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.     

Clinical Trial with Authentic Recombinant Somatropin in Japan

Recombinant somatropin, produced by recombinant DNA technology, was administered by injection in daily doses of 8 IU to six healthy young volunteers. Daily injection for 4 days did not cause any significant change in the results of physical examination, blood count or urinalysis. Non-esterified fatty acid levels increased significantly from 0.45 ± 0.16 to 1.08 ± 0.12 mEq/litre (mean SEM) at 4 hours after the first injection (p<0.001). Plasma IGF-1 levels increased from 0.80 ± 0.14 units/ml to 1.72 ± 0.50, 3.22 ± 1.02, 3.17 ± 1.20 and 3.63 ± 0.78 units/ml at 24 hours after each daily injection for 4 days (p<0.001). Plasma hGH reached peak levels at 3 hours after intramuscular injection of recombinant somatropin, 4 IU, and this peak value was 57.3 ± 2.8 ng/ml. A total of 21 patients with pituitary dwarfism were also treated with recombinant somatropin for 6 months at a dose of 0.5 IU/kg/week. Their heights increased by 2.2–5.0 cm during the 6 months of treatment, which was calculated to be equivalent to 4.4–10.0 cm/year with a mean growth rate of 7.4 ± 0.4 cm/year. Anti-hGH antibody with a titre of 10 was observed in two patients at the end of 6 months of treatment.     

Urine Growth Hormone Determinations Compared with Other Methods in the Assessment of Growth Hormone Secretion

Okuno, A., Yano, K., Itoh, Y., Hashida, S., Ishikawa, E., Mohri, Z-I. and Murakami, M. (Department of Paediatrics, Asahikawa Medical College, Hokkaido; Medical College of Miyazaki, Kiyotake, Miyazaki; and Research and Development Division, Sumitomo Pharmaceuticals Co Ltd, Hyogo, Japan). Urine growth hormone determinations compared with other methods in the assessment of growth hormone secretion. Acta Paediatr Scand [Suppl] 337:74, 1987.
Urinary excretion of hGH was studied in children with short stature using a sensitive sandwich enzyme immunoassay technique. Urinary hGH excretion, in terms of hGH: creatinine ratio, showed excellent correlation with the mean and peak hGH values during physiological and pharmacological tests. It seems that the urinary hGH levels reflect serum hGH profiles during the urine collection period. A border zone for the lower limits of normal hGH levels in the urine was 7.5–13.4 ng/g creatinine for the physiological test at night (from 2000 hours to 0600 hours) and 17.4–35.0 ng/g creatinine for the pharmacological tests. Assessment of hGH secretory status by the urinary hGH levels showed good agreement with the serum hGH response. Measurement of urinary hGH could be used as a diagnostic test for impaired hGH secretion, and the multiple blood drawing required in physiological and pharmacological tests might be replaced by urine sampling.     

Zeta potential of human X- and Y-bearing sperm

The zeta potential of human X- and Y-bearing sperm was measured by two different methods: (i) using an electrophoretic light scattering spectrophotometer, and (ii) using a laser-rotating prism. The X- and Y-bearing sperm were separated by free-flow electrophoresis, and their purities were determined by staining for the F-body using quinacrine mustard. The zeta potential of the sperm in the fraction containing more than 80% Y-bearing sperm was approximately -16 mV, whereas that of sperm in the fraction containing more than 95% X-bearing sperm was approximately -20 mV. In other words, the net negative-charge on the cell surface of human X-bearing sperm is higher than that of Y-bearing sperm.     

Retroperitoneal haematoma due to ruptured microaneurysm of the pancreaticoduodenal artery

A case of retroperitoneal haematoma due to a ruptured microaneurysm of the posterior superior pancreaticoduodenal artery in a 61 year old man is described. Ultrasonography and computed tomography revealed cystic masses near the gall-bladder. Selective coeliac angiography disclosed a microaneurysm of the posterior superior pancreaticoduodenal artery. Surgical extirpation of the cystic masses was performed, and the histological finding was an encapsulated old haematoma.     

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.