Time-dependent Effects of Klebsiella pneumoniae Endotoxin on Hepatic Drug-metabolizing Enzyme Activity in Rats

The time-dependent effects of Klebsiella pneumoniae endotoxin on hepatic cytochrome P450-dependent drug-metabolizing capacity (cytochrome P450 and b₅ content, activity of aminopyrine N-demethylase, p-nitroanisole O-demethylase, aniline hydroxylase and benzphetamine N-demethylase) and on the pharmacokinetics of antipyrine have been determined in rats. Measurement of enzyme activity and antipyrine (after intravenous injection of 20 mgkg^?1) were performed 2, 24 and 96 h after a single intraperitoneal injection of endotoxin (1 mgkg^?1) and after repeated doses (once daily for 4 days). The contribution of tumour necrosis factor α (TNFα) to the endotoxin-induced changes was also examined in rats pretreated with granulocyte colony-stimulating factor (G-CSF). The systemic clearance of antipyrine and the activity of hepatic cytochrome P450-dependent drug-metabolizing enzymes were dramatically reduced 24 h after a single injection of endotoxin, but had returned to control levels by 96 h. The magnitudes of these decreases in these measurements after repeated doses of endotoxin were similar to those seen 24 h after the single dose. The systemic clearance of antipyrine correlated significantly with cytochrome P450 content and aminopyrine N-demethylase activity. In histopathological experiments, moderate hypertrophy of Kupffer cells was observed, with no evidence of severe liver-tissue damage. G-CSF pretreatment suppressed the increased plasma concentrations of TNFα produced 2 h after single endotoxin injection, but did not eliminate the endotoxin-induced decrease in the systemic clearance of antipyrine, suggesting that TNFα is not the sole component responsible for the reduction of cytochrome P450-mediated drug-metabolizing enzyme activity. These results provide evidence that a single intraperitoneal injection of 1·0 mgkg^?1 K. pneumoniae endotoxin in rats reduces hepatic P450 and b₅ levels, and reduces the activity of various cytochrome P450-mediated drug-metabolizing enzymes without causing severe liver-tissue damage. This suggests that the effect of endotoxin on hepatic cytochrome P450-mediated drug-metabolizing isozymes is non-selective.     

Altered intrahepatic pathway of para-umbilical vein in portal hypertension

The object of this study was to determine the frequency and characteristics of altered paraumbilical vein in the hepatic parenchyma, developed from portal hypertension, using computed tomography (CT). Two hundred and ninety-two patients who presented with portal hypertension from 1986 to 1996 were studied retrospectively. The pathway of the dilated para-umbilical vein was demonstrated by contrast-enhanced CT. Thirty-one (11%) patients had a dilated para-umbilical vein arising from the left portal vein into the falciform ligament. In 24 (77%) of these patients, the para-umbilical vein followed the expected route, passing through the fissure of ligamentum teres hepatis. The remaining seven patients (23%) displayed the unusual pathway, with the vein arising from the left branch of the portal vein and passing into the hepatic parenchyma. In these seven patients, four had one collateral vein, and three patients had two collateral veins in the liver parenchyma. The dilated para-umbilical vein frequently passes through the hepatic parenchyma in patients with portal hypertension.     

Synergistic Effect by Co‐Administration of Tamsulosin and Solifenacin on Bladder Activity in Rats

Objectives: We examined the effects of alpha1‐adrenoceptor antagonist (tamsulosin hydrochloride) and antimuscarinic agent (solifenacin succinate) alone or in combination on the urinary adenosine triphosphate (ATP) level and cystometric parameters before and after bladder stimulation. Methods: Female rats were administered tamsulosin hydrochloride (0.5 or 3 µg/kg/h) and/or solifenacin succinate (20 or 100 µg/kg/h) via a subcutaneously implanted osmotic minipump. Rats receiving distilled water were used as control. After 2 weeks, continuous cystometry with physiological saline or 0.1% acetic acid solution was performed. Urinary ATP level was also measured before and after stimulation by 0.1% acetic acid solution. Results: During cystometry with bladder stimulation, the interval between voiding became shorter and the maximum voiding pressure (MVP) became higher in the control group. In the high‐dose tamsulosin and solifenacin groups, the inhibition of urinary frequency was observed. The MVP also became higher in the high‐dose tamsulosin group, but such a change was not seen in the high‐dose solifenacin group. In case of low‐dose administration, either agent alone did not inhibit the increase of urinary frequency and MVP due to bladder stimulation. However, co‐administration of these ineffective low doses of tamsulosin and solifenacin resulted in the inhibition of urinary frequency. The high‐dose or low‐dose solifenacin group and the co‐administration group showed similar inhibition of the increase of urinary ATP after bladder stimulation. Conclusion: Tamsulosin may have a different effect on the bladder and/or the neuronal pathways that is unrelated to ATP, so the combination of tamsulosin and solifenacin may synergistically inhibit urinary frequency after bladder stimulation.     

Influence of Age on the Disposition and Renal Handling of Enprofylline in Rats

Abstract— The effects of ageing on the pharmacokinetics, renal handling and protein binding of enprofylline were investigated in 6-, 13- and 18-month-old male Fischer 344 rats. Concentrations of enprofylline in plasma and urine were determined by HPLC, and pharmacokinetic parameters were estimated by model-independent methods. No significant differences in the volume of distribution, systemic clearance of enprofylline or urinary recovery of unchanged enprofylline (> 85%) were observed among any of the groups of rats. The dissociation constant and free fatty acid concentration in plasma increased with age. Age-dependent decreases in the systemic clearance for unbound drug were observed, and the volume of distribution for unbound drug tended to decrease with age. The ratio of systemic clearance for unbound drug to the glomerular filtration rate (GFR) decreased with ageing. Ageing was associated with decreases in the apparent maximum capacity of transport (V_max) (223·33,160·24 and 142·98 μg min^?1 kg^?1 for 6-, 13- and 18-month-old rats, respectively) and in the tubular secretory intrinsic clearance (V_max/K_m) of enprofylline (75·45, 51·03 and 44·13 mL min^?1 kg^?1, respectively), while a slight change in the Michaelis-Menten constant (K_m) was observed. These results indicate that the mechanism responsible for age-related changes in the disposition and renal handling of enprofylline may be responsible for a decrease in the ability of the tubular anion transport system.     

A Preliminary Report on Autologous Bone Marrow Transplantation for the Treatment of Advanced Non-Hodgkin's Lymphoma

Four patients with advanced non-Hodgkin's lymphoma of unfavorablehistology were treated with marrow-lethal doses of cyclophosphamide(CY) and total body irradiation (TB1) followed by the infusionof cryopreserved autologous marrow. All four patients showedengraftment after autologous bone marrow transplantation andachieved complete remission (CR). Three of them, however, developedrelapse in 1.7, 12.9 and 14.5 mo respectively after the transplantation.The other patient has survived in drug-free CR for more than16.6 mo. There was no treatment-related death although therewere some tolerable complications. These data suggest that theCY-TBI regimen may be effective in inducing CR in patients withadvanced non-Hodgkin's disease but it does not contribute topreventing relapse.     

Comparison of Chromosome Constitution in Chronic Myelocytic Leukemia and Other Myeloproliferative Disorders

The frequency of the Ph¹ chromosome in freshly aspirated marrow cells of14 patients with typical chronic myelocytic leukemia processed by a "directtechnic" without resort to culture or colchicine was significantly higher (>75 per cent) than that observed in the cultured blood cells (< 35 per cent)of the same subjects. The karyotypic abnormally of the abbreviated G-groupchromosome would appear not to be related to therapy, since the frequencywith which it occurred was not materially affected by treatment (including radiation). The Ph¹ chromosome was not observed in any of the metaphases ofblood or marrow of 12 subjects who had developed a leukemia-like picturecomplicating either myelofibrosis, polycythemia vera or myeloid metaplasia. Anew chromosome abnormality—a shortened D-group chromosome—was observed with about the same frequency in the blood and marrow metaphases ofa female patient with treated chronic myelocytic leukemia. This new karyotypicabnormality was associated with the highest frequency of the Ph¹ chromosomein cultured blood cells in the group studied. The Ph¹ chromosome was observed in the metaphases of a patient with the blastic phase of chronic myelocytic leukemia. The variations of the morphology of the Ph¹ chromosome arediscussed and illustrated, especially in relation to the Y-chromosome. In fourpatients with an atypical picture of CML, the Ph¹ chromosome was not observed either in the marrow or cultured blood.

Submitted on April 25, 1962 Accepted on June 7, 1962     

Brain Distribution Characteristics of Xanthine Derivatives and Relation to their Locomotor Activity in Mice

The relationship between the brain distribution and motor activity in mice of the xanthines, theophylline, enprofylline, 1-methyl-3-propylxanthine (MPX) and oxpentifylline was investigated. Their plasma protein binding and hydrophobicity were also examined. When these xanthines were administered orally, enprofylline and oxpentifylline had no effect on motor activity. While theophylline increased motor activity over 10 mg kg^?1, MPX caused a decrease in such activity over 10 mg kg^?1. The protein-binding behaviour varied among these xanthines and was closely related to their hydrophobicity, which is represented as a logarithmic partition coefficient (log PC). MPX had the highest hydrophobicity, while oxpentifylline had the lowest. Brain distribution characteristics varied among these xanthines, with the rank order of their brain penetration ratio, calculated as the ratio of brain to unbound plasma concentrations, being theophylline > oxpentifylline > MPX > enprofylline. The inhibition constants (K_i) for adenosine A₁ receptors and cyclic 3′,5′-adenosine monophosphate (cAMP)-phosphodiesterase (PDE) of these xanthines were 44·6 and 134, > 1000 and 112, 26·4 and 49, and > 1000 and 111 μm for theophylline, enprofylline, MPX, and oxpentifylline, respectively. These findings suggest that the lack of effects of enprofylline and oxpentifylline on motor activity is probably due to their low brain penetration ratio or low adenosine A₁ affinity in comparison with theophylline. The decrease in the motor activity by MPX may be, in part, mediated by cAMP or adenosine.     

The possibility of ''de novo'' cancer in the prostate

BACKGROUND: To investigate the possibility of 'de novo' prostate cancer by analyzing the relationship between high grade prostatic intraepithelial neoplasia (HGPIN) and latent prostate cancer. MATERIALS AND METHODS: Latent prostate cancers found at autopsy were examined and 55 cancer foci with a poorly (Gleason grade 4 and 5) or moderately (Gleason grade 3) differentiated component were selected. The 55 foci were separated into two groups: (i) foci with either a poorly or moderately differentiated component only (single differentiation group, SDG); and (ii) mixed foci with two or more types of differentiation components (mixed differentiation group, MDG). High grade intraepithelial neoplasia was defined as positive if it was observed within 2 mm from the edge of the cancer focus and the relationship between HGPIN and the two groups was investigated. RESULTS: The MDG had 39 cancer foci (71.0%) and there were 16 in the SDG (29.0%). There were 31 foci that were small-volume cancers (<0.2 mL). In the MDG, 13 small-volume cancer foci were HGPIN positive, but in the SDG, none of the small-volume cancers were HGPIN positive. CONCLUSIONS: Small-volume cancer foci without HGPIN in the SDG may be candidates for de novo prostate cancers.