Intracranial neurenteric cyst with recurrence and extensive craniospinal dissemination.

Neurenteric cyst represents a rare cystic lesion of the central nervous system, and is generally thought to result from failure of separation of neuro-ectodermal and endodermal elements during week 3 of embryogenesis. Although recurrences have been reported, only one case of craniospinal dissemination has previously been reported. We describe a unique intracranial neurenteric cyst with recurrence and dissemination to the spinal cord.

Quantitative analysis of liver fibrosis and stellate cell changes in patients with chronic hepatitis C after interferon therapy.

OBJECTIVE: The proliferation and differentiation of stellate (Ito, or fat-storing) cells into myofibroblast-like cells is responsible for the development of liver fibrosis. Using computer image analysis, we evaluated the changes of alpha smooth muscle actin-positive stellate cells and liver fibrosis after interferon-alpha or -beta (IFN-alpha, beta) therapy in patients with chronic hepatitis C. METHODS: Patients with chronic hepatitis C were treated with IFN-alpha or -beta and were divided into three groups on the basis of clinical criteria; a complete responder group (CR, 18 of 51), a partial responder group (PR, 17 to 51), and a nonresponder group (NR, 16 of 51). Liver fibrosis was assessed from specimens stained with Sirius red and was quantitated by computer image analysis. We also evaluated alpha-smooth muscle actin expression in the liver before and after IFN therapy by a semiquantitative scoring method (the alpha-smooth muscle actin index). RESULTS: Before IFN therapy, a large number of stellate cells expressing a-smooth muscle actin were present in the liver biopsy specimens. There was a significant correlation (r = 0.699, p < 0.05) between the change in the percent area of fibrosis and the alpha-smooth muscle actin index before and after IFN therapy in all groups. The complete responder group also showed a significant reduction of a-smooth muscle actin-expressing cells that was correlated with the reduction of serum ALT (r = 0.686, p < 0.05). CONCLUSION: These results suggest a-smooth muscle actin-expressing cells are responsible for liver fibrosis, and the elimination of factors stimulating matrix synthesis (e.g., hepatitis virus) may decrease liver fibrosis.

Utility of a rectal suppository containing the antiepileptic drug zonisamide.

A suppository of zonisamide (ZNS) was investigated from the viewpoint of pharmaceutical evaluation, pharmacokinetics and pharmacological effect. Two types of ZNS suppositories were prepared. One used Witepsol (H-15:S-55 = 3:1) as a lipophilic base and the other polyethylene glycol (PEG, 4000:1500 = 4:1) as a hydrophilic base. The in vitro release rate of ZNS from the PEG suppository was significantly rapid compared with that of ZNS from Witepsol. Male Wistar rats were administered ZNS (20 mg/kg) using an intravenous, oral or rectal (PEG or Witepsol) route. The absorption of ZNS from the PEG suppository was more rapid than that of ZNS from the Witepsol suppository or from the oral preparation. The peak plasma concentration (Cmax) after a rectal administration of ZNS with Witepsol or PEG suppository was significantly higher than that after the oral administration of ZNS. However, the bioavailability of the three preparations was approximately 100%. Male ICR mice were administered ZNS (80 mg/kg) using the oral or rectal (PEG or Witepsol) route. A positive correlation was observed between the electroshock seizure (ES) threshold and ZNS concentration in plasma or brain. Further, there was no significant difference in the ES threshold or the ZNS concentration in plasma or brain among the three preparations. These results indicate that a ZNS suppository is a very useful preparation from the viewpoint of both pharmacokinetics and pharmacological action.

Cytoprotection by glycine against hypoxia-induced injury in cultured hepatocytes.

The aim of this study was to investigate the mechanism of cytoprotection by glycine against hypoxia-induced hepatocellular injury. Incubation under hypoxic conditions (95% N2 and 5% CO2) for 5 h induced about 50% cell death, but administration of glycine remarkably reduced hepatocellular death without preventing a loss in ATP content. Anaerobic glycolysis generated lactic acid, reducing extracellular pH, but glycine had no effect on changes in extracellular pH. Chloride-channel inhibitors [anthracene-9-carboxylic acid (A9C), furosemide, and strychnine] also significantly reduced hepatocellular death induced by hypoxia. These results suggest that the mechanism of protection by glycine against hypoxic injury is not related to the prevention of ATP depletion or to changes in extracellular pH, but may be due to inhibition of chloride ion influx into the hepatocyte.

Protection by glycine against chemical ischemia produced by cyanide in cultured hepatocytes.

The killing of cultured hepatocytes by cyanide accelerated phospholipid metabolism, with a reduction in cytoplasmic pH, but did not accelerate proteolysis. Alkalinization of the cytoplasm by monensin, a protonsodium exchange ionophore, enhanced the loss of viability and acceleration of phospholipid metabolism caused by cyanide. Thus, acidification of the cytoplasm appears to protect against the toxic effects of cyanide. Glycine reduced the killing of hepatocytes, concomitant with reduced phospholipid metabolism. The protective effect of glycine neither enhanced the reduction in cytoplasmic pH nor prevented the depletion of adenosine triphosphate (ATP) by cyanide. The mechanism of the protection exerted by glycine against chemical ischemia can be attributed neither to changes in cytoplasmic pH nor to the prevention of ATP depletion, but appears to be due to other mechanisms that have yet to be identified.

Promotion of rectal absorption of sodium ampicillin by disodium glycyrrhetinic acid 3 beta-O-monohemiphthalate in rats.

The promotional effect on rectal absorption of sodium ampicillin (ABPC) by the glycyrrhetinic acid derivative disodium glycyrrhetinic acid 3 beta-O-monohemiphthalate (GA MHPh) was studied in rats and compared with those of sodium caprate (CAP) and sodium glycocholate (GLY). Duration of the promotive effect of GA MHPh was also studied. Rectal absorption of ABPC was significantly enhanced by addition of GA MHPh at an optimum concentration of about 1.5%. The plasma maximum concentration of ABPC was 78.71 micrograms/ml 10 min after its rectal administration at 100 mg/kg with 1.5% GA MHPh. The bioavailability of ABPC with and without 1.5% GA MHPh was 82.12% and 3.92%, respectively. Thus, absorption of ABPC in the presence of 1.5% GA MHPh was about 21 times that of ABPC alone. GA MHPh was more effective as an absorption promoter than either CAP or GLY. Its promoting action on the mucosal membrane was apparent immediately, reached a maximum at 5 min and remained for at least 20 min after rectal administration of the solution. It is therefore suggested that GA MHPh is a very useful promoter absorption of the hydrophilic drug ABPC when administered rectally.

Protection against acetaminophen-induced liver injury in vivo by an iron chelator, deferoxamine.

BACKGROUND: Recent data indicate that iron ions play a major role in lipid peroxidation, a hepatotoxic effect of acetaminophen (APAP). METHODS: We investigated whether an iron chelator, deferoxamine (DFO), can protect against APAP-induced liver injury in vivo in rats. RESULTS: DFO diminished the increase in serum alanine aminotransferase (ALAT) in a dose-dependent manner after APAP administration and also reduced mortality. Administration of 750 mg/kg APAP resulted in an increased ALAT (11,666 +/- 4633) after 8 h, and the mortality at 24 h was 88%. Pretreatment with 200 mg/kg DFO for 1 h significantly reduced ALAT (to 3406 +/- 894) and mortality (38%). DFO also attenuated histopathologic changes. Treatment with DFO depressed malondialdehyde formation by APAP without inhibiting glutathione depletion in the liver or reducing covalent binding of [3H]APAP to liver proteins. CONCLUSIONS: These results indicate that the protective effect of DFO against APAP-induced liver injury may be attributable not to changes in APAP metabolism but to the chelation of iron, which can catalyze the generation of active oxygen species, in hepatocytes.

Cholesterol metabolism in ExHC (exogenous hypercholesterolemic) rats.

Exogenous hypercholesterolemic (ExHC) rats, that develop hypercholesterolemia for exogenous cholesterol, are an established strain Isolated from Sprague-Dawley (SD) rats by Imai and Matsumura ((1973) Atherosclerosis, 18, 59-64). The present study was carried out to clarify the cause of hyperresponsivity in ExHC rats to dietary cholesterol. As early as one day after feeding a high cholesterol diet (1%) serum cholesterol level was doubled in ExHC rats, while the level of hepatic cholesterol was two-thirds of SD rats. The elevation of serum cholesterol was mainly attributed to the d less than 1.006 g/ml fractions. Cholesterol feeding increased fecal bile acid excretion in both strains, but to a more greater extent in SD rats. Absorption of dietary cholesterol and synthesis of cholesterol in vivo were similar between the strains. The uptake of beta-very-low-density-lipoproteins (beta-VLDL) in vivo and the primary cultured hepatocytes was lower in ExHC rats, when a high-cholesterol diet was fed. Even without feeding of a high-cholesterol diet, preincubation with cholesterol-rich lipoproteins caused a lower association and degradation of beta-VLDL by the hepatocytes from ExHC rats. Incubation of hepatocytes with cholesterol-rich lipoproteins did not affect the secretion of [14C]cholesterol into the density less than 1.006 g/ml fraction, but suppressed the secretion into the medium density greater than 1.006 g/ml fractions. These results suggest that ExHC rats, as compared to SD rats, are defective of hepatic uptake and processing cholesterol to bile acids.

Transient control of serum cholesterol homeostasis in adult ExHC (exogenous hypercholesterolemic) rats by dietary cholesterol during weanling period.

Rats hyper-responsive to a diet containing cholesterol plus cholic acid (exogenous hypercholesterolemic (ExHC) rats) were used to assess if cholesterol feeding at weanling period influences later serum cholesterol homeostasis. Diets containing cholesterol plus cholic acid (atherogenic diet) in early life, when compared to non-atherogenic diet, caused a transient suppression of serum cholesterol elevation in very-low- and low-density lipoprotein fractions during refeeding of the atherogenic diet in later life. Such an effect was not observed when ExHC rats were early given a diet supplemented with cholesterol or cholic acid alone, nor when ordinary Sprague-Dawley rats were given atherogenic diet. Early atherogenic diet caused an increased secretion of cholesterol as very-low-density lipoprotein from the perfused livers of adult ExHC rats. Neither the activity of hepatic cholesterol-7 alpha-hydroxylase of fecal steroid excretion in later life was influenced by the early dietary manipulation. Therefore, the present results show the deferred effect of early dietary manipulation on later serum cholesterol metabolism in ExHC rats, but the underlying mechanism(s) remains to be determined.