The effect of the antimycotic itraconazole on the pharmacokinetics and pharmacodynamics of diazepam

Summary— The azole antimycotic itraconazole is a potent and relatively unspecific inhibitor of cytochrome P450 enzymes and has a potentially dangerous interaction with midazolam and triazolam. The possible interaction between itraconazole and diazepam was investigated in a double-blind, randomized, cross-over study. Ten healthy volunteers were given orally placebo or itraconazole 200 mg a day for 4 days. The challenge dose of 5 mg of diazepam was ingested on the fourth day, after which plasma samples were collected and psychomotor performance tests were carried out for 42 h. Despite a statistically significant small increase in the area under the plasma diazepam concentration-time curve and the elimination half-life of diazepam, there was no clinically significant interaction as determined by the psychomotor performance tests. The lack of significant first-pass metabolism and the different metabolic pathways of diazepam explain the smaller interaction potential of diazepam compared with midazolam and triazolam. Diazepam, unlike midazolam and triazolam, can be prescribed in usual doses for patients receiving itraconazole and probably other inhibitors of P4503A4, at least when diazepam is used as single doses.     

Digital gastrointestinal imaging: the effect of pixel size on detection of subtle mucosal abnormalities

Five radiographs of double-contrast colon examinations demonstrating subtle mucosal changes of inflammatory bowel disease and five radiographs of healthy colonic mucosa were selected and digitized to four levels of resolution. Pixel sizes of 0.1 mm, 0.2 mm, 0.4 mm, and 0.8 mm were used. Ten radiologists interpreted the images, which were displayed on laser-printed film. Analysis of variance with repeated measures was performed and receiver operator characteristic curves were determined. The results demonstrate that the sensitivity in detecting subtle mucosal abnormalities improved as the resolution improved, with the best sensitivity at the highest resolution; more experienced readers detected details well even at the poorer levels of resolution; the resolution necessary for successfully evaluating the colonic mucosa was lower than expected; and given low noise levels, the matrix size used in conventional television fluoroscopy would be adequate for mucosal evaluation.     

Familial cytomegalic adrenocortical hypoplasia: an X-linked syndrome of pubertal failure

Five boys with familial cytomegalic adrenocortical hypoplasia have been followed up for an average of 19 years. Despite treatment with replacement corticosteroids, all 5 failed to show a spontaneous onset of puberty and, when assessed at ages 13 to 19 years, all had both sexual infantilism and skeletal immaturity. Hypogonadism was confirmed by low levels of plasma testosterone, and pituitary reserve of gonadotrophin was shown to be inadequate by testing with gonadotrophin-releasing hormone. Two boys, both with adequate testosterone output on human chorionic gonadotrophin stimulation, were given gonadotrophin therapy, whereas the other 3 were treated with parenterally administered testosterone. With treatment, all 5 patients showed advances in pubertal staging. Although the mechanism of the hypogonadotropism remains unclear, the association of hypogonadotrophic hypogonadism with familial cytomegalic adrenocortical hypoplasia appears to be a constant one and may be considered as a treatable inherited syndrome of pubertal failure.     

Primary and secondary histiocytic lymphoma of the brain: CT features

The authors examined 19 patients with diffuse histiocytic lymphoma of the brain, including 8 with primary disease and 11 with secondary disease. Both primary disease and secondary disease involving the brainstem and deep nuclei exhibited the characteristic CT appearance, consisting of a large, solid, homogeneously enhanced mass with varying amounts of edema. However, most secondary lymphomas outside the brainstem and basal ganglia contained large areas of low attenuation consistent with necrosis. Multifocal lesions were seen only in patients with secondary lymphoma. Systemic chemotherapy for extracranial lymphoma had no effect on the CT appearance of intracranial lesions. The authors suggest that these "unusual" CT patterns are actually typical of a distinct subset of histiocytic lymphomas.     

Non-infective colitis in infancy: evidence in favour of minor immunodeficiency in its pathogenesis

Forty two infants below the age of 2 years presenting with chronic non-infective diarrhoea and shown to have histologically proved colitis were investigated over a five year period. Allergic colitis was the most common cause of colitis, accounting for 62% of the cases. Other colitides diagnosed included: non-specific colitis, autoimmune enterocolitis, and ulcerative colitis accounting for 10% each; severe combined immunodeficiency 7%, and Crohn's disease 3%. A positive family history and a personal history of atopy were obtained in 48% and 29% of the cases respectively. Serum immunoglobulin A, IgG2, and IgG4 were very low in over 50% of the entire cohort of infants with colitis; 66% of those with severe combined immunodeficiency, autoimmune enterocolitis, and ulcerative colitis (n = 11) had low CD3 and CD4 T lymphocytes with an accompanying increase in CD8 in two thirds of those with severe combined immunodeficiency. T lymphocytes were normal in those with allergic colitis. Thus infants with proved non-infective colitis as a group show a high prevalence of IgA, IgG2, and IgG4 deficiency. It is likely that this minor deficiency of mucosa associated immunoglobulin production has a role in the pathogenesis of the colitic process.     

The angiogenic switch in hamster buccal pouch keratinocytes is dependent on TGFbeta-1 and is unaffected by ras activation

This study was undertaken to investigate the mechanisms by which Syrian hamster buccal pouch keratinocytes treated in vivo with 7,12- dimethylbenz[a]anthracene (DMBA), switch from an angio-inhibitory to an angiogenic phenotype. Cells were cultured from pouches at various times after exposure to carcinogen and their angiogenic activity assessed. The angio-inhibitory activity present in conditioned media from normal cells was lost as early as 3 weeks after carcinogen treatment, resulting in weak expression of angiogenic activity. By 5 weeks, cells had become strongly angiogenic due to the secretion of high levels of TGFbeta-1, a potent angiogenic factor. Because the switch to high levels of secreted TGFbeta-1 occurred at the same time as the activation of the H-ras oncogene, non-angiogenic cell lines lacking an activated H-ras oncogene were stably transfected with mutant H-ras and their transformed and angiogenic phenotypes were evaluated. Although ras transfection drove two of the three cultured cell lines to anchorage independence and modestly increased their ability to clone in low serum, it had no effect on the angiogenic phenotype or on the level of secreted active TGFbeta-1. These results demonstrate that the angiogenic phenotype in the hamster buccal pouch model of oral carcinogenesis develops in a step-wise fashion with an early decrease in the production of an inhibitor of angiogenesis and a subsequent marked increase in the secretion of the inducer TGFbeta-1. Although the activation of the H-ras oncogene contributed to anchorage independence, it did not affect the expression of the angiogenic phenotype in this model system.      

Plastoquinol at the quinol oxidation site of reduced cytochrome bf mediates signal transduction between light and protein phosphorylation: thylakoid protein kinase deactivation by a single-turnover flash

Redox-controlled phosphorylation of thylakoid membrane proteins represents a unique system for the regulation of light energy utilization in photosynthesis. The molecular mechanisms for this process remain unknown, but current views suggest that the plastoquinone pool directly controls the activation of the kinase. On the basis of enzyme activation by a pH shift in the darkness combined with flash photolysis, EPR, and optical spectroscopy we propose that activation occurs when plastoquinol occupies the quinol-oxidation (Qo) site of the cytochrome bf complex, having its high-potential path components in a reduced state. A linear correlation between kinase activation and accessibility of the Qo site to plastoquinol was established by quantification of the shift in the g(y) EPR signal of the Rieske Fe-S center resulting from displacement of the Qo-site plastoquinol by a quinone analog. Activity persists as long as one plastoquinol per cytochrome bf is still available. Withdrawal of one electron from this plastoquinol after a single-turnover flash exciting photosystem I leads to deactivation of the kinase parallel with a decrease in the g(z) EPR signal of the reduced Rieske Fe-S center. Cytochrome f, plastocyanin, and P(700) are rereduced after the flash, indicating that the plastoquinol at the Qo site is limiting in maintaining the kinase activity. These results give direct evidence for a functional cytochrome bf-kinase interaction, analogous to a signal transduction system where the cytochrome bf is the receptor and the ligand is the plastoquinol at the Qo site.     

In vivo stimulation of polymeric Ig receptor transcytosis by circulating polymeric IgA in rat liver

Binding of human polymeric IgA ligand to its epithelial cell polymeric Ig receptor, pIgR, has been shown to stimulate pIgR apical transcytosis in an in vitro system, based on polarized confluent MDCK cells expressing rabbit pIgR. The present study aimed at testing whether such a stimulation also occurs in vivo. Transcytosis of pIgR was monitored by rat liver output of total secretory component (SC) into bile, measured by radial immunodiffusion as the sum of free SC and pIgA-bound SC. Whereas in the perfused rat liver system addition of pIgA to the perfusate showed no effect, i.v. injection of human and rat pIgA, but not of monomeric IgA nor PBS, in living rats significantly increased total bile SC output for more than 1 h. Furthermore, depletion of the normal pIgA level circulating in the liver before injecting more pIgA was not required to show the stimulation. Our data thus strongly suggest that stimulation of liver pIgR transcytosis by pIgA ligand binding is physiologically relevant, helping to quickly adjust pIgA transport into bile to increase circulating pIgA levels, without need for increased SC/pIgR synthesis.      

Thromboembolic disease associated with ovarian stimulation and assisted conception techniques

Thromboembolic disease, as a complication of ovarian stimulation and assisted conception techniques, is generally considered to be a rare complication of ovarian hyperstimulation syndrome and, by implication, lower limb in origin. Sporadic cases of unusually sited thromboses, both venous and arterial, have been reported. This paper aims to draw attention to the relatively large number of such thromboses reported in the world literature compared with those cited in previous commentaries, and to emphasize how little is known about their pathogenesis. It is believed that this is an issue which requires to be addressed in order to understand the background pathology to such incidents and if possible to identify women at greatest risk from such potentially debilitating or fatal complications, such that appropriate prophylactic measures can be taken.