Ukaipo niho: the place of nurturing for oral health.

OBJECTIVES: To report on oral-health-related characteristics, beliefs, and behaviours among participants in a randomised control trial of an intervention to prevent early childhood caries (ECC) among Maori children, and to determine whether there were any systematic differences between the intervention and control groups at baseline. DESIGN: Baseline measurements from a randomised control trial (involving 222 pregnant Maori women allocated randomly to either Intervention or Delayed groups) which is currently underway. SETTING: The rohe (tribal area) of Waikato-Tainui. METHODS: Self-report information collected on sociodemographic characteristics, pregnancy details, self-reported general and oral health and health-related behaviours, and oral health beliefs. RESULTS: Other than those in the Delayed group being slightly older, on average, there were no significant differences between the two groups. Some 37.0% were expecting their first child. Most reported good health; 43.6% were current smokers, and 26.4% had never smoked. Only 8.2% were current users of alcohol. Almost all were dentate, and 57.7% described their oral health as fair or poor. One in six had had toothache in the previous year; 33.8% reported being uncomfortable about the appearance of their teeth, and 27.7% reported difficulty in eating. Dental service-use was relatively low and symptom-related; 78.9% needed to see a dentist. Overall, most of the sample believed that it was important to avoid sweet foods, visit dentists and to brush the teeth, while about half thought that using fluoride toothpaste and using floss were important. Some 38.2% felt that drinking fluoridated water was important. Oral-health-related fatalism was apparent, with 74.2% believing that most people usually get dental problems, 58.6% believing that most people will need extractions at some stage, and that most children eventually get dental caries. CONCLUSIONS: Mothers' important role in nurturing the well-being of the young child includes the protection and maintenance of the growing child's oral health (or ukaipo niho). The findings provide important insights into Maori mothers' oral health knowledge, beliefs and practices.

Structure-activity relationships in a series of orally active gamma-hydroxy butenolide endothelin antagonists.

The design of potent and selective non-peptide antagonists of endothelin-1 (ET-1) and its related isopeptides are important tools defining the role of ET in human diseases. In this report we will describe the detailed structure-activity relationship (SAR) studies that led to the discovery of a potent series of butenolide ETA selective antagonists. Starting from a micromolar screening hit, PD012527, use of Topliss decision tree analysis led to the discovery of the nanomolar ET(A) selective antagonist PD155080. Further structural modifications around the butenolide ring led directly to the subnanomolar ETA selective antagonist PD156707, IC50's = 0.3 (ET(A)) and 780 nM (ET(B)). This series of compounds exhibited functional activity exemplified by PD156707. This derivative inhibited the ETA receptor mediated release of arachidonic acid from rabbit renal artery vascular smooth muscle cells with an IC50 = 1.1 nM and also inhibited the ET-1 induced contraction of rabbit femoral artery rings (ETA mediated) with a pA2 = 7.6. PD156707 also displayed in vivo functional activity inhibiting the hemodynamic responses due to exogenous administration of ET-1 in rats in a dose dependent fashion. Evidence for the pH dependence of the open and closed tautomerization forms of PD156707 was demonstrated by an NMR study. X-ray crystallographic analysis of the closed butenolide form of PD156707 shows the benzylic group located on the same side of the butenolide ring as the gamma-hydroxyl and the remaining two phenyl groups on the butenolide ring essentially orthogonal to the butenolide ring. Pharmacokinetic parameters for PD156707 in dogs are also presented.

[125I]-PD151242: a selective radioligand for human ETA receptors.

Our aim was to synthesize a new endothelin ETA selective radioligand, [125I]-PD151242 and characterize the compound in human vascular tissue. Binding of [125I]-PD151242 to sections of human aorta was time-dependent and reached equilibrium after 120 min at 23 degrees C with an association rate constant of 1.26 +/- 0.17 x 10(8) M-1 min-1 (n = 3 individuals +/- s.e.mean). The binding was reversible at 23 degrees C with an observed dissociation rate constant of 0.0025 +/- 0.0006 min-1 (n = 3). Saturation binding assays using [125I]-PD151242 revealed a single population of high affinity ET receptors (n = 3) in aorta (KD = 0.76 +/- 0.17 nM; Bmax = 5.98 +/- 1.56 fmol mg-1 protein), pulmonary (KD = 1.75 +/- 0.20 nM; Bmax = 12.78 +/- 1.39 fmol mg-1 protein) and coronary arteries (KD = 0.51 +/- 0.07 nM; Bmax = 44.9 +/- 1.67 fmol mg-1 protein). ETA selective ligands competed for [125I]-PD151242 binding in aorta with nanomolar affinity (BQ123, KD = 0.41 +/- 0.26 nM; FR139317, KD = 0.55 +/- 0.11 nM) whereas the ETB selective compound, BQ3020, competed with micromolar affinity (KD = 1.36 +/- 0.25 microM). In isolated coronary arteries, PD151242 was a functional antagonist and caused a significant, parallel rightward shift of the ET-1 dose-response curve with a pA2 value of 5.92 (n = 5) and a slope of unity. The high affinity and selectivity of [125I]-PD151242 for ETA receptors will facilitate the characterization of this sub-type in human tissues.

Endothelin receptor antagonists: synthesis and structure-activity relationships of substituted benzothiazine-1,1-dioxides.

The development of benzothiazine-1,1-dioxide derivatives as a new structural class of potent endothelin receptor antagonists is described. Structure-activity relationships (SAR) revealed that PD164800 (1) is a potent antagonist of the ETA receptor subtype.

Structure-activity relationships of a novel series of orally active nonpeptide ETA and ETA/B endothelin receptor-selective antagonists.

The development of nonpeptide, low molecular weight antagonists with high potency, oral activity, and selectivity is an important objective to adequately define the potential role of endothelin (ET) and its isopeptides in human diseases. This report describes the structure-activity relationships, ETA/ETB selectivity, and pharmacokinetics of the PD 155080 and PD 156707 series of orally active nonpeptide ET receptor-selective antagonists. Modification of the substituents around the butenolide ring has led to compounds with differing selectivity for human ETA and ETB receptors. Thus, compounds with increased lipophilicity at R2 show increased ETB affinity and a more balanced ETA/ETB profile. For example, the 4-O-n-pentyl analogue of PD 156707 is a potent competitive inhibitor of [125I]ET-1 and [125I]ET-3 binding to human cloned ETA and ETB receptors, with IC50s of 0.8 nM and 44 nM, respectively. Pharmacokinetic properties can also be significantly influenced by structural modifications at the R2 group. The pharmacokinetics of PD 155719, PD 155080, and PD 156707 were compared in male Wistar rats after a 15 mg/kg intravenous or oral gavage dose (three animals per dose). Plasma concentrations were determined by a specific HPLC assay. Oral bioavailability ranged from less than 5% for PD 155719 to 41% for PD 156707 and 87% for PD 155080.

The design of potent and selective inhibitors of thrombin utilizing a piperazinedione template: part 2.

Potent and selective thrombin inhibitors have been prepared with a piperazinedione template and L-amino acids. Likewise, incorporation of D-amino acids led to potent inhibitors with a novel mode of binding. Herein, the structure activity relationships and structural aspects of these compounds will be described.

Potent bicyclic lactam inhibitors of thrombin: Part I: P3 modifications.

Peptidomimetic inhibitors of general structure 1 have been prepared. Optimization of the binding affinities of these compounds through variation of the P3 hydrophobic residue is described. Selected substituted bicylic lactams displayed interesting pharmacological profiles both in vitro and in vivo.

Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications.

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.

Potent and selective bicyclic lactam inhibitors of thrombin: Part 3: P1' modifications.

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors are described. We have explored the SAR around the P1' site. Modification of the P1' site has been found to affect potency and selectivity.