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.     

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.

     

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.     

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.     

SYSTEMIC LUPUS ERYTHEMATOSUS: A CASE-CONTROL EPIDEMIOLOGIC STUDY IN JAPAN

Background. Systemic lupus erythematosus (SLE) is designated by the Japanese government as one of the intractable diseases and all patients, who suffer from these diseases, are registered to get financial aid for treatment. Using newly registered SLE patients, a case-control study was conducted to evaluate potential risk factors. Methods. Two-hundred and eighty-two women SLE patients, newly registered to receive financial aid for treatment, and 292 randomly selected health examination participants at public health centers (controls) were surveyed from April 1988 through March 1990. By means of a self-administered questionnaire, data concerning demographic variables, smoking and drinking habits, past medical and reproductive history, and family history were collected. Results. Based on unconditional logistic regression analysis, the risk of SLE was significantly increased for current smokers (age-adjusted odds ratio (OR) = 2.31, 95% confidence interval (CI) (1.34–3.97). Alcohol and milk intake were inversely associated with risk. Family histories of asthma and collagen diseases, including SLE, were associated with significantly elevated risk of SLE (OR = 2.07, 95% ci 1.14–3.77; OR = 5.20, 95% CI 1.08–24.95, respectively). Regarding reproductive function, women with menarche at age 15 or later had significantly higher risk than those, who started menstruating before age 12 (OR = 3.82, 95% CI 1.66–8.81 for menarche at > 15 years and OR = 2.90, 95% a 1.14–7.39 for menarche at 16y). Conclusions. Our study suggests several risk factors, including smoking, family history, and reproductive history that may increase the risk of SLE.     

The Effects of N-Benzoyl-β-alanine,a New Nephroprotective Drug,on the Distribution and Renal Excretion of Enprofylline in Rats

Abstract— The effects of the new nephroprotective drug N-benzoyl-β-alanine (BA) on the disposition and renal excretion of the bronchodilator enprofylline, which is actively secreted in urine, were investigated in rats. Enprofylline was administered intravenously at a dosage of 2·5 mg kg^?1 under three different steady-state plasma BA concentrations (100,200 and 400 μg mL^?1) which were achieved by constant infusion rates. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. The presence of BA (400 μg mL^?1) increased the systemic clearance by 25% and the volume of distribution at steady-state by 90%. A significant increase in the dissociation constant, which is the protein binding parameter of enprofylline was observed in the presence of BA (400 μg mL^?1), indicating that BA competitively inhibits the protein binding of enprofylline. However, BA significantly decreased the systemic clearance and volume of distribution for unbound enprofylline. These results suggest that BA, the organic anion transport inhibitor, inhibits renal excretion of enprofylline with a high affinity for renal tubular secretion, although the unbound concentration of enprofylline increases with administration of BA. We conclude that BA decreases the renal tubular secretion of enprofylline probably by reducing the affinity of the tubular transport system, and that these changes have marked effects on the pharmacokinetic behaviour of enprofylline.     

Interaction of Local Anaesthetics with Histamine H1 Receptors in Guinea-pig Ileum

The interaction of amine local anaesthetics and related compounds with histamine H₁ receptors was investigated in guinea-pig ileal longitudinal muscle. Quinacrine, chloroquine, tetracaine and procaine inhibited [³H]mepyramine binding to solubilized membrane from ileal muscle with pK_i values of 5.27 ± 0.11, 5.66 ± 0.01, 4.28 ± 0.08 and 3.97 ± 0.11, respectively. The pK_B values obtained from the initial parallel shift of the dose-response curves for histamine in the presence of these drugs were 549 ± 0.11, 6.14 ± 0.09, 4.86 ± 0.06 and 4.58 ± 0·06, respectively, in reasonable agreement with the pK_i values. The combined dose-ratio test with both local anaesthetics and antagonist (mepyramine) present showed that tetracaine and procaine were competitive and chloroquine was partially competitive, but that quinacrine was not competitive at histamine H₁ receptors. These local anaesthetics inhibited histamine-induced desensitization in guinea-pig ileum. Receptor occupancy (%) by agonist decreased from 95.2 (without inhibitor) to 73.9, 42.8, 35.9 and 33.9 in the presence of quinacrine, chloroquine, tetracaine or procaine, respectively, under the conditions where each inhibitor drug induced half maximum inhibition of desensitization. The results suggested that most of these local anaesthetics interacted competitively at histamine H₁ receptors and inhibited desensitization through their antagonizing actions, whereas quinacrine interacted allo-sterically and inhibited desensitization through a separate action.     

Pharmacokinetic Characteristics of 5-Fluorouracil and Mitomycin C in Intraperitoneal Chemotherapy

Abstract— Eight patients with malignancies confined to the peritoneal space participated in this study. Five hundred milligrams 5-fluorouracil or 10 mg mitomycin C was diluted in 1 L saline. The mixed solution was injected intraperitoneally through the semi-permanent peritoneal catheter. Blood and peritoneal fluid were collected after injection. 5-Fluorouracil concentrations in the peritoneal fluid were 1000 times those in serum, while mitomycin C concentrations were 100 times those in serum. Areas under the concentration vs time curve (AUC) were calculated by the trapezoidal method with extrapolation to infinity. The ratio of peritoneal fluid AUC to serum AUC was about 1400 for 5-fluorouracil and 80 for mitomycin C. Patterns for the absorption and elimination from systemic circulation were similar for both compounds. Drug concentrations in the peritoneal fluid and serum were analysed according to the compartment model. The half-life in the peritoneal fluid (t½_p) and the rate constant from the peritoneal fluid to the systemic circulation (k_a) were nearly equal for both 5-fluorouracil and mitomycin C (t½_p, 1·0 h for 5-fluorouracil and 1·3 h for mitomycin C; k_a 0·71 h^?1 for 5-fluorouracil and 0·68 h^?1 for mitomycin C), although the apparent volume of distribution (Vd_s/F) and clearance in the peritoneal cavity (CL_p) for mitomycin C (78 Lm^?2 and 1.8 L h^?1 m^?2) were about twice the values for 5-fluorouracil (149 L m^?2 and 0·8 L h^?1 m^?2).