Diagnóstico de atresia de la arteria coronaria principal izquierda mediante tomografía computarizada volumétrica cardíaca de 320 detectores / Diagnosis of atresia of the main left coronary artery using 320-detector volumetric cardiac computed tompography

La ausencia congénita del tronco coronario izquierdo es una de las anomalías de arterias coronarias más raras. Presentamos un caso en el que se sospechó este diagnósticomediante angiografía coronaria, confirmándose mediantetomografíacomputarizada (TC) volumétricacardíaca adquirida en un solo latido (AU)

The congenital absence of the left coronary trunk is one of the rarest anomalies of the coronary artery. We present a case in which this anomaly was suspected at cardiac catheterization and confirmed at volumetric cardiac computed tomography (CT) with a single heart beat (AU)

[Diagnosis of atresia of the main left coronary artery using 320-detector volumetric cardiac computed tomography [corrected]]. / Diagnóstico de atresia de la arteria coronaria principal izquierda mediante tomografía computarizada volumétrica cardíaca de 320 detectores.

The congenital absence of the left coronary trunk is one of the rarest anomalies of the coronary artery. We present a case in which this anomaly was suspected at cardiac catheterization and confirmed at volumetric cardiac computed tomography (CT) with a single heart beat.

Design, synthesis and SAR of a series of 2-substituted 4-amino-quinazoline neuropeptide Y Y5 receptor antagonists.

The design of a novel series of NPY-Y5 receptor antagonists is described. Key elements for the design were the identification of weak Y5 hits from a Y1 program, results from a combinatorial approach and database mining. This led to the discovery of the quinazoline 4 and the aryl-sulphonamide moiety as major components of the pharmacophore for Y5 affinity. The synthesis and SAR towards CGP71683A is described.

Solid-phase synthesis of 2,4-diaminoquinazolines.

A highly efficient and versatile solid-phase synthesis of 2,4-diaminoquinazoline library from 2,4-dichloroquinazolines and amines using 3,5-dimethoxy 4-formylphenoxy-polystyrene resin is described.

Synthesis and biological activity of oxo-7H-benzo[e]perimidine-4-carboxylic acid derivatives as potent, nonpeptide corticotropin releasing factor (CRF) receptor antagonists.

A novel series of derivatives of oxo-7H-benzo[e]perimidine-4-carboxylic acid (I) potently displaced radioligand binding of 125I-CRF to both CRF1 and CRF2 receptors. The members of this series antagonized CRF-stimulated cAMP formation and CRF-stimulated corticotropin release from rat pituitary in vivo. These are the first nonpeptide antagonists to show activity at both CRF1 and CRF2 receptors.

An evaluation of the effectiveness of a videotape programme on interobserver reliability in outcome assessment for ankylosing spondylitis.

AIMS: A study was designed to assess the effects of a standardized instructional videotape on training senior medical students to acceptable levels of reliability in performing several commonly used obsever dependent outcome measures in patients with ankylosing spondylilis (AS). METHODS: During a single day, six third-year medical students independently examined five patients with AvS in predetermined order using a Latin Square design, before and after viewing a standardized videotape demonstrating 14 examination techniques. Reliability coefficients were calculated based on the variance components of the analysis of variance (ANOVA) table. RESULTS: Prestandardization reliability coefficients were < 0.80 for three measures. Following standardization 12 reliability coefficients exceeded 0.80. For the majority of measures prestandardization reliability coefficients were high and no further improvement in reliability could be demonstrated. CONCLUSIONS: High levels of interobserver agreement were noted prior to viewing the instructional videotape. This may represent the success of undergraduate clinical skills training programmes, or it may be the result of having reviewed an illustrated instructional text just prior to the initial patient examinations. With the exception of chest excursion, high levels of prestandardization reliability, by necessity, precluded the demonstration of significant effects from viewing the videotape. Nevertheless, the data indicate that senior medical students arc capable of reliably performing quantitative measurement in AS. Recent surveys in Canada and Australia, showing a general lack of quantitative clinical measurement in the longitudinal follow up of AS outpatients by rheumatologists, suggest that the lack of quantitation is not due to inability to reliably perform the measurements.

An evaluation of the effectiveness of a videotape programme on interobserver reliability in outcome assessment for osteoarthritis.

AIMS: A study was designed to assess the effects of a standardized instructional videotape on training senior medical students to acceptable levels of reliability in performing several commonly used observer dependent outcome measures in patients with osteoarthritis (OA). METHODS: During a single day, six third-year medical students independently examined six patients with OA in predetermined order using a Latin Square design, before and after viewing a standardized videotape demonstrating 13 examination techniques. Reliability coefficients were calculated based on variance components of the analysis of variance (ANOVA) table. RESULTS: Preslandardization reliability coefficients were <0.80 for seven measures. Coefficients for the performance of knee goniometry were uniformly low. Following the intervention, all but four reliability coefficients were >/= 0.93. CONCLUSIONS: For many measures, high levels of interobserver agreement were noted prior to viewing the instructional videotape. This may represent the success of undergraduate clinical skills training programmes, or it may be the result of having reviewed an illustrated instructional text just prior to the initial patient examinations. The notable exception was knee goniometry. Despite apparent familiarity with the technique, prestandardization reliability coefficients were very low. However, following the intervention, all coefficients improved dramatically, two-thirds achieving very high levels. These data suggest that skills development in senior medical students is not uniform and that, while reliability is high for many, the assessment of knee range of movement can be improved by viewing an instructional videotape.

Modeling the G-protein-coupled neuropeptide Y Y1 receptor agonist and antagonist binding sites.

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor (GPCR) superfamily and mediate several physiological responses, such as blood pressure, food intake, sedation and memory retention. To understand the interactions between the NPY Y1 receptor subtype and its ligands, computer modeling was applied to the natural peptide agonist, NPY and a small molecule antagonist, BIBP3226. An agonist and antagonist binding domain was elucidated using mutagenesis data for the Y1 receptor as well as for other GPCR families. The agonist and antagonist ligands which were investigated appear to share common residues for their interaction within the transmembrane regions of the Y1 receptor structure, including Gln120, Asn283 and His306. This is in contrast to findings with tachykinin receptors where the binding domains of the non-peptide antagonists have very little in common with the binding domains of the agonist, substance-P. In addition, a hydrogen bond between the hydroxyl group of Tyr36 of NPY and the side chain of Gln219, an interaction that is absent in the model complex between Y1 and the antagonist BIBP3226, is proposed as one of the potential interactions necessary for receptor activation.

Pharmacology of L-744,453, a novel nonpeptidyl endothelin antagonist.

L-744,453 ((+/-)3-[4-(1-carboxy-1-(3,4-methylenedioxyphenyl)methoxy)-3,5-diprop ylphenyl methyl]-3H-imidazo[4,5-c]pyridine) is an endothelin (ET) receptor antagonist from a new structural class, the dipropyl-alpha-phenoxyphenylacetic acid derivatives. L-744,453 competitively and reversibly inhibits [125I]-ET-1 binding to Chinese Hamster Ovary cells expressing cloned human ET receptors (K(i)s: hET(A)=4.3 nM; hET(B)=232 nM), and is selective for endothelin receptors compared to other peptide receptors. It is an antagonist of ET-1 stimulated phosphatidyl inositol hydrolysis in rat uterine slices (IC50=220 nM) and exhibits no agonist activity. This compound also inhibits ET-1 stimulated contraction of rat aortic rings with a K(b) value of 50 nM. L-744,453 protects against ET-1 induced lethality in mice after i.v. (AD50=13 mg/kg i.v.) or oral administration. This compound also antagonizes ET-1 induced increases in diastolic blood pressure in conscious normotensive rats (AD50=0.67 mg/kg i.v.) and anesthetized ferrets (AD50=1.6 mg/kg i.v.). L-744,453 is a potent, selective, orally active endothelin antagonist which may be useful in elucidating the role of endothelin in normal and pathophysiological states.

Non-peptide angiotensin II receptor antagonists. 1. Design, synthesis, and biological activity of N-substituted indoles and dihydroindoles.

A series of N-acylated indoles (12-18), N-alkylated indoles (19-24), N-acylated dihydroindoles (26-30), and N-alkylated dihydroindoles (31-34) were synthesized and evaluated in the in vitro AT1 (rabbit aorta) and AT2 (rat midbrain) binding assay. The carboxylic acid 3-[[N-(2-carboxy-3,6-dichlorobenzoyl)-5-indolyl]methyl]-5,7-dimeth yl- 2-ethyl-3H-imidazo[4,5-b]pyridine (14b) was found to be the most potent AT1 (IC50 = 0.8 nM) antagonist in the N-acylated indole series and displayed a 25-fold higher potency than the parent unsubstituted derivative 14a (AT1 IC50 = 20 nM) and a 22-fold greater potency than the corresponding dihydroindole analog 27 (AT1 IC50 = 18 nM). Replacement of the terminal carboxyl (COOH) of 14a with the bioisostere tetrazole in 16 (AT1 IC50 = 5 nM, AT2 IC50 = 130 nM) not only improved the AT1 potency by 4-fold but also resulted in a 50-fold increase in AT2 activity. In the N-alkylated indole series, the tetrazole 3-[[N-(2-tetrazol-5-yl-6-chlorobenzyl)-5- indolyl]methyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine (24) exhibited the highest AT1 (IC50 = 1 nM) activity, revealing a 230-fold increase in AT1 activity as a result of the incorporation of the isosteric tetrazole for the carboxyl (COOH) of 20 and a nearly 9-fold increase over the corresponding deschloro analog 22 (AT1 IC50 = 8.7 nM). Tetrazole 34 was identified as the most potent (AT1 IC50 = 18 nM) AT1 receptor antagonist in a structurally distinct series of compounds derived from N-alkylation of dihydroindole 25. A new class of highly potent (14b, AT1 IC50 = 0.8 nM; 24, AT1 IC50 = 1 nM) AT1-selective non-peptide AII receptor antagonists derived from N-substituted indoles and dihydroindoles is disclosed. Tetrazole 24 of the N-alkylated indole series displayed good in vivo activity by blocking the AII-induced pressor response for 5.5 h after intravenous administration in conscious normotensive rats at a 1.0 mg/kg dose level.

Non-peptide angiotensin II receptor antagonists. 2. Design, synthesis, and biological activity of N-substituted (phenylamino)phenylacetic acids and acyl sulfonamides.

The design, synthesis, and biological activity of a new class of highly potent non-peptide AII receptor antagonists derived from N-substituted (phenylamino)phenylacetic acids and acyl sulfonamides which exhibit a high selectivity for the AT1 receptor are described. A series of N-substituted (phenylamino)phenylacetic acids (9) and acyl sulfonamides (16) and a tetrazole derivative (19) were synthesized and evaluated in the in vitro AT1 (rabbit aorta) and AT2 (rat midbrain) binding assay. The (phenylamino)phenylacetic acids 9c (AT1 IC50 = 4 nM, AT2 IC50 = 0.74 microM), 9d (AT1 IC50 = 5.3 nM, AT2 IC50 = 0.49 microM), and 9e (AT1 IC50 = 5.3 nM, AT2 IC50 = 0.56 microM) were found to be the most potent AT1-selective AII antagonists in the acid series. Incorporation of various substituents in the central and bottom phenyl rings led to a decrease in the AT1 and AT2 binding affinity of the resulting compounds. Replacement of the carboxylic acid (CO2H) in 9c, 9d, and 9e with the bioisostere acyl sulfonamide (CONHSO2Ph) resulted in a (5-7)-fold increase in the AT1 potency of 16a (AT1 IC50 = 0.9 nM, AT2 IC50 = 0.2 microM), 16b (AT1 IC50 = 1 nM, AT2 IC50 = 2.9 microM), and 16c (AT1 IC50 = 0.8 nM, AT2 IC50 = 0.42 microM) and yielded acyl sulfonamides with subnanomolar AT1 activity. Incorporation of the acyl sulfonamide (CONHSO2Ph) for the CO2H of 9c not only enhanced the AT1 potency but also effected a marked increase in the AT2 potency of 16a (AT2 IC50 = 0.74 microM of 9c vs 0.2 microM of 16a) and made it the most potent AT2 antagonist in this study. Replacement of the CO2H of 9b with the bioisostere tetrazole resulted in 19 (AT1 IC50 = 15 nM) with a 2-fold loss in the AT1 and a complete loss in the AT2 binding affinity. (Phenylamino)phenylacetic acid 9c demonstrated good oral activity in AII-infused conscious normotensive rats at an oral dose of 1.0 mg/kg by inhibiting the pressor response for > 6 h. Acyl sulfonamides 16a-c displayed excellent in vivo activity by blocking the AII-induced pressor response for > 6 h after oral administration in conscious rats at a 3.0 mg/kg dose level. Both acyl sulfonamides 16a and 16c exhibited superior in vivo activity in rats compared to that of (phenylamino)phenylacetic acid 9c.