An extremely rare serovar of Salmonella enterica (Yopougon) discovered in a Western Whip Snake (Hierophis viridiflavus) from Montecristo Island, Italy: case report and review.

Reptiles, including snakes, can be asymptomatically infected with multiple pathogen microorganisms, including Salmonella spp., which is considered an important concern for public and animal health. Small and uninhabited isles are quite ecologically different from mainland and represent interesting fields of study, to discover unexpected biological and microbiological aspects of their wild inhabitants.

Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model.

Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model.

Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor.

The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels of selectivity across the kinome. Herein we report our structure-based optimization strategy of a dibenzodiazepine hit 1, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1 such as 2 and 3.

Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K.

PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment.

Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor.

Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional phosphoinositide 3-kinase (PI3K) inhibitors from different chemical classes with a different selectivity profile. The key to achieve these objectives was to couple a structure-based design approach with intensive pharmacologic evaluation of selected compounds during the medicinal chemistry optimization process. Here, we report on the biologic characterization of the 2-morpholino pyrimidine derivative pan-PI3K inhibitor NVP-BKM120.

Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.

Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma).

Synthesis and in Vitro and in Vivo Evaluation of Phosphoinositide-3-kinase Inhibitors.

Phospoinositide-3-kinases (PI3K) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. A series of 2-morpholino, 4-substituted, 6-(3-hydroxyphenyl) pyrimidines have been reported as potent inhibitors of PI3Ks. Herein, we describe the structure-guided optimization of these pyrimidines with a focus on replacing the phenol moiety, while maintaining potent target inhibition and improving in vivo properties.

Identification and structure-activity relationship of 2-morpholino 6-(3-hydroxyphenyl) pyrimidines, a class of potent and selective PI3 kinase inhibitors.

PI3 Kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration, and differentiation. The PI3 kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations, and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment.

Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors.

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy.

4-(Aminoalkylamino)-3-benzimidazole-quinolinones as potent CHK-1 inhibitors.

CHK-1 is one of the key enzymes regulating checkpoints in cellular growth cycles. Novel 4-(amino-alkylamino)-3-benzimidazole-quinolinones were prepared and assayed for their ability to inhibit CHK-1. These compounds are potent cell permeable CHK-1 inhibitors and showed synergistic effect with a DNA-damaging agent, camptothecin.

Design and structure-activity relationship of heterocyclic analogs of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones as inhibitors of receptor tyrosine kinases.

Herein are described a series of novel heterocyclic analogs of the 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one scaffold. These compounds are potent inhibitors of receptor tyrosine kinases and exhibit favorable pharmacokinetic profiles. The synthesis and SAR of these compounds are described.

Different Pathways in the Base-Promoted Isomerization of Benzyl Oxiranyl Ethers.

The base-promoted isomerization of benzyl oxiranyl ethers was investigated. In particular it was shown that the reaction may proceed toward two main regioisomeric products: a benzyl vinyl ether or a 2-aryl-3-(hydroxyalkyl)oxetane, depending on subtle variations in the substitution on the phenyl ring. Disubstituted oxetanes were obtained in a stereoselective manner, thus providing a good entry to this class of synthetically useful compounds.

Evidence of an adenosine-dependent mechanism in the hypotensive effect of L-arginine in man.

1. The hypothesis that endogenous adenosine could play a role in the haemodynamic response to L-arginine is investigated. 2.

Hemodynamic and hemorheologic effects of i.v. Dilevalol in hypertensive patients.

The authors evaluated the effect of Dilevalol infusion on blood pressure, heart rate, central hemodynamics, and rheologic parameters in hospitalized inpatients affected with mild or moderate hypertension. After a dose-finding phase and a washout period of one week, 10 patients aged fifty to seventy-two-years (median 61.5) were given either a single dose of Dilevalol 60 mg or placebo, and seven days later they underwent the other treatment, according to a single-blind, crossover design.

Plethysmographic evaluation of the vascular effects of human calcitonin gene-related peptide in man.

Calcitonin gene-related peptide (CGRP) is a neuropeptide with potent cardiovascular effects that include positive inotropic and chronotropic actions systemic vasodilation, and hypotension in animals and in man. The mechanism of action of CGRP is still, however, not clear, and in particular it is not known whether vasodilation by CGRP occurs by changes in cutaneous or in muscular blood flow, or both. The aim of the study was, therefore, to evaluate the cutaneous and muscular blood flow, at rest and after ischemic test, induced by an IV bolus 25 micrograms human CGRP infusion in 5 healthy normotensive volunteers, using a strain gauge plethysmographic procedure with venous occlusion.

[The effects of the acute administration of vinburnine on blood rheology, oxygen transport and regional circulation under normal conditions and in hypoxemia. In vivo research].

Vinburnine has been shown to be effective in avoiding chronic ischaemic tissue injury. Many studies have demonstrated the antihypoxic and oxygenation properties of this drug. In our study we have evaluated in two groups of patients the effects on blood rheology, oxygen transport, regional circulation and ergospirometric data of 40 mg vinburnine infused in a systemic vein.

[Calcium dobesilate in the treatment of primary venous insufficiency of the lower limbs. A controlled clinical study].

Fourty patients with lower limb chronic venous insufficiency entered a randomised placebo controlled study with calcium dobesilate for one month. Clinical symptoms and plethysmographic parameters were evaluated before and after therapy in all patients. In the group of patients treated with calcium dobesilate we observed an improvement of clinical and instrumental parameters; no changes were found in the placebo group.

In vivo and in vitro evidence of an adenosine-mediated mechanism of calcium entry blocker activities.

Drugs such as dipyridamole (200 micrograms/kg/min), an adenosine uptake inhibitor, and theophylline (300 micrograms/kg/min), an adenosine receptor antagonist, respectively increased and decreased postischemic hyperemia in normal subjects, as well as in POAD patients. Moreover, dipyridamole pretreatment was able to antagonize the reduction of peak flow induced by nifedipine, and the potentiating effect of flunarizine on postischemic hyperemia was affected significantly by theophylline, thus suggesting a possible interference of calcium entry blocker drugs with the endogenous adenosine system. In a cellular model (polymorphonuclear leukocytes--PMN) the inhibitory effect of calcium entry blockers on stimulated functions (degranulation and free radical production) was highly antagonized by theophylline.

Efficacy of O-(beta-hydroxyethyl)-rutosides at high dosage in counteracting the unwanted activity of oral contraceptives on venous function.

In a double-blind study the effect of a high dosage of O-(beta-hydroxyethyl)-rutosides (HR) was tested in women taking oral contraceptives and suffering from venous insufficiency of the lower limbs. Ten patients were treated for 28 days with HR (3 g/day) and ten with a placebo. In basal conditions and after therapy, the symptoms of venous disorders and the venous function, by means of strain gauge plethysmography, was evaluated in both groups.

[Can normovolemic hemodilution really modify blood flow in the limbs?].

A clinical study on the effects of the normovolemic hemodilution on hemorheological and peripheral hemodynamic parameters has been carried out in patients with peripheral obliterative arterial disease. Two sessions have been performed: the acute test consisted in daily normovolemic hemodilutions for a period of 7 days in 10 patients with the determination of hemorheological and peripheral hemodynamic parameters before and after each treatment. A chronic study was then carried out in 8 patients by applying weekly normovolemic hemodilutions, by evaluating the hemorheological parameters as in the first session and by measuring the peripheral hemodynamic parameters at the beginning, after 5 weeks and at the end of the treatment.

Influence of non-selective and selective beta adrenoceptor blockade on isoxsuprine-dependent hemodynamic and rheologic changes.

The infusion of isoxsuprine was followed by an increase of heart rate and calf blood flow and by a decrease of arterial diastolic pressure and blood viscosity both in normal controls and patients with peripheral obstructive arterial disease. The pre-treatment with a non-selective beta adrenoceptor blocker (propranolol) canceled all the isoxsuprine-dependent changes, while the pre-treatment with a selective beta adrenoceptor blocker (metoprolol) abolished only tachycardia and did not influence the increase of calf blood flow and the decrease of blood viscosity. These findings indicate the different role of vascular beta receptors in the regulation of muscular blood flow and suggest the pharmacologic possibility to unmask the beta2-dependent vasodilation.