Apparently increased trough levels of tacrolimus caused by acute infantile diarrhea in two infants with biliary atresia after liver transplantation

Two infants with biliary atresia who exhibited three-fold increased trough levels of tacrolimus and required reduced doses during episodes of acute infantile diarrhea within 5 months of liver transplantation are described. The cause of the increase was not explained simply by hemoconcentration as a result of significant loss of extracellular fluid during these episodes. It does highlight an important issue: that of the continuing need to carefully monitor the trough levels of tacrolimus in such infants.     

Effect of surfactant lavage in a rabbit model of meconium aspiration syndrome

Meconium aspiration syndrome (MAS) is a frequent cause of respiratory distress in neonates. Recent reports have suggested that surfactant dysfunction contributes to the pathophysiology of MAS and surfactant therapy improves oxygenation of infants with MAS. We evaluated the effect of bronchial lavage with surfactant solution in a rabbit model of meconium aspiration. All animals were given 5 mL/kg of a 20% slurry of human meconium into the endotracheal tube and mechanically ventilated. The animals were then divided into saline lavage (n = 5) or surfactant lavage (n = 5). Lavage was performed an hour after meconium instillation. After the lavage the total amount of meconium recovered was measured. Blood gas was monitored during the experiment. The amount of meconium recovered by saline lavage was 14%, and by surfactant lavage was 57%. The surfactant group had a significant improvement in gas exchange, whereas the saline group had no improvement. It was concluded that the lavage with surfactant solution effectively washed out meconium and improved gas exchange in rabbit model of MAS.     

High-performance Liquid Chromatographic Determination of Trazodone and 1-m-Chlorophenylpiperazine with Ultraviolet and Electrochemical Detector

A high-performance liquid chromatographic (HPLC) assay was developed for the determination of trazodone and its metabolite, 1-m-chlorophenylpiperazine (m-CPP), in plasma. The high level of trazodone in plasma was detected by ultraviolet absorbance at 254 nm and the low level of m-CPP in plasma was detected by coulometric electrochemical detection at 840 mV on the series arrangement of two detectors. Pilsicainide as an internal standard for both compounds was monitored by both detectors. Trazodone and m-CPP in plasma were extracted by a rapid and simple procedure based on CN bonded-phase extraction, and C₈ reversed-phase HPLC separation. Determination was possible for trazodone in the concentration range 100–2000 ng mL^?1 and for m-CPP in the concentration range 5–100 ng mL^?1. The recoveries of trazodone and m-CPP added to plasma were 81·0–84·2 and 68·0–73·2%, respectively, with coefficients of variation of less than 7·3 and 8·2%, respectively. The method is applicable to high level monitoring of trazodone and low level monitoring of m-CPP in plasma of healthy volunteers and patients treated with trazodone.     

No effects of large doses of catecholamines on vascular permeability in isolated blood-perfused dog lungs

Neurogenic pulmonary oedema (NPO) is believed to be induced by intense activation of the sympathetic nervous system, characterized by massive secretion of catecholamines into the blood stream. There is a possibility that NPO is partly the result of increased vascular permeability. However, the mechanism for an increase in pulmonary vascular permeability is not known. The present study was designed to test the hypothesis that large doses of catecholamines increase pulmonary microvascular permeability directly. Adrenaline or noradrenaline (100 and 300 pug) was injected as a bolus into isolated dog lungs perfused with heparinized autologous blood at constant pressure. Adrenaline or noradrenaline produced sustained lung weight loss although both catecholamines increased pulmonary capillary pressure, assessed by double occlusion pressure, by 2–5 mmHg above baseline. Vascular permeability, as measured by the capillary filtration coefficient and the isogravimetric capillary pressure, did not change significantly frombaseline at 30 and 60 min after catecholamine. Finally, the final-to-initial wet lung weight ratio of the catecholamine-treated lungs did not differ from that of saline-injected control lungs. Thus, we conclude that circulating catecholamines, even at supra-physiological doses, do not increase vascular permeability in isolated blood-perfused dog lungs.     

The Effect of Cimetidine on Natural Killer Activity of Peripheral Blood Lymphocytes of Patients with Ovarian Carcinoma

The effect of cimetidine on the natural killer (NK) activityof peripheral blood lymphocytes (PBL) of 32 patients with ovariancarcinoma was studied before and after surgery or chemotherapy.There was no significant difference in the NK activity betweennormal healthy women and patients who had been disease-freefor more than a year after initial surgery, while those in patientswith a large residual tumor after surgery were profoundly suppressed.Cimetidine stimulated the NK activity in the disease-free patientsin vivo or in Vitro. In addition, cimetidine augmented the responseto phytohemagglutinin of PBL from the disease-free patients.The NK activity of PBL of patients with a large residual tumorunder chemotherapy consisting of cisplatinum, adriamycin andcyclophosphamide, "CAP," was about half of that before initiationof chemotherapy. The inhibition of the NK activity by chemotherapywas abrogated by in vitro exposure of the PBL to cimetidine.     

The Preclinical Safety Evaluation of Human Monoclonal Antibody against Cytomegalovirus

The human monoclonal antibody against cytomegalovinis (Mab C23)was examined pharmacokinetically and toxicologically as partof the preclinical studies prior to approval for human use.Rats given repeated intravenous administrations of Mab C23 producedno antibodies against Mab C23 and maintained a blood Mab C23level in a dose-dependent manner. However, pregnant rabbitsproduced antibodies against Mab C23. The half-life of Mab C23in plasma was 15.9 days in rats, which was similar to that ofnormal human serum -globulin (NHSG). Neither behavioral effectsnor circulatory disturbance was found in mice, rats, and dogseven after a single intravenous injection of 100 or 200 mg/kg,which corresponds to 50 or 100 times the intended clinical dosage.The repeated doses of 2, 10, or 20 mg/kg of Mab C23 on six occasionswith 1- or 2-week intervals elicited a transient decrease inleukocyte counts in rats given 10 or 20 mg/kg, but no adverseeffects in cynomolgus monkeys. Mab C23 did not cause any reproductiveor developmental toxicity when administered to rats and rabbitsat dose levels of 20 mg/kg or less. However, pregnant animalsshowed lower plasma levels of Mab C23 than non-pregnant animals.The chromosomal aberration test disclosed no clastogenicityin human lymphocytes. An immunostaining for Mab C23 revealedno localizations in several tissues of cynomolgus monkeys givenintravenous doses of Mab C23. The preclinical safety evaluationin animals other than rabbits, which produced no antibodiesagainst Mab C23, showed that the behavior of Mab C23 is pharmacokineticallysimilar to that of NHSG and is as safe as NHSG, which has longbeen used as a biological agent. However, because there wasa difference in blood levels of Mab C23 between pregnant andnonpregnant animals, its clinical administration to pregnantpatients should differ from that to non-pregnant patients.     

Three cases of pyogenic sacro-iliitis,and factors in the relapse of the disease

Pyogenic sacro-iliitis (PS) is a rare disease in childhood. Three cases of PS are reported that were difficult to diagnose. Scintigraphy and magnetic resonance imaging (MRI) were useful for diagnosis. One patient suffered from an episode of relapse. Seventeen other cases of PS were reviewed in the literature to investigate the incidence of abnormal imaging findings and various factors in disease relapse. It was found that the incidence of abnormal findings by scintigraphy was significantly higher than that by computed tomography (P = 0.0057). The duration of intravenous antibiotic administration of the relapse group (14.7 ± 4.7 days) was significantly shorter than that of the non-relapse group (24.3 ± 10.7 days; P = 0.0376). The statistical analysis suggested that intravenous antibiotic administration is necessary at least for 20 days to prevent a relapse of PS.     

Liver transplantation in a case of hypoproteinemia and coagulopathy

A female infant with hypoproteinemia and coagulopathy associated with hypertyrosinemia was successfully treated with living-related liver transplantation (LRLT). On the 12th day of life plasma amino acid analysis revealed a marked elevation of tyrosine, so the patient was fed on a low-tyrosine and low-phenylalanine diet. However, hepatosplenomegaly. hypotonia, alopecia, eczema and psychomotor delay did not improve and recurrent episodes of disseminated intravascular coagulation (DIC) caused her condition to deteriorate. Liver biopsy on the 230th day revealed marked fatty change accompanied by mild to moderate cholestasis. Therefore. LRLT from her father was performed on the 286th day resulting in improvement of all the aforementioned signs and symptoms. Despite a thorough examination, no diagnosis of a known disorder could be established. However, her elder brother had also been born with severe hypoproteinemia and coagulopathy, and died of DIC on the second day of life. Thus, the disorder is designated as a new entity, namely ‘congenital hypoproteinemia and coagulopathy associated with hypertyrosinemia’.     

Infectious mononucleosis in Japan: Comparison with acute viral hepatitis type A

In order to clarify the characteristics of infectious mononucleosis hepatitis (IMH) in Japan, 20 cases with IMH treated at Kamo Hospital during the past 6 years (Group I) were analysed in comparison with cases of acute viral hepatitis, especially type A. The test for heterophil antibody was positive in only two cases. During the same period 209 cases were treated for acute viral hepatitis (type A: 77 cases = Group A; type B: 61 cases; type non-A, non-B: 71 cases). In Group I the common clinical symptoms and signs were headache, sore throat and lymph node swelling; jaundice was not as common as in Group A. GOT and GPT activities increased moderately in the acute stage, but they were significantly lower than those in Group A. LDH, AP, GGT and LAP activities were disproportionately higher to GPT activity in Group I. Liver biopsy in the convalescent stage showed that lipofuscin deposition and sinusoidal mononuclear cell infiltration were more prominent in Group I, while sinusoidal neutrocyte infiltration and focal necrosis at periportal areas were more common in Group A. Differential diagnosis of the two diseases could be made using these clinical features and histological findings. However, immunological differentiation is required for specific diagnosis because some features such as fever, prolonged elevation of thymol turbidity test, atypical lymphocytes in peripheral blod and predilection for young people were observed in both groups. Furthermore, the present study indicated that IMH is no longer rare and most cases do not demonstrate heterophil antibody in Japan.