Renal secretion of diphosphonates in rats

Renal secretion of diphosphonates in rats. Diphosphonates, characterized by a P—C—P bond, are relatively new experimental drugs used for the treatment of myositis ossificans, dental calculus, nephrolithiasis and Paget's disease. These compounds are not metabolized and the fraction which is not taken up by the skeleton is excreted unchanged in the urine. In the present study, the renal clearances of two14C-labelled diphosphonates, disodium ethane-1-hydroxy-1, 1-diphosphonate (CEHDP) and di-sodium dichloromethylene diphosphonate (CCl2MDP) have been measured in conscious rats. The clearances have been found to be higher than the glomerular filtration rate (GFR), Cdiphosphonate/ GFR being about 1.5. This observation indicates net tubular secretion of both drugs. High plasma concentration of EHDP or Cl2MDP significantly depressed CEHDP, whereas CEHDP was not influenced by varying urine pH, by infusing NH4Cl or NaHCO3, or by simultaneous administration of high doses of para-aminohippurate (PAH), probenecid,N-methylnicotin-amide or Ca-EDTA. High plasma concentration of inorganic phosphate depressed CEHDPand also depressed thein vitro ultrafiltrability of EHDP. In conclusion, these results provide evidence of an active renal transport of diphosphonates which appears distinct from the mechanisms handling organic acids, organic bases and EDTA in the rat kidney.Secretion rénale des diphosphonates chez le rat. Les diphosphonates, caractérisés une liaison P—C—P, sont des médicaments relativement nouvaux utilisés dans le traitement de la myosite ossifiante, des calculs dentaires, de la lithiase urinaire et de la maladie de Paget. Ces substances ne sont pas méta-bolisées et la fraction qui n'est pas captée par le squelette est excrétée sans modifications dans l'urine. Dans ce travail les clearances rénales de deux diphosphonates marqués par le14C, disodium éthane-1-hydroxy-1, 1-diphosphonate (CEHDP) et disodium dichlorométhylène diphosphonate (CCl2MDP) ont été mesurées chez des rats conscients. Ces clearances sont supérieures au débit de filtration glomérulaire (GFR), le rapport Cdiphosphonate/GFR est d'environ 1, 5. Cette observation indique une sécrétion tubulaire nette des deux drogues. Des concentrations plasmatiques élevées de EHDP ou de Cl2MDP dépriment significativement CEHDP alors que CEHDP n'est pas influencé par les variations du pH de l'urine, par la perfusion de NH4Cl ou de NaHCO3, ou Par l'administration simultanée de doses élevées de PAH, de probénécide, deN-methyl-nicotamide ou de Ca-EDTA. Des concentrations plasmatiques élevées de phosphate inorganique abaissent CEHDP et diminuent aussi Pultrafiltrabilitéin vitro de EHDP. En conclusion, ces résultats apportent la preuve d'un transport rénal actif des diphosphonates qui paraît distinct des méchanismes qui assurent le transport des acides organiques, des bases organiques et de l'EDTA dans le rein de rat

How a Guaranteed Annual Income Could Put Food Banks Out of Business

The federal Conservative government recently began phasing in a plan to raise the age of eligibility for Old Age Security from 65 to 67. But a more sensible move for improving the effectiveness of Canada’s social safety-net system may be to actually lower the age below 65 and rely strictly on an income test instead, regardless of age. The government could go a lot further toward the reduction of poverty in Canada by building on the success of its income supports for seniors, and making them available to poor Canadians of all ages. Canada can boast of having one of the lowest rates for poverty among seniors in the world, largely due to its guaranteed income programs for those 65 years and older. When low-income Canadians turn 65 years old and leave behind low-paying, often unstable jobs, their poverty levels drop substantially. What a guaranteed income provides, that their vulnerable job situation did not, is a form of protection against budget shocks — a sudden volatility in income or expenses without the access to savings or credit to smooth things out until stability returns. A guaranteed income provides a kind of “disaster insurance” that can protect someone in a crisis situation from going without necessities such as food or even shelter. Statistics show that the rate of Canadians experiencing “food insecurity” — that is, lack of access to food because of financial constraints — is half that among Canadians aged 65 to 69 years than it is among those aged 60 to 64. Self-reported rates of physical and mental health improve markedly as well after lowincome Canadians move from low-wage, insecure employment to a guaranteed income at the age of 65. That dramatic shift in physical and mental health indicates that expanding guaranteed income programs to younger Canadians is more than a simple cost calculation: there are potential savings to be found as poorer Canadians, given a guaranteed income, become healthier and therefore reduce the burden on the public health-care system. Canadian governments already spend billions of dollars on the downstream effects of poverty, but scant emphasis is put on programs targeting poverty’s roots. There is no evidence, where smaller-scale experiments have been tried, to show that a guaranteed income program creates a serious problem with negative incentives and discourages people from working who otherwise might. But because this is a common worry with working-age guaranteed income eligibility, phasing in the program gradually, by lowering eligibility a few years at a time, will allow ongoing investigation and analysis of the effects, before the program is rolled out on a large scale. The tremendous impact that guaranteed incomes have had on reducing poverty and improving health among seniors is something for which Canadians can be rightly proud. So much so that it is incumbent upon us to investigate whether Canada could use the same policy tools to drastically reduce poverty and improve health among Canadians of all ages

Parathyroid hormone-independent adaptation of the renal handling of phosphate in response to renal mass reduction

Parathyroid hormone-independent adaptation of the renal handling of phosphate in response to renal mass reduction. In man as well as in experimental animals progressive renal failure is associated with a decrease in the fractional reabsorption (FR) of inorganic phosphate (Pi). This response has been considered as an adaptation phenomenon and generally attributed to an increase in parathyroid hormone (PTH) secretion. One report indicates that in chronic thyroparathyroidectomized (TPTX) dogs treated with large doses of vitamin D progressive renal failure can also be associated with a fall in FRPi. However, in this latter study the concomittant administration of vitamin D could have accounted for the observed decrease in FRPi. In our study we investigated whether or not chronic reduction in renal mass leads to a similar decrease in maximal net tubular Pi reabsorption per volume of glomerular filtrate (maximal TRPi/ml GF) in the presence and absence of PTH and without pharmacological supplementation in vitamin D. Male rats were either TPTX or sham-operated (intact). One and two weeks later the animals of both groups were either subtotally nephrectomized (NX) in two stages or sham-operated (control). Four weeks after the second renal operation, the glomerular filtration rate (GFR) and the reabsorption of Pi were determined by clearance methodology under acute sodium chloride and Pi infusion, that is, at endogenous and increased plasma Pi concentrations ([Pi]P1.). Thus maximal TRPi/ml GFR could be determined. In rats with intact parathyroid glands GFR was 1.56 ± 0.10 (mean ±SEM) and 0.54 ± 0.10ml/min in control and NX respectively, whereas maximal TRPi/ml GF was 2.24 ± 0.07 in control and 1.57 ± 0.18 µmol/ml (P < 0.005) in NX. In TPTX rats GFR was 1.66 ± 0.27 and 0.62 ± 0.06ml/min in control and NX respectively, whereas maximal TRPi/ml GF was 3.80 ± 0.20 in control and 2.95 ± 0.13 µmol/ml (P < 0.005) in NX. The marked decrease in maximal TRPi/ml GF observed in TPTX after subtotal NX could not be ascribed to any consistent change in plasma calcium. Our study provides conclusive evidence that the decrease in maximal TRPi/ml GF in response to renal mass reduction can occur to the same degree in the presence or absence of PTH.Adaptation indépendente de l'hormone parathyroïdienne du comportement rénal du phosphate en réponse à la réduction de la masse rénale. Chez l'homme de même que chez l'animal d'expérience l'insuffisance rénale progressive est associée à une diminution de la réabsorption fractionnelle (FR) du phosphate inorganique (Pi). Cette réponse a été considérée comme un phénomène d'adaptation et est généralement attribuée à une augmentation de la sécrétion d'hormone parathyroïdienne (PTH). Un travail indique que chez le chien en état de thyroparathyroïdectomie chronique (TPTX) traité par de larges doses de vitamine D, l'insuffisance rénale progressive peut aussi être associée à une diminution de FRPi. Cependant, dans ce dernier travail, l'administration concomitante de vitamine D peut avoir eu pour conséquence la diminution observée de FRPi. Dans le présent travail nous avons recherché si en présence ou en l'absence de PTH et sans supplémentation pharmacologique en vitamine D la réduction chronique de la masse rénale détermine une diminution semblable de la réabsorption maximale nette tubulaire de phosphate par unité de filtrat glomérulaire (max.TRPi/ml GF). Des rats maies ont été soit thyroparathyroïdectomisés soit soumis à un simulacre d'opération. Une puis deux semaines plus tard, les animaux des deux groupes ont été soit soumis à une néphrectomie subtotale (NX) en deux étapes, soit soumis à un simulacre d'intervention (contrôles). Quatre semaines après la deuxième intervention rénale, le débit de filtration glomérulaire (GFR) et la réabsorption de Pi ont été déterminés par la méthode des clearances sous perfusion aiguë de chlorure de sodium et de Pi, c'est-à-dire aux concentrations plasmatiques de Pi endogène et augmentées ([Pi]P1.). Ainsi on a pu déterminer max.TRPi/ml GF. Chez les rats dont les glandes parathyroïdes sont intactes, GFR était de 1,56 ± 0,10 (moyenne ±SEM) et 0,54 ± 0,10ml/mn chez les contrôles et les NX respectivement alors que max.TRPi/ml GF était de 2,24 ± 0,07 chez les contrôles et de 1,57 ± 0,18 µmol/ml (P < 0,005) chez NX. Chez les rats TPTX GFR était de 1,66 ± 0,27 et 0,62 ± 0,06ml/mn chez les contrôles et NX respectivement, alors que max.TRPi/ml GF était 3,80 ± 0,20 chez les contrôles et 2,95 ± 0,13 µmol/ml (P < 0,005) chez NX. La diminution importante de max.TRPi/ml GF observée chez TPTX après NX ne peut pas être attribuée à une modification importante du calcium plasmatique. En conclusion, notre travail apporte des preuves importantes de ce que la diminution de max.TRPi/ml GF en réponse à la réduction de la masse rénale peut survenir de la même façon en présence ou en l'absence de PTH

The role of bisphosphonates in breast cancer: Development of bisphosphonates

Bisphosphonates are synthetic compounds characterized by a P–C–P group, and are thus analogs of inorganic pyrophosphate. They are used in medicine mainly to inhibit bone resorption in diseases like osteoporosis, Paget's disease and tumor bone disease. They have been used for over a century in industry, and only in 1968 was it shown that bisphosphonates have biological effects. These effects consist mainly of an inhibition of bone resorption and, when given in large amounts, an inhibition of ectopic and normal calcification. While the latter effect is the consequence of a physical-chemical inhibition of calcium phosphate crystal formation, the former is due to a cellular effect involving both apoptosis of the osteoclasts and a destruction of the osteoclastic cytoskeleton, inducing a decrease in osteoclast activity. The biochemical basis of these effects for the nitrogen-containing compounds is an inhibition of the mevalonate pathway caused by the inhibition of farnesylpyrophosphate synthase, which leads to a decrease of the formation of isoprenoid lipids such as farnesylpyrophosphate and geranylgeranylpyrophosphate. The other bisphosphonates are incorporated into the phosphate chain of ATP-containing compounds so that they become non-hydrolyzable. The new P–C–P-containing ATP analogs inhibit cell function and may lead to apoptosis and death of osteoclasts

Language endangerment and language documentation in Africa

Non peer reviewe

The diurnal rhythm of bone resorption in the rat: effect of feeding habits and pharmacolgical inhibitors

Abstract Prevention of low bone mass is important to reducing the incidence of osteoporotic fractures. This paper shows that, in rats, bone mass can be increased by feeding habits per se. Using six-hourly urinary excretion of [3H]tetracycline from prelabeled rats to monitor bone resorption, we previously found a peak of bone resorption following food administration. We now demonstrate that dividing the solid and liquid intake into portions blunts this peak and leads to a decrease in 24-h bone resorption to the level observed in thyroparathyroidectomized animals. Calcium balance increases and, when such feeding schedules are imposed for 30 d, bone mass increases. Dividing the intake is not effective in thyroparathyroidectomized animals, indicating the importance of PTH and/or calcitonin. Administration of calcitonin inhibits practically only the peak of bone resorption, suggesting that it is osteoclast mediated. In contrast, treatment with a bisphosphonate reduces basal bone resorption without a specific effect on the peak, indicating a fundamentally different mechanism of action. This is also supported by the finding that their combined effects are additive. Whether bone mass in humans is also under the control of dietary habits is not known. If so, an increased meal frequency may be used to prevent osteoporosis. (J. Clin. Invest. 1995Invest. . 95:1933Invest. -194