No abstract

We assessed the clinical usefulness of quantitative ultrasound (QUS) in defining the prevalence rates of osteoporosis and osteopenia and their association with fractures of the forearm, vertebrae, and hip. The ESOPO study was conducted in 2001 and assessed a random sample of 11,011 women and 4,981 men, in 83 centers spread all over Italy. A large array of risk factors was investigated, and self-reported history of fractures was collected in a questionnaire. After the patient had undergone interview and a brief physical examination, QUS of the heel was performed, using the Achilles apparatus (GE-Lunar, Madison, USA). The prevalence rate of osteoporosis in women 40-79 years old was approximately 18.5%, while the rate of osteopenia was about 44.7%; in men 60-79 years of age the rates were 10% and 36%, respectively. A strong association with fractures was found for osteoporosis and osteopenia in both men and women, independently of all traditional risk factors, including age. These results confirm the suitability of US measurements as a tool for detecting individuals at risk of fractures.

I.F. 2.95

As a continuation of previous efforts in mapping functional hot spots on the bile acid scaffold, we here demonstrate that the introduction of a hydroxy group at the C11β position affords high selectivity for FXR. In particular, the synthesis and FXR/TGR5 activity of novel bile acids bearing different hydroxylation patterns at the C ring are reported and discussed from a structure-activity standpoint. The results obtained led us to discover the first bile acid derivative endowed with high potency and selectivity at the FXR receptor, 3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic acid (TC-100, 7) which also shows a remarkable physicochemical and pharmacological profile. Compound 7 combines the excellent physicochemical properties of hydrophilic bile acids such as ursodeoxycholic acid, with the distinct ability to specifically bind and regulate FXR activity in vivo, thus providing a bona fide novel therapeutic agent to treat enterohepatic disorders such as cholestasis, NASH, and inflammatory bowel disease.

No abstract

A rapid and eco-friendly synthesis of a sulfonamide library under flow conditions is described. The study illustrates an efficient, safe, and easily scalable preparation of sulfonamides by use of a meso-reactor apparatus, thus demonstrating the impact of flow technologies within drug discovery. Waste minimization, employment of green media, and nontoxic reactants are achieved by the optimization of the flow setup and experimental protocol designed to sequentially synthesize primary, secondary, and tertiary sulfonamides. Isolation of the products involves only extraction and precipitation affording pure compounds in good to high yields without further purification for biological evaluation.

An efficient multistep method for the continuous flow synthesis of thieno[2,3-\ud c]isoquinolin-5(4H)-one-A (TIQ-A), an important pharmacological tool and building block for \ud PARP-1 inhibitors, has been developed. The synthesis involves a Suzuki coupling reaction to \ud generate 3-phenylthiophene-2-carboxylic acid which is transformed into the corresponding acyl \ud azide and readily cyclized by thermal Curtius rearrangement. Statistical Design of Experiments \ud (DoE) was employed as a valuable support for decision-making of further experiments enabling \ud the development of a robust and reliable protocol for large scale preparation. As a result, the \ud reactions are facile, safe, and easy to scale-up. The large scale applicability of this improved flow \ud method was tested by conducting the reactions on multigram scale to produce the desired product \ud in high yield and quality for bio-pharmacological appraisals

A new method for the calorimetric characterization of high-energetic, fast reactions in flow mode was developed. The use of an engineered flow reactor in combination with a process modeling software allowed the deconvolution of the reaction enthalpy from space-resolved temperature profiles. The new procedure was verified in a comparison with a conventional batch calorimeter and subsequently implemented for the thermal characterization of an organolithium flow process. The information collected for this reaction successfully supported a scale-up to the pilot plant. Overall, the new approach resulted in being superior when compared with established procedures, enabling the generation of precise calorimetric data in an accurate scale-down flow device.