Sodium barbital

Sodium barbital is a slow reversible inactivator of rabbit-muscle creatine kinase.[Pubmed:16609694]

Biochem Cell Biol. 2006 Apr;84(2):142-7.

As a depressant of the central nervous system, the clinical effect of Sodium barbital has been extensively studied. Here we report on Sodium barbital as an inhibitor of rabbit-muscle creatine kinase (CK), which plays a significant role in energy homeostasis in the muscles. Although Sodium barbital gradually inhibits the activity of CK with increased concentration, the inhibition effect can be completely reversed by dilution, indicating that the inactivation process is reversible. Detailed kinetics analysis, according to a previously presented theory, indicates that Sodium barbital functions as a non complexing inhibitor, and its inhibition effect on CK is a slow reversible inactivation. In this study, a kinetic model of the substrate reaction is presented, and the microscopic rate constants for the reaction of Sodium barbital with the free enzyme and the enzyme-substrate complexes are determined. Kinetic analysis reveals that Sodium barbital might compete with both creatine and ATP, but mainly with creatine, to inhibit the activity of CK. The results suggest that CK might be a target for Sodium barbital in vivo.

Comparative hyaline droplet nephropathy in male F344/NCr rats induced by sodium barbital and diethylacetylurea, a breakdown product of sodium barbital.[Pubmed:7516096]

Toxicol Appl Pharmacol. 1994 Jun;126(2):224-32.

Hyaline droplet nephropathy in male rats due to alpha 2u-globulin accumulation in proximal tubules is caused by chemicals from several chemical classes. We have previously shown that the well-known sedative/hypnotic barbiturate, Sodium barbital, and its breakdown product, diethylacetylurea, are renal toxins and renal tumor promoters. To determine comparative induction of hyaline droplets in renal tubules by Sodium barbital and diethylacetylurea, male F344/NCr rats, 6 weeks of age, were given diets containing 0, 170, 341, 500, or 1000 ppm of diethylacetylurea or containing 500, 1000, or 4000 ppm of Sodium barbital for periods of 2 or 10 weeks. Rats were terminated at 2 or 10 weeks and the histology of the kidney was evaluated using light microscopy with hematoxylin and eosin staining and staining by the Heidenhain method. Quantitative analysis showed dose responses for the degree of droplet accumulation in the P2 and P3 segments of the proximal tubules. Diethylacetylurea was more potent. Immunohistochemistry and ultrastructural evaluation revealed the nature of the droplets. Western blotting confirmed the presence of alpha 2u-globulin. Renal tubular necrosis, regeneration, and increased levels of cell proliferation using proliferating cell nuclear antigen immunohistochemistry were also found. Female rats similarly exposed to each chemical did not show tubule droplet accumulations nor renal lesions. We confirm for the first time that these two chemicals can be added to the enlarging list of nephrotoxic chemicals inducing alpha 2u-globulin nephropathy and possessing tumor promoting and renal carcinogenic properties.

Promotion by sodium barbital induces early development but does not increase the multiplicity of hereditary renal tumors in Eker rats.[Pubmed:10910958]

Carcinogenesis. 2000 Aug;21(8):1553-8.

Induced cell proliferation is important in the mode of action of many non-genotoxic renal carcinogens. Since Tsc2 mutant (Eker) rats are genetically predisposed to the development of renal cell tumors, they provide a useful animal model in which to study the action of renal carcinogens. Sodium barbital was used as a model non-genotoxic renal carcinogen to test whether a concentration that increased renal tubular proliferation without severe nephrotoxicity would enhance tumor induction in a hereditary tumor model. First, a subchronic concentration-response study was conducted in wild-type male Long-Evans rats to determine increased cell proliferation without severe nephrotoxicity. Rats were dosed with Sodium barbital in the feed at 0, 50, 250, 500, 1000, 2000 or 4000 p.p.m. for 3 or 8 weeks. Cell proliferation within the cortex and nephrotoxicity were quantitated. Enhanced proliferation with minimal nephrotoxicity occurred at 500 p.p.m. A second study was conducted in male Tsc2 mutant rats given Sodium barbital in the feed at 0, 100 or 500 p.p.m. from 9 weeks of age to either 6 or 12 months of age. An additional group of rats was treated with Sodium barbital for 6 months and then provided control feed until 12 months of age. Rats necropsied at 6 months of age had a concentration-dependent increase in preneoplastic and total renal lesions. Sodium barbital-treated rats necropsied at 12 months of age had numbers of lesions that were not different from controls. Total combined preneoplastic and neoplastic lesions in the 6 month, high dose group was the same as the 12 month control group. These data show that Sodium barbital caused progression to the stage of spontaneous renal lesions in Tsc2 mutant rats but did not increase their overall number. These data suggest that enhanced cell proliferation without significant cytotoxicity exerted a promotional influence in this hereditary model.

Oncological outcomes in rats given nephrocarcinogenic exposure to dietary ochratoxin a, followed by the tumour promoter sodium barbital for life: a pilot study.[Pubmed:22069599]

Toxins (Basel). 2010 Apr;2(4):552-71.

The potent experimental renal carcinogenesis of ochratoxin A (OTA) in male rats makes the dietary contaminant a potential factor in human oncology. We explored whether the tumour promoter sodium barbitate could shorten the otherwise long latency between exposure to toxin and tumourigenesis. Young rats, of a hybrid in which mononuclear leukaemia was rare, were given feed contaminated (5 ppm) with OTA for 36 weeks to initiate renal tumourigenesis. Some individuals were thereafter given sodium barbitate (500 ppm in drinking water) for life. Pathological outcomes were studied at or near the end of natural life. Renal tumours in males given barbitate became evident after latency of one year, but only slightly before those without barbitate. In contrast, female mammary tumourigenesis was advanced by at least 6 months synchronously in all rats given the OTA-barbitate regimen compared to tumourigenesis in controls. Diagnosis of malignant mammary angiosarcoma in a female given the OTA-barbitate regimen is a new finding in the rat. The long latency of OTA-induced renal tumourigenesis was not notably susceptible to accelerated promotion by barbitate, contrasting with an apparently marked effect of barbitate on development of mammary tumours.

Systemic and intracerebroventricular administration of sodium barbital induced a place preference in rats.[Pubmed:14557719]

Behav Pharmacol. 2003 Nov;14(7):517-23.

We have shown previously that 15 mg/kg pentobarbital induces a conditioned place preference (CPP), but it is unsuitable for intracranial administration. Since the long-acting barbiturate, Sodium barbital, is soluble at a neutral pH, we tested whether it would induce a CPP when administered centrally. Furthermore, because barbital has a long duration of action, and because we obtained a significant CPP to systemically administered barbital using 30-minute conditioning trials, we tested whether longer conditioning trials would produce a more robust CPP. Using a three-compartment apparatus and an unbiased procedure, we found that systemic administration of barbital induced a significant CPP at 8 and 24 mg/kg, but not 2.7 or 72 mg/kg (i.p.). When rats were conditioned to 24 mg/kg barbital for conditioning trials of (1/2), 1, 3, or 6 hours, only the 30-min conditioning trial produced a CPP. Finally, 240 and 480 microg intracerebroventricular (ICV) barbital induced a significant CPP, but 60 or 120 microg did not. These findings suggest that: (1) like pentobarbital, barbital has reinforcing properties measured in the CPP test; (2) the CPP is impaired, rather than enhanced, by increasing the duration of drug-context pairing; and (3) the reinforcing effects of barbiturates are centrally mediated.