Anatomy of the porta hepatis as a basis for extended hepatoporto-enterostomy for extrahepatic biliary atresia--a new surgical technique.

UNLABELLED: Reports on long-term survival rates after Kasai's HPE reveal that 23% of patients are healthy ten and more years after surgery. Therefore we studied again the anatomy and histology of the porta hepatis and the portal tracts in order to improve this surgical procedure. METHODS: Autopsied livers of 6 children with and 6 without EHBA were investigated with regard to the topographical and histological anatomy of the major intra- and extrahepatic bile ducts. RESULTS: On the basis of anatomical findings we have modified the conventional Kasai's HPE and developed an extended exploration of the porta hepatis. The procedure and surgical technique is described in this paper.

Prognosis of extrahepatic bile-duct atresia after hepatoportoenterostomy.

Clinical and histologic findings from 206 patients operated upon for extrahepatic biliary atresia (EHBA) are analyzed in order to define the prognosis of patients with EHBA. The prospective study took into consideration both initial fibrosis of the liver and the morphology of the porta hepatis (PH) at surgery. Kaplan-Meier survival estimates and statistical calculations demonstrated a relationship between long-term survival and histologic findings in the liver and porta hepatis. The efficacy of HPE is significantly influenced by the morphology of the PH and to a lesser extent by the initial liver fibrosis. Surgery should thus achieve pattern 1 morphology of the PH, but this is problematic because of the close relationship of the vascular and biliary structures in its two lateral zones.

Anatomy of the porta hepatis (PH) as rational basis for the hepatoporto-enterostomy (HPE).

PURPOSE: In a prospective study it was investigated whether and to what degree the morphology of the porta hepatis has a bearing on the early prognosis of children with EHBA. The results will point to consequences of surgery and to the formulation of a rational understanding of the successes and failures of HPE. METHODS: The macroscopy and the microscopy of the liver was studied on native specimen and corrosion preparations of deceased adults, children and embryos. The area potentially draining the bile was determined in excised PH specimen of children with EHBA. The histologically and planimetrically measured areas were correlated to clinical follow-up studies. In order to be able to study exclusively the influence of the PH morphology, the conditions of the intrahepatical structural changes (level of fibrosis, metric and morphic changes of biliary ductules in the Glisson's triads) had to be equal. Under these conditions 61 excised PH specimen were evaluated. The level of fibrosis was determined according to the definition of Schweizer/Müller 1984 (9). RESULTS: 1) Biliary ductules of the PH end in three definable zones according to a regular pattern. 2) Biliary ductules of the PH run in a narrow and immediate relation to the vascular structures. 3) Biliary ductules of the PH are often hidden between the vascular structures of the PH and are not always accessible to preparatory exposure for the anastomosis. 4) The quantity of the bile flow is a significant function of the total area of the biliary ductules secured in the excised PH specimen. 5) Incised biliary ductules at the excision edge may be obstructed again in the scarring of the anastomosis, leading to an early interruption of bile flow. 6) The opening-up of the biliary ductules in the central zone alone is not enough to guarantee a permanent bile flow. Only if intact biliary ductules of the two lateral hepatical lobes are secured, can a positive prognosis be made.

Design, synthesis and enzyme inhibitory activities of new trifluoromethyl-containing inhibitors for angiotensin converting enzyme.

A series of trifluoromethyl-containing analogs of captopril as well as analogs and homologs of enalaprilat were synthesized and evaluated for inhibition of angiotensin converting enzyme (ACE). It was found that direct substitution of trifluoromethyl for methyl produced a very potent captopril analog with an IC50 of 3 x 10(-10) M in vitro. Hydrophobicity and conformational effects of trifluoromethyl group are among the reasons accounting for this activity. Structure-activity relationship is studied based on molecular mechanics calculations using a II-SCF-molecular mechanics program (PIMM) as well as SYBYL molecular mechanics program. It was found that simultaneous incorporation of trifluoromethyl and an indoline residue unexpectedly yielded a less potent captopril analog (IC50 = 8 x 10(-8) M). Enalaprilat analogs derived from replacement of the alanine residue with trifluoronorvaline and trifluoronorleucine residues gave moderately potent compounds (IC50 = 2-6 x 10(-8) M). The structure-activity relationship for these fluoroenalaprilat analogs is discussed in comparison with known analogs.

Renin inhibitors containing new P1-P1' dipeptide mimetics with heterocycles in P1'.

A series of renin inhibitors containing new P1-P1' dipeptide mimetics are presented. The P1-P1' mimetics were obtained from (4S,5S)-3-(tert-butoxycarbonyl)-4-(cyclohexylmethyl)-5-[(omega- mesyloxy)alkyl]-2,2-dimethyloxazolidines 5b, 9, and 11b by nucleophilic substitution of the mesylate groups with the sodium salts of mercapto- and hydroxyheterocycles. Removal of the protecting groups and stepwise acylations with amino acid derivatives provided renin inhibitors with a length of a tripeptide. Replacement of P2 histidine by other amino acids maintained or enhanced renin inhibitory potency. By alteration of P3 phenylalanine, compounds with IC50 values in the nanomolar range and stability against chymotrypsin were obtained. Finally, the effect of the C-terminal heterocycle on the renin inhibition was studied. Compound XVII was examined in vivo for its hypotensive effects. In salt-depleted cynomolgus monkeys, XVII inhibited plasma renin activity and lowered blood pressure after oral administration of a dose of 10 mg/kg.

3-Methyl-2H-1-benzopyran potassium channel activators.

By aldol condensation of 4-chromanones with paraformaldehyde, 3-alkylenechromanones 10 were obtained which gave 3-alkylchromenes following reduction and dehydration. Subsequent 3-chloroperbenzoic acid oxidation produced the versatile epoxide intermediates 15, from which 3,4-epoxy-3,4-dihydro-2,2,3-trimethyl-2H-1-benzopyran-6-carbonitrile (15a) was resolved into its enantiomers by entrainment. In addition to the methyl group, the benzyl, alkyloxymethyl, and 2-nitroethyl residues could be introduced in the 3-position. Treatment of 15a with 2-pyridone simultaneously gave N- and O-substituted products 19a and 20. 19a easily gave 4-(1,2-dihydro-2-oxo-1-pyridyl)chromene 21 by treatment with base. The corresponding pyrrolidinone compounds 26 and 27 were obtained by a slightly modified procedure. Reaction with 2,4-dihydroxypyridine or 3,6-pyridazinediol resulted in the exclusive formation of 4-(heterocyclyloxy)chromanols (31 and 32). Treatment of 15a with 3-amino-6-pyridazinol gave 4-(3-amino-1,6-dihydro-6-oxo-1-pyridazinyl)chromanol derivative 34 lacking an NH bridge. This could be established after methylation of the ring-nitrogen atom (----35). Trans-configurated 3-methyl-4-pyridone compound 36 was obtained by addition of methyllithium to chromene 3. Hyperpolarizing and antispasmodic or relaxing effects of the compounds were determined in organ bath studies using pig coronary arteries precontracted with acetylcholine or rabbit main pulmonary arteries precontracted with noradrenaline. In the 3-methyl series the classical pyridone and pyrrolidinone structures (9, 21, 26, 27) were only weakly active or inactive, but the corresponding 4-(heterocyclyloxy) and 4-(heterocyclylamino) derivatives (31, 32, 35) were even more potent than the demethyl analogues. In conformation/activity investigations it was found that the activity of the 4-substituted benzopyran derivatives seems to be dependent on the relative orientation of their ring systems.