Depression of drug metabolizing activity in the human liver by interferon-α

Summary The depressant effect of interferon- on drug metabolizing activity in the liver has been investigated in 12 patients with chronic active hepatitis B. 7-methoxy-coumarin (7-MC) O-demethylase and 7-ethoxycoumarin (7-EC) O-deethylase, in specimens obtained by liver biopsy, were measured before and after interferon treatment. 7-MC and 7-EC O-dealkylase activity were significantly reduced after interferon treatment, from 13.4 to 9.24 nmol·g^–1 liver·min^–1, and from 3.22 to 2.16 nmol·g^–1 liver·min^–1, respectively. The magnitude of the fall varied widely between individual patients. The study provides the first direct evidence that interferon- can impair the activity of drug metabolizing enzymes in the human liver.     

PTEN loss in intraductal carcinoma of the prostate has low incidence in Japanese patients

Clinical and genomic features of prostate cancer (PCa) vary considerably between Asian and Western populations. PTEN loss is the most frequent abnormality in intraductal carcinoma of the prostate (IDC-P) in Western populations. However, its prevalence and significance in Asian populations have not yet been well studied. In the present study, we evaluated PTEN expression in IDC-P in a Japanese population and its association with ERG expression. This study included 45 and 59 patients with PCa with and without IDC-P, respectively, who underwent radical prostatectomy. PTEN loss was observed in 10 patients with PCa with IDC-P (22%) and nine patients with PCa without IDC-P (17%). ERG expression was relatively frequent in patients with PCa with PTEN loss, although a significant difference was not observed. The co-occurrence of PTEN loss and ERG expression was observed in four patients with PCa with IDC-P and one without IDC-P. PTEN loss and ERG expression did not affect progression-free survival, regardless of the presence of IDC-P. The frequency of PTEN loss in IDC-P is lower in Asian patients than in Western patients. Our results indicate that mechanisms underlying IDC-P in Asian populations are different from those of Western populations.     

Insulin-like growth factor-1 (IGF-1)-induced inhibition of growth hormone secretion is associated with sleep suppression

The hypothalamic growth hormone (GH)-releasing hormone (GHRH) promotes non-rapid eye movement sleep (NREMS). Insulin-like growth factor-1 (IGF-1) acts as a negative feedback in the somatotropic axis inhibiting GHRH and stimulating somatostatin. To determine whether this feedback alters sleep, rats and rabbits were injected intracerebroventricularly (i.c.v.) with IGF-1 (5.0 and 0.25 microgram, respectively) and the sleep-wake activity was studied. Compared to baseline (i.c.v. injection of physiological saline), IGF-1 elicited prompt suppressions in both NREMS and rapid eye movement sleep (REMS) in postinjection hour 1 in rats and rabbits. The intensity of NREMS (characterized by the slow wave activity of the EEG by means of fast-Fourier analysis) was significantly enhanced 7 to 11 h postinjection in rats. Plasma GH concentrations were measured in 30-min samples after i.c.v. IGF-1 injection in rats and a significant suppression of GH secretion was observed 30 min postinjection. The simultaneous inhibition of the somatotropic axis and sleep raises the possibility that the sleep alterations also result from an IGF-1-induced suppression of GHRH. The late increases in NREMS intensity are attributed to metabolic actions of IGF-1 or to a release of GHRH from the IGF-1-induced inhibition.     

Compliance and medication knowledge among elderly Japanese home-care recipients

Objectives: To investigate the risk factors for noncompliance in elderly home-care recipients; and to evaluate to what extent regular home visits and drug counseling by a pharmacist contribute to compliance. Subjects: One hundred and sixty-three elderly home-care recipients aged 62 years and over took part in this study. All subjects were cognitively normal, and taking a regimen of one or more prescribed drugs. Medication use was observed by pharmacist-conducted interviews during home visits. Compliance was estimated by comparing prescribed regimens with medications actually being taken at home. Results: The mean age with (SD) of the subjects was 78.7 (8.3) years. Eighteen per cent were regularly counseled by a pharmacist about medication. Poor compliance with prescribed medications was associated with subjects aged 80 years and over, who were administering their own medication, consuming less than three meals a day, did not have one dose packages, and who were not receiving pharmacist counseling. In multiple logistic regression analyses, frequency of meals (OR 5.99; 95% CI 1.25–28.79), pharmacist counseling (OR 5.32; 95% CI 2.00–14.20), and age (OR 0.96; 95% CI 0.92–1.00) were independent predictors of good compliance for home-care recipients with physical disabilities. Compliance correlated inversely with knowledge of drug names, and drug purposes in the uncounseled group. Compliance, however, positively correlated with knowledge of drug purposes in the counseled group. Conclusion: In this study, compliance among elderly Japanese home-care recipients was found to be associated with receiving pharmacist counseling, frequency of meals, and age. Received: 22 June 1998 / Accepted in revised form: 2 December 1998     

Comparison of effects of xenobiotics on extrahepatic and hepatic microsomal drug-metabolizing enzymes in mice

The content of microsomal protein is the same in both kidneys and small intestine, corresponding to 57% of the control value expressed as 100% in the untreated liver. The contents of P450 and cytochrome b(5), and the activity of NADPH-cytochrome c reductase in the kidney were higher than those in the small intestine, which were 17%, 22% and 41% of controls, respectively, in the former and 5%, 11% and 22% of controls in the latter. As compared with similar measurements made in the liver, the activities of substrate-metabolizing enzymes in these extrahepatic organs were very low. The activities of renal aniline hydroxylase, aminopyrine N-demethylase, 7-ethoxycoumarin O-deethylase, 7-methoxycoumarin O-demethylase and benzo(a)pyrene hydroxylase were 6%, 5%, 3%, 0.6% and 0.2% of controls, respectively. The activities of these enzymes in the small intestine were lower than those in the kidney or below the limits of detection. These results suggested that isoforms or their contents of P450 responsible for these substrate biotransformations are different among liver, kidneys and small intestine. Meantime, this study showed similar significant inductions by phenobarbital and rifampin of small intestinal and hepatic microsomal drug-metabolizing enzymes. In contrast, neither phenobarbital nor rifampin was capable of increasing renal microsomal enzymes, with the exception of benzo(a)pyrene hydroxylase which was induced by rifampin. These findings indicated that both liver and small intestine, but not kidneys contain the same phenobarbital- and rifampin-inducible P450 isoforms, cytochrome b(5) and NADPH-cytochrome c reductase. In addition, CCl(4) could be bioactivated by CYP2E1 to free radicals in the kidney which caused destruction of microsomal enzymes. In mice pretreated with phenobarbital, CCl(4) also attenuated the increase in content of P450 in the small intestine, which appeared to be a result of induction by phenobarbital of CYP2E1.     

A surgical case of growing cavernous angioma at the pontomedullary junction

We described a surgical case of growing cavernous angioma located at the pontomedullary junction. This 52-year-old woman presented with symptoms caused by a small hemorrhage in the right cerebellopontine angle. Magnetic resonance images (MRI) suggested cavernous angioma as the underlying pathology. 9 months after the first episode, the second hemorrhage occurred with a deteriorated neurological state that disappeared under conservative treatment except for right facial paresis and hearing disturbance. During careful observation for 1 year, the size of the lesion gradually increased on MRI and additional neurological deficits including left hemiparesis and right abducent nerve palsy were diagnosed. The first operation was carried out through the right lateral suboccipital approach, but only partial removal of the cavernous angioma was accomplished due to the overlying seventh and lower cranial nerves. After more than 4 months, a third hemorrhagic episode was presented with a sudden onset of right cerebellar signs and facial numbness. The cavernous angioma grew in size to reach the ventrolateral corner of the 4th ventricle with dense hemosiderin deposition around the core lesion on MRI. An enhancement inside the lesion was also demonstrated after gadolinium-diethylenetriaminepenta-acetic acid administration. The second operation through the midline suboccipital approach was selected for the complete resection of the residual cavernous angioma. The lesion was too hard to resect without internal decompression. The pontine part of the lesion was almost totally resected, but manipulation for the medullary part to create a discrete layer between the lesion and surrounding neural tissues was unsuccessful and generated severe bradycardia, so this part of the cavernous angioma had to be left. The problems for the management of cavernous angioma in the brain stem should be discussed, especially focussing on the surgical indication in reference to our experience and previous literatures.     

Measurement of protein C inhibitor in seminal plasma is useful for detecting agenesis of seminal vesicles or the vas deferens

Protein C inhibitor (PCI), a plasma serine protease inhibitor of activated protein C, is present at high concentrations in the seminal plasma of normal subjects and is decreased in some infertile patients. We measured the concentrations of PCI, prostate-specific antigen, and fructose in the seminal plasma of infertile patients (n = 125) and of normal subjects (n = 13). We also measured time-dependent changes in the concentrations of PCI and fructose in seminal plasma after ejaculation. A weak correlation was found between the levels of PCI and fructose (r = 0.268, P = 0.016). The PCI level in seminal plasma of patients with seminal vesicle and/or vasal agenesis was significantly lower (P < .01) than in normal subjects. The level of fructose in seminal plasma decreased in vitro in a time-dependent manner after ejaculation, whereas the concentration of PCI was stable at 48 hours after ejaculation. These data suggest that PCI in seminal plasma, as well as fructose, may become one of the markers for agenesis of seminal vesicles and/or the vas deferens.     

Skp2 protein expression in soft tissue sarcomas.

BACKGROUND: p45 S phase kinase-associated protein-2 (p45(skp2)), a member of the F-box family of proteins, is an important component of the Skp1-Cullin-F-box protein (SCF) ubiquitin-ligase complex (SCF(skp2)). The latter has been implicated in the ubiquitination and degradation of p27(kip1) (p27) and G(1)-S cell cycle progression. The expression and prognostic role of Skp2 in a large series of soft tissue sarcomas has not been previously investigated. METHODS: Clinicopathologic features and immunohistochemical expression of Skp2, p27, and Ki-67 proteins were studied in 182 cases of soft tissue sarcomas (American Joint Committee on Cancer stages II and III). Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. RESULTS: The male to female ratio was 1.2:1, and the median age at the diagnosis was 53 years. The tumors were predominantly located in the lower extremities (n = 163; 90%) and had a median size of 9 cm. High Skp2 expression (> or = 10% of the cells) was identified in 68 tumors (37%), and was correlated with high grade histology (P =.002) and Ki-67 proliferative index (r = 0.44; P <.0001), but not with p27 expression (r = -0.02; P =.80). By univariate analysis, high Skp2 expression was associated with decreased metastasis-free, disease-free, and overall survival. In a multivariate model, high Skp2 expression was an independent predictor for decreased local recurrence-free, disease-free, and overall survival. CONCLUSION: These results indicate that Skp2 expression is associated with cell proliferation and a worse prognosis in soft tissue sarcomas. The lack of an inverse correlation between Skp2 and p27 suggests that additional molecular events associated with either Skp2 expression or p27 proteolysis may be operating in these tumors.     

Inhaled nitric oxide therapy via nasopharyngeal tube in an infant with end-stage pulmonary hypertension

Abstract The delivery of nitric oxide (NO) via a nasopharyngeal tube is an alternative to endotracheal intubation. A male infant with end-stage pulmonary hypertension (PH) due to a severe hypoplastic lung developed a PH crisis on day 145 and received NO inhalation via a nasopharyngeal tube. Clinical improvement was maintained for 7 days with18–22ppm NO inhalation. The patient remained in close physical contact with his parents without the use of sedation. Blood methemoglobin levels remained below 1%. The environmental NO levels were less than 0.06 ppm and NO₂ less than 0.3 ppm throughout the treatment, well within the safety margin. On day 152, the patient succumbed to hypoxemia and heart failure. The use of a nasopharyngeal NO delivery system without sedation, as an alternative to endotracheal intubation with sedation, was a practical method in treating a patient with PH while maintaining a certain quality of life for the patient and the family.