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.     

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.     

Mortality and cerebral metabolism after bilateral carotid artery ligation in normotensive and spontaneously hypertensive rats.

Mortality and cerebral glycolytic metabolism were studied after bilateral ligation of the common carotid artery in normotensive Wistar rats (NTR), and spontaneously hypertensive rats (SHR) derived from Wistar strain. In the first 24 hours after occlusion of carotid arteries, 72 per cent of 108 SHR died, whereas it was fatal in only 16 per cent of 43 NTR. In SHR, cerebral lactate and cerebral lactate/pyruvate ratio (L/P ratio) increased by 12.4 and 12.1 times the control, respectively at five to six hours after ligation, and remained raised even in rats surviving for two to three days thereafter. Changes in cerebral lactate and L/P ratio were minimal in NTR. Cerebral ATP decreased markedly at five to six hours after ligation in SHR studied. These results indicate that bilateral carotid artery ligation causes severe brain damage in SHR but not in NTR, suggesting hypertension per se to be operative for the development of cerebral ischaemia.     

Treatment of Malignant Tumor in the Head and Neck: --Interdisciplinary Collaboration of Surgery and Radiotherapy--

Although the prime importance in treatment of head and neckcancer is eradication of tumors, due attention should be paidto the conservation of many important structures and functionsin the region. Just to mention a few of these important humanfunctions, there are phonation, digestion and facial expression.Simple surgical procedures specialized by otolaryngologistsare no longer satisfactory. Recently, radiotherapy of head and neck cancer has developedto a superlative degree and chemotherapy to a practical degreealthough much still remains to be satisfied. Our aim was toorganize an interdisciplinary group of specialists in surgery,radiotherapy and regional chemotherapy into a composite attackforce. We aimed at most effective treatment with the least ofside effects. Since 1961, our combined approach to cancer of the head andneck in close collaboration with radiotherapists has yieldedmuch improved results. This has led to an increasing numberof patients with satisfactory rehabilitation.

1. 1. Cancer of the maxilla: Even in the advanced cases combinedsurgery, radiotherapy and regional chemotherapy has led to thepreservation of important structures and functions. Many patientsare now allowed to return to social life and to their previousjobs.
2. 2. Cancer of the nasopharynx: Radiotherapy is the firstchoice.When the effect is less satisfactory, chemotherapy anda window-operationof the palate are performed.
3. 3. Tumorsof the tonsils: The majority of patients suffer fromthe reticulumcell sarcoma. Radiotherapy is the first choice.
4. 4. Cancerof the larynx: A full dose of radiotherapy is thefirst choice.Partial resections are done when indicated.
5. 5. Cancer of thetongue, hypopharynx and esophagus: Radiotherapyis the firstchoice in the majority of cases. Some need plasticsurgery.

     

Efficacy of Prophylactic Endoscopic Variceal Sclerotherapy in Patients with Hepatocellular Carcinoma

Abstract: A setrospective study to determine the influence of prophylactic endoscopic sclerotherapy on the survival rate of patients with hepatocellular carcinoma complicated by esophageal varices was conducted. The subjects included 132 patients without esophageal varices at the time of diagnosis (NV group), 37 patients with hepatocellular carcinoma for whom prophylactic sclerotherapy had been performed for risky esophageal varices (PS group) and 26 patients with hepatocellular carcinoma and risky varices for whom prophylaxis was not performed (NPS group). Multiple regression analysis was used to identify factors affecting the survival rate of the 132 patients without esophageal varices. A tumor embolus in the primary branch or main trunk of the portal vein adversely affected long-term survival in these patients. The patients were further divided into 2 subgroups, namely those with (Vp3) and without (Vp0-Vp2) tumor emboli in the main trunk and primary branch of the portal vein. In the Vp0– Vp2 emboli subgroup, the patients who received prophylactic sclerotherapy and the patients without varices had similar survival rates. Patients without prophylactic sclerotherapy had a significantly shorter survival rate than the group without varices and the prophylactic sclesotherapy group (p<0.01 and p<0.05). A significant bleeding rate was observed in the group without prophylaxis and not in the group with prophylaxis. However, in the Vp3 subgroup, the survival rate in each group was identical. Thus prophylactic variceal sclerotherapy is indicated for patients with hepatocellular carcinoma who do not have tumor emboli in the main trunk or primary branch of portal vein.     

Influence of a Bacterial Lipopolysaccharide on the Pharmacokinetics of Tobramycin in Rats

Abstract— The effects of Klebsiella pneumoniae O3 lipopolysaccharide on the renal handling and distribution characteristics of the aminoglycoside tobramycin were investigated in rats. Tobramycin (2 mg kg^?1) and inulin (100 mg kg^?1) were administered intravenously 2 h after administration of 50,250 or 500 μg kg^?1 lipopolysaccharide. Lipopolysaccharide delayed the disappearance of tobramycin from plasma in a dose-dependent manner. A dose-dependent decrease in systemic clearance of tobramycin was observed, although the elimination rate constant and fraction of urinary recovery of unchanged drug were not significantly different in any group. Lipopolysaccharide significantly decreased the central compartment volume of distribution of tobramycin, but did not influence the steady-state volume of distribution. A dose-related increase in the ratio of the rate constant of transfer to the peripheral compartment to the rate constant of transfer from peripheral compartment to central compartment was observed. The glomerular filtration rate was significantly decreased by pretreatment with 250 μg kg^?1 lipopolysaccharide and the clearance ratio was decreased by 20%, indicating that lipopolysaccharide increases the tubular reabsorption of tobramycin. Our findings suggest that K. pneumoniae O3 lipopolysaccharide modifies the glomerular filtration rate and tubular reabsorption without change in the terminal half-life and that drug distribution characteristics from the rapidly-distributing compartment to the peripheral compartment were altered without expansion of the extracellular fluid volume.     

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.     

Decremental Accessory Pathway Conduction After Ablation and Antidromic Atrioventricular Reciprocating Tachycardia 8 Years After Successful Radiofrequency Ablation

Introduction: This is a rare case of antidromic reciprocating tachycardia developing 8 years after successful catheter ablation.
Result: A 15-year-old girl had recurrence of palpitations 8 years after the ablation of manifest right posteroseptal accessory pathway. Atrial burst pacing revealed Wenckebach atrioventricular conduction with preexcitation. Wide QRS tachycardia with identical morphology to sinus rhythm associated with retrograde His potential recorded immediately after the V-wave was induced by isoproterenol infusion. Atrial premature stimulus applied at the identical timing of His potential advanced the subsequent ventricular beat and His potential.
Conclusion: Catheter ablation may produce decremental accessory pathway conduction and rarely cause antidromic atrioventricular reciprocating tachycardia. This may be explained by a presence of "de novo" accessory pathway with decremental conduction properties that became manifest after the first ablation.     

Influence of Immunotherapy on Antisperm Antibody Titer in Unexplained Recurrent Aborters

PROBLEM: The mechanism of the beneficial effect of immunotherapy for human reproductive wastage remains to be elucidated. Because some women with unexplained recurrent spontaneous abortion are immunized with their partner's lymphocytes, it is important to determine whether such immunization results in elevation or enhancement of immunity to spermatozoa, because antigenic cross-reactivity between lymphocytes and spermatozoa has been reported. METHOD: The present study was initiated to evaluate the changes in antisperm antibody titer and lymphocyte subsets after immunotherapy as compared to before immunotherapy. Antisperm antibody detection was performed by SpermCheck Assay, which is based on a modification of the immunobead test. Maternal lymphocyte subsets were analyzed in two-color flow-cytometric experiments. RESULTS: The percentage of antibody-positive sperm decreased significantly (P = 0.0008) after immunotherapy. The percentage of B(CD19 +) cells (P = 0.0003), cytotoxic T(CD8 + and CD11 b -) cells (P = 0.02) and the Th/Ts ratio (P = 0.005) decreased significantly, while suppressor T(CD8 + and CD 11b +) cells increased significantly (P = 0.0002) after the immunotherapy. This suggests that cell-mediated immunosuppression was induced by immunotherapy. CONCLUSION: The data of the present study suggest that antisperm antibodies have potential for use as a marker for a deficiency in maternal genital tract immunosupressor mechanisms and that immunotherapy could be an effective treatment for women with antisperm antibodies who have unexplained recurrent abortions.     

Bile acids inhibit tumour necrosis factor α-induced interleukin-8 production in human colon epithelial cells

To clarify the regulatory mechanism of the production of various inflammatory mediators by intestinal epithelial cells, the effect of bile acids (tauroursodeoxycholate, TUDC; taurochenodeoxycholate, TCDC; and taurocholate, TC) on the cytokine-induced production of interleukin (IL)-8 in a human colon epithelial cell line (HT-29) was examined. HT-29 cells were incubated for 24 h in a culture medium containing tumour necrosis factor α (TNFα; 1 ng/mL) and/or interleukin (IL)-1 β (1 ng/mL) in the presence or absence of bile acids. The IL-8 concentration in the medium was measured by an enzyme-linked immunosorbent assay. The binding assay of TNFα was performed using [125I]-TNFα (100 pmol/L). Interleukin-8 production during incubation with TNFα was markedly reduced in the presence of 0.5 and 1 mmol/L TUDC, 0.5 and 1 mmol/L TCDC and 0.5 and 1 mmol/L TC, by 56, 85, 86, 91, 37 and 70%, respectively. The IL-8 production during incubation with IL-1ß was not significantly reduced in the presence of these bile acids. The specific binding of TNFα to cells was inhibited 33, 47, and 14% by 1 mmol/L TUDC, TCDC and TC, respectively. These findings suggest that bile acids inhibit TNFα-induced IL-8 production by the colonic cells. The suppression may be partly due to inhibition of TNFα binding to the cells by bile acids.