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Biomedical subjects

M Lang

Publications and source records attributed to M Lang.

At least 109 records · Page 6Linked to original sources
PubMed1994

Quantitative determination of CGP 53,437, a new HIV protease inhibitor, in plasma by high-performance liquid chromatography and fluorescence detection.

A specific and sensitive liquid chromatographic assay for CGP 53,437 (I), a potent HIV protease inhibitor, is described. The method is based on a deproteinization step, followed by a liquid-liquid extraction with diisopropyl ether. Then a deprotection step of the primary amine and derivatization using fluorescamine is performed. Chromatography is achieved by isocratic elution with a mobile phase of 63 mM borax buffer (pH 9)-acetonitrile (58:42, v/v). The flow-rate of the mobile phase is 1 ml/min. The derivatives of compound I and its internal standard CGP 54,451, II, fluoresce at 480 nm on excitation at 395 nm. The limit of quantitation which is the lowest concentration of the analyte that can be measured with a coefficient of variation and a deviation from theory of less than 20%, was 5 nmol/l plasma. The analyte is stable for at least seven months in spiked human plasma samples. It is also stable after freezing and thawing cycles. Different human plasma sources and plasma samples from three different species (dog, marmoset, and rat) were tested and no interferences from plasma constituents was observed.

Animals↗
PubMed1994

Development of transforming function during transduction of proto-ras into Harvey sarcoma virus.

Oncogenic retroviruses are generated by transduction of the coding region of a protooncogene and acquire genetic changes during subsequent replication. Critical genetic events which occurred during and after transduction of rat proto-ras-1Ha into Harvey sarcoma virus were identified by evaluating the transforming activity of plausible synthetic progenitor proviruses encompassing the complete proto-ras genomic region with or without various 5' deletions. All progenitor proviruses induced phenotypic transformation of mouse NIH 3T3 cells, although with a 5- to 10-fold lower frequency than Harvey sarcoma provirus. Although no tumor formation was observed in vivo after inoculation in the absence of helper murine retrovirus, both wild-type and progenitor viruses inoculated in the presence of helper virus induced tumors in newborn BALB/c mice. No critical alterations of the p21ras coding region and no deletion of 5' genomic elements were detected in a progenitor virus encompassing the complete proto-ras genomic region that had been isolated from tumors. However, one progenitor virus that included all proto-ras exons induced tumors with a decreased latency. This virus contained a mutation in codon 12 (glycine to valine), which had apparently been selected during tumorigenesis in vivo. During the genesis of Harvey sarcoma virus, critical steps conferring transforming function are therefore transduction of coding proto-ras exons and enhancement of their transforming function by specific amino acid changes in p21ras.

3T3 Cells↗
PubMed1994

Tissue and sex-dependent differences in CYP2A activities in hamsters.

Three enzymatic activities of the CYP2A subfamily, coumarin 7-hydroxylase (COH), testosterone 15 alpha-hydroxylase (T15 alpha OH) and testosterone 7 alpha-hydroxylase (T7 alpha OH), were characterized in liver, kidney and lung microsomes from control, pyrazole (PYR), 3-methylcholanthrene (MC) and phenobarbital (PB) treated female and male Syrian golden hamsters. Sex-dependent changes in the enzymatic activities were found. Among control animals COH and T15 alpha OH activities were higher in males. T7 alpha OH activity was five times higher in female kidneys than in males. Inducers changed this metabolic profile. MC and PB were potent CYP2A inducers in extrahepatic tissues: significant increases were found in COH (5-fold) and T15 alpha OH (12-fold) activities in female MC lung microsomes and T7 alpha OH (7-fold) in MC male kidney microsomes. PB increased significantly activities of COH (5-fold), T15 alpha OH (3-fold) and T7 alpha OH (10-fold) in male kidney microsomes. All inducers significantly increased T7 alpha OH activity in male kidney microsomes but decreased hepatic T7 alpha OH activity in both sexes. PYR treatment decreased hepatic CYP2A activities. Anti-mouse CYP2A4/5 antibody inhibited COH activity by a variable extent depending on the tissue and pretreatment and recognised three 52-, 49-, 48-kDa bands in liver and two major bands in kidney (48 and 49 kDa) and lung (49 and 52 kDa) microsomes. COH and T15 alpha OH activities correlated well with 49 kDa protein (r = 0.95 and r = 0.99, respectively) in lung microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

In vivo study of online liver tissue classification based on envelope power spectrum analysis.

An ultrasonic imaging and signal analysis system, combining a 3.5 MHz linear array B-scanner and an array processor, has been realized for a clinical liver tissue classification study. Based on the complete unprocessed rf data set of a real time B-image, local envelope power spectra averaged over interactively defined regions are computed. These spectra are partially corrected for several tissue type independent effects that affect comparability. A library containing the in vivo data of 65 patients with known liver tissue states in three groups (normal, cirrhotic, fat) was built up. An algorithm based on numerical optimization of parametrized spectrum characteristics combined with a k-nearest-neighbors classifier, applied to the library, leads to correct classification rates of 85.8 to 87.5 percent in discriminating pathological from normal tissue states. The method can be used for k-weighted color coded tissue type imaging with acceptable spatial resolution.

Algorithms↗
PubMed1994

Diagnostic reassessment and treatment response in schizophrenia.

BACKGROUND: The reasons for poor treatment response in some patients with schizophrenia remain unclear. It is possible that misdiagnosis of nonschizophrenic disorders as schizophrenia could result in suboptimal pharmacotherapy in some patients. METHOD: To assess this possibility, 110 severely ill, chronic patients with a referral diagnosis of schizophrenia were comprehensively assessed and rediagnosed according to DSM-III-R criteria. Global Assessment of Function (GAF) and Clinical Global Impressions (CGI) ratings were made at admission and at discharge from the ward, after the implementation of individualized treatment plans. RESULTS: The diagnosis of schizophrenia was confirmed in 80 patients (73%) and revised to another type of psychotic illness in 30 patients (27%). The GAF and CGI ratings were similar at admission in patients with confirmed and revised diagnoses. All patients improved by the time of discharge (p = .0001); however, patients with a revised diagnosis improved more than those with confirmed schizophrenia (p = .02). Patients with a revised diagnosis were less likely to require continued hospitalization on chronic care wards (p = .004). At admission, medication regimens were similar in the two groups of patients. At discharge, patients with a revised diagnosis were less likely to have received neuroleptics (p = .007) and more likely to have received antimanic drugs (p = .0002) or electroconvulsive therapy (p = .0004). CONCLUSION: These findings from a clinical sample suggest that diagnostic reassessment is an important first step in the management of apparently refractory schizophrenia.

Adolescent↗
PubMed1994

[Long-term results of arthrodesis of the upper ankle joint].

From 1985 to 1987 a total of 95 ankle arthrodesis were performed. The retrospective study showed in most cases a bony healing within 14 weeks with a complication rate of 20%, due to reduced conditions of the soft tissue. The follow up examination of 52 patients showed a good to very good result in 48 cases. Nearly 70% of the patients did not use orthopaedic made-to-measure shoes at the time of follow up. Only 4% were dissatisfied with this procedure. Therefore the arthrodesis of the ankle should be preferred in comparison to the arthroplastik.

Adult↗
PubMed1993

Aromatase inhibitors: synthesis, biological activity, and binding mode of azole-type compounds.

The enantiomers of the potent nonsteroidal inhibitor of aromatase fadrozole hydrochloride 3 have been separated and their absolute configuration determined by X-ray crystallography. On the basis of a molecular modeling comparison of the active enantiomer 4 and one of the most potent steroidal inhibitors reported to date, (19R)-10-thiiranylestr-4-ene-3,17-dione, 7, a model describing the relative binding modes of the azole-type and steroidal inhibitors of aromatase at the active site of the enzyme is proposed. It is suggested that the cyanophenyl moiety present in the most active azole inhibitors partially mimics the steroid backbone of the natural substrate for aromatase, androst-4-ene-3,17-dione, 1. The synthesis and biological testing of novel analogues of 3 used to define the accessible and nonaccessible volumes to ligands in the model of the active site of aromatase are reported.

Aromatase Inhibitors↗
PubMed1993

Response of mouse liver coumarin 7-hydroxylase activity to hepatotoxins: dependence on strain and agent and comparison to other monooxygenases.

Acute effects of a single intraperitoneal dose of allyl alcohol (AA, 64 mg/kg), dimethylnitrosamine (DMNA, 30 mg/kg), hexachlorobutadiene (HCBD, 50 mg/kg), carbon tetrachloride (CCl4, 24 mg/kg), cocaine (60 mg/kg) and pyrazole (300 mg/kg) on the hepatic histology and monooxygenases in DBA/2 and C57Bl/6 strains of mice were investigated. All substances caused histologically verified injury to the liver, which varied in appearance and severity depending on the compound and the mouse strain. Responses of P450-catalyzed reactions were highly dependent on the toxin and varied between different monooxygenase (MO) reactions and two mouse strains. In DBA/2 strain, coumarin 7-hydroxylase (COH) activity was increased from 3- to 5-fold by pyrazole, cocaine, HCBD and CCl4. With respect to P450 content and other MO activities, no changes or even decreases were generally observed. Some exceptions to this rule were found: HCBD significantly increased T15 alpha OH, PROD and EROD activities in C57Bl/6 mice, whereas cocaine caused a significant stimulation of T15 alpha OH and PROD in DBA/2 mice, It is concluded that i) different hepatoxins cause different types of liver injury and responses of the monooxygenase complex ("hepatotoxinspecific finger prints"), ii) although DBA/2 and C57Bl/6 mice responded rather similarly to hepatotoxins, also with respect to P450 content and most MO activities, they displayed a profound difference in the behaviour of COH activity, and iii) within the P450 superfamily, the regulation of COH activity seems to be rather unique, also when compared to its structurally close enzyme, testosterone 15 alpha-hydroxylase.

Animals↗
PubMed1993

No proof of linkage between schizophrenia-related disorders including schizophrenia and chromosome 2q21 region.

We examined linkage between schizophrenia and schizophrenia-related disorders and five genetic markers on chromosome 2 in fourteen families ascertained through affected probands in St. Louis and Vienna. The chromosomal region 2q21 was considered a candidate locus for schizophrenia because of a report of a balanced translocation 2;18 (q21;q23) in a schizophrenia family. Linkage analyses were conducted for three disease models: a narrow model including schizophrenia only; an intermediate model including a spectrum of schizophrenia-related disorders; and a broad model including major affective disorders. Multipoint linkage analyses excluded linkage across the region (about 50 cM) for the intermediate disease model. The same was generally true for the broad affection status model. None of the two-point and multipoint analyses showed definite linkage of schizophrenia to any marker. The most prominent positive association was between D2S44 and a broad affection status model, giving a two-point lod score of 1.71 at 0.20 recombination fraction.

Adult↗
PubMed1993

Development of human fetal lung in organ culture compared with in utero ontogeny.

In utero, at around 23 wk gestation, the progenitor epithelium of distal airway differentiates into type I and type II pneumatocytes. Human fetal lung organ cultures, as early as 12 wk gestation, have the competence to self-differentiate. Distal airway epithelial immunoreactivity to cytokeratins CK 7, 8, and 18 decreases with differentiation both in utero and in organ culture, whereas reactivity to epithelial membrane antigen remains constant in both. As distal airways dilate, the mean percentage airspace of fetal lungs in organ culture increases to 58%, equivalent to lung of gestation 26.0 +/- 7.3 wk. In organ culture, capillary blood vessels, visualized by vimentin immunoreactivity, remodel and more closely approximate the epithelium but without direct invasion. In utero, at 23 wk gestation, elastin appears as condensation around airways and forms a basis for secondary crests which, by 29 wk gestation, evolve into alveolar septae. In organ culture, no elastin is deposited, no secondary or alveolar crests form, and the lung retains a simple saccular structure. Differentiation of the terminal airway epithelium and mesodermal maturational events to facilitate gas exchange, such as capillary invasion or secondary-alveolar crest formation, are almost synchronous in human lung in utero but clearly dissociate in organ culture.

Analysis of Variance↗
PubMed1993

Structure-activity relationships and binding model of novel aromatase inhibitors.

The use of aromatase inhibitors is an established therapy for oestrogen-dependent breast cancer in postmenopausal women. However, the sole commercially available aromatase inhibitor, aminoglutethimide, is not very selective. We have therefore developed fadrozole hydrochloride and CGS 20,267, which are both currently under clinical evaluation. This report will present an analysis of structure-activity relationships in the azole series of inhibitors and give an account of the further optimization of our development compounds, starting from CGS 20,267 over CGP 45,688 and leading to CGP 47,645, the most potent aromatase inhibitor in vivo reported to date. In addition, on the basis of comparisons of these azole-type inhibitors with the most potent steroidal inhibitors published in the literature, we propose a CAMM-generated model describing the relative binding modes of these two classes of compounds at the active site of the enzyme.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on estrogen-dependent rat mammary tumors.

The non-steroidal aromatase inhibitor CGS 20,267, at maximally effective doses in non-tumor bearing adult female rats, elicits endocrine effects mimicking those seen after surgical ovariectomy and thus induces a "medical" ovariectomy. We now report on studies characterizing the anti-tumor and endocrine effects of three orally active non-steroidal aromatase inhibitors, CGS 20,267, CGP 45,688 and CGP 47,645, in adult female rats bearing estrogen-dependent DMBA-induced mammary tumors. Doses ranging from 3 to 3000 micrograms/kg were given by gavage once daily for 6 weeks. After 6 weeks of treatment, the ED50 for suppression of tumor volume was 10-30, 100 and 3-10 micrograms/kg for CGS 20,267, CGP 45,688 and CGP 47,645, respectively. The maximally effective dose for anti-tumor efficacy was 300, 1000 and 100 micrograms/kg for each of the three inhibitors, respectively. The observed potent anti-tumor efficacy was accompanied by potent endocrine effects. Thus, disruption of ovarian cyclicity (at maximal doses rats remained in constant diestrus) was observed in all animals from the 2nd or 3rd week of treatment to the end of the 6-week treatment period. Uterine weight, at the maximally effective doses for each of the three inhibitors, was suppressed to between 42 and 28% of pre-treatment levels. This suppression was similar to the suppression of uterine weight (27% of pre-treatment) seen after ovariectomy. Serum estradiol concentrations in rats treated with 300 micrograms/kg CGS 20,267 were significantly suppressed to 12% of pre-treatment levels and serum luteinizing hormone (LH) concentrations were elevated 3 to 4-fold over pre-treatment levels. Thus the potent anti-tumor efficacy seen with each of the three non-steroidal aromatase inhibitors was accompanied in each case by a variety of endocrine effects corresponding to those seen after ovariectomy.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

CGP 53437, an orally bioavailable inhibitor of human immunodeficiency virus type 1 protease with potent antiviral activity.

CGP 53437 is a peptidomimetic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease containing a hydroxyethylene isostere. The compound inhibited recombinant HIV-1 protease with a Ki of 0.2 nM. The inhibition constant versus human cathepsin D and human cathepsin E was 4 nM. Human pepsin and gastricsin were inhibited with Kis of 8 and 500 nM, respectively, and human renin was inhibited with a Ki of 190 microM. The replication of HIV-1/LAV, HIV-1/Z-84, and HIV-1/pLAI was inhibited with a 90% effective dose of 0.1 microM in acutely infected MT-2 cells. The 50% cytotoxic dose was 100 microM. Similar antiviral activity was observed when the compound was added up to 10 h after infection. At the effective concentration, processing of Gag precursor protein p55 was greatly reduced, confirming an action on the late stage of the virus life cycle, as expected. The efficacy of the inhibitor was also demonstrated by using primary human peripheral blood lymphocytes infected with the HIV-1/LAV strain, low-passage clinical isolates obtained from HIV-1-seropositive individuals (including a zidovudine-resistant strain), and HIV-2/ROD. In these cells, CGP 53437 delayed the onset of HIV replication in a dose-dependent fashion (substantial effects with concentrations of > or = 0.1 microM) as long as the inhibitor was maintained in the culture. CGP 53437 was orally bioavailable in mice. Concentrations in plasma 10-fold in excess of the in vitro antiviral 90% effective dose could be sustained for several hours after oral application of 120 mg/kg. Therefore, CGP 53437 has the potential to be a therapeutically useful anti-HIV agent for the treatment of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Lipoprotein(a) serum levels and apolipoprotein(a) phenotypes in children with chronic renal disease.

Lipoprotein(a) [Lp(a)] has recently been characterized as a genetically determined risk factor for atherosclerosis and thrombosis. Normally, Lp(a) serum levels are closely related to the apo(a) phenotype. We studied Lp(a) serum levels and apo(a) phenotypes in 136 young subjects, aged 0.8-24.7 y, including patients with glomerular disease and normal renal function (n = 28), patients with chronic renal failure (n = 20), patients treated by hemodialysis (n = 10), peritoneal dialysis (n = 16), and renal transplantation (n = 23), and in controls (n = 39). Of all, 21 patients had proteinuria in the nephrotic range. The distribution of Lp(a) levels in normal subjects was skewed to the left with 97% having levels below 300 mg/L. A subpopulation with increased Lp(a) levels (13-42%) could be detected in all groups with renal disease, and increased mean serum Lp(a) levels were found in patients with nephrotic range proteinuria, in patients with chronic renal failure, and in patients on peritoneal dialysis. Serum Lp(a) levels were not correlated with age, gender, type of renal disease, renal function or severity of proteinuria, but were correlated with the apo(a) phenotype. For a given phenotype, Lp(a) levels tended to be higher in patients than in controls. We conclude that increased Lp(a) serum levels are frequently found in young patients with chronic renal disease, possibly predisposing them to an increased risk for atherosclerosis and thrombosis.

Adolescent↗