FV-162 is a novel, orally bioavailable, irreversible proteasome inhibitor with improved pharmacokinetics displaying preclinical efficacy with continuous daily dosing.

Approved proteasome inhibitors have advanced the treatment of multiple myeloma but are associated with serious toxicities, poor pharmacokinetics, and most with the inconvenience of intravenous administration. We therefore sought to identify novel orally bioavailable proteasome inhibitors with a continuous daily dosing schedule and improved therapeutic window using a unique drug discovery platform. We employed a fluorine-based medicinal chemistry technology to synthesize 14 novel analogs of epoxyketone-based proteasome inhibitors and screened them for their stability, ability to inhibit the chymotrypsin-like proteasome, and antimyeloma activity in vitro. The tolerability, pharmacokinetics, pharmacodynamic activity, and antimyeloma efficacy of our lead candidate were examined in NOD/SCID mice. We identified a tripeptide epoxyketone, FV-162, as a metabolically stable, potent proteasome inhibitor cytotoxic to human myeloma cell lines and primary myeloma cells. FV-162 had limited toxicity and was well tolerated on a continuous daily dosing schedule. Compared with the benchmark oral irreversible proteasome inhibitor, ONX-0192, FV-162 had a lower peak plasma concentration and longer half-life, resulting in a larger area under the curve (AUC). Oral FV-162 treatment induced rapid, irreversible inhibition of chymotrypsin-like proteasome activity in murine red blood cells and inhibited tumor growth in a myeloma xenograft model. Our data suggest that oral FV-162 with continuous daily dosing schedule displays a favorable safety, efficacy, and pharmacokinetic profile in vivo, identifying it as a promising lead for clinical evaluation in myeloma therapy.

[Dramatic efficacy of chemotherapy with 5-fluorouracil and dacarbazine in a patient with metastatic glucagonoma and cardiac insufficiency]. / Efficacité spectaculaire d'une chimiothérapie par 5-fluoro-uracile et dacarbazine chez un malade atteint de glucagonome métastatique avec insuffisance cardiaque.

Malignant glucagonoma is an exceptional pancreatic endocrine tumour, with frequent dermatologic symptoms, diabetes and degradation of the general health status. Prognosis is unfavourable when liver metastases are present due to the usual inefficiency of chemotherapy. We report here an observation of a patient who was treated for a glucagonoma with multiple liver metastases, migratory necrolytic erythema, dilated cardiomypathy and diabetes that dramatically improved after a dacarbazin-based chemotherapy, allowing subsequent surgical resection of the primary. The patient was still alive and asymptomatic without progressive disease nearly two years after surgery.

Role of directed van der Waals bonded interactions in the determination of the structures of molecular arsenate solids.

Bond paths, local energy density properties, and Laplacian, L(r) = -wedge(2)rho(r), composite isosurfaces of the electron density distributions were calculated for the intramolecular and intermolecular bonded interactions for molecular solids of As(2)O(3) and AsO(2) composition, an As(2)O(5) crystal, a number of arsenate molecules, and the arsenic metalloid, arsenolamprite. The directed intermolecular van der Waals As-O, O-O, and As-As bonded interactions are believed to serve as mainstays between the individual molecules in each of the molecular solids. As-O bond paths between the bonded atoms connect Lewis base charge concentrations and Lewis acid charge depletion domains, whereas the O-O and As-As paths connect Lewis base pair and Lewis acid pair domains, respectively, giving rise to sets of intermolecular directed bond paths. The alignment of the directed bond paths results in the periodic structures adopted by the arsenates. The arrangements of the As atoms in the claudetite polymorphs of As(2)O(3) and the As atoms in arsenolamprite are similar. Like the As(2)O(3) polymorphs, arsenolamprite is a molecular solid connected by relatively weak As-As intermolecular directed van der Waals bond paths between the layers of stronger As-As intramolecular bonded interactions. The bond critical point and local energy density properties of the intermolecular As-As bonded interactions in arsenolamprite are comparable with the As-As interactions in claudetite I. As such, the structure of claudetite I can be viewed as a stuffed derivative of the arsenolamprite structure with O atoms between pairs of As atoms comprising the layers of the structure. The cubic structure adopted by the arsenolite polymorph can be understood in terms of sets of directed acid-base As-O and base-base O-O pair domains and bond paths that radiate from the tetrahedral faces of its constituent molecules, serving as face-to-face key-lock mainstays in forming a periodic tetrahedral array of molecules rather than one based on some variant of close packing. The relatively dense structure and the corrugation of the layers in claudetite I can also be understood in terms of directed van der Waals As-O bonded interactions. Our study not only provides a new basis for understanding the crystal chemistry and the structures of the arsenates, but it also calls for a reappraisal of the concept of van der Waals bonded interactions, how the structures of molecular solids are viewed, and how the molecules in these solids are bonded in a periodic structure.

Peptides enhance magnesium signature in calcite: insights into origins of vital effects.

Studies relating the magnesium (Mg) content of calcified skeletons to temperature often report unexplained deviations from the signature expected for inorganically grown calcite. These "vital effects" are believed to have biological origins, but mechanistic bases for measured offsets remain unclear. We show that a simple hydrophilic peptide, with the same carboxyl-rich character as that of macromolecules isolated from sites of calcification, increases calcite Mg content by up to 3 mole percent. Comparisons to previous studies correlating Mg content of carbonate minerals with temperature show that the Mg enhancement due to peptides results in offsets equivalent to 7 degrees to 14 degrees C. The insights also provide a physical basis for anecdotal evidence that organic chemistry modulates the mineralization of inorganic carbonates and suggest an approach to tuning impurity levels in controlled materials synthesis.

Role of molecular charge and hydrophilicity in regulating the kinetics of crystal growth.

The composition of biologic molecules isolated from biominerals suggests that control of mineral growth is linked to biochemical features. Here, we define a systematic relationship between the ability of biomolecules in solution to promote the growth of calcite (CaCO3) and their net negative molecular charge and hydrophilicity. The degree of enhancement depends on peptide composition, but not on peptide sequence. Data analysis shows that this rate enhancement arises from an increase in the kinetic coefficient. We interpret the mechanism of growth enhancement to be a catalytic process whereby biomolecules reduce the magnitude of the diffusive barrier, Ek, by perturbations that displace water molecules. The result is a decrease in the energy barrier for attachment of solutes to the solid phase. This previously unrecognized relationship also rationalizes recently reported data showing acceleration of calcite growth rates over rates measured in the pure system by nanomolar levels of abalone nacre proteins. These findings show that the growth-modifying properties of small model peptides may be scaled up to analyze mineralization processes that are mediated by more complex proteins. We suggest that enhancement of calcite growth may now be estimated a priori from the composition of peptide sequences and the calculated values of hydrophilicity and net molecular charge. This insight may contribute to an improved understanding of diverse systems of biomineralization and design of new synthetic growth modulators.

Formation of chiral morphologies through selective binding of amino acids to calcite surface steps.

Many living organisms contain biominerals and composites with finely tuned properties, reflecting a remarkable level of control over the nucleation, growth and shape of the constituent crystals. Peptides and proteins play an important role in achieving this control. But the general view that organic molecules affect mineralization through stereochemical recognition, where geometrical and chemical constraints dictate their binding to a mineral, seems difficult to reconcile with a mechanistic understanding, where crystallization is controlled by thermodynamic and kinetic factors. Indeed, traditional crystal growth models emphasize the inhibiting effect of so-called 'modifiers' on surface-step growth, rather than stereochemical matching to newly expressed crystal facets. Here we report in situ atomic force microscope observations and molecular modelling studies of calcite growth in the presence of chiral amino acids that reconcile these two seemingly divergent views. We find that enantiomer-specific binding of the amino acids to those surface-step edges that offer the best geometric and chemical fit changes the step-edge free energies, which in turn results in macroscopic crystal shape modifications. Our results emphasize that the mechanism underlying crystal modification through organic molecules is best understood by considering both stereochemical recognition and the effects of binding on the interfacial energies of the growing crystal.

The role of Mg2+ as an impurity in calcite growth.

Magnesium is a key determinant in CaCO3 mineralization; however, macroscopic observations have failed to provide a clear physical understanding of how magnesium modifies carbonate growth. Atomic force microscopy was used to resolve the mechanism of calcite inhibition by magnesium through molecular-scale determination of the thermodynamic and kinetic controls of magnesium on calcite formation. Comparison of directly measured step velocities to standard impurity models demonstrated that enhanced mineral solubility through magnesium incorporation inhibited calcite growth. Terrace width measurements on calcite growth spirals were consistent with a decrease in effective supersaturation due to magnesium incorporation. Ca(1-x)Mg(x)CO3 solubilities determined from microscopic observations of step dynamics can thus be linked to macroscopic measurements.

A clinical study of amiodarone as a single oral dose in patients with recent-onset atrial tachyarrhythmia.

Forty-five patients with recent-onset sustained atrial tachyarrhythmia (mean heart rate at entry; 140.0 +/- 3.5 beats.min-1) associated with various cardiovascular diseases were treated by oral amiodarone, given as a single loading dose of 25.7 +/- 0.9 mg.kg-1 body weight. Conversion to sinus rhythm was observed in 29 patients during the first 24 h of treatment, leading to a success rate of 64.4%. Five additional patients converted to sinus rhythm with continuation of oral amiodarone, (10-15 mg.kg-1 by day) with a mean delay of 4.2 days. A similar population of 27 patients (mean heart rate at entry; 140 +/- 3 beats.min-1) was treated by intravenous amiodarone, given as a bolus infusion of 3-5 mg.kg-1 over 30 min (mean; 4.1 +/- 0.2 mg.kg-1), followed by a continuous infusion of 10-15 mg.kg-1 for 24 h (mean; 11.1 +/- 0.7 mg.kg-1). Eighteen patients converted to sinus rhythm during the first 24 h of therapy, leading to a success rate of 66.7%. Minor adverse effects of therapy were observed in two patients given oral amiodarone, and in seven given intravenous amiodarone. No major effect was observed. We suggest that amiodarone given as a single oral loading dose of 25-30 mg.kg-1 body weight is an effective, simple and well-tolerated therapy, suitable for most patients with recent-onset ATA.

Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure.

The prognostic value of 123I-metaiodobenzylguanidine (MIBG) imaging was compared with that of other noninvasive cardiac imaging indices in ninety patients (mean age = 52 +/- 7 yr) suffering from either ischemic (n = 24) or idiopathic (n = 66) cardiomyopathy. Patients had different measurements taken: cardiac MIBG uptake, radionuclide left ventricular ejection fraction, x-ray cardiothoracic ratio and echographic M-Mode data. Cardiac MIBG uptake was assessed as the heart-to-mediastinum activity ratio measured on the chest anterior view image obtained 4 hr after intravenous injection. The patients then had follow-up for 1-27 mo, at which time 10 patients had transplants, 22 had died and 58 were still alive. Data from patients with transplants were not used in the analysis, in which multivariate stepwise regression discriminant analysis showed that cardiac MIBG uptake was more potent to predict survival than other indices: H/M (p less than 0.0001), x-ray cardiothoracic ratio (p = 0.0017), echographic end-diastolic diameter (p = 0.0264) and radionuclide left ventricular ejection fraction (p = 0.0301). Moreover, multivariate life table analysis showed that cardiac MIBG uptake was also the best predictor for life duration: H/M (p = 0.0001), radionuclide left ventricular ejection fraction (p = 0.0098) and x-ray cardiothoracic ratio (p = 0.0139); echographic data were not useful. Thus, cardiac MIBG imaging may be helpful for heart transplantation decision making in patients with heart failure.

Profit making in medical illustration.

'Cost recovery' is the name of the game these days. However, cost recovery is not the only way to improve funding. The aim of this paper is to show how a free service can still be maintained by better utilization of the professional skills available in medical illustration departments. All medical departments should have skills which are unique to medical illustration. These are skills which are marketable but which, in many cases, are being grossly undersold. If their full potential is realized many more departments would find themselves in a far healthier state than they are at present.

ECG gated thallium 201 myocardial images: value in detecting multivessel disease in patients on anti anginal therapy 1-3 months after myocardial infarction.

ECG gated 201Tl scintigraphy was compared to non gated images for detecting 2-3 vessel disease 1-3 months after a first uncomplicated myocardial infarction. In all, 111 patients on anti anginal treatment underwent coronary arteriography and stress thallium imaging; 39 showed single vessel disease (SVD), and 72 multivessel disease (MVD). Sensitivity of black and white analog images was 82% for SVD and 8% for MVD. Sensitivity of computerized colored static images was 87% for SVD and 33% for MVD. For gated images, sensitivity was 100% and 92% in patients with SVD and MVD respectively. Specificity for detecting MVD was 95% for black and white images, 77% for computerized colored static images, and 69% for ECG gated images. Thus, ECG gated exercise 201TL scintigraphy is useful for predicting the extent of coronary artery disease 1-3 months after myocardial infarction in patients on anti anginal therapy.

Structural modification of H2-receptor antagonists provide post-H2-receptor gastric antisecretory activity.

Structural analogues (e.g., Wy-46,499) of a known H2-antagonist (Wy-45,662) were found to inhibit acid secretion in the pylorus ligated rat and to block forskolin and DBcAMP-stimulated [14C]amino-pyrine (AP) uptake by rat isolated gastric mucosal cell preparations. Wy-45,662 (N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno [3,4- d]isothiazol-3-amine 1, 1-dioxide), a very potent histamine H2-antagonist and antisecretory agent in the rat (ED50 approximately equal to 0.3 mg/kg), had no effect in vitro at 1 microM on forskolin-induced [14C]AP uptake while 10 nM Wy-45,662 completely suppressed histamine-stimulated [14C]AP uptake. In contrast, the N-benzylated form of Wy-45,662, Wy-46,499, dose-dependently (1 X 10(-7) -3 X 10(-6)M) suppressed forskolin-stimulated [14C]AP uptake while retaining modest antisecretory activity (ED50 approximately equal to 8 mg/kg) in vivo. Wy-46,499's modest antisecretory activity was thus attributable to inhibition via a post-histamine H2-receptor mechanism.

Inhibition of [14C]aminopyrine uptake in rat isolated gastric mucosal cells by two classes of psychotropic agents.

Certain CNS-active compounds decrease gastric acid secretion in vivo. In this study a number of tricyclic antipsychotic or antidepressant compounds together with haloperidol, a nontricyclic antipsychotic agent, were shown to inhibit dibutyryl-cAMP-stimulated [14C]aminopyrine uptake, an index of acid secretory activity in a rat isolated gastric mucosal cell preparation. The observed order of potency was: thioridazine greater than chlorpromazine greater than haloperidol approximately equal to desipramine approximately equal to imipramine greater than clozapine. Comparison of these potencies with those of the known (H+ + K+)ATPase inhibitors timoprazole and omeprazole revealed that the potency of timoprazole was similar to the one of clozapine while omeprazole was intermediate between thioridazine and chlorpromazine. Pirenzepine was ineffective.