Comparison of Phosphate Binding Capacities of PA21, A Novel Phosphate Binder, with those of other Phosphate Binders in vitro and in vivo.

PURPOSE: The phosphate binding capacity of PA21, a novel phosphate binder, was compared with those of other phosphate binders in vitro and in vivo. METHODS: 1) For in vitro studies, PA21, sevelamer hydrochloride, lanthanum carbonate hydrate, calcium carbonate, and ferric citrate hydrate were incubated with a phosphate solution at 37°C for 2 h. Phosphate binding capacity was assessed at simulated gastrointestinal tract pH levels of 2, 5, and 8 for estimation of clinical effects, and the quantity of phosphate adsorbed by each phosphate binder was determined. 2) For in vivo studies, rats were orally administered various phosphate binders after the oral administration of phosphate solution (100 mg/kg) adjusted to pH 2, 5, or 8, and the effects of PA21 and other phosphate binders on the serum phosphorus level of the rats were investigated. RESULTS: 1) The in vitro studies revealed that PA21 and sevelamer hydrochloride adsorbed phosphate better at all tested pH levels than lanthanum carbonate hydrate, calcium carbonate, and ferric citrate hydrate, and PA21 showed the most potent phosphate binding capacity among the tested compounds. 2) The in vivo studies showed that PA21 dose-dependently inhibited the increase in the serum phosphorus level after the administration of phosphate solution and no difference in the extent of inhibition by PA21 was observed at the different pH levels (in contrast to other phosphate binders). CONCLUSION: These results indicated that PA21 has a phosphate binding capacity over the entire pH range of the GI tract.

Asthma in primary care: making guidelines work.

OBJECTIVE: To determine the views of family physicians regarding selected asthma recommendations from a Canadian practice guideline and the supporting evidence, and to identify issues needing further development if family physicians are to find guideline recommendations to be truly useful clinical tools. SETTING: Four urban communities in Nova Scotia, Prince Edward Island and New Brunswick. PARTICIPANTS: Twenty community family physicians representing different practice settings, and varying according to age and sex, were recruited to participate. DATA COLLECTION: Four focus groups were held, each lasting 2 h, at which recommendations from a published asthma guideline were presented for discussion on the applicability to their practices. The data were analyzed using a grounded theory method. RESULTS: Physicians rely on clinical judgment in lieu of objective measures in diagnosing asthma and resist treating every exacerbation with steroids. They thought that the recommendations on smoking and patient education should have been stronger or more prominent. Patient noncompliance limits the usefulness of home peak flow measures. Topics such as allergy assessment and most pharmacological therapies triggered little discussion. DISCUSSION: Asthma guideline developers and those interested in enhancing compliance with recommendations will need to attend to factors such as physician attitudes and beliefs on a variety of issues, including the use of objective measures and the availability of adequate resources to conduct the tests. Similarly, negative patient attitudes toward an increased use of corticosteroids suggest that a public education program would be most helpful regarding that group of recommendations.

Contractile properties of urethral smooth muscles of young and aged female dogs: morphological and pharmacological aspects.

BACKGROUND: Alpha1-adrenoceptors are highly concentrated in the urethral smooth muscles and may play an important role in the contraction of this area. However, detailed examinations of age-related changes of the properties of urethral smooth muscle have rarely been undertaken. METHODS: The contractile properties of urethras from young non-parous and old parous female beagles were determined with a urethral function study, macroscopic autoradiography for urethras using [3H]-labeled tamsulosin and morphometry of the urethral muscles. RESULTS: The antagonistic effect (pA2) of prazosin for norepinephrine was 7.76+/-0.13 in young dogs and 7.62+/-0.06 in aged dogs. The specific binding of [3H]-tamsulosin (a relatively selective alpha1A-adrenoceptor antagonist) was recognized diffusely in proximal urethras with in vitro autoradiography. The density of binding in smooth muscles was approximately 60 and 40% in circular longitudinal layers, respectively, for both dogs. CONCLUSIONS: The female canine urethra had alpha1A, and alpha1L-adrenoceptors. No age-related changes were seen in the function of the proximal urethra, distribution of alpha1-adrenoceptor binding sites and smooth muscle densities.

Inhibition of interleukin 5 production with no influence on interleukin 4 production by an anti-allergic drug, tranilast, in Toxocara canis-infected mice.

Tranilast is well-known as a useful drug for allergic diseases. This drug is believed to exhibit its therapeutic effects by inhibiting the release of chemical mediators from mast cells and basophils. Effects of tranilast on T helper type 2 (Th2) cytokine production were investigated in mice infected with Toxocara canis (Tc). Tranilast reduced interleukin (IL)-5 production in a dose-dependent manner but not IL-4 production at all in lung and spleen cells from Tc-infected mice cultured under stimulation with excretory-secretory antigen. Obvious IL-5 mRNA expression was observed at week 1 in the lung alone, and IL-4 mRNA expression was detected at similar levels at weeks 1-6 of infection in both lung and spleen. IL-5 but not IL-4 mRNA expression in the lung was significantly inhibited by daily administration of 100 mg/kg of tranilast for 1 week. This treatment also reduced the serum IL-5 level. Thus, tranilast inhibited IL-5 but not IL-4 production either in vitro or in vivo. The results imply that IL-5 and IL-4 production by Th2 cells may be controlled through different mechanisms.

KMD-3213, a uroselective and long-acting alpha(1a)-adrenoceptor antagonist, tested in a novel rat model.

KMD-3213, an alpha(1a)-adrenoceptor (AR) antagonist, is under development for the treatment of urinary outlet obstruction in patients with benign prostatic hypertrophy. In the present study, we developed a rat model to investigate simply the effects of alpha(1)-AR antagonists on the intraurethral pressure (IUP) response to phenylephrine. Using this model, inhibitory effects of both i.v. and intraduodenally administered KMD-3213 on the IUP response were evaluated and compared to those of other reference compounds, including prazosin and tamsulosin. In addition, the hypotensive effects of these compounds were estimated to evaluate uroselectivity. Intravenously administered alpha(1)-AR antagonists tested, including KMD-3213, potently inhibited the IUP response in a dose-dependent manner. Although the higher doses of those compounds almost completely inhibited the IUP response, yohimbine failed to inhibit the response. When the in vivo potencies of those compounds on IUP response were correlated with their affinities for the human or animal recombinant alpha(1)-AR subtypes, alpha(1a)-AR gave the best correlation. In this model, KMD-3213 had greater uroselectivity than any other compounds examined, by both i.v. and intraduodenal routes. Moreover, 12, 18, and 24 h after the oral administration of KMD-3213, a dose-dependent inhibition of the IUP response was found, whereas the effect of tamsulosin disappeared at 18 h after the oral administration. These data indicate that KMD-3213 is a highly uroselective alpha(1)-AR antagonist with a longer duration of action. In addition, this model is useful for not only estimation of uroselectivity but also some part of the administration, distribution, metabolism, and excretion of many compounds to discover uroselective compounds.

Regional vascular capacitance in rabbit one-kidney, one clip hypertension.

One-kidney Goldblatt hypertensive rabbits (New Zealand White) were studied after durations of renal artery clipping that varied from 6 to 17 days. Measurements included arterial pressure (ABP), iliac venous pressure (IVP), left atrial pressure (LAP), cardiac output (CO) (by thermodilution), blood volume (BV), cardiopulmonary volume (CPV), and hindleg thermodilution volume (HLV). These were determined at steady-state as well as during acute blood volume expansion. In sham-clipped animals, ABP was 74 +/- 1 mm Hg. This increased to 92 +/- 3 mm Hg by 6 to 9 days post-clipping, to 96 +/- 3 mm Hg by 10 to 13 days, to 89 +/- 4 mm Hg by 14 to 17 days. CO remained near 150 ml/min . kg until Day 13 and fell to 127 +/- 8 ml/min . kg at 14 to 17 days because of a fall in heart rate. Blood volume and stroke volume did not change significantly from 62 +/- 1 ml/kg and 0.60 +/- 0.04 ml/kg, respectively. The development of hypertension was due entirely to changes in peripheral resistance. CPV was 8.5 ml/kg initially and increased significantly as hypertension developed. HLV did not change significantly from about 10 ml/kg. During acute blood volume expansion, hypertensive animals showed smaller transient increases in CO than did sham-clipped normotensives, but the associated blood pressure rise was greater. This reduced vasodilator capacity was accompanied by reduced distensibility of the cardiopulmonary bed. In sham-clipped animals, the cardiopulmonary pressure/volume slope was between 0.05 and 0.07 mm Hg per ml/kg. This increased to 0.44 mm Hg per ml/kg by 14--17 days of clipping. The corresponding value for the hindleg region did not change significantly from 0.2 mm Hg per ml/kg. Cardiac output and stroke volume were directly correlated with cardiopulmonary volume. The slope of this correlation decreased significantly during hypertension. The data suggest that decreased cardiopulmonary compliance in hypertension minimizes transient changes in cardiac output. This is especially important for arterial blood pressure control in view of the impaired vasodilator capacity of the hypertensive circulation.