Failure of cimetidine to affect calcium homeostasis in familial primary hyperparathyroidism (multiple endocrine neoplasia, type 1).

Recent reports that cimetidine, a blocker of histamine H2 receptors, lowered serum calcium and/or immunoreactive parathyroid hormone (PTH) concentrations in primary or secondary hyperparathyroidism prompted us to administer the drug (300 mg, orally, every 6 h) to two patients with hyperparathyroidism accompanying familial multiple endocrine neoplasia type 1. The patients were hypercalcemic (10.9--11.2 mg/dl), hypophosphatemic (2.0--2.4 mg/dl), and hypercalciuric (greater than or equal to 410 mg/24 h), with elevated urinary cAMP and phosphate clearance and inappropriately high serum immunoreactive PTH levels. Multiple observations of these variables over 5 weeks of cimetidine treatment showed no systematic changes; in particular, serum and urinary calcium did not change, and there was no evidence of a decreased PTH effect on the kidneys. The data offer no support for the treatment of familial hyperparathyroidism with cimetidine.

Cimetidine treatment of azotemic secondary hyperparathyroidism.

Cimetidine, an antagonist to histamine H2-receptors, reportedly lowers serum calcium and/or serum immunoreactive parathyroid hormone (iPTH) concentrations in some patients with primary and secondary (azotemic) hyperparathyroidism. We administered the drug orally (300 mg every 6 h) to five normal volunteers and four azotemic patients with secondary hyperparathyroidism who were not undergoing chronic hemodialysis. The normal persons and one azotemic patient took the drug for 5 weeks, and the remaining azotemic patients took it for 1 week. Before treatment, all patients had elevated levels of serum iPTH (two different assay systems), with or without elevated serum calcium concentrations, and increased urinary excretion of cAMP (per 100 ml glomerular filtrate). Cimetidine treatment caused no changes in serum calcium, phosphorus, or iPTH or in urinary cAMP (expressed as nanomoles per g creatinine). Serum creatinine, however, increased significantly in patients (P less than 0.02) and control subjects (P less than 0.025), which yielded statistically significant but spurious increases of urinary cAMP when expressed per 100 ml glomerular filtrate. We conclude that short term cimetidine administration has no effect on parathyroid function in normal persons or those with azotemic hyperparathyroidism. Because of its confusing effect on serum creatinine and a possible (albeit rare) adverse effect on renal function, the drug should be used with caution in azotemic patients not yet requiring chronic dialysis.

Urinary and fecal excretions and absorption of a large supplement of selenium: superiority of selenate over selenite.

A correction needs to be made to the form of selenium used in earlier studies; what was believed to be selenite-Se in solution is now known to have been selenate-Se. In the present study, excretion of Se was followed in 13 women after ingestion of 1 mg Se as selenite or selenate in solution. Fecal excretion of selenate-Se was less than for selenite-Se reflecting a higher apparent absorption [94 +/- 4% (SD), 62 +/- 14%, respectively]. Peak excretion of Se occurred 3 h earlier for selenate-Se than for selenite-Se and was 6 times higher. Total urinary excretion of selenate-Se was 3 times that of selenite-Se and still 2 times as high when expressed as % absorbed dose. Total recovery of Se in urine and feces was similar for both forms. There was remarkable agreement between these results and those reported earlier for selenate-Se (Selovet-1) and selenite-Se.

Selenium in human health and disease with emphasis on those aspects peculiar to New Zealand.

Evidence is accumulating to suggest that selenium (Se) is an essential trace element for man and is reviewed with emphasis on those aspects peculiar to New Zealand. The extremely low Se levels in New Zealand soils results in a low Se content of foods, low dietary intakes, low urinary excretions, and low blood Se concentrations and glutathione peroxidase activities. Of these, plasma Se gives a short-term index of nutritional status while erythrocyte Se and glutathione peroxidase activities give a long-term index. The consequences of the low Se status of New Zealanders are not immediately apparent as a deficiency disease has not been detected in residents consuming a normal diet. However a Se-responsive muscular syndrome has been described in a surgical patient on total parenteral nutrition. Similar groups that might be vulnerable to a Se deficiency are children with metabolic disorders consuming synthetic protein diets, premature babies and infants during the first few months of life, and patients with cancer whose lowered dietary intake is coupled with the traumatic nature of their disease. Other groups that have been studied in relation to a possible role for Se in specific illnesses are patients with cardiovascular disease and hypertension, rheumatoid arthritis and other muscular syndromes and surgical patients with or without cancer. It is not yet possible to predict a minimum Se requirement for health but it appears that the intake of New Zealanders might be on the borderline. At present supplementation by the general population is not justified, but may be necessary for certain vulnerable groups such as patients on restricted diets. The most effective means of supplementation for increasing the Se status of New Zealanders is under study.

Effects of supplementation with high-selenium wheat bread on selenium, glutathione peroxidase and related enzymes in blood components of New Zealand residents.

The effects of supplementation with high-Se wheat bread on selenium (Se) concentrations, glutathione peroxidase (EC 1.11.1.9, GSHPx) activities and related enzymes in the prevention of lipid peroxidation were studied. Four New Zealand women were supplemented with 200 micrograms Se daily for 8-13 weeks followed by a post-dosing period of 9-12 weeks. GSHPx activities increased in whole blood, erythrocytes, plasma and platelets of all subjects but increases were considerably less than those of Se concentrations in whole blood, plasma and erythrocytes. During the post-dosing period Se concentrations and GSHPx activities fell to levels which were in most cases somewhat higher than baseline values. Glutathione-S-transferase activities in erythrocytes, plasma and platelets did not change during the study, nor did superoxide dismutase in erythrocytes and platelets, erythrocyte catalase or plasma alpha-tocopherol. Thus Se supplementation of healthy New Zealand subjects increased GSHPx activities but did not produce any adaptive changes in other components of the lipid peroxidation defense mechanisms.

Selenium distribution in blood fractions of New Zealand women taking organic or inorganic selenium.

Three groups of 11 New Zealand women each received, for 32 wk, yeast tablets with no added selenium (placebo) or 200 micrograms Se/d in tablets either as selenate or as selenium-enriched yeast (SeMet) in a double-blind selenium trial. Plasma and erythrocyte (RBC) samples were collected bimonthly. Gel filtration of plasma from women taking SeMet revealed two major selenium-containing peaks with most of the selenium in the second peak. In contrast, the first peak contained most of the selenium in plasma from women taking selenate. Chromatography of RBC lysates indicated that the majority of the selenium was with hemoglobin (Hb) in women taking SeMet but was about equally distributed between glutathione peroxidase (GSH-Px) and Hb in women taking selenate. The percentage of selenium associated with GSH-Px was found to be greater in RBCs and plasma of women taking selenate than of those taking SeMet.

Selenium and vitamin E supplementation: activities of glutathione peroxidase in human tissues.

Twenty-seven New Zealand women received daily for 4 wk, 200 micrograms selenium as sodium selenite, 170 mg alpha-tocopherol acetate, or a placebo. Se supplementation raised platelet selenoglutathione peroxidase (Se-GSHPx, p less than 0.001) and also Se and Se-GSHPx in whole blood and plasma. Se concentrations and Se-GSHPx activities in liver biopsies taken after supplementation were greater (p less than 0.05) for the Se group and a good correlation was found between Se and Se-GSHPx in liver and muscle for all subjects. Platelet Se-GSHPx correlated well with Se and Se-GSHPx in liver, indicating its suitability for assessing Se bioavailability. This is the first reported study of relationships between Se and Se-GSHPx in human liver and muscle tissue and platelet Se-GSHPx after Se supplementation. These observations verify in man relationships observe in animal studies, giving support to assumptions made in methods for assessing Se status and bioavailability in man, in particular the use of platelet GSHPx.

Blood selenium and glutathione peroxidase activity in normal subjects and in surgical patients with and without cancer in New Zealand.

This study was carried out in Otago, South Island, where most arable land has a low soil selenium content (less than 0.5 microgram/g) and where selenium (Se) responsive diseases in livestock are common. Se concentration in whole blood, erythrocytes and plasma, and activity of glutathione peroxidase (EC 1.11.1.9) were measured in blood from 104 healthy Otago residents, 80 patients with cancer and 66 noncancer surgical patients. The older residents over 60 years had lower blood Se levels (0.047 +/- 0.010 microgram Se/ml blood) than the young and middle-aged (0.060 +/- 0.012 microgram Se/ml). Blood Se levels of cancer patients were no lower than those of elderly subjects and patients without cancer, and were less than half comparable United States values. Blood Se levels were decreasing in two cancer patients, and the lowest values (less than 0.03 microgram Se/ml blood) were obtained for five cancer patients, and two noncancer patients after a long period of inanition; these were similar to values for patients on parenteral nutrition with negligible intakes. Lower blood Se levels were associated with lower serum albumin and enzyme activities. It is suggested that low Se status of cancer patients was more likely a consequence of their illness than the cause of the cancer.

Selenium concentration and glutathione peroxidase activity in blood of New Zealand infants and children.

The blood selenium (Se) concentrations of New Zealand children were lower than those reported for children living in other countries. This low blood Se was primarily determined by the low dietary intake of the children which, in turn, reflects the low Se content of New Zealand soils. Blood Se also varied geographically, with age, and with differences in quantities and types of food eaten. Children with phenylketonuria and maple syrup urine disease on synthetic diets had low Se intakes and blood Se concentrations compared with children on normal diets, and blood Se was seen to decrease with the length of time on these diets. A strong correlation (r = 0.62, P less than 0.001) was found between the blood Se levels and glutathione peroxidase activities for 107 children. Glutathione peroxidase activities of the children were lower than activities observed in New Zealand adults, refelecting their lower blood Se concentrations.

Zinc retention and losses of zinc in sweat by preadolescent girls.

Preadolescent girls, ages 7 to 9 years, were fed levels of zinc ranging from 5.61 to 14.61 mg/day during an 18-day metabolic study. All other nutrients were provided at or above Recommended Dietary Allowance levels. The sweat loss of zinc was measured using an arm-bag method and whole body zinc loss was calculated from whole body nitrogen and arm loss of nitrogen and zinc. Fecal zinc reflected dietary zinc, but urinary zinc remained relatively stable. The mean daily loss of zinc through sweat was calculated to be 1.43 mg. Zinc retentions were not significantly different (P greater than 0.05) though the retention increased generally with intake of zinc. A comparison of these data with previously reported studies indicated that the absorption of zinc was usually in the range of 20 to 30%. Based on sweat losses reported by others and found in this study and on usual absorption of zinc, it appears that diets should provide a minimum of 7 mg of zinc daily for growing children.

Effect of prolonged supplementation with daily supplements of selenomethionine and sodium selenite on glutathione peroxidase activity in blood of New Zealand residents.

Glutathione peroxidase (EC 1.11.1.9, GSH-Px) activities and selenium (Se) concentrations in blood of 12 New Zealand residents were followed during prolonged supplementation with physiological doses (100 microgram Se) of sodium selenite (selenite-Se) or selenomethionine (Semet-Se). GSH-Px activities increased in all subjects but at 17 wk the mean increase was not significantly greater for Semet-Se (6.2 +/- SD 3.2 units/g Hb) than for selenite-Se (3.7 +/- 1.8 units/g Hb). After dosing ceased, GSH-Px activities for most subjects returned to predosing values in 17 to 40 wk, but in some subjects activities remained high. Increases in Se concentrations in whole blood, erythrocytes, and plasma were greater after Semet-Se than after selenite-se. Se concentrations tended to plateau after selenite-Se while after Semet-Se they continued to rise as long as dosing continued. Enzyme activity of one of four subjects supplemented daily with 500 microgram selenite-Se was unchanged, despite a great increase in plasma Se. Blood Se and GSH-Px of 23 New Zealand residents who ingest regular large doses (0.5 to 3 mg Se) mainly of selenite-Se showed that those who dosed weekly had greater values than the less frequent dosers. Three subjects showed extremely high values. It is suggested that each individual might have an optimal level of GSH-Px activity, so that the level reached is a balance between Se intake and other factors, including possible stressor effect of selenite.

Urinary excretion of selenium by New Zealand and North American human subjects on differing intakes.

Lower renal plasma clearances of selenium (CSe 0.1-0.2 ml min-1), indicating excretion of a smaller proportion of Se presented to the kidneys, were found in New Zealand (NZ) residents with low plasma Se ((Se)p 50-70 ng ml-1) on customary intakes below 30 micrograms d-1 Se. North American subjects consuming 80 micrograms d-1 with (Se)p 120-140 ng ml-1 had CSe between 0.2 and 0.3 ml min-1. Several weeks' supplementation with high-Se bread increased NZ subjects' (Se)p to 120-175 ng ml-1 and CSe to 0.4-0.7 ml min-1. (Se)p remained elevated when supplementation ceased, but CSe returned to the basal range within a few days. Americans' clearances showed no such abrupt decrease when their dietary intake was similarly reduced. The NZ residents thus appeared to excrete selenium more sparingly than others. Rapid alterations in clearance after supplements and single doses were probably due to changes in the proportions of different forms of selenium in the plasma.

Combined neutrophil and T-cell deficiency: initial report of a kindred with features of the hyper-IgE syndrome and chronic granulomatous disease.

A six year old female presented with a recent history of pyoderma gangrenosum involving her legs and arms associated with an episode of Mycoplasma-like pneumonia. This was followed by Aspergillus osteomyelitis involving her left ulna and right femur. Both the skin lesions and the osteomyelitis responded to prolonged treatment with antifungal and antibiotic agents. Investigation of this patient revealed (1) an elevated serum IgE (4,800 units/ml), (2) defect in neutrophil chemotaxis that appeared to be due to immune complexes, (3) an abnormal nitroblue tetrazolium (NBT) result (0 percent stimulated and unstimulated), and (4) depressed mitogen responses to concanavalin A, phytohemagglutinin, and pokeweed mitogen, negative results of intradermal skin tests, and negative dinitrochlorobenzene (DNCB) sensitization. The patient's clinically unaffected sibling had similar findings except for a positive DNCB response. In both children, intracellular bacterial killing of catalase-positive and negative organisms was normal. Kindred studies revealed widespread T-cell abnormalities consistent with autosomal dominant inheritance. Tissue typing studies showed that affected siblings shared the A1, B8, DR3 haplotype. This kindred is unique in that both the proband and the sibling have abnormalities of both the hyper-IgE syndrome and chronic granulomatous disease.

Oxygenation of tumors by a hemoglobin solution.

Tumor oxygen tensions were measured using a computer-controlled PO2 microelectrode in two preclinical solid tumor models, the rat 9L gliosarcoma and the rat 13672 mammary carcinoma. Tumor oxygenation profiles were determined under four conditions: (a) during normal air breathing, (b) during carbogen breathing, (c) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with normal air breathing and (d) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with carbogen breathing. Both tumors had severely hypoxic regions under normal air-breathing conditions. Although carbogen breathing increased the oxygenation of the better-oxygenated portions of the tumor, it made no impact on the severely hypoxic tumor regions. Administration of the hemoglobin solution was effective in increasing the oxygenation throughout both tumors under normal air-breathing conditions. The addition of carbogen breathing to administration of the hemoglobin solution eliminated severe hypoxia in the 9L gliosarcoma and markedly reduced the severely hypoxic regions of the 13672 mammary carcinoma. At 24 h after administration of the hemoglobin solution the 13672 mammary carcinoma showed greater hypoxia than before treatment, which was partially corrected with carbogen breathing.

Selenium in human nutrition in New Zealand.

New Zealand's soil has a low concentration of selenium (Se), and its residents have a lower Se status than do most other peoples. However, New Zealanders do not suffer from the Se-responsive ills that afflict their farm animals and some people in China. New Zealanders, particularly those in the South Island, may have adapted to their low Se environment by thriftiness in urinary excretion of Se. Low glutathione peroxidase activities in their tissues have not resulted in noticeable damage or changes. The enzyme activity can be raised to a plateau by Se supplements, but there is no evidence that supplementation leads to better health. Since patterns of coronary heart disease, hypertension, and cancer in New Zealand resemble those in other Western countries, no direct link between these diseases and Se level is likely.

Antifolates can potentiate topoisomerase II inhibitors in vitro and in vivo.

Antifolates have been shown to increase the DNA strand breaks produced by the topoisomerase inhibitor etoposide. PT523 is a potent new antifolate that cannot be polyglutamated. Human SCC-25 squamous carcinoma cells were exposed to methotrexate, trimetrexate or PT523 at a concentration of 5 microM for 24 h along with various concentrations of etoposide or novobiocin during the final 2 h. Isobologram analysis of the treatment combinations indicated that exposure of the cells to PT523/etoposide, methotrexate/etoposide, PT523/novobiocin, methotrexate/novobiocin and trimetrexate/novobiocin resulted in greater than additive cytotoxicity. DNA alkaline elution studies with the same drug combinations indicated that there were three- to four-fold increases in the radiation equivalent (rad equivalent) strand breaks in the cellular DNA with etoposide or novobiocin along with the antifolate compared with the topoisomerase II inhibitors alone. Tumor growth delay studies were carried out in the murine SCC VII squamous carcinoma. PT523 (0.5 mg/kg) and methotrexate (2 mg/kg) were administered by 7-day continuous infusion while trimetrexate (3.75 mg/kg) was administered intraperitoneally daily on days 7-9. Etoposide (10 mg/kg) and novobiocin (100 mg/kg) were administered intraperitoneally on alternate days (7, 9, 11). The combinations of PT523 with etoposide or novobiocin were significantly more effective than methotrexate and etoposide or novobiocin, producing tumor growth delays of 8.4 days and 6.9 days, respectively. Overall, the antifolate/topoisomerase II inhibitor treatment combinations produced tumor growth delays that were apparently additive to greater than additive.

Antiangiogenic treatment (TNP-470/minocycline) increases tissue levels of anticancer drugs in mice bearing Lewis lung carcinoma.

Although the antiangiogenic agent TNP-470 does not, in general, increase the cytotoxicity of anti-cancer therapies in cell culture, the antiangiogenic agents TNP-470 and minocycline individually and especially in combination have been shown to increase the tumor growth delay produced by several standard cytotoxic therapies in the Lewis lung carcinoma. In an effort to understand the mechanism by which the antiangiogenic agent combination TNP-470/minocycline potentiates the antitumor activity of cytotoxic therapeutic agents in vivo, the biodistribution of [14C]-cyclophosphamide and cis-diamminedichloroplatinum(II) was determined 6 h after cytotoxic drug administration in animals bearing Lewis lung carcinoma pretreated with TNP-470/minocycline and in animals without pretreatment. Higher levels of 14C and platinum were found in 9 tissues (including tumor) except blood in animals pretreated with TNP-470/minocycline. The increased drug levels in the tumors may be sufficient to account for the increased tumor growth delays observed previously. DNA alkaline elution of tumors from animals pretreated with TNP-470/minocycline showed increased DNA cross-linking by both cyclophosphamide and cis-diamminedichloroplatinum(II). The possible implications of these results are discussed.

The changing selenium status of New Zealand residents.

OBJECTIVE: The aim of this paper was to compile all the studies of selenium status carried out in Otago and in other areas of New Zealand in order to follow the history of selenium status in New Zealand residents over the last 20 years. DESIGN: Since 1970 baseline blood samples have been collected from several groups of healthy adult subjects, either for the assessment of Se status or to determine baseline Se levels as part of a number of other studies. A comparison has been made of selenium concentrations recorded in recent published and unpublished studies with earlier studies by the Otago research group, and also those by other groups in New Zealand. SETTING: Otago and other New Zealand centres. RESULTS: Blood selenium concentrations of Otago residents were consistently low from 1972 until 1988 at around 0.77 mumol/l, apart from a temporary increase in 1985, and then rose to reach 1.03 mumol/l in 1991 and 1.19 mumol/l in 1992-3. Blood selenium status reflected changes in the importation of Australian wheat. Correlations between selenium and glutathione peroxidase in whole blood and plasma were consistently high prior to 1989, but were no longer significant from 1990. CONCLUSIONS: The lack of a correlation between selenium and glutathione peroxidase in bloods collected after 1990 indicates that at least for glutathione peroxidase, the selenium intake of New Zealanders is now close to that required for saturation. Whether this is sufficient to meet the requirements for other functional selenoproteins or for a possible cancer prevention effect remains to be determined.

Selenium and total parenteral nutrition.

Despite the increasing recognition of selenium (Se) as an essential trace element in man, little is known about its metabolism during total parenteral nutrition (TPN) and the possible development of Se deficiency in high risk patients. From a general population known by its geographical location to have low Se blood levels, we studied a group of 23 surgical patients receiving TPN for at least one week. Whole blood Se levels were less than in the normal general population and, being some of the lowest observed in adult man, approached levels observed in animals with Se-responsive syndromes. Se continued to be lost predominantly in the urine although the Se content of the TPN fluids was very low (less than 0.6 micrograms/24 hr). Patients with excessive volumes of gastrointestinal excretion lost more Se. Se supplementation may be required in some patients receiving TPN.

Selenium supplementation in total parenteral nutrition.

Four adult patients with very low plasma selenium (Se) levels ( less than or equal to 1.5 microgram/100 ml) were given Se supplements while receiving total parenteral nutrition. A comparison was made using the compounds selenomethionine and sodium selenite given either intravenously or by mouth. Urinary excretion and Se plasma responses differed, and indicated that selenomethionine retention was greater. However, the incorporation of Se into the erythrocyte and its enzyme glutathione peroxidase was unpredictable and delayed and was not a good indicator of supplement response. No deleterious effects of supplements were observed. Se supplements are indicated especially in patients with a high risk of developing low Se levels and are best monitored by plasma Se levels.