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.     

The clinical course of Felty's syndrome compared to matched controls

In a cohort of 919 patients with definite or classic rheumatoid arthritis followed prospectively since 1966, we identified 36 patients with Felty's syndrome (FS). Their clinical course was compared to that of 72 matched controls from the same cohort. Patients with FS had more extraarticular features and more infections than control patients. The presence of joint erosions, serial Lansbury indices, and death rates were similar in both groups. Cardiovascular disease was the commonest cause of death in both groups, accounting for 32% of all deaths. Sepsis accounted for 10% of deaths in the group with FS and 13% of deaths in the controls.     

Effects of two synthetic parathyroid hormone-related protein fragments on maternofetal transfer of calcium and magnesium and release of cyclic AMP by the in-situ perfused rat placenta.

Two human parathyroid hormone-related protein (hPTHrP) fragments were tested for effects on maternofetal transfer of 45Ca and Mg across the in-situ perfused rat placenta at 21 days of gestation (term = 23 days). The fetal placental circulation was perfused with a Mg-free Krebs-Ringer solution and the unidirectional maternofetal clearance (Kmf) of 45Ca and Mg compared with that of 51Cr-EDTA, the latter being employed as a paracellular diffusional marker. Placental perfusion with hPTHrP(1-34) (100 ng/ml) or hPTHrP(75-86)amide (50 ng/ml) did not significantly alter the Kmf of 45Ca or that of Mg. In separate rats, however, hPTHrP(1-34) but not hPTHrP(75-86)amide stimulated marked placental cyclic AMP (cAMP) release, the peak response of 63 +/- 7 pmol/min occurring 10 min after the beginning of the peptide perfusion. A lower dose of hPTHrP(1-34) (4 ng/ml) produced a similar peak release of cAMP, as did [Nle8,21, Tyr34]-rPTH(1-34)amide (4 ng/ml) and the adenylate cyclase agonist forskolin (17 mumol/l). Forskolin also rapidly increased the Kmf of 45Ca but not that of Mg or 51Cr-EDTA. The present study indicates that hPTHrP does not acutely affect maternofetal transfer of Ca or Mg across the perfused rat placenta. The data also question the role played by cAMP in the stimulatory actions of forskolin on placental Ca transport.     

Renal transplant function after ten years of cyclosporine.

Although the nephrotoxic side effects of cyclosporine are well known, the impact of long-term CsA on renal transplant function is uncertain. We studied 5-10-year renal function in 347 CsA-treated patients, and in 64 randomly selected non-CsA-treated patients who had a minimum of 55 months of graft function. Non-CsA patients had a lower creatinine (Cr) level at one year than CsA patients (P = .001), with no change in renal function over time (P = .6). In CsA-treated patients there was also no suggestion of progressive renal damage, as evidenced by no change in Cr or 1/Cr. Simple linear regression models of 1/Cr vs. time for the first 10 years posttransplant were fit to the data for each patient. Analysis of the Y-intercept estimates from these regressions showed that age (P = .001), sex (P = .001), cyclosporine toxicity (P = .024), and initial cyclosporine dosage (P = .016) significantly affected the one-year serum Cr. Variables not affecting one-year Cr included donor source, early rejection episodes, late rejection episodes, ATN, diabetes, transplant number, HLA ABDR mismatch (for cadaver transplants), maximum PRA, and PRA at transplant. Analysis of the slope estimates from the regressions revealed that only age (P = .001) and late rejection episodes (P = .001) significantly affected the rate of change in 1/Cr over time. We conclude that, in long-term renal transplant patients, there is no evidence of progressive deterioration in renal function due to CsA nephrotoxicity.     

Internal iliac artery embolisation for the control of severe bladder and prostate haemorrhage

Embolisation of the internal iliac artery was preformed under local anaesthesia in eight patients with severe bladder haemorrhage and in two with severe bleeding from the prostatic bed after prostatectomy. Good and effective control of the bleeding was achieved in six of the patients with bladder haemorrhage, with a partial response in the other two. Both patients with post-prostatectomy bleeding responded well to embolisation, with prompt cessation of the bleeding. This technique is recommended for the control of severe bleeding from the bladder or prostate in the seriously ill patient.     

An unexpected complication following immunoadsorption with a staphylococcal protein a column

Extracorporeal immune adsorption with staphylococcal protein A (SPA) columns can remove immune complexes and immunoglobulins in the treatment of a variety of diseases. We present the case of an elderly man with neuropathy associated with monoclonal gammopathy, treated by 3 on-line SPA procedures. At the completion of these treatments his neuropathy relapsed, progressing to near-total paralysis. Return to a baseline clinical status required several months. The reason for this severe relapse is not clear. Possible explanations include SPA activation of T-lymphocytes, with release of gamma interferon and increased antigen recognition, or removal of an anti-idiotype control mechanism. We advise caution in the application of immunoadsorption to conditions in which it has not yet been evaluated. © 1992 Wiley-Liss, Inc.     

LIPOPROTEIN(α) IN HEALTH AND DISEASE

SUMMARY Elevated plasma levels of Lp(a) do seem to influence the progression of atherosclerosis. Evidence is emerging that certain apo(a) isoforms may be more atherogenic than others, and in transgenic mice free apo(a) has been shown to be associated with accelerated atherosclerosis. Currently it is not known whether treating elevated Lp(a) levels will reduce progression of atherosclerosis and, as therapeutic options are limited, mass screening of Lp(a) levels in populations is not indicated. The presence of raised Lp(a) levels, however, warrants aggressive treatment to reduce other cardiovascular risk factors. Continuing research to investigate the relationship of the apo(a) gene to other genes, including the plasminogen gene and apo(a)-related genes, will add further information pertaining to the evolution, function, regulation and clinical implications of Lp(a).