RESUMEN
Various derivatives of human calcitonin have been synthesized and their biological characteristics compared with those of existing calcitonins. The acute effects of these analogues in reducing serum calcium levels and suppressing appetite were assessed in rats. A calcitonin analogue, PO-1 (CGNLSTCMLGKLSQELHKLQTYPQTAIGVGAP-NH2), having both the N- and C-terminal ten amino acid sequences those of human calcitonin, and the 12 amino acid central region that of salmon calcitonin, was found to have equal effectiveness with salmon calcitonin and elcatonin for reducing serum calcium levels. Strong hypocalcemic activity was also exhibited by PO-23 ([cyclo-Asp1, Lys7]-[des-Gly2]-[Leu8]-PO-1) and PO-29 ([Asp15, Asn17 , Phe19, His20]-PO-23). PO-23 was prepared by replacing the N-terminal Cys-Cys S-S bond of PO-1 with a ring structure composed of an Asp-Lys peptide bond to enhance physicochemical stability. PO-29 was prepared by modifying the central area of the PO-23 molecule to more closely mimic human calcitonin. When tested in vitro, human calcitonin analogues with a [cyclo-Asp1, Lys7] structure showed biological activities on osteoclast-like cells comparable to those of existing calcitonins (salmon calcitonin and elcatonin) in keeping with their relative potencies for in vivo hypocalcemic action. Acute anorectic activity in rats was strong with salmon calcitonin and elcatonin but relatively reduced with human calcitonin analogues having a [cyclo-Asp1, Lys7] structure. The activities of these analogues on kidney cells were also weaker than that of salmon calcitonin or elcatonin. These results suggest that stable human calcitonin analogues with a [cyclo-Asp1, Lys7] structure suppress bone resorption to a degree similar to that of salmon calcitonin or elcatonin with weaker activities on non-osseous tissues which might be related to adverse reaction.
Asunto(s)
Anorexia/inducido químicamente , Huesos/efectos de los fármacos , Calcitonina/análogos & derivados , Riñón/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Calcitonina/farmacología , Técnicas de Cocultivo , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Humanos , Hipocalcemia/tratamiento farmacológico , Radioisótopos de Yodo , Riñón/citología , Masculino , Datos de Secuencia Molecular , Osteoclastos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Homología de Secuencia de AminoácidoRESUMEN
Although levels of serum immunoreactive parathyroid hormone (iPTH) increase with age in women, this could be caused by retention of non-biologically active PTH fragments by the aging kidney. In 102 normal women, aged 30 to 89 yr, serum iPTH increased with age by 58% (r = 0.33, p less than 0.001) with antiserum GP-1M (which has midmolecule specificity) and 43% (r = 0.32, p less than 0.001) with antiserum CH-12M (which may have whole molecule specificity); urinary cAMP/GFR excretion increased by 29% (r = 0.22, p less than 0.05). The results of these assays were validated by comparison with serum levels of biologically active PTH (BioPTH) in immunoextracts of serum followed by renal adenylate cyclase assay in a selected subgroup of 25 of the women. Serum BioPTH correlated with serum iPTH assessed by antiserum GP-1M (r = 0.48, p less than 0.05) and antiserum CH-12M (r = 0.48, p less than 0.05) but not with urinary cAMP. The data are consistent with an increase of parathyroid function with aging: clearly, we do not find decreased parathyroid function as would be expected if age-related bone loss was not mediated, in part, by PTH.
Asunto(s)
Envejecimiento/sangre , Hormona Paratiroidea/sangre , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/orina , Fosfatasa Alcalina/sangre , Calcio/sangre , Creatina/orina , Femenino , Humanos , Persona de Mediana Edad , Fósforo/sangreRESUMEN
Thirty-two patients were treated surgically for symptomatic secondary or tertiary hyperparathyroidism, and 27 of these patients had high resolution (10 mHz) real-time ultrasonography before parathyroidectomy. This preoperative localization study identified one or more enlarged hyperplastic parathyroid glands in all but one patient who had not had a previous parathyroid operation, and in five of six patients who did have previous parathyroid operations. In both of the patients in whom no parathyroid glands were identified by ultrasonography the only abnormal enlarged parathyroid glands were those situated within the superior mediastinum. When large glands are not observed by ultrasonography in patients with severe secondary hyperparathyroidism, the glands are usually situated in the superior mediastinum, behind the trachea or esophagus, or deeply within the neck. The size of the parathyroid glands correlated positively with the serum parathyroid hormone level and with the severity of the secondary hyperparathyroidism. Thus, the preoperative identification of parathyroid glands by ultrasonography not only localizes the site of most hyperplastic parathyroid glands (70 percent of patients), but also detects those patients who have enlarged parathyroid glands, elevated serum parathyroid hormone levels, and severe secondary hyperparathyroidism. These are the patients who are thus unlikely to respond to further medical therapy.
Asunto(s)
Adenoma/patología , Hiperparatiroidismo Secundario/patología , Glándulas Paratiroides/patología , Neoplasias de las Paratiroides/patología , Ultrasonografía/métodos , Adenoma/cirugía , Adolescente , Adulto , Anciano , Fosfatasa Alcalina/sangre , Calcio/sangre , Femenino , Humanos , Hiperparatiroidismo Secundario/cirugía , Hiperplasia , Masculino , Persona de Mediana Edad , Glándulas Paratiroides/cirugía , Hormona Paratiroidea/sangre , Neoplasias de las Paratiroides/cirugía , Fósforo/sangre , Recurrencia , ReoperaciónRESUMEN
1,25 dihydroxycholecalciferol [1,25(OH)2D3] was studied in a double-blind controlled fashion in patients on chronic dialysis. Serum calcium was unchanged in 16 patients on vitamin D3 (D3) (400 to 1200 IU/day). In 15 patients on 1,25(OH)2D3 (0.5 to 1.5 microgram/day), serum calcium increased from 9.05 +/- .15 to 10.25 +/- .20 mg/dl (p less than 0.001), returning to 9.37 +/- .16 mg/dl (p less than 0.001) in the post control period. Patients on D3 showed no reversible decrease in immunoreactive parathyroid hormone levels, but patients on 1,25(OH)2D3 did, from a control of 1077 +/- 258 to 595 +/- 213 microliter equivalents/ml (p less than 0.01), and returned to 1165 +/- 271 microliter equivalents/ml (p less than 0.005). Nine of 12 patients on D3 who underwent serial iliac-crest biopsies showed histologic deterioration, and six of seven who received 1,25(OH)2D3 were improved or unchanged (p less than 0.025). Bone mineral and calcium decreased in patients on D3 (p less than 0.05) but not in those on 1,25(OH)2D3. Hypercalcemia occurred in five of 15 patients. We conclude that 1,25(OH)2D3 has a calcemic effect in chronic dialysis patients, decreases levels of immunoreactive parathyroid hormone, and is associated with histologic improvement in bone disease. Thus, 1,25(OH)2D3 is a valuable adjunct to the management of renal osteodystrophy but requires monitoring of serum calcium to avoid hypercalcemia.
Asunto(s)
Dihidroxicolecalciferoles/farmacología , Hidroxicolecalciferoles/farmacología , Fallo Renal Crónico/terapia , Diálisis Renal , Adulto , Fosfatasa Alcalina/sangre , Antígenos , Huesos/metabolismo , Huesos/patología , Calcio/sangre , Calcio/metabolismo , Colecalciferol/farmacología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/tratamiento farmacológico , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/metabolismo , Ensayos Clínicos como Asunto , Dihidroxicolecalciferoles/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Hipercalcemia/prevención & control , Fallo Renal Crónico/sangre , Fallo Renal Crónico/patología , Masculino , Persona de Mediana Edad , Minerales/metabolismo , Hormona Paratiroidea/inmunología , Fósforo/sangreRESUMEN
1. Five patients with the osteomalacia of chronic renal failure were given 50--100 nmol of 25-hydroxy vitamin D3 intravenously per day for 24--28 days. 2. In all five patients, during administration of 25-hydroxy vitamin D3 there was a substantial rise in the plasma concentration of 25-hydroxy vitamin D from initially abnormally low values. 3. Significant improvement in bone mineralization, intestinal calcium absorption and muscle strength occurred in the three patients with the greatest rise in plasma 25-hydroxy vitamin D.
Asunto(s)
Hidroxicolecalciferoles/uso terapéutico , Fallo Renal Crónico/complicaciones , Osteomalacia/tratamiento farmacológico , Anciano , Calcificación Fisiológica , Calcio/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteomalacia/etiología , Fósforo/sangreRESUMEN
The effect of phosphorus (inorganic phosphate) supplementation was studied in seven postmenopausal women with osteoporosis. Prior to supplementation, all chemical parameters studied in serum and urine were normal. Bone density was below the fifth percentile for age in all but one patient, and the percentage of bone surface involved in resorption was higher than normal. During administration of the phosphorus supplement, fasting serum concentrations of calcium and immunoreactive parathyroid hormone showed no significant changes, while serum phosphorus, urinary calcium, and tubular reabsorption of phosphorus decreased. In four patients studied by balance techniques, calcium balance became positive or less negative. Bone-forming surface decreased and bone-resorbing surface increased in all patients. Bone-resorbing surface was highly correlated with total phosphorus intake. Density of the distal radius changed variably, while density of the midradius increased slightly in all patients.
Asunto(s)
Huesos/patología , Osteoporosis/tratamiento farmacológico , Hormona Paratiroidea/sangre , Fosfatos/uso terapéutico , Anciano , Fosfatasa Alcalina/sangre , Resorción Ósea , Huesos/efectos de los fármacos , Calcio/metabolismo , Calcio de la Dieta , Femenino , Humanos , Hidroxiprolina/orina , Menopausia , Persona de Mediana Edad , Osteoporosis/sangre , Osteoporosis/patología , Fosfatos/metabolismo , Factores de TiempoAsunto(s)
Calcio/metabolismo , Hiperparatiroidismo Secundario/etiología , Fósforo/metabolismo , Diálisis Renal , Uremia/metabolismo , Resorción Ósea/metabolismo , Calcio/uso terapéutico , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Humanos , Hormona Paratiroidea/metabolismo , Fosfatos/sangre , Radioinmunoensayo , Uremia/complicacionesAsunto(s)
Dihidroxicolecalciferoles/uso terapéutico , Hidroxicolecalciferoles/uso terapéutico , Fallo Renal Crónico/complicaciones , Osteomalacia/tratamiento farmacológico , Resorción Ósea/efectos de los fármacos , Calcio/metabolismo , Ensayos Clínicos como Asunto , Dihidroxicolecalciferoles/farmacología , Humanos , Osteoclastos/efectos de los fármacos , Osteomalacia/etiología , Hormona Paratiroidea/sangre , Fósforo/metabolismoAsunto(s)
Hiperparatiroidismo/terapia , Adenoma/cirugía , Calcio/sangre , Humanos , Hiperparatiroidismo/sangre , Hiperparatiroidismo/tratamiento farmacológico , Hiperparatiroidismo/cirugía , Neoplasias del Mediastino/cirugía , Glándulas Paratiroides/cirugía , Hormona Paratiroidea/sangre , Neoplasias de las Paratiroides/cirugía , Fosfatos/uso terapéutico , Fósforo/sangre , RadioinmunoensayoAsunto(s)
Hormonas Ectópicas/sangre , Hipercalcemia/sangre , Neoplasias/sangre , Síndromes Paraneoplásicos Endocrinos/sangre , Hormona Paratiroidea/sangre , Neoplasias Óseas/sangre , Calcio/sangre , Creatinina/sangre , Diagnóstico Diferencial , Femenino , Humanos , Hipercalcemia/complicaciones , Hiperparatiroidismo/complicaciones , Hiperparatiroidismo/diagnóstico , Masculino , Metástasis de la Neoplasia , Neoplasias/complicaciones , Síndromes Paraneoplásicos Endocrinos/diagnóstico , Fósforo/sangre , RadioinmunoensayoAsunto(s)
Calcio de la Dieta , Glándulas Paratiroides/efectos de los fármacos , Hormona Paratiroidea/sangre , Preñez , Animales , Resorción Ósea/efectos de los fármacos , Calcio/sangre , Bovinos , AMP Cíclico/orina , Ácido Edético , Femenino , Hidroxiprolina/orina , Hipocalcemia/inducido químicamente , Absorción Intestinal/efectos de los fármacos , Magnesio/sangre , Microscopía Electrónica , Glándulas Paratiroides/citología , Glándulas Paratiroides/patología , Fósforo/sangre , Fósforo/farmacología , Embarazo , Espectrofotometría AtómicaAsunto(s)
Hiperparatiroidismo Secundario/etiología , Fallo Renal Crónico/complicaciones , Secuencia de Aminoácidos , Animales , Huesos/metabolismo , Calcio/sangre , Calcio/metabolismo , Humanos , Fallo Renal Crónico/metabolismo , Fallo Renal Crónico/fisiopatología , Pruebas de Función Renal , Glándulas Paratiroides/metabolismo , Hormona Paratiroidea/análisis , Hormona Paratiroidea/sangre , Hormona Paratiroidea/metabolismo , Fosfatos/metabolismo , Fósforo/sangre , Radioinmunoensayo , Diálisis Renal , Tasa de Secreción , Especificidad de la Especie , Vitamina D/metabolismoAsunto(s)
Adenoma/genética , Carcinoma/genética , Neoplasias de las Paratiroides/genética , Neoplasias de la Tiroides/genética , Adenoma/sangre , Adenoma/complicaciones , Adulto , Calcitonina/sangre , Calcio/sangre , Carcinoma/sangre , Carcinoma/complicaciones , Femenino , Humanos , Hipercalcemia/complicaciones , Cálculos Renales/complicaciones , Masculino , Hormona Paratiroidea/sangre , Neoplasias de las Paratiroides/sangre , Neoplasias de las Paratiroides/complicaciones , Feocromocitoma/genética , Fósforo/sangre , Síndrome , Neoplasias de la Tiroides/sangre , Neoplasias de la Tiroides/complicacionesAsunto(s)
Fosfatasa Alcalina/sangre , Calcio/sangre , Magnesio/sangre , Hormona Paratiroidea/sangre , Fósforo/sangre , Adolescente , Adulto , Factores de Edad , Desarrollo Óseo , Calcio/metabolismo , Niño , Preescolar , Femenino , Crecimiento , Humanos , Lactante , Iones , Magnesio/metabolismo , Masculino , Hormona Paratiroidea/fisiología , Fósforo/metabolismo , Caracteres SexualesRESUMEN
Parathyroid function was assessed by calcium infusions (4-8 h) in 16 patients with chronic renal insufficiency being treated by long-term hemodialysis. The concentrations of two immunoreactive species of parathyroid hormone in plasma (iPTH-9, mol wt 9500; iPTH-7, mol wt 7000) were estimated by radioimmunoassays utilizing two relatively specific antisera. Control values of the smaller species, iPTH-7, were uniformly high, whereas values of iPTH-9 were normal in 12 of 19 studies. Response of iPTH-7 to calcium infusions was variable, with significant decreases occurring only five times in 27 infusions. Concentrations of iPTH-9, however, decreased during every calcium infusion. In contrast to these acute responses, five of six patients studied during periods of dialysis against both low (< 6 mg/100 ml) and high (7-8 mg/100 ml) calcium concentrations in the dialyzate showed a decrease in values of iPTH-7 during the period of dialysis against the higher calcium concentration. It is concluded that plasma concentrations of iPTH-9 reflect primarily the moment-to-moment secretory status of the parathyroid glands, while concentrations of iPTH-7 reflect more closely chronic parathyroid functional status. It is further concluded that the failure of iPTH-7 to decrease during induced hypercalcemia should not be equated with autonomy of parathyroid gland function.
Asunto(s)
Enfermedades Óseas/etiología , Hiperparatiroidismo/etiología , Diálisis Renal/efectos adversos , Animales , Calcio/administración & dosificación , Calcio/sangre , Bovinos/inmunología , Cromatografía en Gel , Gluconatos/administración & dosificación , Humanos , Sueros Inmunes , Isótopos de Yodo , Fallo Renal Crónico/terapia , Métodos , Peso Molecular , Glándulas Paratiroides/fisiopatología , Hormona Paratiroidea/sangre , Fósforo/sangre , Radioinmunoensayo , Espectrofotometría Atómica , Porcinos/inmunología , Factores de TiempoRESUMEN
Two major species of serum immunoreactive parathyroid hormone (iPTH) were measured in 47 untreated patients with primary osteoporosis by using two highly specific radioimmunoassays. Mean iPTH was normal with one antiserum but was lower than normal (P < 0.001) with the other, iPTH values did not correlate with biochemical parameters or with the proportion of bone-resorbing surfaces in iliac crest bone biopsy specimens. These data suggest that the increased bone resorption is not due to increased parathyroid function in most osteoporotic patients. However, seven of our patients (15%) appear to represent a separate population because they had increased values with one or the other of the antisera.
Asunto(s)
Osteoporosis/fisiopatología , Glándulas Paratiroides/fisiopatología , Anciano , Fosfatasa Alcalina/sangre , Animales , Anticuerpos , Resorción Ósea , Calcio/sangre , Pollos/inmunología , Femenino , Cobayas/inmunología , Humanos , Hiperparatiroidismo/sangre , Sueros Inmunes , Masculino , Métodos , Persona de Mediana Edad , Peso Molecular , Hormona Paratiroidea/sangre , Fósforo/sangre , RadioinmunoensayoAsunto(s)
Calcio/sangre , Hidroclorotiazida/farmacología , Hormona Paratiroidea/sangre , Proteínas Sanguíneas/análisis , Humanos , Hidroclorotiazida/administración & dosificación , Concentración de Iones de Hidrógeno , Magnesio/sangre , Hormona Paratiroidea/análisis , Fósforo/sangre , Potasio/sangre , Unión Proteica/efectos de los fármacos , Radioinmunoensayo , Espectrofotometría AtómicaRESUMEN
In 29 women with postmenopausal osteoporosis, the proportion of total bone surface undergoing resorption or formation was evaluated by microradiography of iliac crest biopsy samples before and after short-term (2(1/2)-4 months) and long-term (26-42 months for estrogen and 9-15 months for anabolic hormone) treatment. After estrogen administration, values for bone-resorbing surfaces decreased, although less prominently after long-term than after short-term therapy. The magnitude of this decrease was positively correlated with the pretreatment value for bone-resorbing surfaces (P < 0.001). When the pretreatment value for bone-resorbing surfaces was used as a covariable, estrogen and anabolic hormone appeared to be equally effective. For bone-forming surfaces, short-term therapy with either hormone had no effect but long-term therapy significantly decreased the values. Serum immunoreactive parathyroid hormone (IPTH) increased significantly after estrogen therapy; the change in IPTH was inversely related to the change in serum calcium (P < 0.001, sign test). We conclude that the primary effect of sex hormones in postmenopausal osteoporosis is to decrease the increased level of bone resorption, perhaps by decreasing the responsiveness of bone to endogenous parathyroid hormone. However, this favorable effect, at least in part, is negated after long-term treatment by a secondary decrease in bone formation. Our data are consistent with the concept that the maximal benefit that can be derived from sex hormone therapy in postmenopausal osteoporosis is arrest or slowing of the progession of bone loss.