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 randomized placebo-controlled study of enalapril in the treatment of erythrocytosis after renal transplantation

BACKGROUND: Erythrocytosis is a common complication of renal transplantationwith an incidence of up to 17%. It is associated with an increasedrisk of complications due to thromboembolic events and has traditionallybeen treated by intermittent venesection. More recently, angiotensin-convertingenzyme inhibitors have been shown to cause a fall in haematocritin a number of groups of subjects and some uncontrolled studieshave shown these drugs to be of possible therapeutic benefitin post renal transplant erythrocytosis. METHODS: We performed a randomized double-blind placebo-controlled studyin 25 patients with post-transplant erythrocytosis. Subjectsreceived either 2.5 mg of enalapril daily or a placebo for 4months and all patients completed the study period without anyserious adverse effects. RESULTS: Haematocrit fell from 52.7 (±SEM 0.7) to 47.1 (±1.8) at 1 month and 46.1 (± 1.2) after 4 months in patientsreceiving enalapril, with no change in the placebo group (P=0.004).We did not demonstrate any change in serum erythropoietin ineither group. CONCLUSION: Angiotensin-converting enzyme inhibitors are a safe and effectiveform of treatment for erythrocytosis developing after renaltransplantation. The mechanism of action, however, is not mediatedby changes in erythropoietin production and remains uncertain.     

Surgical aspects of chronic peritoneal dialysis in the neonate and infant under 1 year of age.

Since 1982 eight patients under 1 year of age with end-stage renal failure have been treated by chronic peritoneal dialysis (CPD) following insertion of an abdominal Tenckhoff catheter. We routinely perform a partial omentectomy now, and in males undertake bilateral exploration of the groins at the time of catheter insertion, with herniotomy or ligation of the patent processus vaginalis as required. Up to January 1990, 19 straight double-cuff catheters had been inserted with a total follow-up of 244.5 patient months. The median age at the initial catheter insertion was 14.6 weeks (range, 2 days to 11 months) and the median weight was 3.89 kg (range, 2.2 to 5.5). Peritonitis was the most common complication, with 46 episodes, representing one episode of peritonitis per 5.3 patient months on dialysis. The frequency of peritonitis has decreased in the last 6 months since all patients have been dialysed by two caregivers. The present rate of peritonitis is 1 episode per 10 patient months on dialysis. One patient has died of septicemia secondary to associated congenital abnormalities, one patient has regained renal function, and two patients have been transplanted, one successfully. Five patients are currently dialysing via their abdominal Tenckhoff catheters and awaiting transplantation. We conclude that neonates and infants under 1 year of age can be treated satisfactorily by CPD to enable successful preparation for transplantation later in childhood.     

Oxygen saturation during endoscopic retrograde cholangiopancreatography: a comparison of two protocols of oxygen administration.

Patients having endoscopic retrograde cholangiopancreatography (ERCP) are generally elderly and require sedation while in the prone position. These factors may be expected to aggravate any risk of arterial hypoxia. This study evaluated two protocols of oxygen administration, one with and one without pre-oxygenation. In 25 patients in whom pre-oxygenation with 4 litres/minute for five minutes before sedation was used, followed by continuous oxygen administration, arterial oxygen saturation did not fall below 90% at any stage during the procedure. By contrast, in 25 patients who were not pre-oxygenated oxygen saturation fell below 90% in nine (36%). As expected, hypoxia occurred most frequently during the early stages of sedation and endoscope insertion. Hypoxia did not occur in association with operations such as sphincterotomy, stone extraction or stent insertion. This study confirms that arterial hypoxia is a common event during ERCP and can be completely prevented by pre-oxygenation with four litres of oxygen given intranasally for five minutes before sedation.     

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).     

Hepatic dysfunction in Alstr?m disease.

Alstr?m disease is a rare disorder; less than 20 cases have been reported. An 11-year-old girl is described with this condition. She has pigmentary retinopathy, sensory neural deafness, obesity, Type II diabetes mellitus, hyperlipidemia, and acanthosis nigricans. However, in addition she developed hepatic dysfunction, pathologically similar to chronic active hepatitis. This may be a further, previously undescribed systemic manifestation of Alstr?m disease.     

Detection of chromosomes and estimation of aneuploidy in human spermatozoa using fluorescence in-situ hybridization

The development and application of fluorescence in-situ hybridization (FISH) has opened the way for comprehensive studies on numerical chromosome abnormalities in human spermatozoa. FISH can be rapidly applied to large numbers of spermatozoa and thus overcomes the major limitation of karyotyping spermatozoa after penetration of zona-free hamster oocytes. The simultaneous hybridization of two or more chromosome-specific probes to spermatozoa and subsequent detection of the bound probes using different fluorescent detection systems enables two or more chromosomes to be localized simultaneously in the same spermatozoon and provides a technique for undertaking reasonable estimates of aneuploidy. The most commonly used probes are those which bind to the centromeric region of specific chromosomes. Most studies to date have concentrated on estimating aneuploidy in spermatozoa from normospermic men, although reports are beginning to appear on aneuploidy in spermatozoa from subfertile and infertile men. Multi- probe FISH studies have generally reported disomy (hyperhaploidy) estimates of 0.05-0.2% per chromosome. There is preliminary evidence that some chromosomes such as X, Y and 21 are predisposed towards higher rates of non-disjunction during spermatogenesis. There are also suggestions of inter-donor variability in aneuploidy frequencies for specific chromosomes, although this requires confirmation in larger studies. While FISH is clearly a powerful technique that has many applications in reproductive medicine, it must also be realized that it does have limitations and the technology itself is still evolving and has yet to be fully validated on spermatozoa.      

Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD)

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha- synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha- synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.