Worsening dyspnea in a man with 2 hearts.

We report a case of dyspnea in a 71-year-old man who underwent heterotopic heart transplantation in 2003. At presentation, electrocardiography showed ventricular fibrillation of the native heart and then a progression to both donor and recipient hearts. Synchronized electrical cardioversion restored sinus rhythm and relieved the patient from his symptoms.

2D-QSAR and 3D-QSAR/CoMFA analyses of the N-terminal substituted anthranilic acid based CCK(1) receptor antagonists: 'Hic Rhodus, hic saltus'.

A research is presented on quantitative structure-activity relationship (QSAR) studies on the more recent class of non-peptidic CCK(1) receptor antagonists. Our results suggest that the balance of hydrophobicity and volume dependent polarizability term plays a key role in the antagonism of CCK(1) receptor. The size of the substitution of ligands at particular position which induce steric fit is crucial as well as their hydrophobic contribution. Indicator variables were used after the best model was found to account for the usual structural features. The CoMFA results show a good variance explanation and the best self-predictivity is slightly lower than 60% with both leave-one-out and random-group methods. The CoMFA molecular fields showed the importance of steric hindrance of the substituent. From the GRIND models it can be deduced that the shape differences of the molecules are secondary in the regulation of the activity, or better, that their polar substituents are capable of occupying the same zones of the space in the most of the cases.

Anthranilic acid based CCK1 receptor antagonists: blocking the receptor with the same 'words' of the endogenous ligand.

The anthranilic acid diamides represent the more recent class of nonpeptide CCK(1) receptor antagonists. This class is characterized by the presence of anthranilic acid, used as a molecular scaffold, and two pharmacophores selected from the C-terminal tetrapeptide of CCK. The lead compound coded VL-0395, endowed with sub-micromolar affinity towards CCK(1) receptors, was characterized by the presence of Phe and 2-indole moiety at the C- and N-termini of anthranilic acid, respectively. Herein we describe the first step of the anthranilic acid C-terminal optimization using, instead of Phe, aminoacids belonging to the primary structure of CCK-8 and other not coded residues. Thus we demonstrate that the CCK(1) receptor affinity depends on the nature of the aminoacidic side chain as well as that the free carboxy group of the alpha-aminoacids is crucial for the binding. The R enantiomers of the most active compounds represent the eutomers of this class of antagonists confirming thus the stereo preference of the receptor. Moreover this SAR study demonstrates that the receptor binding pocket, that host the aminoacidic side chain, results much more tolerant respect to that accommodating the indole ring. As a result, an appropriate variation of the aminoacidic side chain could provide a better CCK(1) receptor affinity diorthosis.

New anthranilic acid based antagonists with high affinity and selectivity for the human cholecystokinin receptor 1 (hCCK1-R).

The anthranilic acid diamides represent the most recent class of nonpeptide CCK(1) receptor (CCK(1)-R) antagonists. Herein we describe the second phase of the anthranilic acid C-terminal optimization using nonproteinogenic amino acids containing a phenyl ring in their side chain. The Homo-Phe derivative 2 (VL-0797) enhanced 12-fold the affinity for the rat CCK(1)-R affinity and 15-fold for the human CCK(1)-R relative to the reference compound 12 (VL-0395). The eutomer of 2 (6) exhibited a nanomolar range affinity toward the human CCK(1)-R and was at least 400-fold selective for the CCK(1)-R over the CCK(2)-R. Molecular docking in the modeled CCK(1)-R and its validation by site-directed mutagenesis experiments showed that the 6 binding site overlaps that occupied by the C-terminal bioactive region of the natural agonist CCK. Owing to their interesting properties, new compounds provided by this study represent a solid basis for further advances aimed at synthesis of clinically valuable CCK(1)-R antagonists.

[Aortic intramural hematoma fissuration: atypical presentation in an aircraft pilot]. / Fissurazione di ematoma intramurale aortico: presentazione atipica in pilota d'aereo.

Aortic intramural hematoma is a life-threatening thoracic aortic pathology. In this report we describe a case of fissuration of an aortic intramural hematoma with atypical clinical presentation, which occurred in an aircraft pilot. The patient was admitted to our emergency room with transient chest pain developed during a flight landing, followed only by persistent abdominal pain. The ECG and cardiac enzymes were normal. A portable two-dimensional transthoracic echocardiogram showed aortic root dilation and pericardial effusion. Transesophageal echocardiography showed aortic intramural hematoma with fissuration into the pericardial space. The angio-computed tomography confirmed the diagnosis. Two hours after admission the patient, with signs of cardiac tamponade, underwent Bentall surgical intervention without complications.