Metabolic N-oxygenation of 2,4-diamino-6-substituted pyrimidines

Biological oxidation of 2,4-diamino-6-substituted pyrimidines have been studied using hepatic microsomes from various mammalian species. The nature of the enzyme(s) involved in the oxidation has been elucidated using various enzyme inhibitors and inducing agents. The 3-N-oxides were formed with 6-piperidino-, 6-diethylamino-, 6-methyl-, and 6-chloro-substituted 2,4-diaminopyrimidines: no evidence of 1-N-oxide formation was obtained. With the 6-hydroxy-, 6-amino-, and unsubstituted 2,4-diaminopyrimidines and melamine, no N-oxidative metabolite was detected. The differences in N-oxide formation was discussed in terms of the effect of substituents on tautomerism and electron distribution. The N-oxygenation was mediated via a cytochrome P450 dependent system.     

Adenocarcinoma cervicis uteri. An appraisal of treatment results for a period of 40 years

A retrospective study was done in 316 patients with primary cervical adenocarcinoma treated at the Research Institute for Clinical and Experimental Oncology in Brno over a period of 40 years (1939-1978). The treatment results were compared to those in 2571 patients with epidermoid carcinomas of the uterine cervix treated at the Institute over the same period. The 5-year survival rate was significantly lower in adenocarcinoma patients (in Stage I patients, 77.8% vs. 84.5%, and, in the whole group, 60.8% vs. 70.3%). The assessment of the treatment results of this study has clearly showed that in cervical adenocarcinomas, surgery combined with radiotherapy was much more effective than radical radiotherapy alone (77.4% vs. 64.7%). In contrast to this, in epidermoid carcinomas the treatment results were better after radical radiotherapy (86.5% vs. 81.3%). Thus, in the prognosis of cervical adenocarcinomas the mass of the tumor, the size of the uterus, as well as the grading play a role. That means that primary cervical adenocarcinomas at early stages can be successfully treated by a combination of radical surgery and radiotherapy, while radiotherapy of advanced stages of this tumor is less successful.     

Effects of dexamethasone on central and peripheral ACTH systems in the rat

To investigate the simultaneous effects of dexamethasone on peripheral and central adrenocorticotropic hormone (ACTH) systems, rats were treated with dexamethasone or saline for 4 days. Pituitary, plasma, hypothalamus and cerebrospinal fluid (CSF) were then collected and analyzed for ACTH immunoreactivity. Additionally, hypothalamic tissue extracts were analyzed for corticotropin-releasing hormone (CRH) immunoreactivity. Dexamethasone significantly lowered peripheral levels of ACTH as measured in pituitary and plasma. Hypothalamic ACTH content significantly increased while CSF ACTH significantly decreased with dexamethasone treatment. Hypothalamic CRH concentrations showed a small but statistically insignificant decrease. These results suggest that prolonged exposure to dexamethasone affects central as well as peripheral ACTH activity, corroborate our previous findings in rhesus monkeys of decreased CSF ACTH in response to prolonged dexamethasone treatment, suggest that dexamethasone may inhibit the release of ACTH from hypothalamic neurons into the CSF, and provide evidence that the effect of dexamethasone on pituitary ACTH content is of greater magnitude than its effect on hypothalamic CRH.     

Differential diagnosis of poisoning by North American mushrooms, with particular emphasis on Amanita phalloides-like intoxication

It is possible to determine the management and prognosis of mushroom poisoning from the history and initial symptoms with a high degree of confidence. The most important intoxications are those involving Amanita phalloides or other potentially fatal amatoxin-containing mushrooms, which have a latent period of ten to 12 hours before the patient becomes symptomatic. Because aggressive gastroenteric decontamination can reduce the extent of hepatic damage, it is important to attempt to determine during this asymptomatic period whether amatoxin exposure has occurred. Various laboratory methods that might be useful are reviewed.     

Evidence for dual modulation of pepsinogen secretion using isoproterenol, carbachol, CCK-8, forskolin, 8 bromo-cAMP, and A23187 probes

The cellular mechanisms by which pepsinogen (PNG) secretion is controlled are not understood. The aim of this study was to explore whether modulation of PNG secretion is mediated by cAMP or calcium-calmodulin (C-C). PNG secretion in isolated rabbit gastric fundic glands (IGG) was tested, using agents believed to act via cAMP or C-C. IGG were stimulated for 30 minutes with histamine (H) 10(-5) M, isoproterenol (I) 10(-5) M, carbachol (C) 10(-5) M, cholecystokinin-octapeptide (CCK-8) 10(-7) M, forskolin (F) 10(-5) M, 8 bromo-cAMP (8B) 10(-3) M, and A23187 (A) 10(-6) M. PNG levels were determined by spectrophotometric assay of hemoglobin digestion products. PNG amounts secreted were (mean per cent above basal levels of total IGG PNG units +/- SEM): H, -0.02 +/- 0.30%; I, 3.5 +/- 0.9%; C, 5.1 +/- 2.2%; CCK-8, 5.3 +/- 1.5%; F, 10.6 +/- 3.8%; 8B, 13.8 +/- 4.5%; A, 2.1 +/- 1.1%. All secretagogues except H stimulated PNG release significantly above basal levels (p less than 0.05). A primary histaminergic mechanism for pepsinogen secretion is unlikely. Since two other adenylate cyclase activators, isoproterenol and forskolin and the 3':5'-cyclic adenosine monophosphate analog 8-bromo cAMP stimulated pepsinogen secretion, cAMP-dependence is probable. Since carbachol, CCK-8, and A23187, which are believed to act via calcium-calmodulin, also stimulated pepsinogen secretion, this system, too, presumably plays a substantial role. Thus the data support a dual 3':5'-cyclic adenosine monophosphate/calcium-calmodulin modulation of pepsinogen secretion.     

What can be expected from the sub-trigonal injection of phenol in the treatment of idiopathic instability of the bladder?

Sub-trigonal phenol injection ensures a satisfactory response in about 50% of patients with detrusor instability. When oral anticholinergic treatment is poorly tolerated or ineffective, this minimally invasive technique has been found, in our series of 11 patients, to be a useful adjunct, at least temporarily.