Elderly patients become more hypothermic during surgery, shiver less postoperatively, and take longer to rewarm than younger patients. Similarly, the vasoconstriction threshold (triggering core temperature) is reduced approximately 1 degree C in elderly patients during nitrous oxide/isoflurane anesthesia. Accordingly, we tested the hypothesis that the vasoconstriction threshold in the elderly is also reduced approximately 1 degree C during nitrous oxide and sevoflurane anesthesia. Eleven young patients aged 30-50 yr and 14 elderly patients aged 60-80 yr were anesthetized with nitrous oxide (50%) and sevoflurane (1%). Mean skin temperature was calculated from four sites. Fingertip blood flow was estimated using forearm minus fingertip skin-temperature gradients, with a gradient of 0 degree C identifying onset of vasoconstriction. The distal esophageal temperature triggering onset of vasoconstriction identified the threshold for this thermoregulatory defense. The data from five patients who did not vasoconstrict at minimum core temperatures of 33-34 degrees C were eliminated, leaving 10 patients in each group. The vasoconstriction threshold was significantly less in the elderly (35.0 +/- 0.8 degrees C) than in younger patients (35.8 +/- 0.3 degrees C), despite similar mean skin temperatures (mean +/- SD, P < 0.01, Student's t-test). Age dependence of thermoregulatory vasoconstriction during nitrous oxide/sevoflurane anesthesia is similar to that previously observed during nitrous oxide/isoflurane anesthesia.
Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA 1−6 . A high throughput screen against LPA 1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA 1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α 1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin, compound 17a had no impact on the mean blood pressure at this dose. These results suggest that LPA 1 antagonists could be used to treat BPH without affecting the blood pressure. Herein, we report the hit-to-lead optimization of a unique series of LPA 1 antagonists and their in vivo efficacy.
A familial disorder was characterized by chorea, ataxia, myoclonus, convulsions, dementia, and mental retardation. In five cases, the main lesion affected cerebellar dentate nuclei, with nerve cell loss, gliosis, chromatolysis, and grumose degeneration. Fibrous glial cell proliferation was detected in the globus pallidus.
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