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Biomedical subjects

M Lang

Publications and source records attributed to M Lang.

At least 73 records · Page 4Linked to original sources
PubMed1998

New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: candidates for clinical development.

On the basis of previously described X-ray studies of an enzyme/aza-dipeptide complex,8 aza-dipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) or orthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis(L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.

Administration, Oral↗
PubMed1998

Pyrazole-inducible proteins in DBA/2 mouse liver bind with high affinity to the 3'-untranslated regions of the mRNAs of coumarin hydroxylase (CYP2A5) and c-jun.

An important mechanism in the up-regulation of cytochrome P-450 2A5 (CYP2A5, coumarin hydroxylase, Coh) is the stabilization of the corresponding mRNA; some evidence suggests that proteins binding to CYP2A5 mRNA may be involved in this stabilization. Here we report that pyrazole, a well known inducer of CYP2A5 and stabilizer of its message, enhances the binding of a set of proteins to 32P-labelled 3'-untranslated region (3'UTR) of CYP2A5 to give 32P-labelled bands of apparent molecular mass 37/39, 45/48 and 70/72 kDa after UV cross-linking/RNase cleavage; in addition, we found different proteins binding to other parts of CYP2A5 mRNA. The 70/72 kDa bands are also formed with the 3'UTR of c-jun. The inducible proteins are found in different cellular subfractions at different concentrations, with a maximum of five-fold induction of binding activity in microsomes. When a gel-mobility-shift assay was combined with UV cross-linking to resolve different pyrazole-inducible RNA-protein complexes into single RNA-binding protein bands, the smallest complex contained a double band of 37/39 kDa, 45/48 kDa bands, 70/72 kDa bands, and additional weaker bands at higher molecular masses (around 120 kDa). This composition was found also for all other complexes detected by gel-mobility-shift assay; occasionally, bands at higher molecular masses were also observed. The proteins of the smallest complex might therefore represent a core with which other proteins interact to build up larger complexes. Binding of proteins 37/39 kDa and 70/72 kDa was located to a 20-base loop and adjacent sequences in a 70 nt AU-rich region of the 3'UTR of the CYP2A5. Based on our previous evidence, this 70-nt sequence may play an important role in the stabilization and processing of the message.

Animals↗
PubMed1998

[Treatment of advanced Budd-Chiari syndrome by liver transplantation].

Budd-Chiari syndrome (BCS) with hepatic vein occlusion is a rare disorder that can effectively be treated in advanced stages with orthotopic liver transplantation. We report on 16 patients who received 18 liver grafts and were followed up for at least 2 years. In 7 patients a hematological disorder was confirmed by bone marrow biopsy. One patient died after 4 months due to cytomegalovirus pneumonia; another patient died after 2 years due to progressive liver failure after portal vein thrombosis. The actuarial 5-year survival rate is 87.5% compared to 85.3% in all other 710 orthotopic liver transplantations performed from September 1988 to December 1995 at our institution. Anticoagulation consisted of intravenous heparin and overlapping continuation with dicoumarin. Three patients received hydroxyurea for thrombocytosis, one patient for 1 week only early after the transplantation. Two postoperative abdominal hemorrhages required laparotomy. Two patients had to be retransplanted, one for thrombosis of the hepatic artery and portal vein after discontinuation of dicoumarin due to GI bleeding and one for hepatic vein thrombosis after insufficient dicoumarin intake. Terminal BCS represents a good indication for orthotopic liver transplantation; however, life-long, closely monitored anticoagulation is essential.

Adolescent↗
PubMed1998

Combined liver-kidney transplantation: long-term follow up in 18 patients.

Since August 1992, 18 patients underwent combined liver and kidney transplantation. Eight patients had lymphocytotoxic antibodies pretransplant and 5 of these patients (27.7%) had a positive crossmatch. Fifteen patients received cyclosporine-based immunosuppression and 3 patients were treated with a tacrolimus-based immunosuppressive protocol. One patient died in the postoperative course due to intractable bleeding episodes after 96 days and one kidney graft was lost due to technical complications. The 1 year survival rate of patients with combined transplantation was 95% vs 87% in patients with liver transplantation alone. None of the patients with a positive crossmatch experienced a hyperacute rejection of the kidney. The long-term patient and graft survival was not impaired in patients with a positive crossmatch. These results suggest that combined liver-kidney transplantation is a safe treatment for end-stage liver and renal disease. A positive crossmatch or positive lymphocytotoxic antibodies are not contraindications for a combined transplantation.

Adult↗
PubMed1998

The impact of donor organ quality on postoperative liver function after orthotopic rat liver transplantation.

The impact of donor factors for posttransplant liver function was evaluated in the model of orthotopic rearterialized liver transplantation in the rat. The effect of donor fasting, parenteral hyperalimentation, hypotension, warm ischemia and endotoxins on histology, clinical chemistry and MEGX test was analyzed in syngeneic and allogeneic recipients of livers stored for 4 hrs on ice. In syngeneic animals, 20 min of warm ischemia led to significantly elevated serum transaminase levels and degree 2 histological damage on POD 2. Endotoxins produced a grade 1 histological damage. All groups had a lower MEGX formation rate compared to controls. In allogeneic animals, warm ischemia was the single most detrimental parameter. The strength of the rejection response on POD 8 did not depend on the type of donor pretreatment. The major finding of this non-survival study is the deleterious effect of warm ischemia and endotoxin on the functional and structural integrity of liver grafts after 4 hrs of cold ischemia.

Animals↗
PubMed1998

Nonfluoroscopic endocardial catheter mapping of atrial fibrillation.

The treatment of drug-refractory atrial fibrillation (AF) remains one of the unsolved problems in cardiology. Surgical interventions have demonstrated that AF can be prevented by multiple incisions within both atria. Recently, this strategy has been translated into a catheter procedure. So far, the ablation approach is not based on individual electrophysiologic data, but constitutes only an anatomic approach. Further insight into the spatial and temporal distribution of the local electrograms during AF is needed. Electroanatomic maps acquired by sequential mapping over 45 seconds at each site during AF in six patients with paroxysmal AF were analyzed off-line. Electrograms were sampled at a mean of 36 +/- 12 sites in the left atrium of each patient. A total of 217 sites were sampled, of which 27.3% (59) represented type A (regular) AF, 9.7% (21) represented type B (totally irregular), and 63.1% (137) represented type C (mixture of type A and B) electrograms. The distribution was analyzed in 20 different segments of the left atrium, and a significantly higher incidence of type A electrograms was found in area 3 (upper lateral pulmonary vein) than at all other sites (P < 0.005). This observation needs further confirmation before any conclusion with regard to catheter ablation can be drawn, particularly because the analysis was based on bipolar recordings from a 4-mm tip electrode.

Aged↗
PubMed1997

Use of a pharmacophore model for the design of EGF-R tyrosine kinase inhibitors: 4-(phenylamino)pyrazolo[3,4-d]pyrimidines.

In the course of the random screening of a pool of CIBA chemicals, the two pyrazolopyrimidines 1 and 2 have been identified as fairly potent inhibitors of the EGF-R tyrosine kinase. Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), the class of the pyrazolo[3,4-d]pyrimidines was then optimized in an interactive process leading to a series of 4-(phenylamino)-1H-pyrazolo[3,4-d]-pyrimidines as highly potent inhibitors of the EGF-R tyrosine kinase. The most potent compounds 13, 14, 15, 17, 19, 22, 26, 28, and 30 of this series inhibited the EGF-R PTK with IC50 values below 10 nM. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, v-Abl and serine/threonine kinases (PKC alpha, CDK1) was observed. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 15, 19, 22, and 23 at IC50 values below 50 nM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 microM, thus indicating high selectivity for the inhibition of the ligand-activated EGF-R signal transduction pathway. Compounds 15 and 19 inhibited proliferation of the EGF-dependent MK cell line with IC50 values below 0.5 microM. In addition, two compounds, 9 and 11, showing satisfactory oral bioavailability in mice after oral administration, exhibited good in vivo efficacy at doses of 12.5 and 50 mg/kg in a nude mouse tumor model using xenografts of the EGF-R overexpressing A431 cell line. From SAR studies, a binding mode for 4-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidines, especially for compound 15, at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4-(Phenylamino)-1H-pyrazolo[3,4-d]pyrimidines represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the potential for further evaluation as anticancer agents.

3T3 Cells↗
PubMed1997

A comparative investigation of DNA adducts, DNA strand breaks and gene mutations induced by benzo[a]pyrene and (+/-)-anti-benzo[a]pyrene-7,8-diol 9,10-oxide in cultured human cells.

Genotoxic effects of benzo[a]pyrene (BP) and its reactive metabolites (+/-)-anti-benzo[a]pyrene-7,8-diol 9,10-oxide ((+/-)-anti-BPDE) were comparatively investigated in vitro with the permanent human fibroblast cell line MRC5CV1. Induced DNA adducts were measured by 32P-postlabeling, DNA strand breakage was determined by the comet assay and the HPRT gene mutation test was used to detect cytotoxicity and mutagenicity. Treatment of MRC5CV1 cells with S9 mix-activated BP or with (+/-)-anti-BPDE resulted in a concentration-dependent increase in DNA adducts and strand breaks. Genotoxic effects of BP and (+/-)-anti-BPDE were detected by 32P-postlabeling and the comet assay with similar sensitivity. However, under the same experimental conditions, a clear induction of gene mutations was only found after (+/-)-anti-BPDE treatment. The relationship between the induction of primary DNA alterations like DNA strand breaks and DNA adducts and the induction of gene mutations is discussed.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗