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.     

Psychopathology in epilepsy

Although the majority of epileptics who are well controlled on medication do not show significant evidence of psychopathology, a subset of epileptics have serious psychiatric disturbances. Risk factors for the development of psychopathology appear to include poorly-controlled seizures, a long duration of seizure disorder with onset in childhood, seizure focus in the temporal lobe, bilateral or multiple discharges on EEG, and structural lesions. All of these factors appear to put the patient at greater risk of brain dysfunction, possibly because of the disruption of limbic functions associated with behavior and personality. The onset of seizures in childhood is likely to affect the development of personality and social functioning adversely. Although not a focus of this article, premorbid personality, psychologic reactions to having epilepsy, and the social problems accompanying the disease are likely to contribute greatly to the development of psychopathology. The development of psychiatric disorders in epilepsy thus appears to be a complex, multifactorial process. No single factor, such as seizure type, EEG findings, lateralization, pathology, or demographic variables is likely to be explanatory. Recent research has focused on accounting for many of these factors, and future investigations should shed further light on why some epileptics develop psychiatric problems and how best to treat these disorders.     

Butyrate infusions in the ovine fetus delay the biologic clock for globin gene switching.

The switch from fetal to adult hemoglobin expression is regulated in many mammalian species by a developmental clock-like mechanism and determined by the gestational age of the fetus. Prolonging fetal globin gene expression is of considerable interest for therapeutic potential in diseases caused by abnormal beta-globin genes. Butyric acid, which is found in increased plasma concentrations in infants of diabetic mothers who have delayed globin gene switching, was infused into catheterized fetal lambs in utero during the time of the normal globin gene switch period. The globin gene switch was significantly delayed in three of four butyrate-treated fetuses compared with controls and was entirely prevented in one fetus in whom the infusion was begun before the globin switch was under way. These data provide a model for investigating and arresting the biologic clock of hemoglobin switching.     

A 22-nucleotide spliced leader sequence in the human parasitic nematode Brugia malayi is identical to the trans-spliced leader exon in Caenorhabditis elegans.

The mRNAs encoding a 63-kDa antigen in the human parasitic nematode Brugia Malayi contain a spliced leader sequence of 22 nucleotides (nt) that is identical to the trans-spliced leader found on certain actin mRNAs in the distantly related nematode Caenorhabditis elegans. The 22-nt sequence does not appear to be encoded near the 63-kDa genes but is present in multiple copies in several locations within the parasite genome, including the 5S rRNA gene repeat. The 5S-linked copies of the 22-nt sequence are transcribed to yield a 109-nt nonpolyadenylated RNA with the 22-nt leader sequence at its 5' end. We suggest that the 22-nt leader is acquired by 63-kDa antigen mRNAs through trans-splicing. These results indicate that trans-splicing is widespread in nematodes and argue for the functional significance of the 22-nt spliced leader exon in nematode mRNA metabolism.     

Improvement in quality of life after initiation of lamotrigine therapy in patients with epilepsy in a naturalistic treatment setting.

Quality of life is impaired in patients with epilepsy and can be improved by effective therapy. Randomised clinical trials have shown that lamotrigine treatment is associated with improved quality of life. However, little information is available on quality of life or treatment effects in patients with epilepsy in the general population. The objective of this study was to estimate the impact of lamotrigine on quality of life in a naturalistic treatment setting. The study included adult patients with epilepsy in whom lamotrigine therapy was initiated. Each subject completed the Quality of Life in Epilepsy Inventory (QOLIE)-31 quality of life questionnaire at inclusion and at a follow-up visit in the next 4 months. Demographic information and medical history were provided by the investigator. These were evaluated as potential determinants of change in quality of life using logistic regression. Three hundred and forty-one patients were evaluated, 192 starting lamotrigine in combination with another drug, 90 as a first-line monotherapy, 45 as a switch from another drug and 14 as a reduction to monotherapy from a previous combination. Baseline scores on the QOLIE-31 ranged from 53.8 in the combination group to 69.5 in the first-line group. 34.6% of patients were considered to be responders, with no significant differences between treatment regimen. Most improvement was seen for the energy-fatigue and medication effects subscales and, for the first-line group, seizure worry. Seizure type was the only determinant of improvement of quality of life identified. In conclusion, lamotrigine treatment is associated with improved quality of life, regardless of treatment regimen.     

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).