Microsomal cytochrome P450 dependent oxidation of N-hydroxyguanidines, amidoximes, and ketoximes: mechanism of the oxidative cleavage of their C=N(OH) bond with formation of nitrogen oxides.

Oxidation by rat liver microsomes of 13 compounds involving a C=N(OH) function (including N-hydroxyguanidines, amidoximes, ketoximes, and aldoximes) was found to occur with the release of nitrogen oxides such as NO, NO2-, and NO3-. The greatest activities were observed with liver microsomes from dexamethasone-treated rats (up to 8 nmol of NO2- nmol of P450(-)1 min-1). A detailed study of the microsomal oxidation of some of these compounds was performed. Oxidation of N-(4-chlorophenyl)-N'-hydroxy-guanidine led to the formation of the corresponding urea and cyanamide in addition to NO, NO2-, and NO3-. Formation of all these products was dependent on NADPH, O2, and cytochromes P450. Oxidation of two arylamidoximes was found to occur with formation of the corresponding amides and nitriles in addition to nitrogen oxides. Oxidation of 4-(chlorophenyl)methyl ketone oxime gave the corresponding ketone and nitroalkane as well as NO, NO2-, and NO3-. These reactions were also dependent on cytochromes P450 and required NADPH and O2. Mechanistic experiments showed that microsomal oxidations of amidoximes to the corresponding nitriles and of ketoximes to the corresponding nitroalkanes are not inhibited by superoxide dismutase (SOD) and are performed by a cytochrome P450 active species, presumably the high-valent P450-iron-oxo complex. On the contrary, microsomal oxidation of N-hydroxyguanidines to the corresponding cyanamides was greatly inhibited by SOD and appeared to be mainly due to O2*- derived from the oxidase function of cytochromes P450. Similarly, microsomal oxidations of N-hydroxyguanidines and amidoximes to the corresponding ureas and amides were also found to be mainly performed by O2*-, as shown by the great inhibitory effect of SOD (70-100%) and the ability of the xanthine-xanthine oxidase system to give similar oxidation products. However, it is noteworthy that other species, such as the P450 Fe(II)-O2 complex, are also involved, to a minor extent, in the SOD-insensitive microsomal oxidative cleavages of compounds containing a C=N(OH) bond. Our results suggest a general mechanism for such oxidative cleavages of C=N(OH) bonds with formation of nitrogen oxides by cytochromes P450 and NO-synthases, with the involvement of O2*- and its Fe(III) complex [(FeIII-O2-) or (FeII-O2)] as main active species.

[Contents of a "basic psychosomatic management" curriculum. Results of a 4-year concomitant evaluation]. / Anforderungen an ein Curriculum "Psychosomatische Grundversorgung". Ergebnisse einer vierjährigen Begleitevaluation.

The results of evaluations proceeding the educational seminar "Psychosomatic Primary Care" in South Baden are presented and analyzed. From 1991 to 1995, approximately 450 physicians took part in these courses. From critical feedback and suggestions for improvement obtained from participants following each course, recommendations for future seminars pertaining to content, structure, process, didactic and evaluation are presented.

The prognostic significance of first and second remission after first and second relapse radiotherapy in Hodgkin's disease.

New aspects concerning the prognostic importance of remission following first treatment and second relapse treatment have resulted from a retrospective study of 175 patients who received primary treatment for Hodgkin's disease between 1964 and 1971. By means of renewed radiotherapy 27 out of 66 (=41%) patients were again brought to full remission with 10 of the 66 (=15%) patients reaching partial remission. The prognosis of the second full remission is equal to that of the first full remission, the prospect of cure being retained. The prognosis of relapse patients following renewed radiotherapy is dependent on: 1. the type of the previous remission, whether full or partial, 2. the localization of the recidive, 3. the primary stage and the presence (or absence) of signs of activity B, 4. the histology, and 5. the age of the patient.