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PDE4(Phosphodieterase 4)	1

Human 5-HT7A receptors positively modulated adenylyl cyclases via Gs subtypes of G proteins in human embryonic kidney 293 cells, and bound 5-hydroxytryptamine (HT) with high and low affinity (K(I) values of 1.5 +/- 0.3 and 93 +/- 4 nM). More than 60% of 5-HT7A receptors, however, displayed the high-affinity 5-HT binding with no sensitivity to 5'-guanylylimidodiphosphate. In this study, we found that select amphipathic agents affected the high-affinity 5-HT binding to 5-HT7A. Oleic acid at low concentrations (<15 microM), but not palmitic, stearic, and arachidonic acids, increased maximal [3H]5-HT binding without affecting its K(D) value and [3H]mesulergine (antagonist) binding. Fatty acid-free bovine serum albumin (FF-BSA), a scavenger of fatty acids and lipid metabolites, substantially reduced maximal [3H]5-HT binding (no change in K(D) value and antagonist binding) but lost its action upon treatment with inactive stearic acid. FF-BSA and oleic acid produced no appreciable effects on [3H]5-HT binding to analogous 5-HT receptors 5-HT1D and 5-HT2C. Among various lysophospholipids, lysophosphatidyl choline (50 microM) decreased maximal [3H]5-HT binding, and a similar zwitterion, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS; 0.1%), increased it (no change in K(D)). Functionally, 5-HT-induced guanosine-5'-O-(3-[35S]thio)triphosphate (GTPgamma35S) binding was enhanced by oleic acid and CHAPS, but reduced by FF-BSA and lysophosphatidyl choline; the amphipathic agents and FF-BSA did not affect dopamine-induced GTPgamma35S binding at D1, a prototypic Gs-coupled receptor. At 5-HT7A, oleic acid, FF-BSA, CHAPS, and lysophosphatidyl choline also brought about corresponding changes in the half-maximal 5-HT concentration for cAMP production, without affecting the maximal and basal levels. We propose that endogenous, amphipathic lipid metabolites may modulate 5-HT7A receptors allosterically to promote high-affinity 5-HT binding and to enable receptors to couple more efficiently to Gs subtypes of G proteins.

01 Sep 2001·PharmacoEconomics Italian Research Articles

Uno studio retrospettivo condotto presso i medici di medicina generale

Author: Silvia Chiroli ; D. Roggeri

This study aim was to evaluate the resource consumption and costs related to gastrointestinal adverse events of non steroidal anti-inflammatory drugs (NSAIDs) from the perspective of the Italian National Health Service. A retrospective, observational study of 3–6 months’ duration. 51 General Practitioners (GPs) in Italy. Participating GPs were asked to fill up, for at least a three months’ period, a report form describing adverse events in pts. with ostheoarthritis and rheumathoid arthritis treated with NSAIDs. 541 adverse events of different severity were recorded. Costs related to one day therapy per event were the following: 1,54 € for gastro-intestinal event (dyspepsia and abdominal pain), 2,41 € for bleeding without hospitalisation, 21,71 € for bleeding with hospitalisation, 2,73 € for ulcer without hospitalisation, 14,06 € for ulcer with hospitalisation, 60,05 € for ulcer complications. Within each category, costs were higher for hospitalised pts. compared with outpatients. When only non-hospitalised pts. were considered, there were wide cost differences among the four categories of adverse events. Treatment costs due to each adverse event related to NSAIDs are relevant. Hospitalisation is the major driver of cost (more than 78% of the total cost); when hospitalisation is not required, the major driver of cost is drug prescription (more than 52%).

01 Aug 2001·BiochemistryQ3 · BIOLOGY

Thermodynamics of HMGB1 Interaction with Duplex DNA

Q3 · BIOLOGY

Article

Author: Knapp, Stefan ; Müller, Susanne ; Bianchi, Marco E.

The high mobility group protein HMGB1 is a small, highly abundant protein that binds to DNA in a non-sequence-specific manner. HMGB1 consists of 2 DNA binding domains, the HMG boxes A and B, followed by a short basic region and a continuous stretch of 30 glutamate or aspartate residues. Isothermal titration calorimetry was used to characterize the binding of HMGB1 to the double-stranded model DNAs poly(dAdT).(dTdA) and poly(dGdC).(dCdG). To elucidate the contribution of the different structural motifs to DNA binding, calorimetric measurements were performed comparing the single boxes A and B, the two boxes plus or minus the basic sequence stretch (AB(bt) and AB), and the full-length HMGB1 protein. Thermodynamically, binding of HMGB1 and all truncated constructs to duplex DNA was characterized by a positive enthalpy change at 15 degrees C. From the slopes of the temperature dependence of the binding enthalpies, heat capacity changes of -0.129 +/- 0.02 and -0.105 +/- 0.05 kcal mol(-1) K(-1) were determined for box A and full-length HMGB1, respectively. Significant differences in the binding characteristics were observed using full-length HMGB1, suggesting an important role for the acid tail in modulating DNA binding. Moreover, full-length HMGB1 binds differently these two DNA templates: binding to poly(dAdT).(dTdA) was cooperative, had a larger apparent binding site size, and proceeded with a much larger unfavorable binding enthalpy than binding to poly(dGdC).(dCdG).

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Pipeline

Pipeline Snapshot as of 23 Jan 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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