The results of this study suggest that although some dentists are using the techniques taught during their undergraduate careers, a large percentage now use techniques with no evidence of clinical effectiveness.
Controversy exists concerning the mode of action of chlorhexidine in plaque inhibition. This study attempted to determine whether an oral reservoir of chlorhexidine was necessary for plaque inhibition. Plaque growth on enamel under the influence of topically applied or rinsed chlorhexidine was closely monitored by clinical scoring, bacterial culturing and scanning electron microscopy. Thus, 3 subjects wore removable acrylic appliances containing enamel inserts. In the first regimen, inserts on one side of the appliances were exposed to 0.2% chlorhexidine and on the other, water for 1 min twice a day for 14 days. In the second regimen, subjects rinsed with 0.2% chlorhexidine for 1 min twice a day for 14 days with the appliances in situ. Results demonstrated that plaque growth assessed by the 3 study methods was very small on chlorhexidine-treated inserts by comparison with water-treated specimens. Importantly, inserts treated with chlorhexidine topically or by rinsing could not be distinguished by any method of evaluation. It is concluded that chlorhexidine achieves plaque inhibition as a result of an immediate bactericidal action during the time of application and a prolonged bacteriostatic action as a result of adsorption to the pellicle coated enamel surface. Consistent with other clinical studies, it is apparent that a progressively desorbing oral reservoir of antiseptic is not the mechanism by which chlorhexidine achieves plaque inhibition on teeth.
The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.
The optimum dose of chlorhexidine delivered by mouthrinse, which balances efficacy against local side-effects, is generally considered to be in the region of 20 mg 2 x daily. Unfortunately, there have been few dose-response studies for chlorhexidine mouthrinses and for these, only limited details are published. The aims of this study were to determine the dose response of chlorhexidine to plaque inhibition and position a 0.1% triclosan rinse within this model. 28 subjects took part in this 7-treatment, double-blind, randomised cross-over 4-day plaque regrowth study. The rinses were 0.01%, 0.05%, 0.1% and 0.2% chlorhexidine, 0.1% triclosan and minus active controls for chlorhexidine and triclosan. On day 1 from a zero plaque baseline, volunteers suspended tooth-cleaning and commenced supervised 2 x daily rinsing with 10 ml volumes of the allocated rinses. On Day 5, plaque was scored by index and area. Treatment differences between the 7 rinses were highly significant. A clear dose-response pattern was seen for chlorhexidine with mean plaque scores decreasing with increasing dose. Even at 0.01%, chlorhexidine showed considerable and significant plaque inhibition compared to control. Triclosan at 0.1% showed limited plaque inhibition and less than 0.01% chlorhexidine. The findings of this study suggest that consideration could be given to low concentration chlorhexidine rinses as adjuncts to oral hygiene.
HIV-1 maturation inhibition (MI) has been clinically validated as an approach to the control of HIV-1 infection. However, identifying an MI with both broad polymorphic spectrum coverage and good oral exposure has been challenging. Herein, we describe the design, synthesis, and preclinical characterization of a potent, orally active, second generation HIV-1 MI, BMS-955176 (2), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen.
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