Recurrent nonalcoholic steatohepatitis and cirrhosis after liver transplantation.

Nonalcoholic steatohepatitis (NASH) may progress to cirrhosis and lead to liver failure. Histologically, NASH is often indistinguishable from liver disease caused by alcohol use; the cause of NASH remains unknown. A subgroup of patients with NASH eventually develops fibrosis and/or cirrhosis, and in many cases, transplantation is performed for end-stage liver disease attributed to steatohepatitis in patients who do not consume alcohol. The patient described received a transplant for end-stage liver disease secondary to NASH with cirrhosis. Postoperatively she did well, with a bout of mild rejection treated successfully at week 9 with prompt normalization of liver tests. Weight and glycemic control were optimized, and steroid therapy was minimized as safely as possible. Repeat liver biopsy at week 66, however, for persistent mild elevation of alkaline phosphatase and gamma-glutamyl-transferase surprisingly revealed the "recurrence" of NASH. Subsequent biopsy revealed NASH with cirrhosis by week 76 after transplantation. Subsequent biopsy at week 87 has confirmed cirrhosis. The patient does not consume alcohol. It is believed to be the first reporting of such a case.

Relation between gastric cancer and previous peptic ulcer disease.

BACKGROUND: It is presently not well understood to what extent peptic ulcer and gastric cancer represent related diseases. AIMS: The objective of this study was to assess past occurrence of gastric and duodenal ulcers in patients with cancer of the gastric cardia or other parts of the stomach. METHODS: The association between peptic ulcer and gastric cancer was studied among patients followed up at hospitals of the US Department of Veterans Affairs. Two populations of 1069 subjects with cancer of the cardia and 3078 subjects with cancer of other parts of the stomach were compared with a control population of 89082 subjects without gastric cancer. In multivariate logistic regressions, presence or absence of cancer served as the outcome variable, while age, sex, race, previous histories of gastric ulcer, duodenal ulcer, peptic ulcer site unspecified, gastric resection, or vagotomy served as modifier variables. RESULTS: Old age, non-white ethnicity, and male sex proved strong and independent risk factors for non-cardiac gastric cancer. A previous history of gastric, but not duodenal ulcer was associated with a significantly raised odd ratio of 1.53 (95% confidence interval: 1.24 to 1.87). Cancer of the cardia affected predominantly whites, and was relatively more common in men than non-cardiac gastric cancer. Past gastric ulcers exerted no significant influence (1.02, 0.67 to 1.56), while duodenal ulcers and peptic ulcer site unspecified were protective (duodenal ulcer: 0.68, 0.47 to 0.95; peptic ulcer disease: 0.66, 0.47 to 1.00). Partial gastrectomy was a risk factor for non-cardiac gastric cancer (1.86, 1.32 to 2.63), but not for cancer of the cardia (1.09, 0.54 to 2.20). CONCLUSION: These epidemiological patterns might stem from underlying differences in the influences of gastritis and acid secretion on the development of the two cancer types.

A54145, a new lipopeptide antibiotic complex: microbial and chemical modification.

A54145 is a complex of acidic lipopeptide antibiotics produced by Streptomyces fradiae NRRL 18158, NRRL 18159, and NRRL 18160. Each antibiotic factor consists of a peptide core bearing an N-terminal acyl substituent. N-Lys-tert-BOC-protected A54145 complex was deacylated by Actinoplanes utahensis; three protected core peptides were isolated. A54145 antibiotic analogs were synthesized by acylation of the tryptophan N-terminus with 2,4,5-trichlorophenyl active esters, followed by deblocking with trifluoroacetic acid.

Kinetics of the aspartyl transpeptidation of daptomycin, a novel lipopeptide antibiotic.

Two degradation products of the lipopeptide antibiotic, daptomycin, were identified and the reaction pathway and kinetics were delineated in aqueous solution at 60 degrees C, pH range 3 to 8 and ionic strength 0.01. The degradation products were 1) a succinimido intermediate (anhydro-daptomycin) formed by attack of side-chain carbonyl on the peptide-bond nitrogen in the asp-gly sequence and 2) a beta-asp daptomycin isomer formed by rehydration of the anhydrodaptomycin succinimide. This aspartyl transpeptidation pathway was found to be reversible. Formation of the anhydrodaptomycin from either daptomycin or beta-asp daptomycin was pH dependent but the pH-rate profiles for anhydrodaptomycin formation were not mechanistically interpretable. The pH-rate profiles for the formation of daptomycin or beta-asp daptomycin from the anhydrodaptomycin were linear with slopes = 1, which is consistent with nucleophilic hydroxide ion attack of the succinimido intermediate at either the alpha-carbonyl, giving rise to the beta-asp daptomycin, or the beta-carbonyl, giving rise to daptomycin.

Synthesis of new analogs of echinocandin B by enzymatic deacylation and chemical reacylation of the echinocandin B peptide: synthesis of the antifungal agent cilofungin (LY121019).

The antifungal antibiotic, echinocandin B (ECB), was modified by a sequential procedure in which the initial step involved enzymatic removal of the native N-linoleoyl group from the N-terminus using an Actinoplanes utahensis culture. The resulting product, ECB nucleus, was reacylated using active esters or acid halides of various substituted acids to give a series of ECB analogs. These analogs possessed anti-Candida activity both in vitro and in vivo (mice). Other studies have shown that one of these, cilofungin, the 4-n-octyloxybenzoyl-ECB analog (LY121019), has excellent anti-Candida activity, low toxicity and is superior to other available antifungal antibiotics.

Enzymatic and chemical modifications of lipopeptide antibiotic A21978C: the synthesis and evaluation of daptomycin (LY146032).

The novel lipopeptide antibiotic A21978C complex is active against Gram-positive organisms. This complex consists of a common peptide nucleus with various lipid acyl groups at the N-terminus characteristic of each individual factor. The fatty acid acyl group is removed by incubation of the A21978C complex with Actinoplanes utahensis to give the peptide nucleus. This peptide nucleus has the same amino acid sequence as A21978C. New analogs of A21978C were synthesized by acylation of the N-terminus of a tert-butoxycarbonyl (tert-BOC)-protected nucleus and subsequent deprotection. 1H NMR showed that the newly introduced acyl group was at the desired N-terminus. Three major groups of analogs were synthesized bearing fatty acid acyl, amino-aroyl and extended peptide side chains. Each analog was evaluated for antimicrobial activity and acute toxicity. Of these analogs, the n-decanoyl analog of A21978C (LY146032) gave the best survival in the mouse acute toxicity test at a high dose of 1,000 mg/kg, iv and was chosen for further study. This analog has been named daptomycin.

Synthesis, antimicrobial evaluation and structure-activity relationships within 23-modified derivatives of 5-O-mycaminosyltylonolide.

A large series of C-23-modified derivatives of 5-O-mycaminosyltylonolide were synthesized, in which the C-23 hydroxyl group was replaced by halo, aryl ether or thioether, azido, amino or dialkylamino substituents via SN2 displacement reactions. The majority of derivatives possessed excellent in vitro activity against a variety of aerobic and anaerobic bacteria. While some of the compounds treated experimental infections in rodents by parenteral administration, none showed any significant efficacy or bioavailability after oral dosing. Novel rearrangement products were obtained from some of the reactions; these were identified as 13,23-cyclopropyl-12,22-exomethylene and 13,23-cyclopropyl-12-alkoxy derivatives.

Actaplanin, new glycopeptide antibiotics produced by Actinoplanes missouriensis. The isolation and preliminary chemical characterization of actaplanin.

Actaplanin (A4696), a new complex of broad spectrum Gram-positive antibiotics is produced by Actinoplanes missouriensis. High performance liquid chromatography was used to show that this complex is composed of several actaplanins. Hydrolytic experiments with acetaplanins A, B1, B2, B3, C1 and G showed that these actaplanins were composed of the same peptide core, an amino sugar and varying amounts of glucose, mannose and rhamnose. The neutral sugar content was determined for each actaplanin. A bioautographic study of aglycone formation during hydrolysis of the actaplanin complex showed that within a short time a simple mixture of two antimicrobially active hydrolysis products was obtained. These substances retained the antimicrobial spectrum and a high percentage of the antibiotic activity of the parent actaplanin complex. Methanolysis of the acetaplanin complex as well as the individual actaplanins resulted in the selective loss of the neutral sugar moieties and the isolation of actaplanin psi (pseudo)-aglycone--the core peptide which still retained an amino sugar group. The 1H NMR spectrum of this substance indicated a similarity to many features of ristocetin psi-aglycone. Hydrolytic studies showed that the amino sugar present in actaplanin was identical with L-ristosamine. It is concluded that the aglycone of actaplanin is a complex peptide composed of aromatic amino acids, and that the actaplanins each possess this aglycone and L-ristosamine but are differentiated by their neutral sugar composition.

A35512, a complex of new antibacterial antibiotics produced by Streptomyces candidus. II. Chemical studies on A35512B.

The glycopeptide antibiotic A35512B was isolated from Streptomyces candidus NRRL 8156 as the major active factor. Chemical degradation studies showed that mild hydrolysis resulted in the release, one molecule each, of four neutral sugars: rhamnose, fucose, glucose and mannose, as well as the liberation of a complex peptide core which retained all the amino acids and from which 3-amino-2,3,6-trideoxy-3-C-methyl-L-xylo-hexopyranose, a new amino sugar, was isolated (2). Oxidative degradation of A35512B resulted in the isolation of a chlorodiphenylether (5), dimethyl 4-methoxyisophthalate (7) and methyl 3,5-bis-(4-methoxycarbonylphenoxy(-4-methoxybenzoate (6). The structure of 5 could not be conclusively elucidated but was shown to be either 5-chloro-2',3-dimethoxy-2,5'-dicarbomethoxy diphenylether (5a) or 2-chloro-2',3-dimethoxy-5,5'-dicarbomethoxy diphenylether (5b) by physical methods. This halogenated fragment was shown to arise from oxidation of constituent amino acid (10) which has the aromatic substitution pattern of fragment (5a or 5b). Base hydrolysis resulted in the isolation of a phenanthridine (9) which arose from 2',4,6-trihydroxybiphenyl-2,5'-diyldiglycine. These chemical degradation studies on A35512B showed that this antibiotic is closely related to the ristocetin class of antibiotics.