Long-term feeding of hydroalcoholic extract powder of Lepidium meyenii (maca) enhances the steroidogenic ability of Leydig cells to alleviate its decline with ageing in male rats.

This study examined whether feeding hydroalcoholic extract of Lepidium meyenii (maca) to 8-week-old (sexually maturing) or 18-week-old (mature) male rats for more than a half year affects serum testosterone concentration and testosterone production by Leydig cells cultured with hCG, 22R-hydroxycholesterol or pregnenolone. Testosterone concentration was determined in the serum samples obtained before and 6, 12, 18 and 24 weeks after the feeding, and it was significantly increased only at the 6 weeks in the group fed with the maca extract to maturing rats when it was compared with controls. Testosterone production by Leydig cells significantly increased when cultured with hCG by feeding the maca extract to maturing rats for 27 weeks (35 weeks of age) and when cultured with 22R-hydroxycholesterol by feeding it to mature rats for 30 weeks (48 weeks of age). Overall testosterone production by cultured Leydig cells decreased to about a half from 35 to 48 weeks of age. These results suggest that feeding the maca extract for a long time to male rats may enhance the steroidogenic ability of Leydig cells to alleviate its decline with ageing, whereas it may cause only a transient increase in blood testosterone concentration in sexually maturing male rats.

Feeding hydroalcoholic extract powder of Lepidium meyenii (maca) enhances testicular gene expression of 3ß-hydroxysteroid dehydrogenase in rats.

Although feeding diets containing the extract powder of Lepidium meyenii (maca), a plant growing in Peru's Central Andes, increases serum testosterone concentration associated with enhanced ability of testosterone production by Leydig cells in male rats, changes in testicular steroidogenesis-related factors by the maca treatment are not known. This study examined the effects of maca on testicular gene expressions for luteinizing hormone receptor, steroidogenic acute regulatory protein and steroidogenic enzymes. Eight-week-old male rats were given the diets with or without (control) the maca extract powder (2%) for 6 weeks, and mRNA levels were determined by reverse transcription quantitative real-time PCR. The results showed that the testicular mRNA level of HSD3B1 (3ß-hydroxysteroid dehydrogenase; 3ß-HSD) increased by the treatment, whereas the levels of the other factors examined did not change. These results suggest that increased expression of 3ß-HSD gene may be involved in the enhanced steroidogenic ability by the maca treatment in rat testes.

Feeding hydroalcoholic extract powder of Lepidium meyenii (maca) increases serum testosterone concentration and enhances steroidogenic ability of Leydig cells in male rats.

Although Lepidium meyenii (maca), a plant growing in Peru's central Andes, has been traditionally used for enhancing fertility and reproductive performance in domestic animals and human beings, effects of maca on reproductive organs are still unclear. This study examined whether feeding the hydroalcoholic extract powder of maca for 6 weeks affects weight of the reproductive organs, serum concentrations of testosterone and luteinising hormone (LH), number and cytoplasmic area of immunohistochemically stained Leydig cells, and steroidogenesis of cultured Leydig cells in 8-week-old male rats. Feeding the extract powder increased weight of seminal vesicles, serum testosterone level and cytoplasmic area of Leydig cells when compared with controls. Weight of prostate gland, serum LH concentration and number of Leydig cells were not affected by the maca treatment. The testosterone production by Leydig cells significantly increased when cultured with 22R-hydroxycholesterol or pregnenolone and tended to increase when cultured with hCG by feeding the extract powder. The results show that feeding the hydroalcoholic extract powder of maca for 6 weeks increases serum testosterone concentration associated with seminal vesicle stimulation in male rats, and this increase in testosterone level may be related to the enhanced ability of testosterone production by Leydig cells especially in the metabolic process following cholesterol.

Effects of instant coffee consumption on oxidative DNA damage, DNA repair, and redox system in mouse liver.

To examine the effects of instant coffee consumption on cancer risk, we analyzed the oxidative DNA damage levels and the DNA repair and redox systems in the livers of coffee-fed mice. Three-week-old male ICR mice were fed with/without 0.1% (w/v) instant coffee solution. At 2, 4, and 8 mo, the levels of 8-hydroxydeoxyguanosine (8-OH-dG), a major form of oxidative DNA damage, and the expression of mouse 8-OH-dG repair-associated genes and redox system-associated genes, the SOD activity, and the LPO level were analyzed. Simultaneously, half of the mice were fed a low vitamin (LV) diet (autoclaved diet) to disturb the defense system against oxidative stresses. As a result, the 8-OH-dG level was increased in the livers of LV diet (+ water)-fed mice for 8 mo, in comparison to those of the 0 M control mice and normal diet (+ water)-fed mice. However, no significant differences between water drinking and coffee drinking were observed, in terms of the 8-OH-dG level. In addition, the 8-OH-dG repair-associated gene expression, the SOD activity, and the LPO level also showed no significant differences between water drinking and coffee drinking in all mouse groups. On the other hand, among the redox system-associated genes, only the expression of GPx1 was changed. These results suggest that instant coffee consumption has little, if any, effect on the risk of liver cancer due to oxidative stresses.

Effect of daily oral minodronate on vertebral fractures in Japanese postmenopausal women with established osteoporosis: a randomized placebo-controlled double-blind study.

UNLABELLED: SUMMARY; A randomized placebo-controlled trial was conducted to examine the effect of daily oral 1 mg minodronate on vertebral fractures in 704 postmenopausal women with established osteoporosis for 24 months. Minodronate treatment reduced vertebral fractures by 59% without serious adverse events. Minodronate is a safe and effective bisphosphonate for osteoporosis treatment. INTRODUCTION: Minodronate increases bone mineral density (BMD) in postmenopausal osteoporotic patients. However, its efficacy in reducing osteoporotic fractures has not been tested. METHODS: To examine anti-fracture efficacy and safety of daily oral minodronate in postmenopausal women with established osteoporosis, a randomized, double-blind, placebo-controlled trial was conducted in 704 postmenopausal women (55 to 80 years) with one to five vertebral fractures and low BMD. Subjects were randomly assigned to receive daily oral 1 mg minodronate (n = 359) or placebo (n = 345) for 24 months, with daily supplements of 600 mg calcium and 200 IU vitamin D(3). RESULTS: Daily 1 mg minodronate for 24 months reduced the risk of vertebral fractures by 59% (95% CI, 36.6-73.3%). Furthermore, when fractures during the first 6 months were eliminated, the risk of vertebral fractures from 6 to 24 months was reduced by 74% in minodronate-treated group. Minodronate treatment also reduced height loss. Bone turnover markers were suppressed by about 50% after 6 months of minodronate treatment and remained suppressed thereafter. The overall safety profile including gastrointestinal safety was similar between the two groups. CONCLUSIONS: Daily oral minodronate is safe, well-tolerated, and is effective in reducing vertebral fracture risk in postmenopausal women with established osteoporosis.

A double-blind dose-ranging study of risedronate in Japanese patients with osteoporosis (a study by the Risedronate Late Phase II Research Group).

To determine the clinical recommended dosage regimen of risedronate for the treatment of involutional osteoporosis in Japanese patients, dose-response relationships for the efficacy and safety of this drug were investigated using a multi-center, randomized, double-blind, parallel group comparative design with four dose levels of risedronate (placebo, 1 mg, 2.5 mg and 5 mg per day). A total of 211 patients diagnosed with involutional osteoporosis according to the criteria proposed by the Japanese Society for Bone and Mineral Research were randomized and received one of the four doses once daily for 36 weeks. All patients were supplemented with 200 mg of calcium daily in the form of calcium lactate. The primary efficacy endpoint was the percent change in bone mineral density of the lumbar spine (L2-L4 BMD) determined by dual-energy X-ray absorptiometry (DXA) from baseline to the time of final evaluation. Changes in biochemical markers of bone turnover and safety profile were also compared. Percent changes in L2-L4 BMD at final evaluation in the placebo, and 1-, 2.5-, and 5-mg risedronate groups were 0.79+/-5.30, 2.71+/-4.93, 5.29+/-3.96, and 5.15+/-4.25% (mean+/-SD), respectively. A linear dose-response relationship was obtained up to a dose of 2.5 mg, whereas no further increase in BMD was observed at 5 mg. The decrease in bone turnover markers, including N-terminal osteocalcin, phosphorus, and urinary deoxypyridinoline, also showed a linear dose-response relationship up to a dose of 2.5 mg. Alkaline phosphatase level decreased linearly up to a dose of 5 mg. Risedronate was well tolerated in this 36-week study with 1- to 5-mg doses. Neither the overall incidence of adverse events nor the percentage of patients without problem in overall safety assessment differed significantly among the dose groups including the placebo group. Based on these results, a once-daily dose of 2.5 mg of risedronate, which is half that used in Caucasians, is recommended for the treatment of involutional osteoporosis in Japanese patients.

A comparison of the effect of risedronate and etidronate on lumbar bone mineral density in Japanese patients with osteoporosis: a randomized controlled trial.

To demonstrate the clinical benefit of 2.5 mg daily risedronate in the treatment of involutional osteoporosis, the effect of risedronate on bone mineral density (BMD) of the lumbar spine was compared with that of etidronate, selected as a representative of the bisphosphonates currently marketed in Japan. In this multicenter, randomized, double-masked, active (etidronate) controlled comparative study, a total of 235 Japanese patients with involutional osteoporosis were randomized to receive either treatment with 2.5 mg/day of risedronate for 48 weeks or intermittent treatment with etidronate (4 cycles of 2 weeks of treatment with 200 mg/day followed by 10-week medication-free periods). All patients received 200 mg of calcium supplement daily in the form of the calcium lactate. Bone mineral density of the lumbar spine (L2-L4 BMD) was determined at 12, 24, 36 and 48 weeks by dual-energy X-ray absorptiometry. The primary endpoint was the percent change in L2-L4 BMD from baseline to the time of final evaluation. Changes in biochemical markers of bone turnover and safety profiles were also compared. A significant increase in L2-L4 BMD was observed at 12 weeks after initiation of therapy in both the risedronate (2.8%) and etidronate (1.8%) groups. The increase in L2-L4 BMD at the time of final evaluation in the risedronate group (4.9%) was significantly greater ( p = 0.002) than that in the etidronate group (3.1%). The changes in bone resorption markers (urinary total deoxypyridinoline and N-terminal telopeptide of type I collagen) from baseline to 48 weeks were -37.6% and -41.3% for risedronate and -22.5% and -26.6% for etidronate, respectively. New vertebral fractures or deterioration of existing fractures were observed in 2.8% (3/106) of the patients in the etidronate group, while no such cases (0/101) were observed in the risedronate group. No significant difference in the incidence of adverse events was found between two treatments. Daily oral risedronate (2.5 mg) exhibited efficacy superior to that of intermittent cyclical etidronate (200 mg) in increasing L2-L4 BMD, and was well tolerated by Japanese patients with involutional osteoporosis.

A novel subtype of prostacyclin receptor in the central nervous system.

Recently, in the course of our search for the prostacyclin receptor in the brain, we found a novel subtype, designated as IP2, which was finely discriminated by use of the specific ligand (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (15R-TIC) and specifically localized in the rostral part of the brain. In the present study, the tritiated compound 15R-[15-(3)H]TIC was synthesized and utilized for more specific research on IP2. The specificity of binding to rat brain regions was confirmed by use of several prostacyclin derivatives including 15S-TIC. Mapping of 15R- and 15S-[3H]TIC binding in adjacent pairs of frozen sections of rat brain demonstrated a quite similar pattern of distribution in almost all rostral brain regions, indicating that the regions may contain only the IP2 subtype. On the other hand, 15R-[3H]TIC binding was very faint as compared with 15S-[3H]TIC binding in the caudal medullary region. High densities of 15R-[3H]TIC binding sites were shown in the dorsal part of the lateral septal nucleus, thalamic nuclei, limbic structures, and some of the cortical regions. Scatchard plot analysis showed two components of high-affinity 15R-[3H]TIC binding in the rostral regions, one with a K(D) value at approximately 1 nM and the other with approximately 30 nM. These results strengthen our previous finding that a different subtype of prostacyclin receptor is expressed in the CNS, and the map with 15R-[3H]TIC obtained here could guide further studies on the molecular and functional properties of the IP2.

Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure.

BACKGROUND: In patients with chronic renal failure (CRF), abnormalities in vitamin D metabolism are known to be present, and several factors could contribute to the abnormalities. METHODS: We measured serum levels of three vitamin D metabolites, 1,25(OH)2D, 24, 25(OH)2D and 25(OH)D, and analyzed factors affecting their levels in 76 nondialyzed patients with CRF (serum creatinine> 1.6 and < 9.0 mg/dl), 37 of whom had diabetes mellitus (DM-CRF) and 39 of whom were nondiabetic (nonDM-CRF). RESULTS: Serum levels of 1,25(OH)2D were positively correlated with estimated creatinine clearance (CCr; r = 0.429; P < 0.0001), and levels of 24,25(OH)2D were weakly correlated with CCr (r = 0.252, P < 0.05); no correlation was noted for 25(OH)D. Serum levels of all three vitamin D metabolites were significantly and positively correlated with serum albumin. Although there were no significant differences in age, sex, estimated CCr, calcium and phosphate between DM-CRF and nonDM-CRF, all three vitamin D metabolites were significantly lower in DM-CRF than in nonDM-CRF. To analyze factors influencing vitamin D metabolite levels, we performed multiple regression analyses. Serum 25(OH)D levels were significantly and independently associated with serum albumin, presence of DM and serum phosphate (R2 = 0.599; P < 0.0001). 24,25(OH)2D levels were significantly and strongly associated with 25(OH)D (beta = 0.772; R2 = 0.446; P < 0.0001). Serum 1,25(OH)2D levels were significantly associated only with estimated CCr (R2 = 0. 409; P < 0.0001). CONCLUSIONS: These results suggest that hypoalbuminemia and the presence of DM independently affect serum 25(OH)D levels, probably via diabetic nephropathy and poor nutritional status associated with diabetes, and that 25(OH)D is actively catalyzed to 24,25(OH)2D in CRF, probably largely via extrarenal 24-hydroxylase. Serum levels of 1,25(OH)2D were significantly affected by the degree of renal failure. Thus, this study indicates that patients with CRF, particularly those with DM, should receive supplements containing the active form of vitamin D prior to dialysis.

[Treatment of osteoporosis by active vitamin D].

Supplementation of active vitamin D has been thought to be reasonable for those who convert insufficiently vitamin D to active form, especially for senile persons. Treatment of osteoporosis by vitamin D are accepted as not only supplementation of vitamin D but also direct activation of bone turnover. Several previous clinical trials suggest active vitamin D prevents fractures more effectively rather than the increase of the bone mass. The calcium intake of Japanese people is less than that of Western countries, and many of Japanese have the vitamin D receptor genotype which is more responsive to vitamin D. Therefore, it is probable that active vitamin D is more effective for Japanese than Western people.

History of vitamin D treatment of renal osteodystrophy.

Vitamin D treatment was tried when renal osteodystrophy was first recognized in the early 20th century, using vitamin D2, D3, or dihydrotachysterol. Large doses of vitamin D2 or D3 (150,000-500,000 IU) were prescribed by monitoring serum calcium, phosphate, and alkaline phosphatase. After the discovery of 1,25-dihydroxycholecalciferol, this compound or 1 alpha-hydroxycholecalciferol was applied to the treatment of renal osteodystrophy. In a preclinical study, especially of 1 alpha-hydroxycholecalciferol, nephritogenoside nephritis was the most responsive condition. These active vitamin D preparations are now widely used in patients with chronic renal failure under hemodialysis. Other active vitamin D compounds, such as hexafluoro-1,25-dihydroxycholecalciferol and 22-oxacalcitriol, are also under investigation.

An adult case of Fanconi syndrome due to a mixture of Chinese crude drugs.

We examined a 35-year-old male case of acquired Fanconi syndrome induced by a mixture of Chinese crude drugs. Renal glycosuria, hypokalemia, hypophosphatemia, metabolic acidosis, a low threshold of tubular bicarbonate excretion, and generalized aminoaciduria were observed after the patient had taken the drugs for 6 months. When he stopped taking them, all laboratory data improved. He took the drugs again on his own judgment, leading to a second bout of Fanconi syndrome. This is the first case in which Chinese crude drugs have been known to cause acquired Fanconi syndrome.

Partial protection of 1 alpha-hydroxyvitamin D3 against the development of diabetes induced by multiple low-dose streptozotocin injection in CD-1 mice.

1 alpha-Hydroxyvitamin D3 (1 alpha-OH-D3), a precursor of active vitamin D3, 1 alpha,25-dihydroxyvitamin D3, was tested in CD-1 mice for its in vivo effect against the development of diabetes induced by administering multiple low doses of streptozotocin (STZ). Daily intraperitoneal (IP) injections of 35 mg/kg body weight of STZ administered for 5 consecutive days to mice from 7 weeks of age induced a delayed-onset hyperglycemia, insulitis, and beta-cell degranulation in 26 of 28 mice. Only 12 of 29 mice developed diabetes when treated with simultaneous daily IP injections of 1 alpha-OH-D3 for 14 consecutive days, with diabetes defined as a plasma glucose level greater than 200 mg/dL. A daily dose of 0.3 micrograms/kg 1 alpha-OH-D3 also protected against the development of hyperglycemia in five of 13 mice, whereas 0.2 micrograms/kg 1 alpha-OH-D3 was ineffective, indicating a dose-related effect. Histological study showed that, among the 1 alpha-OH-D3-treated mice, the pancreatic islets of euglycemic mice showed neither massive islet infiltration nor beta-cell degranulation, whereas those of the hyperglycemic mice showed insulitis. However, when diabetes was chemically induced with a single high dose of STZ, the simultaneous administration of 1 alpha-OH-D3 to mice failed to protect against the development of hyperglycemia; all five mice so treated developed hyperglycemia. Their pancreatic islets did not show insulitis. Therefore, it is suggested that 1 alpha-OH-D3 may protect against the development of diabetes following administration of multiple low doses of STZ, probably via an immune mechanism.

Effects of dietary phosphorus restriction on secondary hyperparathyroidism in hemodialysis patients during intermittent oral high-dose 1,25(OH)2D3 treatment.

Phosphorus (P) retention plays an important role in the pathogenesis of secondary hyperparathyroidism (2nd HPT) in chronic renal failure. In recent years, periodic intravenous or intermittent oral administration of high doses of 1,25(OH)2D3 has been reported to improve severe 2nd HPT in hemodialysis patients. The present study was performed to determine the effects of dietary P restriction on 2nd HPT in hemodialysis patients treated with intermittent oral high-dose 1,25(OH)2D3. A high dose of 1,25(OH)2D3 was administered orally twice a week at the end of hemodialysis in 20 hemodialysis patients with 2nd HPT. Dietary P content was estimated from records of the patients' food intake, made twice during the treatment period. Based on this information, dietitians developed appropriate meal plans and instructed the patients. After 8 weeks of the treatment, serum c-parathyroid hormone (c-PTH) and alkaline phosphatase (ALP) levels decreased significantly, from 18.8 +/- 1.9 ng/ml and 347.1 +/- 30.7 U/liter to 9.4 +/- 1.2 ng/ml and 268.3 +/- 19.6 U/liter, respectively. Serum P levels increased gradually during the first 4 weeks of the treatment. Dietary P intake was reduced significantly, from 908 +/- 49 mg/day to 734 +/- 39 mg/day, after the nutritional instructions. As a result of the dietary P restrictions, serum P levels were significantly decreased in the 8th week as compared with those in the 4th week. Serum Ca levels remained unchanged throughout the observation period. There was a significant relationship between the mean values for serum P levels during the study and the percent suppression of serum c-PTH.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of uremic serum on 1,25-dihydroxyvitamin D3-induced differentiation of a human promyelocytic leukemia cell line, HL-60.

The mechanism by which resistance to 1,25 dihydroxyvitamin D3 (1,25-(OH)2D3) occurs in patients with chronic renal failure was studied. This agent induces differentiation and 1,25-(OH)2D3-24-hydroxylase activity in the mitochondria of the human promyelocytic leukemia cell line, HL-60, via a steroid-hormone receptor mechanism. HL-60 cells were cultured in RPMI 1640 medium supplemented with 10% normal or uremic serum. Treatment of these cells with 10(-8)M 1,25-(OH)2D3 for 5 days in a medium containing 10% uremic serum from 4 patients with chronic renal failure resulted in a maturation of the cells amounting to 30.3 +/- 18.7% (mean +/- SD) and 32.5 +/- 11.2%, as obtained by NBT reduction assay and NSE assay, respectively. These values were significantly lower than those obtained with 10% serum from 3 normal controls (66.6 +/- 12.8%, 58.3 +/- 10.9%, p less than 0.02). The treatment of HL-60 cells with 1,25-(OH)2D3 in a mixture of 5% normal plus 5% uremic serum caused cell differentiation to an extent similar to that in 10% uremic serum, which suggests the presence of a substance(s) having 1,25-(OH)2D3-inhibitory activity in the uremic serum. Exposure of HL-60 cells to uremic serum significantly impaired their responsiveness to 1,25-(OH)2D3 as assessed by the induction of the cell's ability to hydroxylate the C-24 position of 1,25-(OH)2[3H]D3. The mechanism by which uremic serum confers an impaired cellular response to 1,25-(OH)2D3 seemed to be due, in part, to a decrease in 1,25-(OH)2D3 receptor levels. A significant positive correlation was observed between intracellular cAMP levels and 1,25-(OH)2D3-induced HL-60 cell maturation. In summary, the mechanism by which uremic serum confers 1,25-(OH)2D3 resistance upon HL-60 cells seemed to be due to the presence of 1,25-(OH)2D3-inhibitory activity in uremic serum, which may modulate cellular responsiveness to 1,25-(OH)2D3 by such mechanisms as reducing 1,25-(OH)2D3 receptor levels in the cells, in part through alteration in cAMP metabolism.

Effect of intermittent oral 1,25(OH)2D3 therapy on bone Gla protein in dialysis patients.

Serum Bone Gla Protein (BGP) levels were measured by both immunoradiometric assay (IRMA) and radioimmunoassay (RIA) to investigate the effect of intermittent 1,25(OH)2D3 administration to dialysis patients who could not tolerate an increase in an active vitamin D3 dose and/or calcium to control secondary hyperparathyroidism due to hypercalcemia. The administration of active vitamin D3 gradually increased the serum BGP to more than 3 times the original level by the 8th week. At the 12th week after starting the active vitamin D3 therapy, mean BGP was about twice the original level, which was about half the maximum level at the 8th week. The BGP (IRMA)/BGP (RIA) ratio was increased significantly at 4th and 8th weeks compared to the original level. During this period, serum calcium, phosphorous, or intact molecule PTH (I-PTH) levels showed insignificant changes, with a slight reduction in the mid molecule PTH (m-PTH) level, and a significant reduction in ALP. Serum BUN and creatinine levels were not changed significantly. These data suggest that BGP was increased through direct stimulation of osteoblasts by the active vitamin D3, and the increase was not due to deterioration of secondary hyperparathyroidism. The reduction of the increase in the BGP level at the 12th week with insignificant biochemical changes suggest that activation of osteoblasts by vitamin D3 may be transient. In conclusion, intermittent active vitamin D3 increases serum BGP, without deterioration of major biochemical changes even in patients with moderate to severe secondary hyperparathyroidism, although the increase may be transient. These facts suggest that the serum BGP of hemodialysis patients is controlled at least in part by active vitamin D3.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of rat brain prostaglandin D synthase by inorganic selenocompounds.

Various inorganic selenocompounds dose-dependently inhibited the rat brain prostaglandin (PG) D synthase, both in the purified enzyme preparation and in the crude brain supernatant. All of the quadrivalent selenium compounds tested had a very limited range of IC50 values in the purified enzyme (11-12 microM) and in the brain supernatant (9-15 microM). A divalent selenium compound was also inhibitory, but a hexavalent selenium compound was ineffective. In contrast, organic selenocompounds such as selenomethionine and selenourea had no effect on the PGD synthase activity. Furthermore, sodium sulfate and sodium sulfite up to 10 mM did not inhibit the activity. The inhibition by selenium required the preincubation of the metal with sulfhydryl compounds such as dithiothreitol (DTT), indicating that the formation of selenotrisulfide or some other adduct(s) is essential for the inhibition. Furthermore, the inhibition was reversed by an excess amount of dithiothreitol, suggesting that the selenotrisulfide derivative of DTT binds to the SH group of the PGD synthase. The kinetic analysis revealed the inhibition by selenite to be noncompetitive with a Ki value of 10.1 microM. On the other hand, glutathione-dependent PGD synthase from rat spleen was much less inhibited, and PGF synthase and PGD2 11-ketoreductase activities were not inhibited by the selenium compound.

Parathyroid hormone secretion in diabetes mellitus.

To investigate the parathyroid function in diabetes mellitus, we performed an oral phosphate load in 6 diabetic patients and 6 nondiabetic subjects without renal failure (serum creatinine less than 1.5 mg/dl). Each subject received a total of 2.0 g of phosphate daily per os on 5 consecutive days. Blood and urine samples were obtained daily before and 2 h after the administration of phosphate in the morning. All subjects responded with a similar increase in the serum phosphorus concentration and fall in the ionized calcium concentration. Intact parathyroid hormone levels rose by 2.6-fold in the control subjects but by less than 1.5-fold in the diabetic subjects. It was concluded that hyporesponsiveness of the parathyroid hormone to phosphate administration was found in the diabetic patients without renal failure.

Biological activity of 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3 in the chick.

A newly synthesized fluorinated analogue of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3 (26,27-F6-1,25-(OH)2D3) has been compared with 1,25(OH)2D3 as to its biological activity in vitamin D-deficient chicks. One day-old, white Leghorn cockerels were fed a rachitogenic diet for 5 weeks. They were then given vehicle or 32.5, 130 or 325 pmol of 26,27-F6-1,25(OH)2D3 or 1,25(OH)2D3 in a solution of propylenglycol:ethanol (95:5 v/v) sc every day for 2 weeks. Twenty-four hours after the last dose, the animals were sacrificed and their femurs were removed. 26,27-F6-1,25(OH)2D3 was more active than 1,25(OH)2D3 in stimulating growth, healing of rachitic cartilage visualized by soft X-ray radiography, elevation of serum inorganic phosphorus, and mineralization of rachitic bone. These biological differences between two compounds were observed only for the dose of 130 pmol. However, this fluorinated compound has less binding ability than 1,25(OH)2D3 to fetal chick intestinal cytosol receptors. The mechanism of the higher potency of this analogue is still unknown, but its affinity to the 1,25(OH)2D3 receptor does not account for the higher activity. Since 26-hydroxylation can be postulated as the inactivation step in vitamin D metabolism, these results suggest that the reason for increased activity of this fluorinated analogue is most likely its slower metabolism.