Pharmacokinetics and pharmacodynamics of ()-sotalol in healthy male volunteers

1 We investigated the pharmacokinetics and pharmacodynamics of (±)-sotalol administered orally to healthy male volunteers in single doses of 40, 80 and 160 mg and in multiple doses of 80 mg twice daily for 7 consecutive days.
2 In the single dose studies, the half-life of (-)-sotalol (7.2-8.5 h) was significantly ( P < 0.01) shorter than that of (+)-sotalol (9.1-11.4 h) while the renal clearance of (-)-sotalol (110.6-126.4 ml min^-1) was significantly ( P < 0.01) faster than that of (+)-sotalol (102.2-110.1 ml min^-1). In the multiple dose studies, similar differences in the pharmacokinetics of (+)- and (-)-sotalol were observed. In addition, the pharmacokinetics of both (+)- and (-)-sotalol on day 4 were shown to be essentially the same as those on day 7.
3 In pharmacodynamic examinations, (±)-sotalol prolonged QTc intervals on electrocardiograms dose-dependently after single doses of 80 and 160 mg (3.81 ± 2.96%, 13.23 ± 5.66%). The correlation between the plasma concentration of (±)-sotalol and prolongation of QTc intervals was nearly linear, and showed no hysteresis.
4 In conclusion, we demonstrated that QTc interval was prolonged with a linear correlation to the plasma concentration of (±)-sotalol. In addition, our study suggested that differences in the pharmacokinetics of (+)- and (-)-sotalol may be attributable to faster urinary excretion of (-)-sotalol.     

A Clinical Trial of Topical Bleaching Treatment with Nanoscale Tretinoin Particles and Hydroquinone for Hyperpigmented Skin Lesions

BACKGROUND: Although combined use of tretinoin (all-trans-retinoic acid; atRA) and hydroquinone improves various hyperpigmented lesions, the pharmacologic instability of atRA and atRA-induced irritant dermatitis are difficult unsolved problems. OBJECTIVE: The objective was to evaluate the efficacy and adverse effects of a newly formulated gel containing inorganic-coated atRA nanoscale particles (nano-atRA gel). METHODS: Nano-atRA gel was used in our two-phased bleaching protocol: 5% hydroquinone and 7% lactic acid ointment were used along with nano-atRA gel in the bleaching phase (2-8 weeks), and 5% hydroquinone and 7% ascorbic acid ointment were used alone during the healing phase (4-8 weeks). Eighty-four patients with facial hyperpigmented lesions were enrolled in this study, and 77 of them (88 lesions) followed up for more than 10 weeks were analyzed. RESULTS: Hyperpigmentation was improved in 84 of 88 lesions (95.5%) after a mean treatment period of 14.3 weeks and was almost eliminated in 52 lesions (59.1%). Nano-atRA gel caused exfoliation and scaling similar to that seen with conventional atRA gel, whereas the erythema seen in the bleaching phase appeared to be weaker. CONCLUSION: Nano-atRA gel can improve hyperpigmentation to a similar extent as conventional atRA gel. It also induces irritant dermatitis, but with less erythema.     

CONGENITAL GOITRE AND HYPOTHYROIDISM WITH IMPAIRED IODIDE ORGANIFICATION AND HIGH THYROID PEROXIDASE CONCENTRATION

A sibship of thirteen subjects whose parents were first cousins was studied for a defect in thyroid hormone synthesis. Five sibs were goitrous and had congenital hypothyroidism. All but one showed a positive perchlorate discharge test (PDT). Three other subjects were goitrous and euthyroid (one with a positive PDT), and the remaining five sibs were euthyroid with a presumably normal thyroid. However, an abnormally exaggerated TSH response to TRH was observed not only in the hypothyroid patients but also in six of the other subjects, indicating a decreased thyroid feedback at the pituitary level in the presence of a normal serum concentration of thyroid hormones. In two hypothyroid patients a normal serum T3, low serum T4 and a low reverse T3 were observed. Microscopic studies of thyroid tissue from three of the sibs disclosed marked cellular hyperplasia with no lymphocytic infiltration anywhere in the tissue. Peroxidase activity was determined on tissue from three sibs by three different assay procedures. It was within the normal range in one patient and was significantly elevated in the other two. There was no evidence for a qualitatively defective peroxidase. The defect in thyroid function in this family does not appear to involve a peroxidase deficiency. Thyroglobulin isolated from the thyroid glands of two of the goitrous, hypothyroid subjects was poorly iodinated but was judged to be normal by immunoreactive and ultracentrifugation procedures. Although the nature of the thyroid metabolic defect in this family was not elucidated, the evidence suggests a genetic defect, probably involving a recessive gene.     

Hepatic Proteins in Regenerating Liver

Abstract  Albumin immunoreactivity in the liver was examined on days 2, 5 and 10 after two-thirds partial hepatectomy by light and ultrastructural immunoperoxidase methods and the ultrastructural area of the rough endoplasmic reticulum (ER) in hepatocytes was measured. Albumin immunoreactivity was seen in the rough ER and Golgi apparatus of all hepatocytes in the hepatectomized liver and ultrastructural analysis showed a significantly greater area of rough ER on day 5 than on days 2 or 10. Albumin mRNA was studied by the in situ hybridization technique using radioisotopes and their numbers were determined visually. Albumin mRNA was present as grains in all hepatocytes and the grains varied in number during regeneration of the liver, being more abundant on day 5 than on days 2 or 10. The activity of [³H]-leucine incorporated into albumin synthesis, an indicator of translational activity, was higher on days 5 and 10 than on day 2 and was highest on day 5. In conclusion, albumin synthesis varied during liver regeneration after partial hepatectomy, being reduced at the peak of cell proliferation on day 2 and being most active on day 5.     

Effect of continuous pressure on histopathological changes in denture-supporting tissues

summary The histopathological changes in denture-supporting tissues were studied in relation to continuous pressure exerted through an experimental denture base. The experimental dentures were designed to load continuous pressures (1.5, 3.4 or 4.9 kPa) to the palate of molar region of rat. Histopathological changes caused by the continuous pressure were observed, and the intensity of the pressure was also estimated. A high correlation was observed between the histopathological changes under the denture base and the intensity of the continuous pressure. In groups exposed to 4.9 and 34 kPa, the continuous mechanical pressure caused bone resorption; in 1.5 kPa group, no evidence of bone resorption was observed. The epithelium and lamina propria mucosa under the denture base, which were compressed by the continuous pressure, recovered histopathologically depending on the decrease of the pressure caused by bone resorption; no quantitative recovery of the absorbed bone tissue was observed. No inflammatory change was induced by the continuous pressure. From the histopathological results observed in this study, the possibility of the existence of a threshold for bone resorption induced by continuous pressure was suggested.