Basic and clinical studies on norfloxacin in the pediatric field

Pharmacokinetic , bacteriological and clinical studies on norfloxacin (NFLX), a quinolone-carboxylic acid antibacterial agent, were conducted in the pediatric field. 1. Serum concentrations and urinary excretion of NFLX after single dose of 2.2 approximately 5.6 mg/kg (mean 4.4 +/- 1.2 mg/kg) were determined in 13 children with ages between 6 and 11 years. The mean peak serum concentration of the drug was 0.37 +/- 0.20 micrograms/ml at 2 hours after administration. The mean half-life of the drug in serum was 2.8 +/- 0.4 hours and the serum concentration at 8 hours was 0.11 +/- 0.06 micrograms/ml. The mean urinary concentration reached a maximum of 125.2 +2- 166.2 micrograms/ml in pooled urine from 0 to 2 hours and the mean urinary recovery rate in the first 8 hours after administration was 22.1 +/- 6.0%. A dose-response relationship was observed between doses/body weight and peak serum concentrations. 2. The clinical efficacy, bacteriological efficacy and the safety of NFLX were evaluated in 65 pediatric patients with ages between 2 years 10 months and 15 years 7 months with infections. In 62 assessable cases (acute purulent tonsillitis 9 cases, acute pneumonia 3 cases, chronic rhinitis 1 case, urinary tract infections 15 cases, and acute colitis 34 cases), clinical efficacies were excellent in 48 cases, good in 13 cases, and fair in 1 case with an overall efficacy rate of 98.4%. Staphylococcus aureus 1 strain, Staphylococcus epidermidis 1 strain, Escherichia coli 10 strains, Salmonella sp. 5 strains, Morganella morganii 1 strain, Pseudomonas aeruginosa 3 strains, Haemophilus parainfluenzae 1 strain and Campylobacter jejuni 12 strains were isolated from the patients as pathogens. Bacteriologically, all of these strains were eradicated except that 3 strains of C. jejuni only decreased. With regard to side effects, dizziness and nausea were observed in 1 case each but they were slight and the continuation of the treatment was possible. No abnormal laboratory test data were observed. From the above results, NFLX was considered to be a useful drug for the treatment of pediatric infections.     

Deficiency of insulin receptor substrate-1 impairs skeletal growth through early closure of epiphyseal cartilage.

Morphological analyses in and around the epiphyseal cartilage of mice deficient in insulin receptor substrate-1 (IRS-1) showed IRS-1 signaling to be important for skeletal growth by preventing early closure of the epiphyseal cartilage and maintaining the subsequent bone turnover at the primary spongiosa. Introduction: IRS-1 is an essential molecule for intracellular signaling by IGF-I and insulin, both of which are potent anabolic regulators of cartilage and bone metabolism. To clarify the role of IRS-1 signaling in the skeletal growth, morphological analyses were performed in and around the epiphyseal cartilage of mice deficient in IRS-1 (IRS-1(-/-)), whose limbs and trunk were 20-30% shorter than wildtype (WT) mice. MATERIALS AND METHODS: The epiphyseal cartilage and the primary spongiosa at proximal tibias of homozygous IRS-1(-/-) and WT male littermates were compared using histological, immunohistochemical, enzyme cytohistochemical, ultrastructural, and bone histomorphometrical analyses. RESULTS: In and around the WT epiphyseal cartilage, IRS-1 and insulin-like growth factor (IGF)-1 receptors were widely expressed, whereas IRS-2 was weakly localized in bone cells. Chronological observation revealed that height of the proliferative zone and the size of hypertrophic chondrocytes were decreased in WT mice as a function of age, and these decreases were accelerated in the IRS-1 (-/-) cartilage, whose findings at 12 weeks were similar to those of WT at 24 weeks. In the IRS-1(-/-) cartilage, proliferating chondrocytes with positive proliferating cell nuclear antigen (PCNA) or parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor immunostaining had almost disappeared by 12 weeks. Contrarily, TUNEL+ apoptotic cells were increased in the hypertrophic zone, at the bottom of which most of the chondrocytes were surrounded by the calcified matrix, suggesting the closure of the cartilage. In the primary spongiosa, bone volume, alkaline phosphatase (ALP)+ osteoblasts, TRACP+ osteoclasts, and the osteopontin-positive cement line were markedly decreased. Bone histomorphometrical parameters for both bone formation and resorption were significantly lower in IRS-1(-/-) mice, indicating the suppression of bone turnover. CONCLUSION: The IRS-1(-/-) epiphyseal cartilage exhibited insufficient proliferation of chondrocytes, calcification of hypertrophic chondrocytes, acceleration of apoptosis, and early closure of the growth plate. Thus, the data strongly suggest that IRS-1 signaling is important for the skeletal growth by preventing early closure of the epiphyseal cartilage and by maintaining the subsequent bone turnover at the primary spongiosa.     

Comparative study of G- and D-cell population in the dog stomach

Since somatostatin is a local hormone controlling gastric acid secretion and gastrin release, quantitative histopological distribution of the G-cells and D-cells in the canine whole stomach was investigated by the specific immunoperoxidase staining technique. The G-cells were identified only in the pyloric antrum and the estimated total number of G-cells was 15.5 X 10(6) cells. Most of the D-cells were also found in the pyloric antrum but a few were found scattered diffusely throughout body and fundus of the stomach. The estimated total number of D-cells was 11 X 10(6) cells in the pyloric antrum and 4 X 10(6) cells in the corpus and fundus. The G-/D-cell ratio in the antrum was 1.4:1. The number of G-cells as well as D-cells per unit mucosal surface area was significantly higher on the greater curvature and the proximal part of the antrum than on other areas of the antrum. Thus, the pattern of distribution in G-cells was similar to that of D-cells and there was a highly significant correlation between G- and D-cells per unit mucosal surface area. It would appear that under normal conditions, the number of G- and D-cells in the antrum are in good balance and may play an important role in the control mechanisms related to gastric secretion.     

A case of Cushing's syndrome caused by an adrenal black adenoma

A black adenoma of the adrenal cortex was surgically removed from an 18-year-old female who had clinical and laboratory findings characteristic of Cushing's syndrome. The electron microscopic study revealed typical features of steroid-producing cells, including a prominent smooth and rough endoplasmic reticulum, and mitochondria. In addition, many of the adenoma cells contained numerous pigmented granules which were lipofuscin. Three months after the surgery, the hormone levels returned to the normal range. The Japanese literature of functional black adenoma is reviewed.     

Effect of S-8666 on Cl- transport in the rabbit connecting tubule perfused in vitro.

S-8666, [6, 7-dichloro-5-(N, N-dimethylsulfamoyl)-2, 3-dihydrobenzofurancarboxylic acid] is a potent diuretic with uricosuric action. Although the major site of action of S-8666 has been proven by the in vitro microperfusion study to be the thick ascending limb of Henle's loop, clearance studies in the rat suggested that this drug has an additional thiazide-like action. To provide direct evidence that S-8666 acts also on distal nephron segments, we examined effect of S-8666 on Cl- flux across the rabbit connecting tubule perfused in vitro. The drug suppressed the lumen-to-bath Cl- flux by 96 +/- 41 (S.E.)pmol.mm-1.min-1 (n = 9) without affecting transmural voltage. To demonstrate that S-8666 acts on the connecting tubule cell, the target of thiazide diuretics, we compared effects of S-8666 and trichlormethiazide on the basolateral membrane voltage of the connecting tubule cell. Both drugs added to the lumen caused a small but significant hyperpolarization of the basolateral membrane without affecting transmural voltage. We conclude that S-8666 is a unique uricosuric diuretic having actions on both thick ascending limb of Henle's loop and connecting tubule.     

Increased expression of gp91phox homologues of NAD(P)H oxidase in the aortic media during chronic hypertension: involvement of the renin-angiotensin system.

Although vascular cells express multiple members of the Nox family of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, including gp91phox, Nox1, and Nox4, the reasons for the different expressions and specific roles of these members in vascular injury in chronic hypertension have remained unclear. Thus, we quantified the mRNA expressions of these NAD(P)H oxidase components by real-time polymerase chain reaction and evaluated superoxide production and morphological changes in the aortas of 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar Kyoto rats (WKY). The aortic media of SHRSP had an approximately 2.5-fold greater level of Nox4 mRNA and an approximately 10-fold greater level of Nox1 mRNA than WKY. The mRNA expressions of gp91phox and p22phox in SHRSP and WKY were comparable. SHRSP were treated from 24 weeks of age for 8 weeks with either high or low doses of candesartan (4 mg/kg/day or 0.2 mg/kg/day), or a combination of hydralazine (30 mg/kg/day) and hydrochlorothiazide (4.5 mg/kg/day). The high-dose candesartan or the hydralazine plus hydrochlorothiazide decreased the blood pressure of SHRSP to that of WKY, whereas the low-dose candesartan exerted no significant antihypertensive action. Media thickening and fibrosis, as well as the increased production of superoxide in SHRSP, were nearly normalized with high-dose candesartan and partially corrected with low-dose candesartan or hydralazine plus hydrochlorothiazide. These changes by antihypertensive treatment paralleled the decrease in mRNA expression of Nox4 and Nox1. These results suggest that blood pressure and angiotensin II type 1 receptor activation are involved in the up-regulation of Nox1 and Nox4 expression, which could contribute to vascular injury during chronic hypertension.