Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In patients with either Paget's disease or hypercalcaemia associated with malignancy (HCM) we have assessed the parathyroid response to pamidronate therapy, both by immunoassay of serum intact parathyroid hormone PTH (1-84) and by measurement of indirect parameters of PTH bioactivity, tubular maximum reabsorption of phosphate (TmPO4/GFR) and nephrogenous cyclic AMP (NcAMP). In 12 patients with Paget's disease, therapy with pamidronate produced a small but significant decrease in adjusted serum calcium within the reference interval which was accompanied by a progressive increase in PTH (1-84) secretion and a corresponding fall in TmPO4/GFR and increase in NcAMP. In 12 patients with HCM pretreatment, PTH (1-84) concentrations were suppressed, whilst mean TmPO4/GFR was reduced and NcAMP was increased, compatible in most patients, with parathyroid hormone-related peptide (PTHrP) driven hypercalcaemia. Therapy with pamidronate produced the expected fall in serum calcium but caused an increase in PTH (1-84) secretion in the presence of absolute hypercalcaemia. The initial subnormal TmPO4/GFR decreased further to a nadir on day 5, and there was a corresponding further increase in NcAMP. By day 7, however, when PTH (1-84) concentrations were maximal, there was a significant paradoxical rise in TmPO4/GFR and a corresponding decrease in NcAMP. These data are consistent with a variable trigger point for PTH (1-84) secretion, one consequence of which is a reduction in the risk of hypocalcaemia following pamidronate. The results have major clinical implications for the interpretation of PTH (1-84) measurements in patients who are being treated or about to be treated for bone disease or for hypercalcaemia of malignancy (HCM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Direct and indirect assessment of the parathyroid hormone response to pamidronate therapy in Paget's disease of bone and hypercalcaemia of malignancy. 184 62

The biological properties of a new synthetic analog of parathyroid hormone-related protein [PTHrP-(7-34)NH2] were examined in vivo using a well characterized thyroparathyroidectomized (TPTX) rat model. The phosphaturic and urine cyclic AMP response induced by infusion of PTHrP-(1-34)NH2 (0.16 nmol/h) was inhibited by 70% (P less than 0.01, n = 6) by co-infusion of PTHrP-(7-34)NH2 at a 10-fold molar excess (1.6 nmol/h). The 7-34 PTHrP analog also antagonized the PTHrP-(1-34)NH2-induced hypercalcemia and rises in blood 1,25-dihydroxyvitamin D concentrations. However, when infused alone at a higher dose rate (8 nmol/h), PTHrP-(7-34)NH2 displayed significant PTH agonist activity. This profile contrasts to that of [Tyr-34]bPTH-(7-34)NH2 which is comparatively less potent (10-20-fold) with respect to its antagonist activity but has no appreciable agonist activity in vivo.
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PMID:A 7-34 analog of the parathyroid hormone-related protein has potent antagonist and partial agonist activity in vivo. 185 Jun 33

A 74-year-old male was urgently admitted to our hospital because of consciousness disturbance. Laboratory data showed remarkable hypercalcemia (7.8 mEq/L), hypophosphatemia, low % TRP, low intact PTH level, normal nephrogenic cyclic AMP and normal 1,25 (OH)2D level. Serum bone Gla protein, which was thought to express osteoblastic activity, was low. Serum tartarate resistant acid phosphatase and urinary excretion of hydroxyproline, which were thought to express osteoclastic activity, were high. CT scan showed an enlarged mass in the left renal pelvis, which was found to be a squamous cell carcinoma (SCC) by biopsy through percutaneous nephroscopy. Bone scintigram appeared normal. Therefore, we diagnosed it as renal pelvic SCC with humoral hypercalcemia of malignancy (HHM) and performed left nephrectomy. After nephrectomy, serum calcium returned to normal. But after a few weeks, lung metastasis appeared and serum calcium was reelevated. As to PTH related protein (PTHrP) which was thought to induce HHM, PTHrP content of the resected tumor measured by RIA assay was 13 pmol/g wet weight of tissue, which suggested that this tumor might have been producing PTHrP.
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PMID:[A case of renal pelvic squamous cell carcinoma accompanied with humoral hypercalcemia of malignancy]. 192 Oct 23

The enzyme carbonic anhydrase has been suggested as a critical participant in osteoclast-mediated bone resorption. In humoral hypercalcemia of malignancy (HHM) intense osteoclastic bone resorption is principally responsible for the observed hypercalcemia. We therefore undertook to examine the effect of the carbonic anhydrase inhibitor acetazolamide on the hypercalcemia induced by the H500 Leydig cell tumor in Fisher rats, a well-described model of HHM. Acetazolamide treatment for 10 h at 10 mg/h resulted in a significant fall in serum calcium in the five drug-treated animals (14.2 +/- 0.9 to 11.5 +/- 0.1 mg/dl, p less than 0.05). Conversely, the six animals infused with vehicle alone showed a significant rise in serum calcium (12.5 +/- 0.5 to 13.8 +/- 0.1 mg/dl, p less than 0.05). At the end of the infusion, the acetazolamide-treated animals had a significantly lower mean serum calcium than those receiving vehicle alone (11.5 +/- 0.1 versus 13.8 +/- 0.1, p less than 0.05). There was no significant change in serum phosphorus, urine calcium, urine phosphorus, or nephrogenous cyclic AMP excretion between the two groups. Acetazaolamide and HTS 5-(3-hydroxybenzoyl)-2-thiophenesulfonamide, another carbonic anhydrase inhibitor, both significantly inhibited in vitro bone resorption induced by 5 X 10(-9) M 36Tyr(1-36)-PTHrP-amide (PTHrP, parathyroid hormone-related protein). Acetazolamide also inhibited the resorption induced by 10(-8) M (1-141)-PTHrP and 2.5 X 10(-9) M (1-74)-PTHrP. We conclude that acetazolamide is effective in lowering the serum calcium in animals with humoral hypercalcemia of malignancy. The data are consistent with the hypothesis that the mechanism of action for this effect is direct inhibition of osteoclast-mediated bone resorption.
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PMID:Treatment of humoral hypercalcemia of malignancy in rats with inhibitors of carbonic anhydrase. 196 58

46-year-old male patient was born in Niigata Prefecture and thereafter lived in Tokyo. In late January 1985, he noticed swelling of the bilateral inguinal lymph-nodes followed by fever and lumbago. In February, he consulted a local doctor and hepatosplenomegaly, marked leukocytosis and renal dysfunction were pointed out and he was referred to our hospital on February 22nd. The clinical laboratory data on admission were as follows; WBC 23,200/microliter, serum-Ca 18.4 mg/dl, BUN 85.3 mg/dl, creatinine 5.4 mg/dl, antibody to ATLV x160. ATL was diagnosed by biopsy of lymph nodes and examinations of peripheral blood and bone marrow hemogram. Remission was achieved in March by the treatment with adriacin. Renal failure and hypercalcemia also improved. However his respiratory dysfunction gradually worsened. The chest radiographies++ showed pulmonary edema, although there was no clinical evidence of heart failure. When his condition became stable, TBLB was performed and revealed extensive deposition of calcium along alveolar septae, suggesting that pulmonary edema was induced by the metastatic calcification of the lung. After the second treatment for ATL, he died of pneumonia. The autopsy showed calcium deposition not only in the lung but in pyramids of the kidney and in sub-serous layer of the small intestine. There was no tumor cell invasion into the bone or parathyroid gland. High urinary c-AMP together with normal levels of PTH suggested that the hypercalcemia in this case was induced by PTH-related protein. It was concluded that careful treatment for hypercalcemia is important as regards the occurrence of pulmonary edema.
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PMID:[An autopsy case of adult T-cell leukemia complicated with metastatic calcification of the lung]. 204 Dec 50

To investigate whether parathyroid hormone-related protein (PTHrP), a hypercalcemia-inducing factor responsible for malignancy-associated hypercalcemia (MAH), is excreted into urine of these patients, radioimmunoassay was established using antiserum specific for the C-terminal region of PTHrP-(127-141). Immunoreactive PTHrP (iPTHrP) was detected in the urine of all patients with MAH (n = 6) in whom nephrogenous cyclic AMP excretion was elevated. However, iPTHrP was not detected in the urine of normal subjects (n = 25) or hypercalcemic patients with primary hyperparathyroidism (n = 8). In normocalcemic patients with malignant disorders iPTHrP was not detected in the urine in most cases (24 of 25 patients) but was detectable in 1 of 25 patients. iPTHrP was also detected in the urine of hypercalcemic nude mice transplanted with PTHrP-producing tumors, but not in the urine of control and normocalcemic nude mice transplanted with PTHrP-nonproducing tumor. Furthermore, size-exclusion high-performance liquid chromatography revealed that the molecular weight of iPTHrP is about 2000-6000 daltons in the urine of patients as well as tumor-bearing nude mice. These data indicate that the fragments of the C-terminal region of PTHrP are excreted into the urine of patients with MAH and in a few normocalcemic patients with malignancies, suggesting that the measurement of iPTHrP in the urine is potentially useful in the differential diagnosis of hypercalcemia, particularly in differentiating humoral hypercalcemia of malignancy and primary hyperparathyroidism.
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PMID:Urinary excretion of parathyroid hormone-related protein fragments in patients with humoral hypercalcemia of malignancy and hypercalcemic tumor-bearing nude mice. 204 34

Tumors from patients with humoral hypercalcemia of cancer produce a parathyroid hormone-related protein (PTHRP). We have developed two region-specific immunoassays capable of measuring PTHRP in plasma: an immunoradiometric assay directed toward PTHRP amino acid sequence 1 to 74 and a radioimmunoassay directed toward PTHRP amino acid sequence 109 to 138. Sixty normal subjects had low or undetectable plasma PTHRP (1 to 74) concentrations (mean, 1.9 pmol per liter) and undetectable PTHRP (109 to 138) concentrations (less than 2.0 pmol per liter). Patients with humoral hypercalcemia of cancer (n = 30) had elevated levels of both PTHRP (1 to 74) (mean, 20.9 pmol per liter) and PTHRP (109 to 138) (mean, 23.9 pmol per liter). The plasma concentrations of immunoreactive PTHRP correlated with the levels of urinary cyclic AMP excreted; in some patients, the concentrations decreased after the tumors were resected. Patients with chronic renal failure (n = 15) had plasma PTHRP (1 to 74) concentrations similar to those in the normal subjects, but their plasma PTHRP (109 to 138) concentrations were elevated (mean, 29.6 pmol per liter). The levels of both peptides were normal in patients with hyperparathyroidism and those with hypercalcemia due to various other causes. Breast milk contained high concentrations of PTHRP. An anti-PTHRP (1 to 36) immunoaffinity column failed to extract PTHRP (109 to 138) immunoactivity from plasma, suggesting that the C-terminal region circulates as a separate peptide. We conclude that plasma PTHRP concentrations are high in the majority of patients with cancer-associated hypercalcemia and that the circulating forms of PTHRP in such patients include both a large N-terminal (1 to 74) peptide and a C-terminal (109 to 138) peptide. Measuring the concentrations of PTHRPs may be useful in the differential diagnosis of hypercalcemia.
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PMID:Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. 232 83

Hypercalcemia and leukocytosis of malignancy have been highlighted over a decade. We report a case of a gallbladder cancer with marked hypercalcemia and leukocytosis. A 54-year-old woman was admitted to the hospital because of remittent fever and left hypochondric pain. The computed tomographic scan of the abdomen revealed the cancer of the gallbladder with liver metastases. The patient's medical condition deteriorated as the tumor was rapidly growing up. Her medical course was marked by hypercalcemia and an increase in mature neutrophils. Medical therapy with normal saline, furosemide, indomethacin, prednisolone, and calcitonin failed to ameliorate hypercalcemia. On the twenty-ninth hospital day the serum calcium was elevated to 17.6 mg/dl which responded to 1000 micrograms of mithramycin while leucocytosis continued. Despite the chemotherapy with doxorubicin and tegafur, the tumor continued to grow. Leukocytosis was attributed to the elevated colony-stimulating factor activity which was two-fold of control. The parathyroid hormone and nephrogeneous cyclic AMP levels were normal with low vitamin D levels. Hypercalcemia was attributed to a parathyroid hormone-like substance because of a decrease in %TRP in the presence of normal renal function and the normal parathyroid hormone level. Autopsy revealed an undifferentiated adenocarcinoma of the gallbladder with multiple liver metastases, and bone resorption in the vertebral column and sternum without evident bone metastasis.
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PMID:A case of a gallbladder cancer with marked hypercalcemia and leukocytosis. 253 86

The SK-Luci-6 cell line, established from a large-cell anaplastic lung tumor of a patient with humoral hypercalcemia of malignancy (HHM), was investigated to identify osteolytic factors produced that might mediate HHM. Most HHM-associated tumors are thought to produce parathyroid hormone-related proteins or transforming growth factor (TGF) alpha. SK-Luci-6 cells formed s.c. tumors and induced hypercalcemia in athymic nude mice. Serum-free conditioned medium from SK-Luci-6 cultures induced bone resorption in neonatal mouse calvariae in vitro, and also contained TGF-beta activity and mitogenic activity. SK-Luci-6 cell conditioned medium did not displace [125I]epidermal growth factor binding to cell receptors or stimulate cyclic AMP formation in rat osteosarcoma cells, suggesting that the conditioned medium did not contain TGF-alpha or parathyroid hormone-related proteins. The osteolytic, TGF-beta, and mitogenic activities copurified in several chromatographic separations: gel filtration in acid and then in guanidine HCl; ion exchange; and reverse phase. The results suggest that in the HHM-associated SK-Luci-6 tumor, the causative osteolytic factor produced by the tumor cells is not a parathyroid hormone-related protein or TGF-alpha but, rather, may be a TGF-beta.
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PMID:Copurification of osteolytic and transforming growth factor beta activities produced by human lung tumor cells associated with humoral hypercalcemia of malignancy. 253 57

The isolated perfused rat kidney was used to study the effects of parathyroid hormone-related protein (PTHrP) on renal cyclic AMP (cAMP) and electrolyte excretion. A perfusate of PTHrP(1-34) increased cAMP excretion from 0.14 +/- 0.09 (S.E.M.) nmol/l glomerular filtrate (GF) in controls to 24.67 +/- 5.14 (P less than 0.01) and decreased calcium excretion from 0.278 +/- 0.033 to 0.162 +/- 0.011 mumol/l GF (P less than 0.01). Human PTH(1-34) (0.7 nmol/l) caused no significant change in calcium excretion, whilst the rise in cAMP excretion was similar to that with PTHrP. PTHrP(1-34) (7 nmol/l) further increased cAMP production to 366.7 +/- 100.8 nmol/l GF (P less than 0.01), higher than the rise with hPTH(1-34) (7 nmol/l) which was 76.7 +/- 46.8 (P less than 0.05). With the higher concentrations of both peptides (7 nmol/l), calcium excretion was further reduced to 0.090 +/- 0.009 mumol/l GF (P less than 0.01), whilst phosphate excretion increased with both PTHrP and PTH. PTHrP (7 nmol/l) caused a fall in urinary pH compared with controls (P less than 0.05). At low and high concentrations of both hormones, urinary pH was lower with PTHrP than hPTH (P less than 0.01). Thus PTHrP, like PTH, acts on the kidney to increase cAMP and phosphate excretion and reduce calcium excretion, but PTHrP may be more effective. Disparate effects on urinary pH could be reflected in the clinical features of humoral hypercalcaemia of malignancy.
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PMID:Actions of synthetic parathyroid hormone-related protein(1-34) on the isolated rat kidney. 253 69


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