Nucleosides and nucleotides. 107. 2-(cycloalkylalkynyl)adenosines: adenosine A2 receptor agonists with potent antihypertensive effects.

Adenosine receptor-binding profiles in rat brain tissues and antihypertensive effects in spontaneously hypertensive rats (SHR) of a series of 2-(cycloalkylalkynyl)adenosines (2-CAAs) and their congeners are described. The structure-activity relationship of this series of compounds is discussed, focusing on the length of the alkynyl side chain and bulkiness of the terminal cycloalkyl substituents in terms of binding activity and cardiovascular effects. All the 2-CAAs had a preferential affinity for A2 receptors. Of these derivatives, 2-(3-cyclopentyl-1-propyn-1-yl)adenosine (10b) exhibited the most selective affinity for A2 receptors (Ki ratio: A1/A2 = 70) on the basis of receptor binding. In the C-2 binding region of adenosine, compounds often have potent and/or selective A2 activity from introduction of an acetylenic group at the C-2 position followed by one methylene residue further followed by a hydrophobic substituent such as a cycloalkyl ring at the terminal position of the alkynyl side chain. Intravenous injection of 10b up to 100 micrograms/kg had a potent hypotensive effect without a marked decrease in heart rate in anesthetized SHR. Compounds 10j-s, with a hydroxyl group in the C-3" position of the alkynyl side chain, had a potent affinity for both A1 and A2 receptors, but they were not highly selective for A2 receptors. These compounds caused a marked bradycardia upon intravenous administration in anesthetized SHR. Oral administration of 10b (0.1-1 mg/kg) had a potent and long-lasting antihypertensive effect in conscious SHR.     

An analysis of risk factors of perioperative bleeding in surgical repair of abdominal aortic aneurysm

BACKGROUND: In surgical repair of abdominal aortic aneurysm (AAA), excessive bleeding which causes postoperative complications is sometimes observed. To determine the risk factors of perioperative excessive blood loss, this retrospective study was performed. METHODS: Design. A retrospective study. Setting. An academic medical center. Participants. One hundred and forty patients underwent elective surgical repair of an abdominal aortic aneurysm (AAA) at our institution from 1995 through 1997. Measurements. The present study includes critical review of 140 consecutive charts of patients undergoing elective surgical repair of AAA. Preoperative laboratory data, intraoperative data and amount of blood loss to identify risk factors of perioperative blood loss. Factors which were found to be significantly associated with the amount of perioperative blood loss were preoperative plasma fibrin degradation product (FDP) level (r=0.445), amount of immediate re-infusion of shed blood (r=0.438), and duration of operation (r=0.411). RESULTS: Preoperative fibrinogen level correlated with perioperative blood loss little (r=-0.187). Preoperative platelet count or the other coagulation profile did not affect the amount of perioperative blood loss. The patients whose preoperative FDP were more than 40 microg x ml(-1) significantly increased the risk of excessive blood loss compared with less than 40 microg x ml(-1). CONCLUSIONS: The significant preoperative risk factor of perioperative blood loss was only FDP level in present study. Especially, the patients whose preoperative FDP were more than 40 microg x ml(-1) increased the risk of excessive blood loss.     

No Improvement of Adult Height in Non-growth Hormone (GH) Deficient Short Children with GH Treatment

It is still in doubt whether the standard-dose growth hormone (GH) used in Japan (0.5 IU/kg/week, 0.167 mg/kg/week) for growth hormone deficiency is effective for achieving significant adult height improvement in non-growth hormone deficient (non-GHD) short children. We compared the growth of GH-treated non-GHD short children with that of untreated short children to examine the effect of standard-dose GH treatment on non-GHD short children. GH treatment with recombinant human growth hormone (rhGH) was started before the age of 11 yr in 64 boys and 76 girls with non-GHD short stature registered at the Foundation for Growth Science who have now reached their adult height. In 119 untreated boys and 127 untreated girls whose height standard deviation score (SDS) was below –2 SD at the age of 6 yr, height growth was followed until 17 yr. Height SDS was significantly lower before GH treatment in the GH-treated group than at the age of 6 yr in the untreated group, in both sexes. Adult height and adult height SDS were significantly greater in the untreated group than in the GH-treated group, in both sexes, although the change in height SDS did not differ significantly. Height SDS was significantly lower before GH treatment in the GH-treated group than at the age of 6 yr in the untreated group, so 57 boys and 57 girls whose height SDS at the age of 6 yr in the untreated group closely matched the height SDS before GH treatment in the GH-treated group were chosen for comparison. Height SDS did not differ significantly between the GH-treated group before GH treatment and the untreated group at the age of 6 yr, nor were there differences between these subgroups in adult height, adult height SDS, or height SDS change, in either sex. The effect of GH treatment is reported to be dose-dependent and doses over 0.23 mg/kg/week are reported to be necessary to improve adult height in non-GHD short children. Currently, the GH dose is fixed at 0.175 mg/kg/week in Japan, and we expected to find, and indeed concluded, that ordinary GH treatment in Japanese, non-GHD short children does not improve adult height.     

Prolonged oral treatment with an essential amino acid L-leucine does not affect female reproductive function and embryo-fetal development in rats.

L-leucine, an essential amino acid, is one of the most popular ingredients in dietary supplements. To investigate a possibility of its embryo-fetal toxicity in rats, 11- to 12-week old dams were orally administered an aqueous solution of L-leucine at doses of 300 or 1000 mg/kg body weight on gestational days 7-17. Body weight and feed intake was evaluated throughout the whole course of pregnancy (days 0-20). L-Leucine did not influence body weight, but at a dose of 1000 mg/kg, slightly enhanced feed intake on days 14 and 18 of pregnancy. Caesarean section (day 20) revealed no influences on the litter size and weight of live-born fetuses, the number of corpora lutea, implantation index or the quality of placenta, and the minor increase in feed intake was considered irrelevant to the pregnancy outcomes. Fetuses were evaluated in a battery of external, visceral and skeletal examinations. No effects of L-leucine on gender ratio and external abnormalities, and no significant treatment-related variations in visceral and skeletal pathologies were observed. These results suggested that L-leucine, administered orally during organogenesis at doses up to 1000 mg/kg body weight, did not affect the outcome of pregnancy and did not cause fetotoxicity in rats.     

Phospholamban p.Arg14del Cardiomyopathy: A Japanese Case Series

Phospholamban p.Arg14del is reported to cause hereditary cardiomyopathy with malignant ventricular tachycardia (VT) and advanced heart failure. However, the clinical courses of Japanese cardiomyopathy patients with phospholamban p.Arg14del remain uncharacterized. We identified five patients with this variant. All patients were diagnosed with dilated cardiomyopathy (DCM), developed end-stage heart failure and experienced VT requiring implantable cardioverter defibrillator discharge. Four patients survived after implantation of a left ventricular assist device (LVAD), while one patient who refused LVAD implantation died of heart failure. Based on the severe course of the disease, we propose genetic screening for phospholamban p.Arg14del in DCM patients.     

Therapy of Acute Hypertension in Hospitalized Children and Adolescents

Renovascular disease is a cause of hypertension in 10 % to 15 % of prepubertal children. Interventions to address hypertension and causes of renovascular disease continue to advance. Successful interventions to treat renovascular disease include medical, angiographic, and surgical means, used alone or, more often, as combination therapy. Medical therapy is used to control the blood pressure prior to further intervention or in specific instances as long-term single therapy. Judicious use of percutaneous angioplasty and surgical intervention is usually successful in children with renal artery stenosis, although up to two-thirds of children will remain on antihypertensive medication after the procedure. Outcomes of combination therapy will continue to improve with advances in the use of antihypertensive medication in children, improvements in percutaneous angiography techniques, and progress in vascular surgical expertise.     

Evaluation of beam hardening and photon scatter by brass compensator for IMRT

When a brass compensator is set in a treatment beam, beam hardening may take place. This variation of the energy spectrum may affect the accuracy of dose calculation by a treatment planning system and the results of dose measurement of brass compensator intensity modulated radiation therapy (IMRT). In addition, when X-rays pass the compensator, scattered photons are generated within the compensator. Scattered photons may affect the monitor unit (MU) calculation. In this study, to evaluate the variation of dose distribution by the compensator, dose distribution was measured and energy spectrum was simulated using the Monte Carlo method. To investigate the influence of beam hardening for dose measurement using an ionization chamber, the beam quality correction factor was determined. Moreover, to clarify the effect of scattered photons generated within the compensator for the MU calculation, the head scatter factor was measured and energy spectrum analyses were performed. As a result, when X-rays passed the brass compensator, beam hardening occurred and dose distribution was varied. The variation of dose distribution and energy spectrum was larger with decreasing field size. This means that energy spectrum should be reproduced correctly to obtain high accuracy of dose calculation for the compensator IMRT. On the other hand, the influence of beam hardening on k_Q was insignificant. Furthermore, scattered photons were generated within the compensator, and scattered photons affect the head scatter factor. These results show that scattered photons must be taken into account for MU calculation for brass compensator IMRT.