The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

A Chinese adolescent girl with Fechtner-like syndrome

We describe a 15-y-old girl with Fechtner-like syndrome, who is the first Chinese reported to have this rare syndrome. She presented with left homonymous hemianopia and neuroimaging revealed haemorrhage in both parietal and occipital lobes. Peripheral blood smear showed macrothrombocytopenia and intracytoplasmic inclusion bodies inside leucocytes. Thrombocytopenia and proteinuria responded to intravenous immunoglobulin and pulsed methylprednisolone. This case illustrates that life-threatening haemorrhage can occur in patients with Fechtner syndrome. Although there was no effective treatment reported in the literature, high dose steroid and immunoglobulin seemed to be useful in our patient. Our patient also had nephritic-nephrotic syndrome with renal insufficiency, which is unusual in adolescent female patients.     

Study of the drug release mechanism from tyrphostin AG-1295-loaded nanospheres by in situ and external sink methods.

The present study focused on in vitro release of polylactide-nanoencapsulated tyrphostin AG-1295, a potential agent for local therapy of restenosis. The drug was formulated in matrix-type nanoparticles, termed nanospheres (NS) using the nanoprecipitation method. AG-1295 is a model for low-molecular weight lipophilic compounds, the release behavior of which cannot be adequately characterized by existing methods. An in vitro release technique suitable for optimizing the nanoparticulate formulation release behavior was developed through a novel external sink method and an in situ release method utilizing the environmental sensitivity of the AG-1295 fluorescence spectrum. Similar tendencies were demonstrated by both methods in drug release studied as a function of selected NS preparation variables. The release properties of the drug fractions varying in their binding mode to the carrier particles were studied by the external sink method. The NS surface-adsorbed drug exhibited a significantly higher release rate compared to the drug entrapped in the polymeric matrix. The in situ release of the encapsulated drug was analyzed using the diffusion models of release from a matrix-type sphere. The release was shown to be a composite process, with a burst phase attributed largely to the rapid dissociation of the surface-bound AG-1295. The diffusion-controlled phase exhibited an alteration in kinetic pattern obviously due to the drug distribution between polymeric matrix compartments differing in their permeability. Drug in vitro release investigation may be effectively used to characterize the drug-carrier interaction and internal carrier structure in nanoparticulate formulations, as well as optimize the release behavior in respect to their therapeutic application.     

Solid and papillary epithelial neoplasms of the pancreas: CT findings

Five female patients and one male patient with solid and papillary epithelial neoplasms of the pancreas were examined with computed tomography (CT). The mean age of the patients was 27 years (range, 13-46 years). All cases showed well-encapsulated, round or lobulated masses consisting of both cystic and solid areas. Cystic portions showed CT numbers that suggested hemorrhagic necrosis. There were no internal septations within the masses. In three tumors located in the head of the pancreas, dilatation of the biliary tree was absent or minimal, although the masses were large. Two tumors contained calcifications. One tumor demonstrated metastatic deposits in liver and lymph nodes. Metastatic masses appeared similar to the primary pancreatic mass. Solid and papillary neoplasm of the pancreas should be the primary diagnostic consideration when characteristic CT findings are detected in a young female patient.     

Cytokine expression and endothelial cell and lymphocyte activation in human cardiac allograft rejection: an immunohistochemical study of endomyocardial biopsy samples.

We used monoclonal antibodies and immunohistochemical staining of frozen tissue sections to study the expression of cytokines in human cardiac allograft rejection. The 113 endomyocardial biopsy samples were stained for interleukin (IL)-2, IL-6, and interferon-gamma. The findings were compared to expression of the endothelial cell adhesion molecule ICAM-1, and the lymphocyte receptor for the adhesion molecule VCAM-1, VLA-4. Four biopsy samples from patients with idiopathic cardiomyopathy served as controls. IL-2 was not expressed in lymphocytes of controls and only occasionally in mild or moderate cellular rejection, humoral rejection, and Quilty lesions. IL-2 expression was prominent in severe cellular rejection. Interferon-gamma expression increased in proportion to the severity of cellular rejection and was not expressed in other conditions. IL-6 staining, which was only observed in occasional cases, was mild. Cytokine and adhesion molecule expression tended to increase with the severity of cellular rejection. This study shows that cytokine expression can be documented in human allograft endomyocardial biopsy samples with immunohistochemical techniques. The findings support the concept of an important role for cytokines in human cardiac allograft rejection.     

Two-year comparative trial on the immunogenicity and adverse effects of purified chick embryo cell rabies vaccine for pre-exposure immunization

The human diploid cell rabies vaccine (HDCV) has been shown to be highly immunogenic when used for pre-exposure immunization. However, the high cost of the product and the adverse reactions seen following booster doses of HDCV have limited its use. A purified chick embryo cell (PCEC) rabies vaccine was compared with the HDCV by two routes of administration for reactogenicity, antibody response, duration of antibody, and anamestic response to boosters over a 2 year period. The study showed that the two vaccines were comparable in their immunogenicity and reactogenicity after initial three dose series. No adverse reactions were noted following the 2 year booster with PCEC. The PCEC can be produced at less than one-half the cost of the HDCV.