Biomedical subjects

H Bischoff

Publications and source records attributed to H Bischoff.

At least 19 recordsLinked to original sources

PubMed2006

Treatment of non-small cell lung cancer with intensity-modulated radiation therapy in combination with cetuximab: the NEAR protocol (NCT00115518).

BACKGROUND: Even today, treatment of Stage III NSCLC still poses a serious challenge. So far, surgical resection is the treatment of choice. Patients whose tumour is not resectable or who are unfit to undergo surgery are usually referred to a combined radio-chemotherapy. However, combined radio-chemotherapeutic treatment is also associated with sometimes marked side effects but has been shown to be more efficient than radiation therapy alone. Nevertheless, there is a significant subset of patients whose overall condition does not permit administration of chemotherapy in a combined-modality treatment. It could be demonstrated though, that NSCLCs often exhibit over-expression of EGF-receptors hence providing an excellent target for the monoclonal EGFR-antagonist cetuximab (Erbitux) which has already been shown to be effective in colorectal as well as head-and-neck tumours with comparatively mild side-effects. METHODS/DESIGN: The NEAR trial is a prospective phase II feasibility study combining a monoclonal EGF-receptor antibody with loco-regional irradiation in patients with stage III NSCLC. This trial aims at testing the combination's efficacy and rate of development of distant metastases with an accrual of 30 patients. Patients receive weekly infusions of cetuximab (Erbitux) plus loco-regional radiation therapy as intensity-modulated radiation therapy. After conclusion of radiation treatment patients continue to receive weekly cetuximab for 13 more cycles. DISCUSSION: The primary objective of the NEAR trial is to evaluate toxicities and feasibility of the combined treatment with cetuximab (Erbitux) and IMRT loco-regional irradiation. Secondary objectives are remission rates, 3-year-survival and local/systemic progression-free survival.

Adult↗

PubMed2001

Enzyme-catalyzed condensation reaction in a mammalian alpha-amylase. High-resolution structural analysis of an enzyme-inhibitor complex.

Mammalian alpha-amylases catalyze the hydrolysis of alpha-linked glucose polymers according to a complex processive mechanism. We have determined the X-ray structures of porcine pancreatic alpha-amylase complexes with the smallest molecule of the trestatin family (acarviosine-glucose) which inhibits porcine pancreatic alpha-amylase and yet is not hydrolyzed by the enzyme. A structure analysis at 1.38 A resolution of this complex allowed for a clear identification of a genuine single hexasaccharide species composed of two alpha-1,4-linked original molecules bound to the active site of the enzyme. The structural results supported by mass spectrometry experiments provide evidence for an enzymatically catalyzed condensation reaction in the crystal.

Acarbose↗

PubMed2001

Combinatorial synthesis of cholesterol ester transfer protein-mRNA ligands and screening by nondenaturating gel-electrophoresis.

RNA, as one of the biomolecules with the most structural and functional diversity, is an attractive therapeutic target.(1) Employing combinatorial chemistry methods, small peptide ligands were found, which bind to a short RNA with important biological functions. A 23-nt RNA oligonucleotide from the cholesterol ester transfer protein mRNA was chosen as a molecular target.(2) A 27-nt RNA oligonucleotide from the human immunodeficiency virus type-1 (HIV-1) TAR RNA was used to control the binding specificity.(3) Tetrapeptide libraries, composed of the amino acids Lys, Tyr, Leu, Ile, and Arg, with and without C- and N-terminal lysines, were synthesized by a combination of combinatorial and divergent solid-phase synthesis. Gel-shift affinity screening was used to extract the peptides with the best RNA binding properties. The peptide Lys-Tyr-Lys-Leu-Tyr-Lys-Cys-NH(2) (1) showing micromolar affinity to its RNA target was characterized with circular dichroism (CD), ultra violet (UV) measurement, and (1)H NMR spectroscopy.

5' Untranslated Regions↗

PubMed2001

Modulating angiotensin II-induced inflammation by HMG Co-A reductase inhibition.

Angiotensin (Ang) II is capable of producing inflammatory changes by signals through its AT1 receptor. Reactive oxygen species production, adhesion molecule expression, chemokines, and other mediators are involved. Nuclear factor-kappaB (NK-kappaB) and activator protein 1 (AP-1) are two of the transcription factors activating the responsible genes. We have studied Ang II-independent modulating effects in a double transgenic rat model harboring the human renin and angiotensinogen genes. We have recently focused on the protective effects of HMG-CoA reductase inhibition and review these data here. We found that cerivastatin decreased mortality, lowered blood pressure, preserved renal function, decreased cardiac hypertrophy, and inhibited the entire chain of inflammatory events. Furthermore, NF-kappaB and AP-1 activation was sharply attenuated. We also observed that cerivastatin blocked ERK1/2 phosphorylation in vivo and in vitro. Cerivastatin also inhibited phorbol ester-transmitted events in vascular smooth muscle cells. Because Rho, a member of the Ras protein superfamily is important to Ang II-dependent and -independent vascular smooth muscle signaling events, we suggest that cerivastatin may act by inhibiting the prenylation, membrane anchoring, and subsequent activation of Ras proteins. These data may in part explain cholesterol-independent, HMG-CoA reductase-related, protective effects.

Angiotensin II↗

PubMed2000

Crystal structures of human pancreatic alpha-amylase in complex with carbohydrate and proteinaceous inhibitors.

Crystal structures of human pancreatic alpha-amylase (HPA) in complex with naturally occurring inhibitors have been solved. The tetrasaccharide acarbose and a pseudo-pentasaccharide of the trestatin family produced identical continuous electron densities corresponding to a pentasaccharide species, spanning the -3 to +2 subsites of the enzyme, presumably resulting from transglycosylation. Binding of the acarviosine core linked to a glucose residue at subsites -1 to +2 appears to be a critical part of the interaction process between alpha-amylases and trestatin-derived inhibitors. Two crystal forms, obtained at different values of pH, for the complex of HPA with the protein inhibitor from Phaseolus vulgaris (alpha-amylase inhibitor) have been solved. The flexible loop typical of the mammalian alpha-amylases was shown to exist in two different conformations, suggesting that loop closure is pH-sensitive. Structural information is provided for the important inhibitor residue, Arg-74, which has not been observed previously in structural analyses.

Acarbose↗

PubMed1999

Immobility as a major cause of bone remodeling in residents of a long-stay geriatric ward.

Residents of a long-stay geriatric ward at the University Hospital Basel were included in a study to investigate the effects of hypovitaminosis D and immobility. All 91 women (mean age 82.5 years) and 92 men (mean age 78.7 years) were enrolled in the study. Measurements included bone resorption, as measured by urinary deoxypyridinoline (dpd), serum 25-hydroxyvitamin D (25OHD), serum intact parathyroid hormone (iPTH), and their correlations with a four grade mobility score. Mobility score reflected the degree of weight bearing, ranging from walking independently to primarily bed bound. In 86% of all residents, serum 25OHD levels were below the normal limit of 12 ng/ml. Secondary hyperparathyroidism (HPT) was detected in 24% of all patients, using 55 pg/ml as the upper limit for serum iPTH. No significant correlation was found between urinary dpd and serum 25OHD or serum iPTH. Mobility index and both urinary dpd (f: P = 0.001, r = 0.37; m: P < 0.0001, r = 0.47) and serum calcium (female: P = 0.007, r = 0.28; male: P = 0.02, r = 0.24) were positively related. In institutionalized elderly people with a high prevalence of vitamin D deficiency serum intact PTH levels did not correlate with bone resorption as measured by urinary deoxypyridinolin. However, more immobile subjects had significantly higher excretion rates for urinary dpd and higher serum calcium levels. Our results suggest that in elderly people immobility may contribute to bone loss that might preempt the development of secondary HPT through elevation of serum calcium.

Activities of Daily Living↗

PubMed1999

Type I osteogenesis imperfecta: diagnostic difficulties.

A 65-year-old woman presented with vertebral fractures of the lumbar spine and a history of pathological fractures following minor trauma, which had occurred before the onset of menopause. Her past medical history was significant for intermittent low back pain since childhood, which was attributed to thoracolumbar scoliosis. A diagnosis of unclassifiable osteoporosis was made until invasive diagnostic procedures suggested a mild form of type I osteogenesis imperfecta (OI). In unclear or atypical perimenopausal osteoporosis and diagnosis of OI should be considered.

Absorptiometry, Photon↗

PubMed1999

Allosteric inhibition of glycogen phosphorylase a by the potential antidiabetic drug 3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarbo xylate.

The effect of the potential antidiabetic drug (-)(S)-3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarbox ylate (W1807) on the catalytic and structural properties of glycogen phosphorylase a has been studied. Glycogen phosphorylase (GP) is an allosteric enzyme whose activity is primarily controlled by reversible phosphorylation of Ser14 of the dephosphorylated enzyme (GPb, less active, predominantly T-state) to form the phosphorylated enzyme (GPa, more active, predominantly R-state). Upon conversion of GPb to GPa, the N-terminal tail (residues 5-22), which carries the Ser14(P), changes its conformation into a distorted 3(10) helix and its contacts from intrasubunit to intersubunit. This alteration causes a series of tertiary and quaternary conformational changes that lead to activation of the enzyme through opening access to the catalytic site. As part of a screening process to identify compounds that might contribute to the regulation of glycogen metabolism in the noninsulin dependent diabetes diseased state, W1807 has been found as the most potent inhibitor of GPb (Ki = 1.6 nM) that binds at the allosteric site of T-state GPb and produces further conformational changes, characteristic of a T'-like state. Kinetics show W1807 is a potent competitive inhibitor of GPa (-AMP) (Ki = 10.8 nM) and of GPa (+1 mM AMP) (Ki = 19.4 microM) with respect to glucose 1-phosphate and acts in synergism with glucose. To elucidate the structural features that contribute to the binding, the structures of GPa in the T-state conformation in complex with glucose and in complex with both glucose and W1807 have been determined at 100 K to 2.0 A and 2.1 A resolution, and refined to crystallographic R-values of 0.179 (R(free) = 0.230) and 0.189 (R(free) = 0.263), respectively. W1807 binds tightly at the allosteric site and induces substantial conformational changes both in the vicinity of the allosteric site and the subunit interface. A disordering of the N-terminal tail occurs, while the loop of chain containing residues 192-196 and residues 43'-49' shift to accommodate the ligand. Structural comparisons show that the T-state GPa-glucose-W1807 structure is overall more similar to the T-state GPb-W1807 complex structure than to the GPa-glucose complex structure, indicating that W1807 is able to transform GPa to the T'-like state already observed with GPb. The structures provide a rational for the potency of the inhibitor and explain GPa allosteric inhibition of activity upon W1807 binding.

Allosteric Regulation↗

PubMed1998

Preclinical and clinical pharmacology of cerivastatin.

Cerivastatin, a new, entirely synthetic, and enantiomerically pure 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is pharmacologically potent and hepatically selective, with an uncomplicated pharmacokinetic profile. In vitro and acute in vivo studies in animals demonstrated that cerivastatin is markedly more pharmacologically potent than other statins. In rats and dogs, cerivastatin inhibited hepatic cholesterol synthesis at concentrations 100-150 times lower than lovastatin. Cerivastatin's potent inhibition of HMG-CoA reductase (the rate-limiting step in cholesterol biosynthesis) is confirmed by its cholesterol-lowering properties, combined with significant triglyceride-decreasing effects, and dose-dependent increases in low-density lipoprotein (LDL) receptor binding in the liver. The antiatherogenic effects of cerivastatin extend beyond serum lipid and lipoprotein reductions to potent inhibition of migration of smooth muscle cells in vitro and reductions in the accumulation of cholesterol ester in the arterial tissue of rabbits. The high pharmacologic potency of cerivastatin, coupled with high liver selectivity, enable cerivastatin to be administered at 1-5% of the dose of currently available HMG-CoA reductase inhibitors. At ultra-low doses in the range 0.01-0.8 mg/day, cerivastatin proved to be both safe and well tolerated when administered to healthy volunteers in a series of ascending single- and multiple-dose studies. Cerivastatin has an uncomplicated pharmacokinetic profile; it can be administered to both young and elderly patients, male and female, without the need for dosage adjustments. Because no clinically significant pharmacokinetic drug interactions occur with cerivastatin, it may be the preferred HMG-CoA reductase inhibitor for patients on multiple-drug therapy including warfarin and digoxin.

Animals↗

PubMed1998

[Ultrafast MRI phlebography of the lungs].

AIM: Improved detection of pulmonary-venous pathologies by imaging the pulmonary veins without arterial overlay. MATERIAL AND METHODS: Sequential 3D imaging of the pulmonary arterial and arteriovenous phase was performed with an ultrafast 3D FLASH sequence successively acquiring eight 3D data sets every 2.9 s within a single breathhold. For an 8 cm thick 3D slab an interpolated spatial resolution of about 1.4 x 1.9 x 3.3 mm could be achieved. Different protocols for contrast media dose and infusion rate were used. For selective visualization of the pulmonary veins, the pulmonary arterial phase was subtracted from a subsequent arteriovenous phase with the highest venous signal. 5 healthy volunteers, 8 patients with history of a cerebrovascular accident (CVA) of unknown etiology an suspected pulmonary-venous thrombosis and 9 patients with compression of the pulmonary vasculature by centrally growing malignancies were evaluated. RESULTS: With higher infusion rate and lower contrast media dose, arteries and veins could be better separated by their enhancement kinetics. In all cases a complete visualization of the main pulmonary veins, segmental and subsegmental veins up to the fourth order of each lung segment was achieved without any overlay of pulmonary arteries. No thrombi of the pulmonary veins were found in patients with CVA. The obstruction of pulmonary arteries and veins due to vessel compression could be selectively visualized. CONCLUSION: Ultrafast multiphase 3D-Gd-MRA is a new reliable method for selective 3D visualization of pulmonary veins.

Adult↗

PubMed1998

Preclinical review of cerivastatin sodium--a step forward in HMG-CoA reductase inhibition.

Epidemiological studies have established that elevated concentrations of plasma cholesterol, particularly the low density lipoprotein (LDL) cholesterol, is one of the major risk factors for the development of arteriosclerosis and ischemic heart disease. Treatment with HMG-CoA reductase inhibitors (vastatins) has become the most successful drug treatment in lowering total plasma and LDL cholesterol concentrations in the last years. The vastatins already available for treatment are therapeutically used in a dose-range between 10 and 80 mg/day. The new enantiomerically pure pyridine derivative cerivastatin sodium has demonstrated its efficacy in significantly lower doses in the microgram-range, not only in preclinical but also in clinical studies with daily doses of only 0.1-0.3 mg. The differences in the therapeutic doses are reflected by the Ki- and IC50-values from enzyme inhibition tests in comparison with various HMG-CoA reductase inhibitors. Cerivastatin sodium exhibits much higher enzyme affinity with factors between 70 and almost 200. The Ki-value for cerivastatin sodium was 1.3 x 10(-9) M in comparison to 150 x 10(-9) M for lovastatin. The extremely high enzyme affinity of cerivastatin sodium was also reflected in its high activity in vivo. In acute in vivo studies cerivastatin sodium inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate in both rats and dogs by 50% after oral administration at doses of 0.002 mg/kg body weight (ED50-values). This dose was comparable to 0.3 mg/kg of lovastatin. In subchronic dog studies a dose of 0.03 mg/kg lowered the serum LDL cholesterol concentration by 35% which is comparable with doses of 8-10 mg lovastatin/kg. Interesting results were observed in cholestyramine-primed dogs when 0.1 mg cerivastatin sodium/kg p.o. markedly decreased the serum triglycerides up to 70%. Cerivastatin shows a favourable pharmacokinetic profile with high liver selectivity. Rat studies have shown almost complete absorption and rapid hepatic clearance. Cerivastatin was highly bound to plasma proteins of rats, dogs and humans (>98%). Cerivastatin metabolites were excreted mainly via feces. The metabolism of cerivastatin sodium in man follows two metabolic pathways, demethylation to metabolite M1 and stereospecific hydroxylation to M23. The three major metabolites M1, M23 and the hydroxylated and demethylated metabolite M24 are highly active inhibitors not only in vitro but also in vivo. The human specific metabolites M23 and M24 inhibited the HMG-CoA reductase isolated from rat liver with the same potency as the parent compound cerivastatin sodium (IC50: 1.0-1.2 x 10(-9) M). M1 was slightly less active. Corresponding pharmacological activity was observed in vivo. M23 and M24 inhibited [14C]cholesterol synthesis from [14C]acetate in rat liver with ED50)-values between 0.001 and 0.002 mg/kg body weight which is similar to cerivastatin sodium and M1 exhibited an ED50-value of <0.006 mg/kg The strong inhibitory activity of these metabolites, in addition to cerivastatin's high enzyme affinity may explain the extraordinary pharmacological activity of cerivastatin and its ultra-low dose in man and demonstrates cerivastatin to be the most active HMG-CoA reductase inhibitor amongst all vastatins.

Animals↗

PubMed1998

BEACOPP: a new regimen for advanced Hodgkin's disease. German Hodgkin's Lymphoma Study Group.

The BEACOPP chemotherapy regimen for advanced Hodgkin's disease employs a rearranged schedule permitting a shortened three-week cycle. With haematological growth factor support, the dosages of cyclophosphamide, etoposide and adriamycin could be moderately escalated. The 3-armed multicentre HD9 trial (recruitment 1993-1998; 1300 patients randomised) aimed to compare BEACOPP with the standard COPP/ABVD chemotherapy and to detect and measure the gain in efficacy, if any, due to moderate dose escalation of BEACOPP. Eight cycles were given, followed by local irradiation. The most recent interim analysis, with 689 evaluable patients, circa 40% of all expected events and a median observation time of 27 months, showed significant differences in progression rate (P) and in two-year freedom from treatment failure (F) between the treatment arms, with escalated BEACOPP (P = 2%, F = 89%) better than baseline BEACOPP (P = 9%, F = 81%) better than COPP/ABVD (P = 13%, F = 72%). Survival was not significantly different. Acute toxicity was more severe due to dose escalation, but remained manageable. These preliminary results suggest that BEACOPP improves efficacy. Moderate dose escalation is feasible with G-CSF support and appears likely to make a worthwhile improvement in the cure rate. The results must await confirmation (or otherwise) by the final analysis including all randomised patients and sufficiently mature data.

Adolescent↗

PubMed1998

BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group.

PURPOSE: The HD9 trial aims to evaluate whether moderate dose escalation and/or acceleration of standard polychemotherapy is beneficial for advanced-stage Hodgkin's disease (HD). Two variants of a novel bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) scheme (standard and escalated dose) are compared with cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). PATIENTS AND METHODS: The randomized, three-arm trial recruited patients in stages IIB and IIIA with risk factors and stages IIIB and IV. BEACOPP in baseline dose contains all drug dosages of COPP/ABVD (except vincristine and procarbazine) rearranged in a shorter, 3-week cycle. Escalated BEACOPP uses higher doses of cyclophosphamide, doxorubicin, and etoposide with granulocyte colony-stimulating factor (G-CSF) support. After eight chemotherapy cycles, initial bulky and residual disease is irradiated. The trial is monitored and analyzed by means of a sequential strategy. RESULTS: An interim analysis with 505 assessable patients and a median follow-up of 23 months showed a significant inferiority (according to sequential monitoring strategy) of the COPP/ABVD regimen in progression rate and freedom from treatment failure (FFTF) compared with the pooled results of both BEACOPP variants. The 24-month FFTF rate was 75% for COPP/ABVD and 84% for BEACOPP pooled (P = .034). There was 12% progressive disease with COPP/ABVD and 6% with BEACOPP pooled. Differences in survival were not significant in sequential analysis. The acute toxicity of baseline BEACOPP resembled that of COPP/ABVD; escalated BEACOPP showed increased but manageable hematologic toxicity. CONCLUSION: Combined with local irradiation, BEACOPP in one or both variants shows superior disease control compared with COPP/ABVD, with acceptable acute toxicity. Further follow-up is required to assess the effect of dosage and the effect on survival and late toxicities.

Adolescent↗

PubMed1998

D-glucose combined chronic toxicity and carcinogenicity studies in Sprague-Dawley rats and Syrian golden hamsters.

After an initial period of 16 weeks with increasing concentrations, D-glucose was administered at 30% in the diet to 50 male and 50 female Sprague-Dawley rats from the 17th to the 112th study week. Additional 10 male and 10 female animals were treated for 14 months and then sacrificed for interim examination. Groups of 60 male and 60 female Syrian golden hamsters received D-glucose in the form of 20% solution in tap water for a period of 80 weeks. In each case, groups consisting of an equal number of untreated animals served as controls. General behavior and mortality were not affected by the treatment. The rats and hamsters treated with glucose showed significantly higher body weights of up to a maximum of 16% in male and 26% in female rats, or 15% in male and female hamsters. In rats, the increase was evident by week 14, and in the hamsters by week 10. Glucose-dosed rats displayed a slightly increased feed intake and a reduced water intake. Both parameters, however, were not influenced in hamsters. Hematological and histopathological examination showed no pertinent changes in hematopoetic tissue. Sharply increased blood glucose and renal glucose excretion values were present in rats beginning with 18 months and were indicative of the development of non-insulin-dependent diabetes mellitus (NIDDM). The insulin concentrations in peripheral blood were not appreciably affected, although there was a trend to higher values in males at all evaluation times and in females only at 3 months. Pathological evaluation did not show any compound related non-neoplastic lesions. The incidences of islet cell adenomas in the pancreas of male rats were significantly increased and the cortical adenomas in the adrenals of females were decreased. In addition, the mammary gland adenomas (in females) and the Leydig cell tumors of the testes were decreased. In hamsters, the incidence of adrenocortical adenomas were increased in the females. No other pertinent neoplastic changes were observed. In conclusion, the increases and decreases in benign neoplasms of hormone-sensitive tissues, appear to be the result of nutritionally/metabolism-induced modulation of the homeostasis in these 4 tissues in both species, and not the result of chronic glucose administration.

Adrenal Cortex Neoplasms↗

PubMed1998

Elevated PTH levels in hypovitaminosis D are more rapidly suppressed by the administration of 1,25-dihydroxy-vitamin D3 than by vitamin D3.

OBJECTIVE: To assess markers of bone metabolism in two groups of inpatients with hypovitaminosis D and elevated PTH levels receiving two different vitamin D medications. METHODS: 26 patients with secondary hyperparathyroidism (2 degrees HP) were treated either with 800 IU cholecalciferol and 1000 mg calcium or 0.5 microgram calcitriol plus 500 mg calcium daily for 6 months. 25-OH-vitamin D3, 1,25-dihydroxy-vitamin D3, intact PTH, calcium and urinary N-telopeptides of bone collagen I were measured at baseline, 3 and 6 months. RESULTS: PTH levels decreased earlier in the calcitriol group than in the cholecalciferol group. After six month no difference could be documented. Lowering of urinary N-telopeptides excretion was observed in both groups. CONCLUSION: The use of both forms of vitamin D supplementation appears to be useful for patients with hypovitaminosis D, elevated PTH levels and high telopeptide excretion.

Administration, Oral↗

PubMed1997

The structure of glycogen phosphorylase b with an alkyldihydropyridine-dicarboxylic acid compound, a novel and potent inhibitor.

BACKGROUND: In muscle and liver, glycogen concentrations are regulated by the reciprocal activities of glycogen phosphorylase (GP) and glycogen synthase. An alkyl-dihydropyridine-dicarboxylic acid has been found to be a potent inhibitor of GP, and as such has potential to contribute to the regulation of glycogen metabolism in the non-insulin-dependent diabetes diseased state. The inhibitor has no structural similarity to the natural regulators of GP. We have carried out structural studies in order to elucidate the mechanism of inhibition. RESULTS: Kinetic studies with rabbit muscle glycogen phosphorylase b (GPb) show that the compound (-)(S)-3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5, 6-tricarboxylate (Bay W1807) has a Ki = 1.6 nM and is a competitive inhibitor with respect to AMP. The structure of the cocrystallised GPb-W1807 complex has been determined at 100K to 2.3 A resolution and refined to an R factor of 0.198 (Rfree = 0.287). W1807 binds at the GPb allosteric effector site, the site which binds AMP, glucose-6-phosphate and a number of other phosphorylated ligands, and induces conformational changes that are characteristic of those observed with the naturally occurring allosteric inhibitor, glucose-6-phosphate. The dihydropyridine-5,6-dicarboxylate groups mimic the phosphate group of ligands that bind to the allosteric site and contact three arginine residues. CONCLUSIONS: The high affinity of W1807 for GP appears to arise from the numerous nonpolar interactions made between the ligand and the protein. Its potency as an inhibitor results from the induced conformational changes that lock the enzyme in a conformation known as the T' state. Allosteric enzymes, such as GP, offer a new strategy for structure-based drug design in which the allosteric site can be exploited. The results reported here may have important implications in the design of new therapeutic compounds.

Adenosine Monophosphate↗

PubMed1997

Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA reductase inhibitor.

The pyridine derivative cerivastatin is a new entirely synthetic and enantiomerically pure inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. As a sodium salt cerivastatin is present in the active, open ring form. Cerivastatin inhibited the membrane-bound (non-solubilized) HMG-CoA reductase of the native microsomal fraction isolated from rat liver with a Ki value of 1.3 x 10(-9) M. The reference compound lovastatin was 100-fold less potent and exhibited a Ki value of 150 x 10(-9) M. Cerivastatin inhibited the cholesterol synthesis in the human hepatoma cell line HepG2 cells with a similar IC50 value of 1.0 x 10(-9) M. In vivo studies reflected its high in vitro activity. In both rats and dogs, cerivastatin inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate with an oral ED50 value of 0.002 mg/kg body weight, while lovastatin exhibited an oral ED50 value of 0.3 mg/kg in rats, showing again the ratio of 100 or more between cerivastatin and lovastatin. In the small intestine and testes, cerivastatin was at least 50-fold less active with oral ED50 values higher than 0.1 mg/kg, which is indicative for a high liver selectivity of cerivastatin. In cholestyramine-primed dogs cerivastatin dose-dependently lowered the serum cholesterol concentrations by up to 59% with 0.1 mg/kg after 20 days. Interestingly, the serum triglycerides were markedly reduced by 53 and 76% with 0.03 and 0.1 mg/kg, respectively. In normal chow fed dogs the low density lipoprotein (LDL) concentrations were reduced by up to 75% after 0.1 mg cerivastatin/kg. The ratio of HDL/LDL increased by 81% compared with a change of only 14% in the placebo treated control group. The antiatherogenic effect of cerivastatin was shown in rabbits fed a diet enriched with 0.2% cholesterol. After 9 weeks on diet 0.1 mg cerivastatin/kg decreased the accumulation of cholesterol ester in the arterial tissue by 73%. In summary, these data as compared to published data on other HMG-CoA reductase inhibitors demonstrate cerivastatin to be the most active compound in this class. Vastatins used in therapy are effective in mg doses, while cerivastatin offers a new low dose therapy in the microg range.

Administration, Oral↗

PubMed1997

[The intracavitary administration of contrast medium in the aftercare of complicated thoracic empyema with long-term drainage: x-ray fluoroscopy compared to computed tomography].

PURPOSE: To define the value of conventional radiography compared with CT in the follow-up of complicated, long-term tube drained pleural empyema after intracavitary application of contrast medium. METHODS: 28 patients with complicated pleural empyema (stage III) and long-term tube drainage were submitted to fluoroscopy of the pleural cavity and a CT of the thorax after contrast medium had been instilled into the pleural space. Both examinations were judged by the following criteria: number and morphology of pleural cavities, quality of drainage and accompanying thoracic disease. RESULTS: 49 pleural cavities were diagnosed. Judgement of drainage corresponded in 79% of cases and differed in 21% with proof of further not drained cavities only on CT. 4 bronchopleural fistulas were diagnosed by fluoroscopy, of which only 2 were evident on CT. Accompanying thoracic disease was reliably detected by CT only. CONCLUSIONS: Diagnosis of bronchopleural fistulas and judgement of the pleural drainage is best possible using fluoroscopy after application of contrast medium into the pleural space. CT is most accurate to detect further cavities that have not been drained, to look for concomitant thoracic disease, and to judge the morphology of the pleural cavity. Conventional radiography of the pleural space is effective and recommended to be used as a first line investigation for the follow-up of stage III empyemas. Patients in poor general condition (fever, elevated blood markers indicating inflammation) should be examined by both fluoroscopy and CT.

Adolescent↗