Nine ether-extractable metabolites of cyclosporine were isolated from urine of dog and man and from rat bile and feces and purified by preparative HPLC and TLC. Structural assignments were mainly based on spectroscopic data (1H NMR, 13C NMR, MS) and the results of the amino acid analysis after hydrolysis with hydrochloric acid. All the identified metabolites retained the intact cyclic oligopeptide structure of the parent drug. Structural modifications originated from enzymatic oxidation at specific sites of the peptide subunits. Transformation processes principally involved hydroxylation at the terminal carbon atom (eta-position) of the C9-amino acid 1 and the gamma-position of the N-methylleucines 4, 6, and 9, as well as N-demethylation of the N-methylleucine 4. Regioisomeric monohydroxylated cyclosporines (metabolites 1, and 17) and N-demethylcyclosporine (metabolite 21) were the primary metabolites resulting from hydroxylation of the C9-amino-acid 1 and the N-methylleucine 9, and from N-demethylation of the N-methylleucine 4. Dihydroxylated derivatives of cyclosporine (metabolites 8, 10, and 16) were generated by further oxidation of metabolite 1 on one of the other N-methylleucines (4 or 6) or on the C9-amino acid 1, or of metabolite 17 on the N-methylleucine 9. More extensive modifications were observed for metabolite 9, a dihydroxy-N-demethylcyclosporine, which could have been formed from the dihydroxy derivative 16 by N-demethylation or from the N-demethylcyclosporine 21 by dihydroxylation. Metabolite 18 differed from 17 (monohydroxycyclosporine) by the presence of a cyclic ether moiety, formally derived by intramolecular addition of the beta-hydroxyl group to the double bond of the C9-amino acid 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

[Fetal and neonatal supraventricular paroxysmal tachycardias].

The authors report 3 cases of fetal supraventricular tachycardia which carried on into neo-natal life. In one case the tachycardia was discovered in the 35th week of amenorrhoea and was able to be followed up to term. In this respect the means of making a definite diagnosis are as follows : a cardiotocogram when one happens to be able to observe the beginning or the end of an attack (in which case a definite "plateau" shape is found) and especially a fetal electrocardiogram obtained transparietally in pregnancy or by means of an internal electrode in labour. Supraventricular tachycardia is usually of marked degree and comes in isolated episodes and is not to be confused with tachycardia that is found accompanying fetal distress, occurring in pathological pregnancies. The obstetrician can therefore delay while carrying out intensive supervision of the case, which is particularly directed to searching for signs of generalised feto-placental oedema. After birth the child should be transferred to an intensive care unit where the tachycardia, if it persists, should be reduced in order to avoid serious asystolies. The outlook for the baby if there is no congenital malformation is good, since the trouble with the cardiac rhythm is usually a reflection of lack of maturity in the cardiac conduction tissues.

Electrocardiography↗