrophils in FMF patients both during the attack and remission.

Adolescent↗
PubMed1990

[Effect of sodium thiosulfate on cisplatin-induced ototoxicity].

The effect of sodium thiosulfate (STS) on cisplatin (CDDP)-induced ototoxicity in the guinea pigs was studied by surface preparation, outer hair cell counting, electrocochleographic, light and electron microscopic techniques. Seventy-eight guinea pigs were divided into five groups. Group I received intraperitoneal CDDP (2.5 mg/kg/day) alone: group V as control; the other three groups were given the same doses of CDDP as group I with intramuscular STS (600 mg/kg/day) administered 30 min before (group II) or 30 min (group III) and 6 hr (group IV) after CDDP. The results showed that CDDP produced serious ototoxicity both functionally and histologically when given without STS. The first row of outer hair cells (OHC) in basal turn was first damaged. The inner hair cells (IHC) were more resistant than the OHC. The pattern of destruction is similar to that produced by aminoglycosides. Concomitant use of STS, however, significantly reduced CDDP-induced ototoxicity. Transmission electron microscopy showed the degeneration of mitochondria to be the major and earliest sign of OHC damage induced by CDDP. Our present study documented the good protective efficacy of STS against CDDP cochleotoxicity. STS did not reverse the pathological changes already caused by CDDP. This study provided some experimental evidence for the prevention of CDDP ototoxicity in clinical cancer chemotherapy.

Animals↗
PubMed1990

[Cytological research on the action of sodium thiosulfate on the process of induced acute pancreatitis in rats].

The influence of sodium thiosulfate (STS) on the process of experimental acute pancreatitis (EAP) in rats was studied by cytomorphology, morphometry, autoradiography and cytophotometry. The influence was shown to vary at different stages of disease development. At the first stage ("primary effect" state) STS leads to the increase in the stability of exocrine pancreacytes (EP) against the toxins and to the decrease in the activity of proteases formed during necrobiosis. This results in the drop of the number of degrading EP and of the degree of inter- and intracellular oedema, and brings about shifts towards the normal values of the nucleus cytoplasm shapes, the nucleus/cytoplasm ratio, the EP population structure and their RNA and protein content. At the second stage STS stimulates DNA synthesis in EP and their proliferation leading to accelerated restoration of the number of viable cells. STS also stimulates the regeneration process hence preventing pancreatitis from passage to its chronic form. The mechanism of STS action of EP functions in normal cells and during pathogenesis is discussed.

Acute Disease↗
PubMed1990

ESR spin-trapping studies on the formation of thiosulfate and sulfide radical anions in aqueous solutions.

The first spin-trapping evidence for the formation of thiosulfate (S2O3-.) and sulfide (S-.) radical anions from the reactions of hydrogen peroxide with thiosulphate and sulphide ions, respectively, was presented by electron spin resonance (ESR) spectroscopy using 3,5-dibromo-4-nitrosobenzenesulfonate (DBNBS, 1a) as a spin-trap in aqueous solutions. From the facts that the short-lived radical anions, S2O3-. and S-., could be detected during the oxidation with H2O2, it is suggested that these radical anions may become one of the candidates for the toxicity of sulfide ion in the living body.

Benzenesulfonates↗
PubMed1989

[Effect of sodium thiosulfate on the antitumor effect and nephrotoxicity of CDDP in human gastric cancer transplanted in nude mice].

Sodium thiosulfate (STS) is known to decrease the nephrotoxicity of cisplatin (CDDP). CDDP has been recognized effective in some type of gastric cancers, and there has been an attempt to examine the optimal dose of STS, which suppresses the CDDP-induced nephrotoxicity without interfering its anticancer effect. The gastric cancer cell lines (KATO-III and MKN 45) were transplanted into BALB/c nu/nu mice. CDDP was injected intraperitoneally once a week 5 times with various doses of STS, and the effects of STS on the antitumor effect as well as the nephrotoxicity of CDDP were examined. The antitumor effect of CDDP (9 mg/kg) was suppressed by 30% with the simultaneous injection of 372 mg/kg (50 fold-molar radio of STS to CDDP) and abolished by 1,488 mg/kg (200 fold-molar radio) of STS. The elevated serum BUN and the kidney content of platinum following CDDP administration were at the normal ranges in the nude mice received these doses of STS. Also, the atrophic and regenerative changes of the kidney tubules induced by CDDP were scarcely observed in these nude mice. From these results, only 50 fold-molar radio of STS to CDDP suppresses the nephrotoxicity of CDDP without interfering its antitumor effect, and this rather smaller amounts of STS is considered to be optimal. Further studies, however, will be needed for clinical application.

Animals↗
PubMed1988

[The influence of sodium thiosulfate on the antitumor effect of cisplatin in human gastric cancer cell lines].

It is well known that the sodium thiosulfate (STS) decrease not only the nephrotoxicity which is a dose limiting factor of cisplatin (CDDP) chemotherapy but also its antitumor activity. Therefore, we examined the antitumor effect of CDDP in the human gastric cancer cell lines under various concentrations of STS. The cell lines used were KATO-III, MKN 28, MKN 45 and MKN 74. The consistency of STS in relation to CDDP (2.0 ng/ml) was 25-250 fold-molar ratio. The chemosensitivity of CDDP was positive in the 3 cell lines, KATO-III, MKN 28 and KATO-III in order. When STS was used with 50 fold-molar ratio in KATO-III and MKN 28 and 100 fold in MKN 45, a CDDP colony inhibition rate of more than 80% was maintained. This results suggest that the antitumor effect of CDDP will not be suppressed not so much when the low dose of STS was used in CDDP with STS chemotherapy, even though used through the same route of administration and simultaneously.

Cell Line↗
PubMed1988

[Studies on an appropriate intra thoracic administration of cisplatin and sodium thiosulfate in malignant pleural effusion].

Twenty-eight patients with malignant pleural effusion received instillation of cisplatin (CDDP) into the pleural cavity to examine the pharmacokinetics and side effects of CDDP Thirteen patients received high-dose CDDP (120 mg/m2-160 mg/m2) in combination with sodium thiosulfate (STS), while 15 others received CDDP alone (80 mg/m2). Total Pt and non-protein-bound Pt (free Pt) concentrations in the pleural effusion and plasma were determined by flameless atomic absorption spectrometry. In one patient, Pt concentrations of intact CDDP and STS-bound CDDP were determined using high performance liquid chromatography and flameless atomic absorption spectrometry. Instillation of CDDP at 160 mg/m2 into the pleural cavity was achieved by concurrent use of STS in the large dose (STS 20 g/m2 1 hr later, totalling 625-fold molar ratio to CDDP). When CDDP was combined with STS, there was alleviation in hematological, renal and auditory toxicity but not in nausea, vomiting or anorexia. When CDDP was instillated into the pleural cavity at 150 mg/m2 (in combination with STS equivalent to 200-fold molar ratio to CDDP), a high Pt concentration of intact CDDP could be maintained in the pleural effusion over a prolonged period of time, recording 8.80 micrograms/ml even as late as 12 hr after instillation. On the other hand nearly all of the free Pt concentration for the first 2 hr was considered to be due to intact CDDP. Once systemically administered, STS quickly moved into the pleural effusion, binding with CDDP in the pleural cavity and thus probably reducing its anti-tumor effect. STS did not greatly affect the plasma concentration of total Pt when it was administered at a 100-fold molar ratio to CDDP, yielding only p poor effect. Our findings suggest that malignant pleural effusion could be effectively treated by the instillation of CDDP 80 mg/m2 into the pleural cavity.

Aged↗
PubMed1987

[Two-route chemotherapy using the anticancer drug cis-diamminedichloroplatinum(II) and its antidote, sodium thiosulfate].

We described the efficacy of "two-route chemotherapy (TRC)", in which the anticancer drug, cis-diamminedichloroplatinum (II) (DDP), is injected locally, in combination with its antidote, sodium thiosulfate (STS), given systemically. First, we tested the protective effect of sulfur-containing compounds against DDP toxicity, and found STS to be the most potent antidote of DDP. On the basis of this finding, we developed TRC using DDP and STS, and applied it for liver and lung metastasis, bladder cancer, and peritoneal disseminated tumors in experimental animals, resulting in remarkable antitumor effects without serious side effects, especially nephrotoxicity. Furthermore, we obtained an optimal increase in the lifespan of rats bearing limb tumors when we tried TRC in combination with the angiotensin II (AT-II)-induced hypertension method. We also clarified that the protection of STS against DDP toxicity was mainly due to the diminution of the active platinum level in blood. We briefly reviewed the clinical trials of TRC, and discussed the improvements which still have to be made.

Animals↗
PubMed1987

Efficacy of two-route chemotherapy using cis-diamminedichloroplatinum(II) and its antidote, sodium thiosulfate, in combination with angiotensin II in a rat limb tumor.

We combined the angiotensin II (AT-II)-induced hypertension method with "two-route chemotherapy" (TRC), using cis-diamminedichloroplatinum(II) (CDDP) and its antidote, sodium thiosulfate (STS). The efficacy of the modified TRC was evaluated in rats bearing a limb tumor (transitional cell carcinoma). Immediately after infusing CDDP (15 mg/kg) and AT-II (15 micrograms/kg) via the femoral artery for 5 min, 1580 mg/kg STS (200-fold molar ratio to 15 mg/kg of CDDP) were administered i.v. for a further 5 min. Other treatments were as follows: 5 mg/kg of CDDP mixed or not mixed with 15 micrograms/kg of AT-II were given intraarterially (i.a.); 5 mg/kg of CDDP alone were injected i.v.; CDDP (15 mg/kg, i.a.) and STS (1580 mg/kg, i.v.) were simultaneously administered, without AT-II (conventional TRC). The antitumor effects of the modified TRC, evaluated by regression of tumor growth and extended life span, were superior to the other treatments. On the other hand, nephrotoxicity, loss of body weight, and leukopenia, seen in the rats given TRC with AT-II, occurred less than or at the same rate as in rats given other treatments. Thus, the TRC with AT-II was the most effective treatment given to rats bearing a regionally confined tumor. The feasibility of clinical application of modified TRC using i.a. CDDP plus AT-II and i.v. STS is discussed.

Angiotensin II↗
PubMed1987

Inhibition of beta-propiolactone-induced mutagenesis and neoplasia by sodium thiosulfate.

Studies have been initiated to find compounds that can trap direct-acting carcinogens within the stomach. Sodium thiosulfate (STS) is a potent nucleophile and in initial experiments was found to inhibit mutagenesis resulting from exposure of Salmonella typhimurium strain TA100 to the direct-acting carcinogens beta-propiolactone and styrene oxide. In in vitro experiments STS was shown to maintain its nucleophilicity in the acid pH range. It reacted with beta-propiolactone as rapidly at pH 2 as at pH 7.4. Thus STS has the prerequisite attributes to inhibit the carcinogenic effects of electrophiles in the stomach. Experiments were performed in which STS was administered by p.o. intubation to female A/J mice 5 min before p.o. administration of beta-propiolactone. Under these conditions, inhibition of formation of the forestomach tumors occurred. The data obtained suggest that use of nucleophiles to protect against direct-acting carcinogens is a potential strategy for chemoprevention.

Animals↗
PubMed1987

[Combination effects of cis-dichlorodiammineplatinum (II) and sodium thiosulfate on renal dysfunction].

Forty-five patients with lung carcinoma were randomized to receive CDDP alone (STS (-) group) or combination of sodium thiosulfate (STS (+) group). Among the 45 patients, 42 had primary lung carcinoma and four had metastatic lung carcinoma. The combination of CDDP and STS infusion was performed in twenty-three patients and CDDP alone in 22 patients. The patients given STS were evaluated for renal function and pharmacokinetics. Urinary excretion of beta 2 microglobulin (BMG) and urinary concentration of N-acetyl-beta-D-glucosaminide (NAG), which reflect the function of the proximal tubules, were almost normal in the STS (+) group, but abnormally high in the STS (-) group. For serum BMG, BUN, creatinine, and 24-h creatinine clearance, which reflect glomerular function, no significant differences were found between the two groups. Urinary platinum excretion over 24 h was 29% in the STS (+) group and 21% in the STS (-) group. Total concentration of serum platinum after 24-h administration of CDDP was 2.1 micrograms/ml in the STS (+) group and 2.4 micrograms/ml in the STS (-) group. This study indicated that the combination of CDDP and STS promotes urinary excretion of CDDP, and rescues the dysfunction of the proximal tubules.

Blood Urea Nitrogen↗
PubMed1985

[Systemic chemotherapy with high-dose cisplatin and sodium thiosulfate rescue].

Intravenous bolus injection of an 80- to 120-mg/m2 dose of cisplatin followed by "rescue" with sodium thiosulfate (STS) was tried in the treatment of 7 patients with advanced tumor. STS was given continuously i.v. six hours after cisplatin injection, combined with methylprednisolone and metoclopramide as antiemetics. Four patients were evaluable, consisting of one CR, one PR and two NC. Severe nausea and emesis occurred in two patients and irreversible renal dysfunction occurred in one. The clinical use of the STS rescue regimen was discussed in conjunction with our basic investigation of "STS-rescue" in an animal model.

Adult↗
PubMed1986

[Pharmacokinetic study of cisplatin and sodium thiosulfate in two-route-infusion chemotherapy].

In seven patients with head and neck cancer, two-route-infusion chemotherapy using cisplatin (CDDP) and sodium thiosulfate (STS) was performed and their pharmacokinetics were studied. As for the time of administration of STS, the treatment courses were classified into 4 groups: STS was given 10 minutes after the administration of CDDP in group I, 30 minutes in group II, 60 minutes in group III and the same schedule as group II in addition to prior loading of STS in group IV. The peak level of plasma CDDP was 1.27-3.33 micrograms/ml and the half-lives of the alpha-phase in groups I, II, III and IV were 58, 97, 126 and 44 minutes, respectively. The peak level of plasma non-protein-bound CDDP was 1.00 +/- 0.45 micrograms/ml and the half-life was 53 minutes. The peak level of plasma STS was 32.2 and 33.3 mg/dl and the half-life was 95 minutes. No serious side effect was observed but slight nausea and anorexia occurred in two courses. This study suggests that the liberation of CDDP from protein-bound CDDP was achieved by administration of STS and that the urinary excretion of CDDP from the plasma was also increased immediately after the administration of STS. The mechanism of relief of CDDP side effects by STS is supposed to involve both a neutralizing action CDDP and reversal of CDDP-induced, cross-linked DNA.

Cisplatin↗
PubMed1985

[Systemic chemotherapy with super-high dose cisplatin and sodium thiosulfate (STS) rescue in mice].

We have devised a new systemic chemotherapy using cisplatin (DDP) with sodium thiosulfate (STS) rescue; basically, STS was given repeatedly 6 hours after DDP administration combined with metoclopramide. The effect of STS-rescue on the antitumor activity of DDP was studied using a BALB/c syngeneic fibrosarcoma (KKN-1). A graded dose of DDP was given i.p. with or without STS-rescue and its effects were evaluated according to N. C. I. protocol. A DDP dose-related antitumor activity was observed and the minimal effective doses were calculated as 8.2 and 9.8 mg/kg for groups treated with DDP alone and with STS-rescue, respectively. When STS-rescue was combined, however, super-high doses of DDP (9-16.5mg/kg) could be administered and this resulted in a 52% increase in chemotherapy index.

Animals↗
PubMed1985

"Two-route chemotherapy" using high-dose intra-arterial cis-diamminedichloroplatinum (II) and systemic sodium thiosulfate, its antidote, for rat limb tumor.

The effect of "two-route chemotherapy (TRC)" using a combination of cis-diamminedichloroplatinum (II) (DDP) and its antidote, sodium thiosulfate (STS) on rat limb tumor was studied. TRC in which 20 mg/kg of DDP and two doses of 1,054 mg/kg of STS (100-fold molar ratio to DDP) were given via the femoral artery and the femoral vein, respectively, provided significantly better antitumor effects evaluated by tumor weight than did intra-arterial or intra-venous DDP (5 mg/kg) without STS. Side effects were evaluated by the BUN levels and by changes in body weight after the treatments. In the group of TRC, increase in BUN levels was protected completely and body weight loss was slight.

Animals↗
PubMed1983

Efficacy of "two-route chemotherapy" using intra-arterial cisplatin and iv sodium thiosulfate, its antidote, in rat bladder tumor.

The efficacy of "two-route chemotherapy (TRC)" using a combination of cisplatin (DDP) and its antidote, sodium thiosulfate (STS), was evaluated in rat bladder tumor. TRC in which 20 mg/kg of DDP and two doses of 1054 mg/kg of STS (100-fold molar ratio to DDP) were given during interruption of arterial flow for 30 minutes through the abdominal aorta and femoral vein, respectively, provided significantly better antitumor effects evaluated by tumor weight and survival time than did intra-arterial or iv DDP (4 mg/kg) without STS. These three modalities revealed a similar toxicity in rats. Dose- and time-related efficacy of DDP and a high sensitivity of a transitional cell carcinoma of the rat to DDP were noted in TRC. Nephrotoxicity assessed by increase in BUN levels was minimum. The particular combination of intra-arterial DDP and iv STS presented here is applicable to regionally confined human bladder cancer.

Animals↗
PubMed1984

[Pharmacokinetics of cisplatin and the effect of sodium thiosulfate].

The pharmacokinetics of cisplatin (cis-dichlorodiammineplatinum (II), CDDP) have been studied in 11 patients. Plasma and urine CDDP concentrations were determined by flameless atomic absorption spectrophotometry. The treatment schedule was administered either by a 3-hour and 4-hour i.v. infusion or a 1.5-hour i.a. infusion. In the 3-hour i.v. infusion, the peak level of plasma total CDDP was 4.09 micrograms/ml after the end of infusion and non-protein-bound CDDP was 0.78 microgram/ml. Plasma total CDDP level declined with two peaks, the half-life of the alpha phase being 3.3 hours and that of the beta phase being 5.29 days. The half-life of non-protein-bound CDDP was 1.6 hours. CDDP might have remained for a long time, because CDDP values were obtained 3 weeks after infusion and urinary recovery of CDDP showed low values. Its urinary recovery was 40.3% of the dose infusion in the first 24 hours and 48.0% in 96 hours. The protein-binding of CDDP was inhibited by sodium thiosulfate(STS) and renal urinary excretion was enhanced. Our data suggest that STS can be applied as a neutralizer of CDDP.

Cisplatin↗
PubMed1984

"Two-route chemotherapy" using high-dose ip cisplatin and iv sodium thiosulfate, its antidote, for peritoneally disseminated cancer in mice.

We studied the effects of "two-route chemotherapy (TRC)" using cisplatin given ip and its antidote, sodium thiosulfate (STS), given iv on mice bearing peritoneally disseminated cancer. Initially, a pharmacokinetic analysis of cisplatin given ip and STS given iv or sc was made. The plasma concentrations of non-protein-bound and total platinum increased rapidly to a maximum at 10 mins after ip administration of cisplatin alone. When STS alone was given sc, the peak level in the plasma was much lower than that given iv. The superiority of the iv route for STS administration was observed in the lethal toxicity tests. The iv administration of STS to mice 1 min after cisplatin given ip was the best protocol to protect against the lethal toxicity of cisplatin. The protective conditions were applied to TRC in which STS was given iv 1 min after ip cisplatin to mice bearing peritoneally disseminated cancer. Significantly superior antitumor effects were observed in mice given TRC by evaluating survival time as compared with mice given a single treatment with cisplatin at an equitoxic level. The nephrotoxic and hematotoxic effects were slight in TRC.

Animals↗