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Biomedical subjects

S E Papapoulos

Publications and source records attributed to S E Papapoulos.

At least 55 records · Page 3Linked to original sources
PubMed1997

Long-term effects of bisphosphonates on the growing skeleton. Studies of young patients with severe osteoporosis.

Osteoporosis in children and adolescents is relatively uncommon and usually secondary to identifiable causal factors. There are no generally accepted therapies for patients with no treatable underlying cause of disease. Any treatment of young patients with bone-acting compounds should be not only effective but also devoid of adverse effects on bone growth and remodeling. For many years we have been studying the effects of bisphosphonates-an effective treatment of postmenopausal osteoporosis-on the growing skeleton. We review here our experience in the treatment of young patients with osteoporosis with special emphasis on issues of skeletal safety and effectiveness, and we discuss the available literature data. We studied 12 patients aged between 10.7 and 17.2 years with symptomatic osteoporosis and multiple fractures treated with the bisphosphonates pamidronate or olpadronate for periods between 2 and 8 years continuously. Linear growth continued normally on treatment; there was even a catch-up growth in prepubertal patients, and there was no excessive suppression of bone remodeling, assessed biochemically. Bone biopsies obtained at various stages during treatment showed bone of normal lamellar structure without mineralization defects. There was an increase in calcium balance, already evident within 10 days, the level of which was maintained for at least 3 years of treatment. This was associated with progressive increases in bone mineral density along a different slope from that of healthy peers as well as correction of vertebral deformities on X-rays in patients given bisphosphonates before puberty. Treatment was well tolerated and clinical improvement was remarkable. Our studies, supported by literature data, strongly suggest that bisphosphonate therapy can be beneficial to young patients with osteoporosis for whom no other options are currently available, and justify planning controlled studies in more common conditions for which no treatment is currently available, such as osteogenesis imperfecta.

Adolescent↗
PubMed1997

The role of interleukin-6 in the induction of hypercalcemia in renal cell carcinoma transplanted into nude mice.

Hypercalcemia is a well known complication of renal cell carcinoma (RCC). As RCCs can produce IL-6, and IL-6 may stimulate bone resorption and cause mild hypercalcemia, we examined whether IL-6 is involved in renal cancer-associated hypercalcemia in vivo. Three human renal cell carcinoma tumor lines (RC-8, RC-9, and NC-65) growing in nude mice were studied. Tumors were implanted s.c., and parameters of bone metabolism and serum human IL-6 levels were determined in relation to tumor volume (TV). All three tumor lines secreted human IL-6, although in different quantities. The maximum level of IL-6 in RC-8 was 434 pg/ml (TV, 200 mm3), that in RC-9 was 81 pg/ml (TV, 1800 mm3), and that in NC-65 was 2368 pg/ml (TV, 1800 mm3). Hypercalcemia developed in RC-8 and RC-9 tumor-bearing animals, but not in NC-65-bearing animals. The hypercalcemia in both RC-8 and RC-9 tumor lines was associated with elevated levels of PTH-related peptide (PTHrP) and loss of trabecular bone volume. Serum calcium and phosphate concentrations showed an almost linear relationship with plasma PTHrP independently of the tumor line and serum IL-6 levels. No hypercalcemia occurred in the NC-65 animals, which had the highest levels of IL-6, but no detectable plasma PTHrP and PTHrP messenger RNA expression in the tumor. Administration of neutralizing antibodies to IL-6 to RC-8 animals normalized serum calcium concentrations and PTHrP values and induced a significant inhibition of tumor growth. No such effect on tumor growth of anti-IL-6 was seen in the other two tumor lines. The normalization of serum calcium in RC-8 mice is most likely attributed to the growth-inhibiting effect of anti-IL-6 on RC-8 tumor. We conclude that IL-6 secreted by RCC does not contribute directly to hypercalcemia, but may enhance hypercalcemia by stimulating the tumor growth of a subpopulation of PTHrP-secreting carcinomas.

Animals↗
PubMed1997

Bisphosphonates: structure-activity relations from a clinical perspective.

Bisphosphonates, synthetic compounds containing two phosphonate groups bound to a central (geminal) carbon (P-C-P) and two additional chains (R1 and R2, respectively) bind strongly to calcium crystals, inhibit their growth and suppress osteoclast-mediated bone resorption. The availability of two side chains allows numerous substitutions and the development of a variety of analogs with different pharmacological properties. The R1 structure together with the P-C-P are primarily responsible for binding to bone mineral and for the physicochemical actions of the bisphosphonates and a hydroxyl group at R1 provides optimal conditions for these actions. The R2 is believed to be responsible for the antiresorptive action of the bisphosphonates and small modifications or conformational restrictions of this part of the molecule may result in marked differences in antiresorptive potency. The presence of a nitrogen function in an alkyl chain or in a ring structure in R2 greatly enhances the antiresorptive potency and specificity of bisphosphonates for bone resorption and most of the newer potent bisphosphonates contain a nitrogen in their structure. Recent evidence, however, suggests that the whole bisphosphonate molecule is essential for antiresorptive action. Thus, although the basic structural requirements for bisphosphonate actions have been defined, precise structure-activity relations have not been defined yet. These are essential for elucidating their molecular mechanism of action and for the rational design of compounds for various clinical indications.

Bone Resorption↗
PubMed1997

Oral pamidronate in the prevention and treatment of skeletal metastases in patients with breast cancer.

Bone metastases are common in patients with breast cancer and cause considerable morbidity and deterioration of the quality of life. The main pathogenetic mechanism is stimulation of osteoclastic bone resorption by factors produced by the cancer cells. Pamidronate given intravenously suppresses bone resorption and is an effective treatment of malignancy-associated hypercalcemia. Recent data indicate that it can also reduce skeletal morbidity in normocalcemic patients with breast cancer and osteolytic metastases. In a series of studies we examined the long-term efficacy of oral pamidronate in the prevention and treatment of skeletal metastases in patients with breast cancer. In patients with bone metastases oral pamidronate given for a median period of about 20 months reduced significantly skeletal morbidity and had a favourable effect on selective aspects of the quality of life of the patients. Treatment did not alter the radiological course of the disease or the overall survival of the patients. In contrast, oral pamidronate given to patients with advanced breast cancer but no demonstrable bone metastases did not prevent or delay the appearance of the first clinical or radiological manifestation of bone metastases. This treatment is therefore very effective in patients with established metastatic bone disease. More studies are needed to define the place of pamidronate (and of other bisphosphonates) in the prevention of bone metastases in patients at risk.

Bone Neoplasms↗
PubMed1996

Bone sialoprotein peptides are potent inhibitors of breast cancer cell adhesion to bone.

Bone and bone marrow are important sites of metastasis formation in breast cancer. Extracellular matrix proteins with attachment properties are generally believed to play a key role in tumorigenesis and metastasis formation. We have investigated whether mammary carcinoma cells (MDA-MB-231) can recognize constructs of the fairly bone-specific human bone sialoprotein, which encompass the RGD sequence (EPRGD-NYR). Exogenously added bone sialoprotein peptides with this amino acid sequence in their backbone structure, but not the more common fibronectin-derived GRGDS peptide, strongly inhibited breast cancer cell adhesion to extracellular bone matrix at micromolar concentrations. Most cyclic derivatives with the EPRGDNYR sequence were more effective inhibitors of tumor cell adhesion to bone than their linear equivalents. Furthermore, changes in the RGD-tripeptide of the backbone structure of the constructs, removal of the NYR flanking sequence, or a different tertiary cyclic structure significantly decreased their inhibitory potencies. In addition, the RGE-analogue EPRGENYR was capable of inhibiting breast cancer cell adhesion to bone, albeit to a lesser extent. We conclude therefore, that the inhibitory potency of the bone sialoprotein-derived peptides on breast cancer cell adhesion to bone is not solely due to a properly positioned RGD-motif alone but is also determined by its flanking regions, together with the tertiary structure of the EPRGDNYR peptide. Synthetic cyclic constructs with the EPRGDNYR sequence may, therefore, be potentially useful as antiadhesive agents for cancer cells to bone in vivo.

Amino Acid Sequence↗
PubMed1996

Increased bone mass with pamidronate treatment in rheumatoid arthritis. Results of a three-year randomized, double-blind trial.

OBJECTIVES: Osteoporosis is a frequent complication of rheumatoid arthritis (RA). We therefore investigated the effect of oral pamidronate therapy as a specific bone-sparing agent in RA. METHODS: The study design was a 3-year randomized, double-blind trial of 300 mg oral pamidronate/day compared with placebo in 105 RA patients. Bone mineral density (BMD) measured at 12-month intervals was the primary efficacy parameter. RESULTS: In 3 years, lumbar spine and forearm BMD increased significantly in the pamidronate-treated group (by 8.4 +/- 6.9% [mean =/- SEMI] [P < 0.00011 and 5.2 =/- 6.5% [P < 0.005], respectively), compared with nonsignificant changes in the placebo-treated patients (increase of 0.6 =/- 5.2% and decrease of 1.2 =/- 5.8%, respectively). Femoral neck BMD increased in the pamidronate-treated group (by 2.6 =/- 8.6%) and decreased significantly in the placebo-treated group (by 4.0=/- 1.3% [P < 0.005]). The changes in BMD with time at all 3 measurement sites were significantly different between the treatment groups (P < 0.0001). Changes in radiographic signs of joint damage and in disease activity were similar in the 2 groups. CONCLUSION: The present study provides the first evidence that long-term treatment with an orally administered bisphosphonate overcomes bone loss and increases bone mass when compared with placebo. This finding may have significance with regard to the treatment of patients with RA.

Adult↗
PubMed1996

Does supportive pamidronate treatment prevent or delay the first manifestation of bone metastases in breast cancer patients?

The effect of pamidronate treatment on the first development of bone metastases was investigated in 124 patients with breast cancer, with either locally advanced disease (n = 33) or extraskeletal metastases (n = 91), but no bone metastases in a randomised, multicentre, open controlled study. Patients were assigned to treatment with oral pamidronate, 300 mg/day, (n = 65) or to a control group (n = 59). Tumour therapy was freely allowed. A first clinical event of skeletal morbidity occurred in 22% pamidronate and 20% control patients; unequivocal first radiological manifestation of bone metastases was found in 36% pamidronate and 27% control patients (n.s.). The actuarial risk of a first skeletal event was similar in both groups. Quality-of-life measurements of bone metastases-related aspects showed no differences between the two groups. 19 patients withdrew from the study because of gastrointestinal complaints attributed to pamidronate. We conclude that supportive oral pamidronate treatment (300 mg/day) does not prevent nor delay the development of bone metastases in breast cancer patients at risk.

Adult↗
PubMed1996

The flare in serum alkaline phosphatase activity after orchiectomy: a valuable negative prognostic index for progression-free survival in prostatic carcinoma.

PURPOSE: We determined whether an early flare in serum alkaline phosphatase activity after orchiectomy was of prognostic value for progression-free survival in patients with advanced prostatic carcinoma. MATERIALS AND METHODS: A retrospective analysis of a data base from a Dutch multicenter study on prostatic carcinoma was done to determine the prognostic value of a flare in alkaline phosphatase activity after orchiectomy in 112 patients with metastatic (75%) or locally advanced (25%) disease. Cox's proportional hazards models and Kaplan-Meier survival curves were used. RESULTS: Of the patients 50% had initially increased alkaline phosphatase levels and a flare in activity was demonstrated in 87% 2 to 4 weeks after orchiectomy. The prostate specific antigen nadir (cutoff 4 ng./ml.) 6 months after orchiectomy was of significant prognostic value for progression-free survival. A flare in alkaline phosphatase activity after orchiectomy demonstrated an early significant prognostic value for progression-free survival, independent of the serum alkaline phosphatase activity. CONCLUSIONS: The simplicity, ready availability and cost-effectiveness of serum alkaline phosphatase activity as a prognostic index render it attractive to the clinician, particularly early in the course of prostatic carcinoma. Measuring the flare in alkaline phosphatase activity within 1 month of orchiectomy may permit early identification of patients in whom the disease is likely to progress rapidly and who would potentially benefit from aggressive treatment.

Aged↗
PubMed1996

Prediction of the outcome of treatment of Paget's disease of bone with bisphosphonates from short-term changes in the rate of bone resorption.

In Paget's disease of bone, bisphosphonate therapy is usually given for 3-6 months, at which point the success of treatment is assessed by measuring serum alkaline phosphatase activity. The changes, however, in bone resorption and formation after bisphosphonate therapy are predictable, and their correct interpretation may allow a rational therapeutic approach applicable to the individual patient. We addressed this issue in 21 patients with active Paget's disease treated with 2 different nitrogen-containing bisphosphonates for 10 days. Urine samples were collected daily before and during treatment for the measurement of the following collagen degradation products, as indexes of bone resorption; cross-linked N-telopeptide of collagen type I (NTx), free deoxypyridinoline with 2 different assays, and hydroxyproline. Independently of the structure of the bisphosphonate used, the magnitude of decrease in urinary NTx with treatment was greater than that of both deoxypyridinoline assays and practically identical to the decrease in excess of urinary hydroxyproline. The degree of suppression of NTx on the 9th and 10th days of treatment correlated with the lowest serum alkaline phosphatase activity obtained during 1 yr of follow-up. All patients in whom serum alkaline phosphatase activity normalized during follow-up showed a suppression of NTx greater than 75% of the initial values after 10 days of treatment. We conclude that urinary NTx is a sensitive and specific index to follow the efficacy of bisphosphonate therapy in patients with Paget's disease and that measurements of its values before and after a short period of treatment can provide a simple and convenient way to predict the final therapeutic outcome and to avoid unnecessary continuation of treatment in many patients with Paget's disease of bone.

Adult↗
PubMed1995

Interleukin-6 and the acute phase response during treatment of patients with Paget's disease with the nitrogen-containing bisphosphonate dimethylaminohydroxypropylidene bisphosphonate.

Bisphosphonates suppress bone resorption and are used in the management of bone diseases with increasing frequency. In some patients treated for the first time with potent nitrogen-containing bisphosphonates, there is a transient febrile reaction and transient hematological changes suggestive of an acute phase response. Because IL-6 is considered to be an important mediator of the acute phase response, we examined the changes in circulating IL-6 bioactivity in 38 patients with Paget's disease treated with the nitrogen-containing bisphosphonate (3-dimethyl-amino-1-hydroxypropylidene)-1,1-bisphosphonate (dimethyl-APD). 16 patients who had never received such bisphosphonate were treated with oral dimethyl-APD (100-400 mg/day) and 22 (9 for the first time) with intravenous dimethyl-APD 4 mg/day. Treatment was given for 10 days. Eleven of 38 patients, all first treatments, showed an increase in body temperature of more than 0.5 degrees C exceeding 37 degrees C associated with a significant decrease in lymphocyte count and an increase in serum CRP values. These changes were transient and did not occur in the patients with no febrile response. In patients with a febrile reaction circulating IL-6 bioactivity increased significantly and this increase generally preceeded the rise in temperature. Moreover, patients with an acute phase response had significantly higher peak IL-6 values than those without (128 +/- 30 vs. 31 +/- 4 U/ml, p < 0.001). The peaks in plasma IL-6 were further correlated with the peaks in temperature and in serum CRP values (r = 0.49, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Reaction↗
PubMed1995

Uninterrupted oral bisphosphonate (pamidronate) therapy of patients with osteoporosis is not associated with chronic stimulation of parathyroid hormone secretion.

We have previously reported that long-term uninterrupted treatment of patients with osteoporosis with oral pamidronate is associated with increases in bone mineral content (BMC) of the lumbar spine which could not be explained by the antiresorptive action of the drug alone, raising the possibility of an additional effect of the treatment on skeletal tissue. Administration of suppressive doses of the bisphosphonate to patients with excessive osteoclastic resorption is followed by transient decreases in serum calcium and increases in parathyroid hormone (PTH) concentrations. It is possible, therefore, that chronic pamidronate therapy may stimulate PTH secretion, which in turn has been previously shown to have anabolic effects on the skeleton. To test this hypothesis we examined the changes in serum calcium. PTH and phosphate concentrations every 6 months in 33 patients with vertebral osteoporosis and no biochemical evidence of increased bone turnover, treated with oral pamidronate 150 mg daily. Serum alkaline phosphatase and urinary hydroxyproline excretion decreased significantly by 20% and 28%, respectively, after 6 months of treatment and remained at this level for the following 18 months. These changes were associated with significant increases in spinal BMC, as expected. Serum calcium, PTH and phosphate did not change from baseline values either in the whole group or when the patients were divided according to the use or not of calcium supplements. Our results exclude chronic stimulation of PTH secretion as a factor contributing to long-term increases in bone mass in patients with osteoporosis and adequate calcium intake during continuous oral pamidronate therapy.

Administration, Oral↗
PubMed1995

Differential regulation of plasminogen activation in normal keratinocytes and SCC-4 cells by fibroblasts.

The plasminogen activator (PA)/plasmin system is thought to be involved in processes such as tumor invasion and wound healing, during which epithelial and mesenchymal cells come close together. However, information on regulation of the PA/plasmin system during epithelial-mesenchymal interactions is scarce. Therefore, we examined the in vitro modulation of the production and activity of the components of the PA/plasmin system in squamous carcinoma cells (SCC-4) and normal human keratinocytes in relation to cell density and the presence or absence of fibroblasts (3T3 cells). There was an inverse relation between cell density and mRNA expression for urokinase-type plasminogen activator (u-PA) and u-PA receptor in both SCC-4 cells and keratinocytes. In addition, such a relation was found for plasminogen activator inhibitor types 1 (PAI-1) and 2 (PAI-2) in SCC-4 monocultures, but not in keratinocyte monocultures. In contrast to monocultures, variation of cell density did not affect the mRNA expression of the components of the PA/plasmin system in cocultures of SCC-4 cells or keratinocytes with 3T3 cells. However, the relative expression of mRNAs in co-cultures was clearly different from that in monocultures, especially at low cell density. For most of the components of the PA/plasmin system, a decrease in mRNA expression and u-PA receptor protein was observed at most cell densities, whereas for PAI-1 only in keratinocytes a marked increase was documented. Zymography of supernatants revealed that the levels of both free u-PA and PA-PAI were increased in SCC-4/3T3 co-cultures, whereas in keratinocytes/3T3 co-cultures, only levels of the PA-PAI complex were increased, while the amount of free u-PA activity decreased. This occurred despite the increase u-PA immunoreactivity and was probably caused by the markedly elevated levels of immunoreactive PAI-1. The results of the present study reveal that the production and synthesis of various components of the PA/plasmin system in keratinocytes and SCC-4 cells depend on the density of epithelial cells and are modulated by fibroblasts, probably through a direct cell-cell or cell-matrix contact. Fibroblast-induced modulations are similar in keratinocytes and SCC-4 cells except for the regulation of PAI-1, which is markedly enhanced only in keratinocytes. This suggests that the modulation of PA activity in the direct microenvironment may be different under physiologic and pathologic conditions.

3T3 Cells↗
PubMed1995

Parathyroid hormone related protein and interleukin-6 mRNA expression in larynx and renal cell carcinomas from normocalcaemic and hypercalcaemic patients.

AIMS: To determine the expression of parathyroid hormone related protein (PTHrP) and interleukin-6 (IL-6) mRNAs and their possible relation in malignant tumours, derived from patients with and without hypercalcaemia, commonly associated with humoral hypercalcaemia of malignancy. METHODS: PTHrP and IL-6 mRNA expression was studied by northern blot analysis in tumour specimens from 13 consecutive patients. Six patients (two with hypercalcaemia) had squamous cell carcinomas of the larynx and seven (one with hypercalcaemia) had renal cell carcinomas. RESULTS: There was no relation between the histological features of the tumours and the expression of either PTHrP or IL-6 mRNAs. PTHrP mRNA was detected in all squamous cell carcinomas, expression being highest in the two patients with hypercalcaemia. In the renal cell carcinomas PTHrP mRNA was expressed only in the patient with hypercalcaemia. IL-6 mRNA was detected in nearly all tumours studied but there was no apparent relation between its expression and that of PTHrP mRNA or serum calcium concentrations. CONCLUSIONS: PTHrP mRNA expression is increased in patients with hypercalcaemia but is not related to IL-6 mRNA expression. The results suggest a quantitative relation between PTHrP gene expression and hypercalcaemia, and imply that different mechanisms account for this expression in squamous and renal cell carcinomas.

Adult↗
PubMed1995

Skeletal metabolism in patients with osteoporosis after discontinuation of long-term treatment with oral pamidronate.

Bisphosphonates are used with increasing frequency in the treatment of patients with osteoporosis. Continuous administration of low doses of nitrogen-containing bisphosphonates by mouth is the preferred mode of therapy. The skeletal half-life of bisphosphonates is long, however, and little is known about their long term effects on skeletal metabolism. We examined the changes in biochemical parameters of bone turnover [serum alkaline phosphatase and urinary hydroxyproline (OHP)], in bone mineral density, and in fracture frequency after discontinuation of long term (mean, 6.5 yr, range, 5-9 yr) therapy with oral pamidronate (150 mg/day) in 30 patients with osteoporosis and vertebral fractures. Serum alkaline phosphatase and urinary OHP were significantly lower at the end of long term treatment (90% and 72% of basal values, respectively). Serum alkaline phosphatase had increased to basal values within 6 months of stopping treatment, whereas OHP increased significantly to a maximum average of 92% of pretreatment values. There was no change in the every 6-month bone mineral density measurements of the lumbar spine and the femoral neck during the 2 yr after stopping treatment. Spine fracture index, calculated by the method of Raymakers and co-workers, was 0.83 +/- 0.12 before treatment, 0.85 +/- 0.12 at the end of treatment, and 0.85 +/- 0.13 2 yr after stopping treatment (nonsignificant). There was also no significant change in the rate of new vertebral fractures on or up to 2 yr after stopping treatment (48.5 of 1000 and 46.5 of 1000 patient yr, respectively). Our data demonstrate that the sustained suppression of bone turnover induced by long term treatment with pamidronate is readily reversible on stopping treatment. The beneficial effect of this treatment regimen on the skeleton, however, appears to be maintained for at least 2 yr after discontinuation of treatment.

Administration, Oral↗
PubMed1995

Recovery of serum calcium concentrations following acute hypocalcemia in patients with osteoporosis on long-term oral therapy with the bisphosphonate pamidronate.

Bisphosphonates, synthetic compounds that are taken up preferentially by the skeleton and that suppress bone resorption, are currently used in the management of patients with osteoporosis. Long-term uninterrupted administration of low oral doses is the preferred mode of treatment in current clinical trials with newer bisphosphonates. These compounds have, however, a long residence time in the skeleton, and there is no information about their long-term effects on blood calcium homeostasis. We examined the effect of long-term therapy with oral bisphosphonate on blood calcium homeostasis following an acute hypocalcemic stimulus. Twenty patients with vertebral osteoporosis (10 untreated controls and 10 treated with oral pamidronate, 150 mg/day for at least 5 yr) were given intravenous infusions of sodium EDTA, and the concentrations of calcium and PTH in blood were followed for 24 h. Serum calcium concentrations decreased similarly in both groups (maximum decrease 0.21 mmol/L and 0.22 mmol/L, respectively). The recovery of serum calcium concentrations was identical in both groups, and all patients had normal concentrations at 24 h. Plasma PTH increased to a peak of 17.3 +/- 2.5 pmol/L in the control group and to 17.0 +/- 3.1 pmol/L in the pamidronate-treated patients. During the whole study period, there was no difference in either the peak PTH response or in the recovery of plasma PTH values between the two groups. However, when only PTH responses between 60 min and 24 h were examined, there were differences between the two groups. Plasma PTH values, although strictly within the normal range, were significantly higher in the pamidronate-treated patients (P = 0.001). There were no differences in the calcemic responses during this period. Further, there were no detectable changes in immunoreactive PTH-related protein in either group after the EDTA infusions. In conclusion, our study showed that longterm therapy with oral pamidronate does not affect the calcemic response to an acute hypocalcemic stimulus in patients with osteoporosis.

Acute Disease↗
PubMed1995

Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia.

We report five novel mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism. Each gene defect is a missense mutation (228Arg-->Gln, 139Thr-->Met, 144Gly-->Glu, 63Arg-->Met, and 67Arg-->Cys) that encodes a nonconservative amino acid alteration. These mutations are each predicted to be in the Ca(2+)-sensing receptor's large extracellular domain. In three families with FHH linked to the Ca(2+)-sensing-receptor gene on chromosome 3 and in unrelated individuals probands with FHH, mutations were not detected in protein-coding sequences. On the basis of these data and previous analyses, we suggest that there are a wide range of mutations that cause FHH. Mutations that perturb the structure and function of the extracellular or transmembrane domains of the receptor and those that affect noncoding sequences of the Ca(2+)-sensing-receptor gene can cause FHH.

Calcium↗
PubMed1994

Use of a rat model for the simultaneous assessment of pharmacokinetic and pharmacodynamic aspects of bisphosphonate treatment: application to the study of intravenous 14C-labeled 1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonate.

Bisphosphonates are drugs that suppress osteoclast-mediated bone resorption and are used with increasing frequency in the treatment of skeletal disorders. Therapeutic regimens are largely based on pharmacodynamic information because of difficulties in obtaining and interpreting pharmacokinetic data. We describe here the application of a permanently cannulated rat model, previously used in other areas of endocrine research, to the simultaneous study of pharmacokinetic and pharmacodynamic properties of the newly developed bisphosphonate EB-1053 [1-hydroxy-3-(1-pyrrolidinyl)propylidene-1,1-bisphosphonate]. Two groups of five rats each received daily intravenous injections of [14C]EB-1053 (0.025 and 0.1 mg/day, respectively); a third group (n = 7) received only normal saline injections and served as control. Treatment was given for at least 20 days. A fourth group (n = 3) received IV injections of the bisphosphonate on three separate occasions. Following IV administration, EB-1053 was rapidly cleared from the circulation. Urinary excretion of radioactivity reached about 55% of the daily administered dose within 48 h and remained at this level during the whole treatment period, indicating continuing retention of the bisphosphonate. Bone resorption, assessed biochemically as the hydroxyproline to creatinine ratio in urine, was suppressed effectively with both doses used. Suppression reached a maximum around day 4 and remained at the same level until the end of treatment. Accumulation of the bisphosphonate in the skeleton was therefore not associated with a cumulative effect on bone resorption. This strongly suggests that in treatment planning a distinction should be made between surface-bound and hence biologically active bisphosphonate from the drug which is incorporated in bone during bone turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗