Bisphosphonate-functionalized hyaluronic acid showing selective affinity for osteoclasts as a potential treatment for osteoporosis

2015 ◽  
Vol 3 (8) ◽  
pp. 1197-1207 ◽  
Author(s):  
Sujit Kootala ◽  
Dmitri Ossipov ◽  
Jeroen JJP van den Beucken ◽  
Sander Leeuwenburgh ◽  
Jöns Hilborn
Keyword(s):  
Hyaluronic Acid ◽  
Potential Treatment ◽  
Term Administration ◽  
High Doses

Bisphosphonate-functionalized hyaluronic can potentially reduce long-term administration of high doses of BPs.

Effects of long-term administration of high doses of medroxyprogesterone acetate on hormone receptors and target organs in the female rat

1984 ◽  
Vol 103 (3) ◽  
pp. 287-293 ◽  
Author(s):  
F. Di Carlo ◽  
S. Racca ◽  
G. Conti ◽  
E. Gallo ◽  
G. Muccioli ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Medroxyprogesterone Acetate ◽  
Prolactin Receptor ◽  
Female Rats ◽  
Serum Prolactin ◽  
Target Organs ◽  
Term Administration ◽  
Pituitary Glands ◽  
High Doses

ABSTRACT The changes in oestrogen, progesterone and prolactin receptor levels in target organs, and the macroscopic and microscopic modifications of uterus, ovary, adrenal and pituitary gland induced by long-term administration of high doses of medroxyprogesterone acetate (MPA) were investigated in female rats. Medroxyprogesterone acetate was injected i.m. for 30 days at daily doses of 7·5, 15 and 75 mg/kg. Oestrogen and/or progesterone-binding capacities were remarkably reduced at all doses of MPA used both in the uterus and pituitary gland. Furthermore, MPA caused a very evident reduction in the weight of pituitary glands, ovaries, adrenals and uterus. In all MPA-treated rats corpora lutea were absent from the ovaries, whereas the adrenals showed a significant reduction in the thickness of the cortex. In accordance with this, there was no evidence of ACTH-producing cells in the pituitary glands. Prolactin-producing cells were also absent, while GH-producing cells were present. Serum prolactin levels were significantly reduced at all doses of MPA used. A dramatic reduction of prolactin receptor concentrations was observed in the liver and the ovaries of MPA-treated rats. The results suggest that MPA acts as an antioestrogenic drug both by reducing the number of oestrogen receptors in target tissues and by changing the structure (and perhaps the function) of those organs (pituitary glands, ovaries and adrenals) which are, directly or indirectly, a source of oestrogens. The decreased synthesis of prolactin and the reduction of the number of prolactin receptors (which, on the contrary, are both increased by oestrogens) might be considered as additional antioestrogenic effects of MPA. J. Endocr. (1984) 103, 287–293

scholarly journals Long-term interleukin-6 administration stimulates sustained thrombopoiesis and acute-phase protein synthesis in a small primate-- the marmoset

Blood ◽  
1994 ◽  
Vol 83 (8) ◽  
pp. 2093-2102
Author(s):  
B Ryffel ◽  
BD Car ◽  
G Woerly ◽  
M Weber ◽  
F DiPadova ◽  
...  
Keyword(s):  
Acute Phase ◽  
Interleukin 6 ◽  
Neutralizing Antibodies ◽  
Acute Phase Protein ◽  
Acute Phase Protein Response ◽  
Phase Protein ◽  
Term Administration ◽  
High Doses ◽  
Protein Response

Interleukin-6 (IL-6) has been ascribed significant roles in both hematopoiesis and the immune response, although its contribution to host defence as a whole is poorly understood. Because short-term IL-6 treatment was previously shown to stimulate megakaryocytopoiesis, we investigated the effect of long-term administration of IL-6 on megakaryocytopoiesis and other systemic parameters in nonhuman primates. We chose a small primate, the marmoset (Callithrix jacchus), which enabled long-term administration at high doses. Recombinant human IL-6 (rhIL-6) administered at doses of up to 1,000 micrograms/kg/d over 4 and 9 weeks caused a sustained twofold to threefold increase of thrombocyte counts, peaking at 4 weeks. Thrombocyte counts declined thereafter, despite continuing IL-6 administration. The number of bone marrow megakaryocytes at 4 and 9 weeks was not increased compared with controls, but the ploidy grade was augmented, suggesting that IL-6 effects are restricted to mature megakaryocytes in vivo. An acute-phase protein response was observed within 24 hours after the first IL-6 administration and reached a maximum after 1 week of IL-6 administration at 25 micrograms/kg. Serum C-reactive protein, haptoglobin, and ceruloplasmin were increased, whereas albumin and transferrin levels declined. The acute-phase protein response was not associated with any morphologic evidence of hepatocellular damage. The increased levels of Ig and soluble IL-2 receptor in the serum levels reflected systemic immunostimulation. There was no evidence of renal mesangioproliferative pathology. Antibodies against rhIL-6 developed within 2 weeks, continuously increasing during the course of the study. High titers of neutralizing antibodies appeared concomitantly with the decrease in platelet counts and decline in acute-phase proteins. Therefore, despite the pleiotropic effects of IL-6 observed in vitro, long-term administration of IL-6 caused a selective and sustained stimulation of thrombopoiesis in marmosets that was only ablated by the appearance of neutralizing antibodies, and high doses were well tolerated in marmosets. A long-term targeting of IL-6 to cells of the megakaryocytic lineage, without evoking general toxicity, confirms the potential therapeutic usefulness of rhIL-6 for the chronic treatment of thrombocytopenic patients.

scholarly journals Long-term interleukin-6 administration stimulates sustained thrombopoiesis and acute-phase protein synthesis in a small primate-- the marmoset

Blood ◽  
1994 ◽  
Vol 83 (8) ◽  
pp. 2093-2102 ◽  
Author(s):  
B Ryffel ◽  
BD Car ◽  
G Woerly ◽  
M Weber ◽  
F DiPadova ◽  
...  
Keyword(s):  
Acute Phase ◽  
Interleukin 6 ◽  
Neutralizing Antibodies ◽  
Acute Phase Protein ◽  
Acute Phase Protein Response ◽  
Phase Protein ◽  
Term Administration ◽  
High Doses ◽  
Protein Response

Abstract Interleukin-6 (IL-6) has been ascribed significant roles in both hematopoiesis and the immune response, although its contribution to host defence as a whole is poorly understood. Because short-term IL-6 treatment was previously shown to stimulate megakaryocytopoiesis, we investigated the effect of long-term administration of IL-6 on megakaryocytopoiesis and other systemic parameters in nonhuman primates. We chose a small primate, the marmoset (Callithrix jacchus), which enabled long-term administration at high doses. Recombinant human IL-6 (rhIL-6) administered at doses of up to 1,000 micrograms/kg/d over 4 and 9 weeks caused a sustained twofold to threefold increase of thrombocyte counts, peaking at 4 weeks. Thrombocyte counts declined thereafter, despite continuing IL-6 administration. The number of bone marrow megakaryocytes at 4 and 9 weeks was not increased compared with controls, but the ploidy grade was augmented, suggesting that IL-6 effects are restricted to mature megakaryocytes in vivo. An acute-phase protein response was observed within 24 hours after the first IL-6 administration and reached a maximum after 1 week of IL-6 administration at 25 micrograms/kg. Serum C-reactive protein, haptoglobin, and ceruloplasmin were increased, whereas albumin and transferrin levels declined. The acute-phase protein response was not associated with any morphologic evidence of hepatocellular damage. The increased levels of Ig and soluble IL-2 receptor in the serum levels reflected systemic immunostimulation. There was no evidence of renal mesangioproliferative pathology. Antibodies against rhIL-6 developed within 2 weeks, continuously increasing during the course of the study. High titers of neutralizing antibodies appeared concomitantly with the decrease in platelet counts and decline in acute-phase proteins. Therefore, despite the pleiotropic effects of IL-6 observed in vitro, long-term administration of IL-6 caused a selective and sustained stimulation of thrombopoiesis in marmosets that was only ablated by the appearance of neutralizing antibodies, and high doses were well tolerated in marmosets. A long-term targeting of IL-6 to cells of the megakaryocytic lineage, without evoking general toxicity, confirms the potential therapeutic usefulness of rhIL-6 for the chronic treatment of thrombocytopenic patients.

The efficacy and safety of long-term administration of alpha-interferon and lamivudine in patients with chronic hepatitits B

2001 ◽  
Vol 120 (5) ◽  
pp. A572-A572
Author(s):  
F JABOLI ◽  
E RODA ◽  
C FABBRI ◽  
S MARCHETTO ◽  
F FERRARA ◽  
...  
Keyword(s):  
Alpha Interferon ◽  
Efficacy And Safety ◽  
Term Administration

1608: Long-Term Treatment with High Doses of Sildenafil Does Not Up-Regulate the Levels of Phosphodiesterase 5 (Pde5) in the Rat Penis

2004 ◽  
Vol 171 (4S) ◽  
pp. 424-424 ◽  
Author(s):  
Monica G. Ferrini ◽  
Eliane G. Valente ◽  
Jacob Rajfer ◽  
Nestor F. Gonzalez-Cadavid
Keyword(s):  
Term Treatment ◽  
Long Term Treatment ◽  
High Doses ◽  
Phosphodiesterase 5

STUDIES IN THE SUPPOSED GOITROGENOUS EFFECT OF TAP WATER IN HELSINKI

1960 ◽  
Vol XXXIII (IV) ◽  
pp. 630-636
Author(s):  
F.-E. Krusius ◽  
P. Peltola
Keyword(s):  
Tap Water ◽  
Physiological Saline ◽  
Normal Weight ◽  
The Body ◽  
Iodine Uptake ◽  
Redistilled Water ◽  
Detectable Difference ◽  
Term Administration ◽  
Long Term Experiment

ABSTRACT The study reported here was performed in order to examine the tap water of Helsinki for its alleged goitrogenous effect. In a short-term, 24-hour experiment with rats, kept on an iodine-poor diet, we noticed no inhibition of the 4-hour 131I uptake, as compared with that of animals receiving physiological saline instead of tap water. Two similar groups of rats receiving 1 and 2 mg of mercazole in redistilled water showed a distinct blockage of the 4-hour uptake, which proved the effect of this substance. In a long-term experiment of 5 weeks' duration there was no detectable difference in the body weight, thyroid weight and the 4-hour 131I uptake when the rats receiving tap water or distilled water to which 0.45 per cent of sodium chloride was added were compared with each other. Replacement of tap water by a 10 mg per cent solution of mercazole in redistilled water enlarged the thyroid to double its normal weight and increased the 131I uptake to approximately five times that of the controls. Thus our experiments failed to demonstrate any goitrogenous effect in the tap water of Helsinki. Changes similar to those produced by a long-term administration of mercazole, i. e. an enlargement of the thyroid and an increased thyroidal iodine uptake, have been shown to be due to milk collected from goitrous areas. The observations here reported confirm the importance of milk in the genesis of the goitre endemia of Helsinki. Attention is further called to the fact that a thyroidal enlargement combined with an increased thyroidal iodine uptake cannot always be taken as a sign of iodine deficiency because similar changes may be produced by the administration of goitrogens.

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