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.     

Transneuronal degeneration of thalamic neurons following deafferentation: quantitative studies using [3H]thymidine autoradiography.

Transneuronal degeneration of thalamic neurons following partial deafferentation was studied using [3H]thymidine autoradiography. Timed-pregnant female Sprague-Dawley rats received systemic injections of [3H]thymidine on embryonic day (E) 13, 14 and/or 15. On the day of birth, pups were anesthetized by hypothermia and subjected to unilateral enucleation, unilateral removal of the inferior colliculus or sham lesion. Animals were sacrificed on postnatal day 10 or 30 and the brains processed for autoradiography. Material from sham-lesioned animals demonstrates that neurons destined for the dorsal lateral geniculate nucleus (LGd) undergo final mitoses on E13, 14 and 15. Neurons in the ventral medial geniculate nucleus (MGv) undergo final mitoses on E13 and 14. Thirty days following neonatal unilateral eye removal, the contralateral LGd displays a loss of approximately 30-35% of [3H]thymidine labeled neurons. Neonatal unilateral removal of the inferior colliculus results in a loss of approximately 30-40% of labeled neurons in MGv. For both LGd and MGv, shorter survival times reveal less severe cell loss. Late generated (E15) LGd neurons show less severe loss following enucleation than do earlier generated neurons. These results document the degree of cell loss in sensory thalamic nuclei following deafferentation and demonstrate that [3H]thymidine autoradiography provides a useful quantitative method for assessing anterograde transneuronal cell loss in targeted populations of neurons in the developing central nervous system.     

Interaction between free radicals and excitatory amino acids in the formation of ischemic brain edema in rats

Both oxygen free radicals and excitatory amino acids have been implicated as important cellular toxins in ischemic brain. Recent in vitro studies suggest that there may be a mutual interaction between these two mediators. We explored the relation between oxygen free radicals and excitatory amino acids in the development of ischemic brain edema in vivo. Male Sprague-Dawley rats were treated with the free radical scavenger dimethylthiourea 1 hour before ischemia or with the excitotoxin antagonist MK-801 30 minutes before ischemia produced by occlusion of the middle cerebral artery. Groups of seven or eight animals were treated with vehicle, low-dose (375 mg/kg) dimethylthiourea, high-dose (750 mg/kg) dimethylthiourea, low-dose (0.5 mg/kg) MK-801, high-dose (2.0 mg/kg) MK-801, or both high-dose dimethylthiourea and low-dose MK-801. After 4 hours of ischemia, brain water content was determined. In eight vehicle-treated controls, mean +/- SEM water content of tissue in the center of the ischemic zone was 83.29 +/- 0.18%. A significant reduction of brain edema was observed in all drug-treated groups: for example, 50.2% (p less than 0.001) in the high-dose dimethylthiourea group, 53.7% (p less than 0.001) in the low-dose MK-801 group, and 66.4% (p less than 0.001) in the combined dimethylthiourea and MK-801 group. Combined treatment with dimethylthiourea and MK-801 provided no significant additive effect over that resulting from treatment with MK-801 alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

A study of a method for distribution analysis of skin color

Background/aims: The objective and quantitative assessment of the skin is important in medical and cosmeceutical research. Assessment of color is an important element for analyzing the surface of the skin, which is usually determined subjectively by a doctor or using color analysis devices. These devices, however, cannot provide correct color information because color is construed from the mean value of the observation region, and analysis of color distribution is impossible. The purpose of this paper is to develop an objective analysis method to permit skin color measurement of each pixel unit of an image and analyze the distribution of skin surface color. Methods: The Skin Color Distribution Analyzer (SCDA) is an analysis method newly developed at the Research Institute for Skin Image at Korea University. The SCDA system presented in this paper performed a novel form of quantitative and objective analysis of skin color distribution using each pixel color model parameter found in image wavelength information. In this paper, distribution analysis was conducted on normal skin and skin lesions and skin affected by artificially induced irritant contact dermatitis and pigmented nevous. The method selected a grade using a color model parameter. Twenty healthy Korean males participated in this study. A comparative study of the eight anatomical areas was performed, including the exposure and non‐exposure parts and the medial aspect and the lateral aspect of the forearm. A reliability test for the SCDA system was also conducted with a spectrometer (SPEC) using the color analysis method. Results: Each skin lesion was precisely segmented by grade and each parameter hada different statistical significance for results of analysis of distribution in pigmented nevous and the artificially induced irritant contact dermatitis. Parameters L^*, b^*, a^*, and EI showed salient traits. Showed resemble measured result in the SCDA system and the SPEC of normal skin. The exposed site, in comparison with the non‐exposed site, showed a notable difference in the L^* parameter and a significant statistical difference in the x and z parameters, except b^*. The comparison of the medial and lateral aspects of the forearm showed a notable difference in the L^* parameter and a significant statistical difference in the parameters except y and b^*. In the reliability test result using the SCDA system and the SPEC, the SCDA system was highly reliabile in terms of the CV value in all color model parameters. Conclusions: The color distribution analysis method using the SCDA system has revealed an aspect that the existent method of medical research has not shown, and is considered to be more reliable than other methods. This method can provide better study findings because it can be applied to other fields in addition to the medical science field and the ripple effect is thought to be bigger in other science field too.     

Voiding patterns in men and women with lower urinary tract symptoms combined with nocturia

AIM: We evaluated differences between men and women with lower urinary tract symptoms (LUTS) combined with nocturia. METHODS: A total of 71 age-matched female-male pairs (median 58, range 20-81 years) who had moderate to severe LUTS and nocturia of more than once per night were enrolled in this study. RESULTS: In the younger group (<50 years), the International Prostate Symptom Score (I-PSS) results of the sexes were not significantly different. However, although total I-PSS results in the elderly group (> or =50 years) were not significantly different, quality of life index scores for women were higher (P = 0.002). On frequency-volume (FV) charts, mean total daytime voided volume (DVV) was significantly higher in younger men than in younger women (P = 0.017), but the mean nocturnal polyuria index (NPi) for women was higher than that for men (P = 0.047). However, maximum DVV (P = 0.009), mean DVV (P < 0.0001), total DVV (P < 0.0001), and mean nocturnal urine volume (P = 0.009) were significantly higher in elderly men than in elderly women. However, numbers of daytime voids were not different. CONCLUSION: Elderly women with LUTS have lower functional bladder capacities than elderly men, as suggested by their smaller mean voided volumes. However, no significant differences were observed between numbers of daytime voids, which was probably due to the smaller total daytime voided volumes of elderly women. In addition, although NPi for younger women and nocturnal urine volume for elderly men was higher, no other differences were observed in terms of other night-time parameters.     

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.     

Changes in heart rate and rhythm after intramuscular succinylcholine with or without atropine in anesthetized children

The effects of intramuscular injections of succinylcholine with or without atropine on heart rate and rhythm were studied in 50 unpremedicated children 6-18 months of age. All had anesthesia induced with N2O-O2 and halothane 2% by face mask. Sixty seconds later, one of four study drugs or drug combinations was injected into the deltoid muscle of patients in groups 1-4. Following injection, halothane concentration was reduced to 1%, and ventilation was controlled. Patients given atropine only (0.02 mg/kg), succinylcholine only (4 mg/kg), or a combination of both (4 mg/kg succinylcholine plus 0.02 mg/kg atropine) showed transient increases in heart rate to 106 +/- 7.5%, 113 +/- 11.8%, and 109 +/- 10.1% (mean +/- SD) of control, followed by a decrease to 78 +/- 6.7%, 79 +/- 9.4%, and 80 +/- 10.5%, respectively, in 2-3 min after injection. Patients given a combination of succinylcholine (4 mg/kg) plus a higher dose of atropine (0.03 mg/kg) also had a transient increase in heart rate to 107 +/- 7.5%, followed by a decrease to 82 +/- 11.8% 2 min after injection. However, this group differed from the other three groups in presenting a second, prolonged increase in heart rate to 115 +/- 9.0% of preinjection levels. Patients in group 5 (controls) received no injections. Their heart rate decreased to 76 +/- 10.78% of preinduction level within 90 sec of induction, and remained unchanged thereafter. We conclude that succinylcholine (4 mg/kg) can be used intramuscularly with or without atropine (0.02 mg/kg) in lightly anesthetized young children without producing severe bradycardia.(ABSTRACT TRUNCATED AT 250 WORDS)