Nitroprusside intoxication: protection of alpha-ketoglutarate and thiosulphate.

Protection against the lethal effects of sodium nitroprusside (SNP) was observed in mice after treatment with alpha-ketoglutarate (AKG), either alone or in combination with sodium thiosulphate (STS). The LD50 of SNP was 12.0 (11.0-13.0) mg/kg in mice. Ip injection of AFG (500 mg/kg twice in 20 min) increased the LD50 1.7-fold in mice. STS (1 g/kg, ip) alone increased the LD50 5.5-fold. Furthermore, combined administration of AKG and STS increased the LD50 6.9-fold. SNP elicited increased cyanide levels in blood of mice in a dose-dependent manner. SNP (10 mg/kg, sc) administration gave rise to blood cyanide levels of 73.2 +/- 3.0 microM, 30 min after treatment. Ip injection of AKG significantly decreased blood cyanide levels by 30% in mice 30 min after treatment with 10 mg SNP/kg. A single injection of STS (1 g/kg) or a combination of AKG and STS reduced in blood cyanide levels by 88 or 98%, respectively, in mice after treatment with 10 mg SNP/kg. In addition, the increase in blood cyanide levels induced by injection of 50 mg SNP/kg was markedly inhibited by a combination of AKG and STS or (to a lesser extent) by STS alone. These results suggest that the combined administration of AKG and STS, by preventing the increase in blood cyanide levels induced by SNP, may afford protection against the toxic effects of SNP.     

Cyanide intoxication: protection with chlorpromazine.

Protection against cyanide intoxication in mice can be enhanced by the administration of chlorpromazine, providing it is given with sodium thiosulfate, or the sodium thiosulfate-sodium nitrite antidotal combination. Protency ratios which were derived from the LD50 values were compared in groups of mice premedicated with chlorpromazine (10 mg/kg) and/or sodium thiosulfate (1 g/kg) and/or sodium nitrite (100 mg/kg). These results indicate that the administration of chlorpromazine alone provides no protection against the lethal effects of cyanide. Chlorpromazine also does not enhance the protective effect of sodium nitrite; however, it strikingly potentiates the effectiveness of sodium thiosulfate either alone or in combination with sodium nitrite.     

Effect of atropine on cyanide-induced acute lethality in mice

The effects of atropine on acute lethality induced by cyanide were investigated in mice. The LD₅₀ value of cyanide (s.c. injection) was 8.4 (7.6–9.3) mg/kg. However, the LD₅₀ value of cyanide (s.c.) was significantly increased by 1.5-fold when atropine (32 mg/kg) was injected s.c. in mice. Furthermore, the combined administration of atropine (32 mg/kg). Ca²⁺ (500 mg/kg) and sodium thiosulfate (1 g/kg) tremendously increased the LD₅₀ value by 5.6-fold in mice although sodium thiosulfate or Ca²⁺ alone increased the LD₅₀ 2.5- or 1.5-fold. On the other hand, although the LD₅₀ value of cyanide (intracerebroventricular injection (i.v.t.)) was 52.0 (47.4–57.0) μ/brain, the LD₅₀ value of cyanide (i.v.t.) was significantly increased by 1.3- or 1.61-fold in mice 10 min after s.c. injection of atropine (32 mg/kg) or Ca²⁺ (500 mg/kg). Furthermore, the combined administration of atropine and Ca²⁺ increased the LD₅₀ value of cyanide by 2.1-fold. These results suggest that atropine inhibits cyanide-induced acute lethality and promotes the antagonistic effect of thiosulfate and Ca²⁺ in mice.     

The efficacy of alpha-ketoglutaric acid in the antagonism of cyanide intoxication

It has been reported that compounds containing carbonyl groups can readily react with cyanide. Pyruvic acid, an alpha-ketocarboxylic acid, has been shown to antagonize the lethal effects of cyanide. It is suggested that its mechanism of action rests in its ability to react with or "bind" cyanide. In this study, alpha-ketoglutaric acid, also an alpha-ketocarboxylic acid, was evaluated for its ability to counteract the lethal effects of cyanide. alpha-Ketoglutaric acid increased the LD50 value of cyanide (6.7 mg/kg) by a factor of five, a value statistically equivalent to that ascertained in mice pretreated with sodium thiosulfate and sodium nitrite. The combination of alpha-ketoglutaric acid and sodium thiosulfate increased the LD50 value of cyanide to 101 mg/kg. Addition of sodium nitrite to the alpha-ketoglutaric acid/sodium thiosulfate regimen increased the LD50 value of cyanide to 119 mg/kg. Unlike sodium nitrite, no induction of methemoglobin formation was observed with alpha-ketoglutaric acid pretreatment. It is apparent from these studies that the administration of alpha-ketoglutaric acid in conjunction with sodium thiosulfate resulted in fewer animal deaths than sodium nitrite and sodium thiosulfate without the dangerous formation of methemoglobin.     

Enzyme therapy in cyanide poisoning: Effect of rhodanese and sulfur compounds

Crystalline bovine liver rhodanese (thiosulfate: cyanide sulfurtransferase, EC 2.8.1.1) was evaluated as an antidote in combination with different sulfur compounds against cyanide poisoning in mice. The prophylactic antidote effect, when the antidote was injected i.v. 1 min prior to i.p. injection of cyanide, was dependent on both the dose of the enzyme and the dose of the sulfur compound. An optimal dose of the enzyme of about 2,000 U/kg (3 mg/kg of pure enzyme) was found. This enzyme dose combined with 2 mmol/kg of sodium thiosulfate raised the LD₅₀ for potassium cyanide 7.6 times. When thiosulfate was replaced with equimolar doses of ethanethiosulfonate and propanethiosulfonate, the corresponding values were 10.3 and 9.3 times, respectively. Maximum antidote effect was obtained when the doses of ethanethiosulfonate and propanethiosulfonate were raised to 4 mmol/kg, increasing the LD₅₀ for cyanide 20.8 and 15.4 times, respectively. On the other hand, when given without rhodanese, ethanethiosulfonate and propanethiosulfonate were no better antidotes than thiosulfate.Rhodanese and a sulfur compound given therapeutically to mice when symptoms of cyanide poisoning had occurred, also had a very good antidote effect. The prophylactic antidote effect of rhodanese plus thiosulfate rapidly decreased with increasing time interval between injection of the antidote and cyanide. Thus, when rhodanese and thiosulfate were given 20 min prior to cyanide, the antidote effect was of the same order as that of thiosulfate alone. The antidote effect of the latter did not decrease significantly within the same time interval.Enzyme activity in plasma decreased rapidly after i.v. injection of rhodanese, and enzyme activity in urine was detected following injection. No appreciable inactivation occurred when the enzyme was incubated with whole blood in vitro, but a strong and rapid inhibition, about 85%, of the enzyme occurred in fresh mouse urine in vitro.     

The in vivo effects of cyanide and its antidotes on rat brain cytochrome oxidase activity.

The in vivo effects of sodium cyanide and its antidotes, sodium nitrite, sodium thiosulfate and 4-dimethylaminophenol (DMAP), as well as the alpha-adrenergic blocking agent phentolamine, on rat brain cytochrome oxidase were studied. The course of inhibition was time-dependent and a peak of 40% was attained between 15 and 20 min after the s.c. injection of 1.3 LD50 (12 mg/kg) of cyanide. Pronounced dose-dependence was observed in the inhibition of the enzyme, at this relatively low, but lethal dose. Further observation was impossible because of rapidly lethal effects of cyanide. In animals artificially ventilated with room air, observation was possible up to 60 min. However, maximum inhibition was also 40%. When antidotes were applied 30 min after 20 mg/kg of cyanide, marked reactivation of cytochrome oxidase activity was observed with all antidotes (particularly with thiosulfate) except for phentolamine which had no effect. Prevention of methemoglobin forming with toluidine blue did not affect the reactivating ability of nitrite or DMAP, thus suggesting more complex protective mechanisms then simple methemoglobin formation. The high efficacy of thiosulfate may be attributed to its rhodanese catalyzed, direct binding to free blood cyanide, leading thus to its dissociation from cytochrome oxidase. The theory that cytochrome oxidase inhibition is a basic mechanism of cyanide toxicity could not be disproved.     

Stereospecific effect of naloxone hydrochloride on cyanide intoxication

Cyanide intoxication in mice can be antagonized by the opiate antagonist, (-)naloxone HCl, alone or in combination with sodium thiosulfate and/or sodium nitrite. Potency ratios, derived from LD50 values, were compared in groups of mice pretreated with sodium nitrite (sc, 100 mg/kg), sodium thiosulfate (ip, 1 g/kg), and (-)naloxone HCl (sc, 10 mg/kg) either alone or in various combinations. These results indicate that naloxone HCl provides a significant protection against the lethal effects of potassium cyanide. The protective effect of sodium thiosulfate, but not sodium nitrite, was enhanced with (-)naloxone HCl. The combined administration of sodium nitrite and sodium thiosulfate was further enhanced with (-)naloxone HCl. This protective effect of naloxone HCl against the lethal effect of cyanide appears to be restricted to the (-)stereoisomer, as the (+)stereoisomer, the inactive opiate antagonist, is also inactive in protecting against the lethal effects of cyanide. The mechanism of antagonism is discussed.     

Effects of various known and potential cyanide antagonists and a glutathione depletor on acute toxicity of cyanide in mice

To compare the protective potencies of a large number of known and potential cyanide antagonists in one stock of mice, groups (N = 10) of male CF-1 Swiss-Webster mice were given a single maximal or near-maximal intraperitoneal injection of each substance. Ethyl maleate, a glutathione (GSH) depletor and potential enhancer of cyanide toxicity, was given to other groups. Thirty min later, the mice were given subcutaneous injections of graded doses of KCN. In untreated control mice, the 24-hr median lethal dose (LD50) of KCN was 11 mg/kg of body weight (potency ratio, PR = 1.0). In comparison, protective effects of traditional antagonists thiosulfate and nitrite produced PR values of 1.48 and 2.95, respectively. Tetrathionate, sulfate, dithionite, methionine, hydroxocobalamin, ascorbate, pyridoxal phosphate, alpha-ketoglutarate, alpha-ketobutyrate, GSH, GSH disulfide (GSSG) and selenite were similar in efficacy to thiosulfate (P less than 0.05; PR values 1.35-1.59). Cysteine, diethyldithiocarbamate (DEDC), and cobaltous chloride were more effective than thiosulfate (PR values 1.68, 1.69, and 1.85, respectively). Phentolamine and dicobalt EDTA were ineffective, whereas papaverine enhanced toxicity (PR 0.72). Agents with significant PR values (greater than or equal to 1.14) but which were less effective than thiosulfate included sulfite, dimercaptosuccinic acid, pyruvate, citrate, alpha-ketovalerate, naloxone, and corn oil. Ethyl maleate in corn oil markedly enhanced KCN lethality (PR 0.57 compared to corn oil alone), and caused prolonged illness in several mice. Vitamin E in corn oil had no effect. Dual mixtures of thiosulfate with other selected substances were also tested.(ABSTRACT TRUNCATED AT 250 WORDS)     

Screening for antagonistic agents to the lethal toxicity of neocarzinostatin. II. Effects of various drugs in inhibiting the toxicity of neocarzinostatin in vivo

In clinical chemotherapy with neocarzinostatin (NCS) against cancers, side effects such as leukopenia, anorexia, vomiting and nausea were mainly observed when parenteral administration was used. To prevent these adverse side effects without changing the anticancer activity of the drug, we attempted to apply the two-route-infusion chemotherapy using NCS and antidotes for the NCS treatment devised by Baba. This report presents the results of our study on effects of some antidotes on the acute toxicity of NCS in mice and also on the antitumor activity of NCS against Sarcoma-180 in mice (ICR-JCL strain) when used with tiopronin. The results are summarized as follows. 1. LD50 values of NCS administered via intravenous route increased 2.3- to 3.2-fold when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered subcutaneously together with NCS, 1.3- to 1.4-fold when 50 or 100 mg/kg of sodium thioglycolate was used. When antidotes were given prior to the administration of NCS, 1.8- to 5.4-fold increase in LD50 values of NCS resulted with 300, 500 or 1,000 mg/kg of tiopronin administered 1 hour prior to NCS, 2.3-fold increase resulted with 2,000 mg/kg reduced glutathione, 1.2-fold increase with 100 mg/kg of sodium thioglycolate and 1.9-fold increase with 1,000 mg/kg of L-cysteine monohydrochloride monohydrate. Furthermore, 4.8- to 13.1-fold increase in LD50 of NCS occurred when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered 15 minutes prior to NCS. When these antidotes were administered 1 hour after the administration of NCS, however, no changes in the LD50 value occurred. 2. The LD50 value of NCS given intraperitoneally increased 1.6- to 5.8-fold when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered intravenously at the same time as NCS, 1.4- to 1.6-fold when tiopronin was given 1 hour prior to NCS, intraperitoneally and 1.3- to 1.7-fold when it was given 1 hour after NCS. 3. It was recognized that the acute toxicity of NCS was the most effectively reduced by tiopronin, but only slightly by glutathione, sodium thioglycolate or L-cysteine monohydrochloride monohydrate. The action of tiopronin was the most effective when it was given subcutaneously 15 minutes prior to NCS administered intravenously. 4. The combination chemotherapy on Sarcoma-180 in mice using NCS intraperitoneally and tiopronin intravenously was markedly effective when these agents were given simultaneously.     

苦参总黄酮抗心律失常的实验研究

苦参总黄酮自苦参根提得,约含0.3%。给小鼠尾静脉注射LD₅₀为103.1±7.66 g/kg。按Lawson氏法选择吸入氯仿产生心室纤颤阳性率达80%以上的小鼠(体重25～30 g),进行实验。静注苦参总黄酮后,对小鼠吸入氯仿所致心室纤颤有明显地对抗作用,其ED₅₀为28.9±1.1 g/kg,治疗指数为3.56。在同样条件下,硫酸奎尼丁的治疗指数为2.89。给家兔静注苦参总黄酮8 g和30 g/kg,30～60分钟后,能明显对抗氯仿-肾上腺素引起的心律失常。完全对抗率分别为40%和70%。给大鼠静注乌头碱引起心律失常,静注苦参总黄酮20～40g/kg,有明显地治疗作用。第一次治疗的有效率达63%,第二次治疗的有效率为84%。给麻醉大鼠静脉注射苦参总黄酮30 g/kg和60 g/kg,呈现明显地负性自律性作用,负性频率作用和负性传导作用。这些作用随剂量的增加而增强。它们可能是治疗心律失常的药理基础。     

Success of pyridostigmine, physostigmine, eptastigmine and phosphotriesterase treatments in acute sarin intoxication.

The acute toxicity of organophosphorus (OP) compounds in mammals is due to their irreversible inhibition of acetylcholinesterase (AChE) in the nervous system, which leads to increased synaptic acetylcholine levels. The protective actions of intravenously (i.v.) administered pyridostigmine, physostigmine, eptastigmine, and an organophosphate hydrolase, phosphotriesterase, in acute sarin intoxication were studied in mice. The acute intragastric (i.g.) toxicity (LD50) of sarin with and without the pretreatments was tested by the up-and-down method. The mice received pyridostigmine (0.06 mg/kg body weight), physostigmine (0.09 mg/kg body weight), the physostigmine derivative eptastigmine (0.90 mg/kg body weight) or phosphotriesterase (104 U/g, 10.7 microg/g body weight) 10 min prior to the i.g. administration of sarin. Physostigmine was also administered with phosphotriesterase. Phosphotriesterase was the most effective antidote in sarin intoxication. The LD50 value for sarin increased 3.4-fold in mice receiving phosphotriesterase. Physostigmine was the most effective carbamate in sarin exposure. The protective ratios of physostigmine and pyridostigmine were 1.5- and 1.2-1.3-fold, respectively. Eptastigmine did not give any protection against sarin toxicity. Both the phosphotriesterase and physostigmine treatments protected the brain AChE activities measured 24 h after sarin exposure. In phosphotriesterase and physostigmine-treated mice, a 4- and 2-fold higher sarin dose, respectively, was needed to cause a 50% inhibition of brain AChE activity. Moreover, the combination of phosphotriesterase-physostigmine increased the LD50 value for sarin 4.3-fold. The animals pretreated with phosphotriesterase-ephysostigmine tolerated four times the lethal dose in control animals, furthermore their survival time was 2-3 h in comparison to 20 min in controls. In conclusion, phosphotriesterase and physostigmine were the most effective treatments against sarin intoxication. However, eptastigmine did not provide any protection against sarin toxicity.     

Efficacy of immediate and subsequent therapies against soman-induced seizures and lethality in rats

The purpose of the present study was to examine the efficacy of a triple combination of drugs with adequate anticonvulsant effects and a dual combination with inadequate anticonvulsant effects followed by adjunct therapy. The results showed that combined intramuscular injections of HI-6 (42 mg/kg), atropine (14 mg/kg), and avizafone (3 mg/kg) administered 1, 16, and 31 min. after exposure to a soman dose of 4 x LD(50) completely terminated seizures with a moderate mortality rate (25%). When the soman dose was lowered to 3 x LD(50) the anticonvulsant effect was complete, and no rats died within 24 hr. Rats challenged with 5 x LD(50) of soman all died within 10 min. Without avizafone in the combination, seizures induced by 3 or 4 x LD(50) of soman could not be terminated unless an adjunct therapy consisting of procyclidine (6 mg/kg), diazepam (10 mg/kg), and pentobarbital (30 kg/kg) was given, and the mortality rate was comparatively high (78%). Administration of the adjunct therapy alone 6-16 min. after 4 x LD(50) of soman stopped the seizure activity, but all the rats died within 24 hr. Marked neuropathology was found in the piriform cortex and amygdala, whereas the hippocampal CA1 field was effectively protected when both the triple combination and the dual combination plus adjuncts had stopped seizures 35-55 min. after onset. It is concluded that termination of soman-induced seizures at an early stage (<20 min.) is crucial to avoid neuronal pathology.     

Liver damage does not increase the sensitivity of mice to cyanide given acutely

The major detoxification pathway for cyanide (CN) in many species is a biotransformation to the less toxic thiocyanate (SCN). Hepatic thiosulfate: cyanide sulfurtransferase (rhodanese) is the principal enzyme demonstrating in vitro catalytic activity. Despite the assumed importance of the hepatic enzyme for CN detoxification in vivo, the effects of liver damage (surgical or chemical) on cyanide lethality in animals have not been examined previously. Male CD-1 mice were pretreated with carbon tetrachloride (CCl4, 1 ml/kg, i.p.) 24 h prior to the administration of sodium cyanide (NaCN). In other experiments CCl4 was given in the same doses at both 48 h and 24 h prior to NaCN. Hepatotoxicity was documented by elevated serum glutamicpyruvic transaminase (SGPT) activity, by histologic evaluation of the extent of cellular necrosis, by electron microscopy of the mitochondrial fraction, and by the increased duration of zoxazolamine-induced paralysis. Lethality was not changed by CCl4 pretreatments when NaCN was given alone in doses of 4 or 6 mg/kg or at a dose of 10.7 mg/kg following sodium thiosulfate (Na2S203, 1 g/kg, i.p.). A small but statistically significant protective effect was exhibited by CCl4 when NaCN was given at a dose of 16 mg/kg following the administration of Na2S203. Rhodanese activity as measured in mitochondrial preparations fractionated from the livers of mice pretreated with CCl4 was not different from that in animals given the corn oil vehicle even though electron micrographs showed extensive mitochondrial damage. No difference in CN lethality was evident between sham-operated mice and partially (2/3) hepatectomized mice at 24 h post-surgery. An intact healthy liver does not appear to be essential for cyanide detoxification in mice whether or not thiosulfate is also given. Because rhodanese activity was slightly but significantly higher in mitochondria lysed by Triton X-100 than in intact mitochondria, the mitochondrial membrane may constitute a barrier to Na2S203.     

Protection against soman-induced seizures in rats: relationship among doses of prophylactics, soman, and adjuncts

The combined effects of physostigmine and procyclidine (antagonizing muscarinic, nicotinic, and NMDA receptors) were tested against various doses of soman. Physostigmine (0.1 mg/kg) in combination with procyclidine doses of 1, 3, or 6 mg/kg effectively prevented the development of convulsions and hippocampally monitored seizures when the doses of soman were 1.3, 1.6, or 2 × LD50, respectively. Results from [³H]MK-801-binding experiments showed that procyclidine inhibits the phencyclidine site at the NMDA receptor in a concentration-dependent manner. Physostigmine (0.1 mg/kg) and procyclidine in a dose of 1 mg/kg did not prevent convulsions or seizures when the soman dose was 1.6 × LD50. Subsequent treatment with scopolamine in doses of 0.5 or 1 mg/kg immediately after (3 min) seizure onset showed that only the highest dose produced a reliable termination. When scopolamine (1 mg/kg) was given later (10 min) after onset of seizures, no effect was obtained. The sustained seizures were subsequently treated with diazepam (10 mg/kg) and pentobarbital (30 mg/kg) and finally terminated 25 min after onset. In rats given inadequate prophylaxis, both modified convulsions and seizures were seen. It is suggested that moderate doses of prophylactics should be preferred to avoid adverse effects on cognitive functions because insufficient prophylaxis can be compensated for by adjunct treatment.     

Protection against cyanide-induced convulsions with alpha-ketoglutarate

Protection against convulsions induced by cyanide was observed after treatment with alpha-ketoglutarate, either alone or in combination with sodium thiosulfate, a classical antagonist for cyanide intoxication. However, sodium thiosulfate alone did not protect against cyanide (30 mg/kg)-induced convulsions. gamma-Aminobutyric acid (GABA) levels in brain were decreased by 31% in KCN-treated mice exhibiting convulsions. The combined administration of alpha-ketoglutarate and sodium thiosulfate completely abolished the decrease of GABA levels induced by cyanide. Furthermore, sodium thiosulfate alone also completely abolished the decrease of GABA levels. These results suggest that the depletion of brain GABA levels may not directly contribute to the development of convulsions induced by cyanide. On the other hand, cyanide increased calcium levels by 32% in brain crude mitochondrial fractions in mice with convulsions. The increased calcium levels were completely abolished by the combined administration of alpha-ketoglutarate and sodium thiosulfate, but not affected by sodium thiosulfate alone. These findings support the hypothesis proposed by Johnson et al. (Toxicol. Appl. Pharmacol., 84 (1986) 464) and Robinson et al. (Toxicology, 35 (1985) 59) that calcium may play an important role in mediating cyanide neurotoxicity.     

Antagonism of acute amphetamine intoxication by haloperidol and propranolol

The antidotal effects of a butyrophenone neuroleptic, haloperidol (HAL), and a β-adrenergic blocking agent, propranolol HCl (PRO), against the acute toxicity of d-amphetamine sulfate (AS) were determined. Alteration by such treatments of 2 biochemical changes implicated in the lethal mechanism(s) of AS also were examined. Male Sprague-Dawley rats (130–160 g) were injected ip with 64.8 mg/kg (1.5 × LD50) of AS. At 5 or 15 min after AS, sc injections of either PRO (10 or 20 mg/kg), HAL (0.5 or 1.0 mg/kg), or a combination of PRO (20) and HAL (1.0) were given. Both doses of PRO and of HAL afforded considerable protection against AS lethality compared to saline posttreated controls. However, the combination did not protect as well as did the more effective single agent, HAL. Hypoglycemia at 25 min after AS was prevented only by HAL (0.5 mg/kg) injection at 15 min post-AS. The 4–6-fold elevation of plasma lactate at 25 min after AS was prevented by posttreatment with PRO (20 mg/kg), but not by the HAL doses, which greatly reduced lethality. The data do not indicate that prevention of these biochemical effects of AS was critical to reduction of mortality. It is suggested that HAL and PRO deserve consideration as useful alternative or supplemental antidotes to those presently recommended for human acute intoxications from amphetamine-like drugs.     

Acute, sublethal cyanide poisoning in mice is ameliorated by nitrite alone: complications arising from concomitant administration of nitrite and thiosulfate as an antidotal combination

Sodium nitrite alone is shown to ameliorate sublethal cyanide toxicity in mice when given from ～1 h before until 20 min after the toxic dose as demonstrated by the recovery of righting ability. An optimum dose (12 mg/kg) was determined to significantly relieve cyanide toxicity (5.0 mg/kg) when administered to mice intraperitoneally. Nitrite so administered was shown to rapidly produce NO in the bloodsteam as judged by the dose-dependent appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. It is argued that antagonism of cyanide inhibition of cytochrome c oxidase by NO is the crucial antidotal activity rather than the methemoglobin-forming action of nitrite. Concomitant addition of sodium thiosulfate to nitrite-treated blood resulted in the detection of sulfidomethemoblobin by EPR spectroscopy. Sulfide is a product of thiosulfate hydrolysis and, like cyanide, is known to be a potent inhibitor of cytochrome c oxidase, the effects of the two inhibitors being essentially additive under standard assay conditions rather than dominated by either one. The findings afford a plausible explanation for an observed detrimental effect in mice associated with the use of the standard nitrite-thiosulfate combination therapy at sublethal levels of cyanide intoxication.     

Toxicological studies on cefuroxime sodium.

The intravenous LD50 of cefuroxime sodium for mice was 10.4 g/kg. The maximum dosage administered in other acute toxicity tests was well tolerated by mice (10 g/kg, subcutaneous), by rats (4 g/kg, intravenous, 5 g/kg, subcutaneous) and by cats, dogs and monkeys (2 g/kg, intramuscularly). Cefuroxime sodium was administered subcutaneously (s.c.) or intramuscularly (i.m.) for 3 months to rats (100, 300 or 900 mg/kg/day) followed by a recovery period, and also for 6 months to rats and dogs (50, 150 or 450 mg/kg/day) and for 1 month to monkeys (150 or 450 mg/kg/day). In all these tests there were no serious toxic effects. Minor haematological changes were attributable in part if not entirely to haemorrhage and tissue reaction at the site of injection of large doses. In rats large doses caused some increase in urine volume and electrolyte excretion, and slightly aggravated an age related nephropathy. Administration to rats intravenously (i.v.) for1 month of up to 400 mg/kg/day had no toxic effects. In reproduction studies on mice and rabbits there were no adverse effects on fertility, organogenesis or the rearing of young.     

Effects of dehydroepiandrosterone sulfate on serum steroid hormones in pregnant rabbits (author's transl)

After the administration of dehydroepiandrosterone sulfate (DHAS) (0,10,30,70 mg/kg, i.v.) to rabbits during late pregnancy, serum concentration of DHAS, dehydroepiandrosterone (DHA), testosterone (T), estradiol (E2) and progesterone (Prog) were determined by radioimmunoassay. Serum levels of DHAS increased dose-dependently, and were reduced biphasically to normal levels at 24 hr after the administration. Similarly, the levels of DHA, T and E2 increased, and reached the maximum at 30 min after, though the increase of DHA or T was one-thousandth that of DHAS, and that of E2 was about one-hundred-thousandth. On the other hand, Prog concentration in sera decreased to 50 approximately 60% of that before the injection at 30 min after (p less than 0.05). These results suggest that the changes observed in E2 and Prog levels after the injection of DHAS into pregnant rabbits corresponded to the changes of endogeneous E2 and Prog seen in early parturition in women.     

Cyanide intoxication in sheep; therapeutics

Various cyanide antidotes were evaluated by comparing the effects of delay in time of therapy following oral administration of sodium cyanide in sheep. Successful therapy of lethal doses of sodium cyanide could be accomplished with the more potent antidotes for up to 30 minutes following administration of sodium cyanide. Either 660 mg/kg sodium thiosulfate or 1 mg/kg p-aminopropriophenone were effective antidotes for moderate lethal doses (7.6 mg/kg) of sodium cyanide. The conventional low dosage nitrite/thiosulfate (6.7 mg/kg and 67 mg/kg) was much less effective. Larger doses (15.2 mg/kg) of sodium cyanide were effectively antagonized by either 660 mg/kg sodium thiosulfate alone or in combination with 1.5 mg/kg p-aminopropriophenone or 22 mg/kg sodium nitrite. At high cyanide dosage, p-aminopropriophenone alone was less effective than sodium thiosulfate alone. Sodium thiosulfate at high dosage appears to be the antidote of choice. This more closely satisfies the requirements of high efficacy and low toxicity for an antidote. Sodium nitrate or other antidotes may be used in conjunction with sodium thiosulfate, but their use is not necessary for high efficacy.