scholarly journals Inhibition of FGFR Signaling Partially Rescues Hypophosphatemic Rickets in HMWFGF2 Tg Male Mice

Endocrinology ◽  
2017 ◽  
Vol 158 (10) ◽  
pp. 3629-3646 ◽  
Author(s):  
Liping Xiao ◽  
Erxia Du ◽  
Collin Homer-Bouthiette ◽  
Marja M Hurley
Keyword(s):  
Cortical Bone ◽  
Bone Mineral ◽  
Term Treatment ◽  
Hypophosphatemic Rickets ◽  
Fgf Receptor ◽  
Tissue Density ◽  
Long Term Treatment ◽  
Fgfr Signaling ◽  
Total Body

Abstract Transgenic mice harboring high molecular weight fibroblast growth factor (FGF)2 isoforms (HMWTg) in osteoblast lineage cells phenocopy human X-linked hypophosphatemic rickets (XLH) and Hyp murine model of XLH demonstrating increased FGF23/FGF receptor signaling and hypophosphatemic rickets. Because HMWFGF2 was upregulated in bones of Hyp mice and abnormal FGF receptor (FGFR) signaling is important in XLH, HMWTg mice were used to examine the effect of the FGFR inhibitor NVP-BGJ398, now in clinical trials for cancer therapy, on hypophosphatemic rickets. Short-term treatment with NVP-BGJ398 rescued abnormal FGFR signaling and hypophosphatemia in HMWTg. Long-term treatment with NVP-BGJ398 normalized tail, tibia, and femur length. Four weeks NVP-BGJ398 treatment significantly increased total body bone mineral density (BMD) and bone mineral content (BMC) in HMWTg mice; however, at 8 weeks, total body BMD and BMC was indistinguishable among groups. Micro-computed tomography revealed decreased vertebral bone volume, trabecular number, and increased trabecular spacing, whereas femur trabecular tissue density was increased; however, NVP-BGJ398 rescued defective cortical bone mineralization, increased thickness, reduced porosity, and increased endosteal perimeter and cortical tissue density in HMWTg. NVP-BGJ398 improved femur cancellous bone, cortical bone structure, growth plate, and double labeling in cortical bone and also increased femur trabeculae double labeled surface, mineral apposition rate, bone formation rate, and osteoclast number and surface in HMWTg. The decreased NPT2a protein that is important for renal phosphate excretion was rescued by NVP-BGJ398 treatment. We conclude that NVP-BGJ398 partially rescued hypophosphatemic rickets in HMWTg. However, long-term treatment with NVP-BGJ398 further increased serum FGF23 that could exacerbate the mineralization defect.

scholarly journals Slower Elimination of Tofacitinib in Acute Renal Failure Rat Models: Contribution of Hepatic Metabolism and Renal Excretion

Pharmaceutics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 714
Author(s):  
Sung Hun Bae ◽  
Sun-Young Chang ◽  
So Hee Kim
Keyword(s):  
Rheumatoid Arthritis ◽  
Renal Failure ◽  
Acute Renal Failure ◽  
Hepatic Metabolism ◽  
Term Treatment ◽  
Concentration Time ◽  
Long Term Treatment ◽  
Total Body ◽  
Body Clearance

Tofacitinib is a Jak inhibitor developed as a treatment for rheumatoid arthritis. Tofacitinib is metabolized mainly through hepatic CYP3A1/2, followed by CYP2C11. Rheumatoid arthritis tends to increase renal toxicity due to drugs used for long-term treatment. In this study, pharmacokinetic changes of tofacitinib were evaluated in rats with gentamicin (G-ARF) and cisplatin-induced acute renal failure (C-ARF). The time-averaged total body clearance (CL) of tofacitinib in G-ARF and C-ARF rats after 1-min intravenous infusion of 10 mg/kg was significantly decreased by 37.7 and 62.3%, respectively, compared to in control rats. This seems to be because the time-averaged renal clearance (CLR) was significantly lower by 69.5 and 98.6%, respectively, due to decreased creatinine clearance (CLCR). In addition, the time-averaged nonrenal clearance (CLNR) was also significantly lower by 33.2 and 57.4%, respectively, due to reduction in the hepatic CYP3A1/2 and CYP2C11 subfamily in G-ARF and C-ARF rats. After oral administration of tofacitinib (20 mg/kg) to G-ARF and C-ARF rats, both CLR and CLNR were also significantly decreased. In conclusion, an increase in area under plasma concentration-time curves from time zero to time infinity (AUC) of tofacitinib in G-ARF and C-ARF rats was due to the significantly slower elimination of tofacitinib contributed by slower hepatic metabolism and urinary excretion of the drug.

Increase of Total Body Potassium and Decrease of Exchangeable Sodium after Long-Term Treatment with a β-Receptor-Blocking Agent (Prindolol) in Essential Hypertension

1976 ◽  
Vol 51 (s3) ◽  
pp. 551s-554s
Author(s):  
H. M. Brecht ◽  
E. Werner ◽  
W. Schoeppe
Keyword(s):  
Essential Hypertension ◽  
Plasma Renin Activity ◽  
Plasma Renin ◽  
Term Treatment ◽  
Renin Activity ◽  
Exchangeable Sodium ◽  
Total Body Potassium ◽  
Long Term Treatment ◽  
Total Body

1. The effect of long-term treatment with prindolol on blood pressure, total body potassium (Kt), exchangeable sodium (Nae) and plasma renin activity was investigated in twelve patients with essential hypertension. 2. Systolic and diastolic pressures were significantly reduced from 164/112 to 127/90 mmHg under basal conditions. 3. Before treatment Na. in patients with essential hypertension was significantly higher than in normotensive individuals. After an average of 16 weeks on prindolol Nae in patients with essential hypertension was significantly decreased, despite an average increase in body weight of 2 kg in the patients. 4. In contrast to the decrease in Nae, Kt was found to be significantly increased after long-term treatment with prindolol. Kt values of patients before and after prindolol, however, did not differ significantly from the corresponding sex- and age-dependent normal values. 5. Plasma renin activity was slightly diminished under basal and orthostatic conditions; the stimulatory effect of orthostasis was not abolished but reduced by prindolol. 6. It is suggested that the changes in sodium balance contribute to the anti-hypertensive effect of prindolol in patients with essential hypertension.

P.3.c.019 Risk of pathological decrease of bone mineral density in patients on parenteral risperidone long-term treatment

2011 ◽  
Vol 21 ◽  
pp. S478-S479
Author(s):  
R. Marin ◽  
R. Lozano ◽  
M.D. Vazquez ◽  
M.J. Santacruz ◽  
F. Sebastian ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Term Treatment ◽  
Mineral Density ◽  
Long Term Treatment

Renal Hypophosphatemic Rickets: Growth Acceleration After Long-Term Treatment with 1,25-Dihydroxyvitamin-D3

PEDIATRICS ◽  
1980 ◽  
Vol 66 (3) ◽  
pp. 445-454 ◽  
Author(s):  
James C. M. Chan ◽  
Robert D. Lovinger ◽  
Peter Mamunes
Keyword(s):  
Serum Alkaline Phosphatase ◽  
Bone Age ◽  
Term Treatment ◽  
Hypophosphatemic Rickets ◽  
Phosphorus Concentration ◽  
Calcium Excretion ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3 ◽  
Long Term Treatment

Treatment with 1,25-dihydroxyvitamin-D3 and phosphorus supplementation for as long as 48 months was evaluated in six patients with renal hypophosphatemic rickets. Previous phosphorus supplementation of 1,800 to 4,000 mg/sq m of body surface area per day was continued while 1,25-dihydroxyvitamin-D3 at 17 to 80 ng/kg of body weight per day was given orally in place of vitamin-D2. The serum calcium concentration stayed within the normal range in the majority of patients, while the serum phosphorus concentration rose from 2.5 ± 0.4 to 3.4 ± 1.2 mg/100 ml after one month (P < .01). With rare exceptions, serum alkaline phosphatase and parathyroid hormone concentrations stayed normal throughout the study. Healing of rickets was demonstrated by radiography. In five patients, growth velocity was evaluated for 12 months before and after therapy. Growth accelerations were 123% to 235% of that expected for changes in chronologic age and 114% to 200% expected for changes in bone age after therapy. Orally administered, 1,25-dihydroxyvitamin-D3 increased renal calcium excretion and calcium retention was achieved by virtue of the decreased fecal calcium loss. In contrast, 1,25-dihydroxyvitamin-D3, even at doses up to 4 µg/day (80 ng/kg/day) did not significantly alter renal phosphaturia. The phosphorus retention was therefore achieved as the result of the decreased fecal phosphate excretion. The absence of hypercalcemia even at high doses of 1,25-dihydroxyvitamin-D3 and the enhanced linear growth support the long-term therapeutic value of 1,25-dihydroxyvitamin-D3 in renal hypophosphatemic rickets.

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