379 Long-Term Treatment with Lamivudine Up to Ten Years: Predictive Value of Host and Virus Related Risk Factors for the Development of HBV Resistance

treatment of GERD is limited.We have discovered a GABA B receptor agonist [(R)-(3amino-2-fluoropropyl)phosphinic acid; AZD3355] and determined its effects on TLESR.For comparative purposes, the effects of baclofen and GABA (endogenous ligand) were also assessed.Experiments were carried out in Labrador retrievers using standard Dentsleeve manometry.To further characterize AZD3355, the compound was given once daily at 7 µmol/kg p.o. for 14 days (n=6), and TLESRs were measured after the 1st, 3rd, 7th and 14th dose.In other experiments, the duration of action of AZD3355 was determined (n=4-6).Results: AZD3355 inhibited TLESRs in dogs with an ED 50 ≈7 µmol/kg (p.o.).Increasing the dose up to 100 µmol/kg only slightly accentuated the effect but almost complete inhibition (90±10%) was seen at 300 µmol/kg.This dose was close to the threshold for induction of CNS side-effects (500 µmol/kg).The dose-response curve for baclofen had a regular monophasic shape, and maximal inhibition (some 90%) was achieved at 7 µmol/kg p.o.At 10 µmol/ kg, typical GABA B mediated side-effects were noted.Due to low oral availability and short plasma t ½ , GABA was continuously infused i.v.The maximal inhibition of TLESR afforded by GABA was 53±16% at 2.6 µmol/kg x min.There was no tolerance development to AZD3355: inhibition of TLESR was 33±12% on day 1, 41±4% on day 3, 32±10% on day 7 and 30±5% on day 14.In the duration of action study, AZD3355 (7 µmol/kg) inhibited TLESR by 50±8% when measured 30 min after dosing.The corresponding figures for 3, 5 and 8 h were 36±10%, 21±11% and 10±6%, respectively.At 35 µmol/kg, AZD3355 provided 60±8% inhibition 30 min after administration.At 3, 5, 8, 12 and 18 h, the inhibition was 49±7%, 71±8%, 51±8%, 36±6% and 26±12%, respectively.Conclusion: AZD3355 reproducibly inhibits TLESRs in dogs.The similarity between the dose-response curves for AZD3355 and GABA, a peripherally restricted agonist, suggests that AZD3355, in contrast to baclofen, reduces TLESR through a peripheral site of action.AZD3355 does not induce tolerance after once daily administration for 14 days, and has a dose-dependent duration of action.The favorable properties of AZD3355 make it a candidate for the treatment of GERD with the prospect of becoming the first purpose-designed reflux inhibitor.