Recurrence of Acute Duodenal Ulcer

Nizatidine, 300 mg once nightly, was compared with cimetidine, 800 mg once nightly, for treatment of 212 adult out-patients with acute duodenal ulcers in an eight-week randomized, double-blind, multicentre trial. Patients were endoscoped at weeks 2, 4 and 8, regardless of ulcer healing status. No significant differences in ulcer healing rates between treatment groups were seen at weeks 2 and 4, but at week 8, nizatidine had a significantly higher ulcer healing rate (P=0.036) than cimetidine (86% versus 74%, respectively). Patients with healed ulcers at either week 2 or week 4 had a final endoscopy performed at week 8. The rate of ulcer recurrence was significantly greater (P=0.021) in the cimetidine group at week 8 compared with the nizatidine group: 21% versus 7.3%, respectively. Increasing tolerance to H2 receptor antagonist therapy with prolonged use may explain the higher recurrence rate of cimetidine. Both drugs provided equally rapid and effective symptomatic relief from epigastric pain after two weeks of therapy. Both were equally safe and free from treatment-related adverse effects

Structure of a D2 dopamine receptor–G-protein complex in a lipid membrane

The D2 dopamine receptor (DRD2) is a therapeutic target for Parkinson's disease(1)and antipsychotic drugs(2). DRD2 is activated by the endogenous neurotransmitter dopamine and synthetic agonist drugs such as bromocriptine(3), leading to stimulation of G(i)and inhibition of adenylyl cyclase. Here we used cryo-electron microscopy to elucidate the structure of an agonist-bound activated DRD2-G(i)complex reconstituted into a phospholipid membrane. The extracellular ligand-binding site of DRD2 is remodelled in response to agonist binding, with conformational changes in extracellular loop 2, transmembrane domain 5 (TM5), TM6 and TM7, propagating to opening of the intracellular G(i)-binding site. The DRD2-G(i)structure represents, to our knowledge, the first experimental model of a G-protein-coupled receptor-G-protein complex embedded in a phospholipid bilayer, which serves as a benchmark to validate the interactions seen in previous detergent-bound structures. The structure also reveals interactions that are unique to the membrane-embedded complex, including helix 8 burial in the inner leaflet, ordered lysine and arginine side chains in the membrane interfacial regions, and lipid anchoring of the G protein in the membrane. Our model of the activated DRD2 will help to inform the design of subtype-selective DRD2 ligands for multiple human central nervous system disorders.The structure of the D2 dopamine receptor in complex with its G protein reveals how dopamine receptors are activated and, importantly, how a G-protein-coupled receptor can interact with its G protein in a phospholipid membrane