Potential toxic effects of superselective injection of amobarbital sodium on microvasculature: a study in an animal model.

PURPOSE: To determine whether microvascular damage occurs from superselective intraarterial injection of amobarbital sodium using the swine endovascular embolization model. METHODS: Thirty-four swine underwent percutaneous femoral puncture for superselective catheterization of the proximal artery of the rete. Varying concentrations of amobarbital sodium were prepared (12.5 to 100 mg/mL solution) in either normal saline or sterile water (105 mOsm/L to 1138 mOsm/L) of which one concentration was infused slowly into one ipsilateral rete. Control infusions were also performed. Histopathologic changes were evaluated at 30 minutes and 10 days after infusion, using standard light and electron microscopy techniques. RESULTS: Moderate vasospasm occurred only in three swine at 100 mg/mL amobarbital sodium in normal saline. Light microscopy showed no significant histologic changes in the retia at any of the tested concentrations of amobarbital sodium. Electron microscopy showed ultrastructural alterations in the intima only at the higher amobarbital sodium concentrations. CONCLUSIONS: Concerns for inducing significant damage to cerebral microvasculature by superselective injection of amobarbital sodium at the usually recommended concentrations and doses are probably not justified.

Identification of 5-ethyl-5-(2-methylbutyl)barbituric acid as an impurity of manufacture in amobarbital.

Amobarbital [5-ethyl-5-(3-methylbutyl)barbituric acid], USP, was found to contain an impurity that was not associated with hydrolysis and decomposition of the barbiturate ring. The impurity was isolated by semipreparative HPLC and was identified as 5-ethyl-5-(2-methylbutyl)barbituric acid (1) by MS (electron impact and chemical ionization) and 1H NMR. The substitution pattern on the alkyl side chain was verified by using the achiral NMR shift reagent tris(6,6,7,7,8,8,8-heptafluoro-2,2- dimethyl-3,5-octanedionato)europium(III). Older samples of amobarbital, USP, contained greater than 6% of 1, whereas recent samples of amobarbital, USP, contained less than 1% of 1. Because the pharmacological profiles of 1 and amobarbital in rodents are comparable, the impurity probably does not constitute a clinically significant problem for humans.

Promotion by sodium barbital of renal cortical and transitional cell tumors, but not intestinal tumors, in F344 rats given methyl(acetoxymethyl)nitrosamine, and lack of effect of phenobarbital, amobarbital, or barbituric acid on development of either renal or intestinal tumors.

Comparative effects of four barbiturates, phenobarbital (PB), amobarbital (AB), sodium barbital (NaBB), and barbituric acid (BA) on the development of neoplasms in the intestinal tract and other organs were investigated in rats following initiation with methyl(acetoxymethyl)nitrosamine (DMN-OAc). Four-week-old F344/NCr male rats were given a single i.p. injection of 0.05 nmol DMN.OAc in 5 ml sterile phosphate buffered saline/kg body weight. Two weeks after DMN.OAc treatment, the animals were provided with either tap water or drinking water containing 500 p.p.m. of PB, NaBB, AB, or BA for the remaining experimental period. Control groups received a single i.p. injection of 5 ml of sterile phosphate buffer/kg body weight and 2 weeks later were given either tap water or drinking water containing 500 p.p.m. of one of the barbiturates listed above. Rats were killed at 52 weeks or 80 weeks after DMN.OAc injection. DMN.OAc induced multiple intestinal tumors that occurred mostly in the mucosa of the small intestine, especially the terminal ileum. None of the barbiturates had any effect on either incidence or multiplicity of intestinal tumors. PB significantly enhanced the development of hepatocellular tumors as well as thyroid follicular cell neoplasms in DMN.OAc initiated rats, while the subsequent administration of NaBB, but not other barbiturates, resulted in the development of renal cortical and pelvic transitional cell tumors. This is the first demonstration of promotion of carcinogenesis in renal pelvic transitional epithelium, a cell type not previously recognized as vulnerable to initiation by DMN.OAc given i.p. NaBB without prior administration of DMN.OAc induced severe nephropathy and focal hyperplasia of both renal cortical tubular and pelvic transitional cell epithelium. No such effects were observed with either PB, AB, or BA. Our results failed to confirm the earlier findings of others that intestinal epithelial carcinogenesis could be promoted by continuous oral administration of NaBB. However, these results strongly support and extend our previous conclusions that some barbiturates have broad organ specificities and promote epithelial carcinogenesis in more than one organ and tissue.

Comparative tumor-promoting activities of phenobarbital, amobarbital, barbital sodium, and barbituric acid on livers and other organs of male F344/NCr rats following initiation with N-nitrosodiethylamine.

Tumor-promoting abilities of four barbiturates, phenobarbital [(PB) CAS: 50-06-6], amobarbital [(AB) CAS: 57-43-2], barbital sodium [(BB) CAS: 144-02-5], and barbituric acid [(BA) CAS: 67-52-7], on the development of neoplasms in livers and other organs of rats following initiation with N-nitrosodiethylamine [(DENA) CAS: 55-18-5] were compared. Four-week-old F344/NCr male rats were given a single ip injection of 75 mg DENA/kg body weight. Beginning 2 weeks later, they were given either tap water (group 1) or drinking water containing 500 ppm of PB (group 2), the sodium salt of BB (group 3), AB (group 4), or BA (group 5) for the remaining experimental period. Control groups (groups 6-10) received an ip injection of saline alone and 2 weeks later were given either tap water or drinking water containing barbiturates as listed above. Animals were sacrificed at either 52 weeks or 78 weeks. None of the barbiturates altered the growth and survival of animals. PB and BB increased liver weights and significantly enhanced the development of hepatocellular foci and hepatocellular adenomas at 52 weeks and hepatocellular foci, hepatocellular adenomas, and trabecular carcinomas at 78 weeks in DENA-treated rats. No such enhancing effects were observed with AB or BA. PB or BB did not significantly enhance the incidence of nonhepatic tumors at 52 weeks. However, at 78 weeks BB significantly enhanced the development of renal tubular adenomas and carcinomas, while PB enhanced the development of thyroid follicular cell neoplasms in DENA-treated rats. These results clearly showed that barbiturates exhibited structure-promoting activity relationships and that their promoting abilities were not restricted to liver alone. Substitution of both hydrogen atoms at the C-5 position of the pyrimidine ring by alkyl or aryl groups appears to be essential but not sufficient for tumor-promoting activity of barbiturates.

[Table for determining minimal toxic dosage]. / Tablichnyi metod opredeleniia minimal'noi toksicheskoi dozy.

The authors suggest a rapid, simple and economical method for the measurement of the minimal toxic dose for the drugs with marked dose-effect dependence. The method is based on the use of the precalculated tables, with minimal consumption of laboratory animals. The data obtained, while providing for statistical significance, make it possible to measure, as the minimal toxic dose, the TD10 rather than the TD16, which raises the method sensitivity.

Sex difference of barbiturate-protection in experimental cerebral ischemia in spontaneously hypertensive rats (SHR).

Survival time following bilateral carotid occlusion was significantly longer in spontaneously hypertensive rats (SHR) anesthetized with barbiturate than in those with ether. Under barbiturate anesthesia, female SHR survived longer (16.6 h) than did males (10.9 h), whereas such sex difference was not found in those with ether anesthesia. The present results indicate sex difference of barbiturate-protection in cerebral ischemia.

Clotting activity in the rat following acute barbiturate treatment.

Adult male rats were subjected to intraperitoneal (i.p.) saline (controls) or barbiturates (20 mg/rat) as a single injection. Seventeen hours later the rats were sacrificed and plasma collected. Hematocrit (HCT), Platelet count (PLT), prothrombin time (PT), partial thromboplastin time (APTT), and coagulant activity for factors II, V, VII, VIII, X and XII, plus fibrinogen were determined. The data indicates that a single injection of phenobarbital and secobarbital had a greater effect on clotting activity than did barbital or amobarbital. This was primarily reflected in the hepatic synthesized clotting factors, plus the platelets.

[Possible biochemical mechanism of the toxic effects of barbiturates]. / Vozmozhnyi biokhimicheskii mekhanizm toksicheskogo deistviia Barbituratov.

Administration of amytal or phenobarbital to rats results in inhibition of liver respiration determined by oxygen uptake in isolated tissue preparations. Increasing doses of phenobarbital cause an increase of inhibition of liver respiration. In vitro addition of vitamin K3 to liver preparations from rat treated by amytal or administration of vitamin K3 after barbiturate-induced intoxication reverses the inhibition of respiration. It is also shown that the lethal effects of amytal are significantly lowered after administration of vitamin K3. It is concluded that the toxic effects of barbiturates are partially due to the inhibition of mitochondrial respiration at the level of NADH-dehydrogenase.

[Comparative evaluation of the antitoxic activity of central nervous system analeptics and their combinations in barbamyl poisoning]. / Sravnitel'naia otsenka antitoksicheskoi aktivnosti analeptikov tsentral' nervnoi systemy i ikh kombinatsii pri otravlenii barbamilom

Tests conducted on rats poisoned with increasingly lethal doses of sodium amytal demonstrated the antitoxic activity of an analeptic mixture to be superior to that of picrotoxin, strichnine, corasol and caffeine entering into its composition and also to the activity of bemegride. As to the degree of antitoxic activity in poisoning of mice with sodium amytal (one LD50) the CNS analeptics are arranged in the following descending oder of their action: analeptic mixture, picrotoxin, bemegride, corasol, strychnine. In poisoning with higher doses of sodium amytal (LD84) corasol, strychnine and caffeine are ineffective, the most productive being analeptic mixture and picrotoxin. Bemegride proves effective only in a single dose of 2.8 LD50 for intact animals.