Defining Substance Use Disorders: Do We Really Need More Than Heavy Use?

Aims: The aim of the study was to explore whether the concept of heavy substance use over time can be used as definition of substance use disorder. Methods: Narrative review. Results: Heavy use over time clearly underlies the neurobiological changes associated with current thinking of substance use disorders. In addition, there is evidence that heavy use over time can explain the majority of social problems and of burden of disease (morbidity and mortality). A definition of substance use disorders via heavy use over time would avoid some of the problems of current conceptualizations, for instance the cultural specificity of concepts such as loss of control. Finally, stressing the continuum of use may avoid the high level of stigmatization currently associated with substance use disorders. Conclusion: ‘Heavy substance use over time' seems to be a definition of substance use disorders in line with results of basic research and epidemiology. Additionally, it reduces stigmatization. This approach should thus be further explore

The Tangible Common Denominator of Substance Use Disorders: A Reply to Commentaries to Rehm et al. (2013a)

In response to our suggestion to define substance use disorders via ‘heavy use over time', theoretical and conceptual issues, measurement problems and implications for stigma and clinical practice were raised. With respect to theoretical and conceptual issues, no other criterion has been shown, which would improve the definition. Moreover, heavy use over time is shown to be highly correlated with number of criteria in current DSM-5. Measurement of heavy use over time is simple and while there will be some underestimation or misrepresentation of actual levels in clinical practice, this is not different from the status quo and measurement of current criteria. As regards to stigma, research has shown that a truly dimensional concept can help reduce stigma. In conclusion, ‘heavy use over time' as a tangible common denominator should be seriously considered as definition for substance use disorde

Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli

Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C β-lactamase from Escherichia coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied β-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D β-lactamases, our data support the proposal that bicyclic boronates are broad-spectrum β-lactamase inhibitors that work by mimicking a high energy ‘tetrahedral’ intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful β-lactamase inhibition

The tangible common denominator of substance use disorders: a reply to commentaries to Rehm et al. (2013a).

In response to our suggestion to define substance use disorders via 'heavy use over time', theoretical and conceptual issues, measurement problems and implications for stigma and clinical practice were raised. With respect to theoretical and conceptual issues, no other criterion has been shown, which would improve the definition. Moreover, heavy use over time is shown to be highly correlated with number of criteria in current DSM-5. Measurement of heavy use over time is simple and while there will be some underestimation or misrepresentation of actual levels in clinical practice, this is not different from the status quo and measurement of current criteria. As regards to stigma, research has shown that a truly dimensional concept can help reduce stigma. In conclusion, 'heavy use over time' as a tangible common denominator should be seriously considered as definition for substance use disorder

Synthesis of small and medium size monocyclic hydroxamic acids

International audienc

Reaction of Diaziridine-3,3-dicarboxylic Acid Dihydrazide with Acetone

Using the reaction of diaziridine-3,3-dicarboxylic acid dihydrazide with acetone, new bicyclic diaziridines 7a,b have been obtained instead of expected tricyclic heterocycle 8

Facile Synthesis of Coumarin Bioisosteres—1,2-Benzoxathiine 2,2-Dioxides

A simple and reproducible procedure for the synthesis of bioisosteres of coumarin—1,2-benzoxathiine 2,2-dioxide is presented. The developed method is based on the intramolecular aldol cyclization of derivatives of mesylsalicyl aldehydes in the presence of strong organic bases, where best results were obtained with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). It has been shown that depending on the nature of the substituent in the aromatic ring, intermediate aldol adducts (3,4-dihydro-1,2-benzoxathiin-4-ol 2,2-dioxides) in different ratios with title compound are formed. Dehydration of the intermediate aldols with POCl3 led to full conversion into 1,2-benzoxathiine 2,2-dioxide derivatives. The scaffold of 1,2-benzoxathiine 2,2-dioxide is unequivocally proven by a single-crystal X-ray structure

Functionalization of 3-Chlorobenzaldehyde

2-Substituted 3-chlorobenzaldehydes were prepared from the corresponding 2-(3-chlorophenyl)-1,3-dioxolanes using an ortho-lithiation strategy. The 6-chloro-2-formylbenzamide exists only in a ring form, but 6-chloro-2-formylbenzoic acid esters were isolated in both forms as open chain and cyclic tautomers. 7-Chloro-3-hydroxy-3H-isobenzofuran-1-one reacted with nucleophilic reagents at the carbonyl or quaternary carbon depending on the character of nucleophile