Lactose drives Enterococcus expansion to promote graft-versus-host disease.

Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that Enterococcus also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. Enterococcus growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates Enterococcus outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic Enterococcus domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.

2-Amino-Benzo[d]isothiazol-3-one derivatives: synthesis and assessment of their antiplatelet/spasmolytic effects.

We describe a series of 2-amino-benzo[d]isothiazol-3-one derivatives (2-8), which were synthesized and screened in vitro for inhibition of platelet aggregation and for their spasmolytic activity, with the awareness that the development of antiplatelet agents with additional vasodilation activity could be beneficial in the treatment of various vaso-occlusive disorders. The tested compounds show a powerful antiplatelet activity and various modifications resulted in molecules possessing antiaggregating effects as well as spasmolytic actions.

Comparison of in vitro and ex vivo antiplatelet effects of 1,2-benzisothiazolin-3-one and its 2-amino derivative.

The in vitro and ex vivo antiplatelet effects of 2-amino-1,2-benzisothiazolin-3-one (1) are compared with those of its parent compound 1,2-benzisothiazolin-3-one (2) and with acetylsalicylic acid (ASA) against different agonists. 2-Amino-1,2-benzisothiazolin-3-one inhibits adenosine diphosphate (ADP)-, arachidonic acid (AA)- and collagen-induced human platelet aggregation in vitro, with IC50 values of 8.90 x 10(-5), 1.50 x 10(-6) and 5.11 x 10(-8) mol/l, respectively. The strong inhibitory activity is significant not only for collagen but also for AA-induced aggregation. The same compound inhibits ex vivo collagen- and particularly AA-induced rabbit platelet aggregation at the tested dose of 10 mg/kg i.m. In view of the potential use of 2-amino-1,2-benzisothiazolin-3-one as antithrombotic agent, the log P values for both 1,2-benzisothiazolin-3-one derivatives 1 and 2 are determined, to gain an understanding of the significance of the 2-amino group in the 1,2-benzisothiazolin-3-one moiety with respect to the biological activity under study.

Synthesis and antiplatelet effects of 2-amino-1,2-benzisothiazolin-3-one.

The synthesis of a new compound, 2-amino-1,2-benzisothiazolin-3-one, is described and its antiplatelet activity was studied. A good platelet aggregation inhibitory activity of the tested drug was clearly demonstrated both in vitro and ex vivo, presumably through an effect on arachidonic acid cascade or directly on thromboxane A2 (TXA2) receptors. An early and long lasting effect on bleeding time has also been observed. The results suggest that 2-amino-1,2-benzisothiazolin-3-one could be a potential antithrombotic agent.

Synthesis, hypoglycemic and toxicological evaluation of new 1,2-benzisothiazolyl derivatives.

The synthesis of 1,2-benzisothiazol-3-ylguanidines, 1,2-benzisothiazol-3-ylbenzensulphonylureas and 1,2-benzisothiazol-3-ylbenzensulphonamides is described. Some of the new compounds showed moderate hypoglycemic activity but most of them caused serious acute toxic effects.

Synthesis and local anesthetic activity of alkylaminoacyl derivatives of 3-amino-1,2-benzisothiazoles.

Two series of new alkylaminoacylamino-1,2-benzisothiazoles were synthetized and assayed for anesthetic activity. The above-mentioned compounds were prepared by reaction between the appropriate amines and 3-(haloacyl)amino-1,2-benzisothiazoles, which had been obtained by acylation of a 3-amino-1,2-benzisothiazole with the required haloacylchloride. The local anesthetic activity of the compounds, isolated as hydrochlorides, was tested for surface, infiltration and trunkular anesthesia. Several compounds proved to be active in infiltration and trunkular anesthesia, whereas no compound showed local surface anesthesia. On the basis of the results obtained the structure-activity relationships were examined.

[Synthesis and anti-inflammatory, antipyretic and analgesics properties of 5-(1,2-benzisothiazolyl)tetrazoles]. / Sintesi e proprietà antiflogistiche antipiretiche ed analgesiche di 5-(1,2-benzisotiazolil)tetrazoli.

Tetrazole analogs of a series of known 1,2-benzisothiazolalkanoic acids were synthesized and tested for anti-inflammatory, antipyretic and analgesic activities in comparison with their corresponding carboxylic acids. The benzisothiazoliltetrazoles showed high antipyretic activity and each tetrazole, except one, was appreciably more potent than the corresponding acid. The examined tetrazoles are generally inactive as anti-inflammatory agents and weakly active in the mouse writhing test, with effect comparable with those of the corresponding carboxylic acids.

[Synthesis and antiphlogistic, antipyretic and analgesic properties of 5-benzisothiazolylalkanoic acids and their functional derivatives]. / Sintesi e proprietà antiflogistiche, antipiretiche ed analgesiche di acidi 5-benzisotiazolilalcanoici e di loro derivati funzionali.

A new series of 3-methoxy-1,2-benzisothiazol-5-ylacetic acid analogs and some of their functional derivatives were synthesized and tested for their analgesic, antipyretic and anti-inflammatory activities. From an analysis of the relationship between structure and pharmacological activity, it was observed that modifications in the acid group induced useful variations in the parameters studied.

[Biological properties of 1,2-benzisothiazole compounds. Spasmolytic effect of N-(cyclohexylaminoethyl)-1,2-benzisothiazole-3-carboxyamides benzene-substituted on segments of human myometrium in virto]. / Proprietà biologiche di composti 1,2-benzisotiazolici. Effetto spasmolitico di N(cicloesilaminoetil)-1,2-benzisotiazol-3-carbossiamidi benzene sostituite su segmenti di miometrio umano "in vitro"

A report is given on the spasmolytic effect of two benzisothiazolcarboxyamides (compound A and compound B). These drugs were able to inhibit the stimulant action of histamine on human isolated myometrium. The potency of the two compounds exceeded by ten times that of ritodrine (a beta adrenergic stimulant), the efficacy was slightly higher (20-30%) than that of papaverine. This pharmacological effect is discussed on the light of the spectrum of activites of the benzisothiazolcarboxyamidic compounds.