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At least 19 recordsLinked to original sources
PubMed1993

In vivo metabolism of the vitamin D analog, dihydrotachysterol. Evidence for formation of 1 alpha,25- and 1 beta,25-dihydroxy-dihydrotachysterol metabolites and studies of their biological activity.

Dihydrotachysterol (DHT), a reduced vitamin D analog in which the A-ring has been rotated through 180 degrees is a biologically active molecule which can be used to study the structural requirements for the calcemic and cell differentiating properties of the vitamin D hormone, 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25-(OH)2D3), as well as to investigate the specificity of the enzyme systems that catalyze the formation of this hormone. In this study we showed that dihydrotachysterol was metabolized in vivo into a significant polar metabolite observed on straight-phase high performance liquid chromatography (HPLC) which subsequently split into two peaks on reverse-phase HPLC. These two metabolites were identified by HPLC and gas chromatography-mass spectrometry techniques as 1 alpha,25-(OH)2DHT and 1 beta,25-(OH)2DHT. This pair of metabolites was formed from either DHT2 or DHT3. Standard 1 alpha,25-(OH)2DHTs were generated in vitro from chemically synthesized 1-hydroxydihydrotachysterol precursors using a liver hepatoma cell system. Both 1 alpha,25-(OH)2D2 and 1 alpha,25-(OH)2DHT3 showed a binding affinity to the mammalian vitamin D receptor only 50-100 less than 1 alpha,25-(OH)2D3 whereas 1 beta,25-(OH)2DHTs showed poor binding. On the other hand 1 beta,25-(OH)2DHT3 bound to the rat vitamin D transport protein (DBP) with stronger affinity than did 1 alpha,25-(OH)2DHT3. When tested in a COS-1 cell transfection assay system using a rat osteocalcin vitamin D responsive element coupled to a growth hormone reporter gene, 1 alpha,25-(OH)2DHT3 showed a biological activity only 10 times lower than 1 alpha,25-(OH)2D3. It is therefore suggested that 1 alpha,25-(OH)2DHT probably represents the metabolite of DHT responsible for some of its in vivo effects although we cannot rule out in vivo effects of other metabolites identified. Our studies suggest that 1 alpha,25-dihydroxylated DHTs represent a promising novel group of vitamin D analogs worthy of study for cell differentiation as well as calcemic properties.

Animals↗
PubMed1994

A prospective, double-blind study of growth failure in children with chronic renal insufficiency and the effectiveness of treatment with calcitriol versus dihydrotachysterol. The Growth Failure in Children with Renal Diseases Investigators.

Because controlled trials in adults have shown accelerated deterioration of renal function in a small number of patients receiving calcitriol for renal osteodystrophy, we initiated a prospective, randomized, double-blind study of the use of calcitriol versus dihydrotachysterol in children with chronic renal insufficiency. We studied children aged 1 1/2 through 10 years, with a calculated glomerular filtration rate between 20 and 75 ml/min per 1.73 m2, and with elevated serum parathyroid hormone concentrations. Ninety-four patients completed a mean of 8.0 months of control observations and were randomly assigned to a treatment period; 82 completed the treatment period of at least 6 months while receiving a calcitriol dosage (mean +/- SD) of 17.1 +/- 5.9 ng/kg per day or a dihydrotachysterol dosage of 13.8 +/- 3.3 micrograms/kg per day. With treatment the height z scores for both calcitriol- and dihydrotachysterol-treated groups showed no differences between the two groups. In relation to cumulative dose, there was a significant decrease in glomerular filtration rate for both calcitriol and dihydrotachysterol; for calcitriol the rate of decline was significantly steeper (p = 0.0026). The treatment groups did not differ significantly with respect to the incidence of hypercalcemia (serum calcium concentration > 2.7 mmol/L (> 11 mg/dl)). We conclude that careful follow-up of renal function is mandatory during the use of either calcitriol or dihydrotachysterol because both agents were associated with significant declines in renal function. There was no significant difference between calcitriol and dihydrotachysterol in promoting linear growth or causing hypercalcemia in children with chronic renal insufficiency. Dihydrotachysterol, the less costly agent, can be used with equal efficacy.

Calcitriol↗
PubMed1999

Hypercalcemia-induced renal insufficiency during therapy with dihydrotachysterol.

During vitamin-D therapy drug accumulation and intoxication should be considered. In the present study we report on five patients with renal insufficiency during therapy with dihydrotachysterol or calcitriol. Four patients received dihydrotachysterol for 29 (7-44) years and one patient received calcitriol for 4 years to treat hypoparathyroidism after thyroid surgery. As confirmed by renal biopsy impairment of renal function was due to calcifications as a consequence of prolonged hypercalcemia. The effective duration of dihydrotachysterol is ten days as compared with five days for calcitriol. Severe hypercalcemic episodes with dihydrotachysterol are longer-lasting than those with the shorter acting vitamin-D derivatives. Further, they occur with higher incidence as was shown by our own observations and previously published data by other workers. Hence, impairment of renal function during therapy with dihydrotachysterol should be considered as being due to hypercalcemia and hypercalciuria.

Aged↗
PubMed2001

[Severe Vitamin D(dihydrotachysterol)-intoxication with temporary anemia and hypercalcemia responsive to bisphosphonates]

Severe Vitamin D(dihydrotachysterol)-intoxication with temporary anemia and hypercalcemia responsive to bisphosphonates. HISTORY AND FINDINGS: A 31-year old female patient presented with pain of her skeletal system. 6 months prior to her presentation, she underwent thyroid surgery for Graves disease. She also suffered from endocrine orbitopathy. Afterwards, she expirienced surgical hypoparathyroidism and received dihydrotachy-sterol (A.T.10 (R)) in a dose of up to 4 mg per day. The physical examination was unremarkable except for the presence of Graves' ophthalmopathy and a swelling at the left ancle. INVESTIGATIONS: Upon admittance, she had severe hypercalcemia (serum calcium: 4.1 mmol/l) with plasma intact PTH levels below the limit of detection, renal failure (serum creatinine: 5.5 mg/dl) and normocytic anemia (initial hemoglobin: 8.3 g/dl, upon rehydration: 6.6 g/dl). TREATMENT AND COURSE: Upon rehydration and induced diuresis, the renal function improved and the serum calcium came down rapidly in the early treatment phase. However, serum calcium remained elevated at around 3.0 mmol/l after 4 weeks. Only after the use of the bisphosphonate pamidronate (15 mg), serum calcium returned into the normal range and remained there. Treatment for hypoparathyroidism had to be reinstituted only 20 weeks after dihydrotachysterol had been discontinued. The anemia had resolved without any treatment at that time. CONCLUSIONS: Treatment with dihydrotachysterol and other long-acting Vitamin D preparations has to be monitored closely because of the risk of severe hypercalcemia, which may be difficult to treat. In our case, dihydrotachysterol was still active until week 20 after the drug was discontinued. Anemia should be considered as a side effect of dihydrotachysterol intoxication and does not warrant elaborate differential diagnosis in this context. A single administration of a bisphosphonate turned out to be of major therapeutic benefit and resulted in a lasting correction of hypercalcemia. Therefore, bisphosphonates should become part of the treatment regimen for vitamin D intoxication.

Journal Article↗
PubMed1981

Hypercalcaemia due to dihydrotachysterol treatment in patients with hypothyroidism after thyroidectomy.

Hypercalcaemia is a recognised complication of hypothyroidism. We describe three patients who developed hypercalcaemia after thyroidectomy when thyroid supplements were discontinued. They were treated with thyroxine, dihydrotachysterol, and calcium after operation, and in all three cases serum calcium concentrations remained constant during combined treatment. Thyroxine treatment was discontinued several weeks before a radioiodine scan was performed; dihydrotachysterol and calcium were continued throughout. Serum calcium concentrations rose to hypercalcaemic levels in all cases. Elimination of dihydrotachysterol from plasma may be delayed in hypothyroidism, resulting in hypervitaminosis D. It is advisable to reduce the dose of dihydrotachysterol and to check serum calcium concentrations regularly in patients whose thyroid treatment is interrupted.

Adult↗
PubMed1974

Metabolism of dihydrotachysterol and 5,6-trans-cholecalciferol in the chick and the rat.

Dihydrotachysterol and 5,6-trans-cholecalciferol are biologically active analogues of cholecalciferol (vitamin D) with a similarity in steric structure to 1,25-dihydroxycholecalciferol, the active form of the vitamin. The question arises as to the nature of the active form of these analogues. High specific radioactivity (14)C- and (3)H-labelled forms of dihydrotachysterol and 5,6-trans-cholecalciferol and its 25-hydroxy derivative were synthesized and their metabolism was studied in chicks and rats. All these steroids were very rapidly metabolized compared with cholecalciferol; 20% of the dihydrotachysterol dose was excreted in bile in the first 24h, about 50% as a carboxylic acid derivative. Although polar metabolites were detected in tissues, no 1-hydroxy form was observed. Larger proportions of the parent steroid and its 25-hydroxy metabolite were detected in tissues compared with cholecalciferol, but no single metabolite was detected at the intracellular site of action of cholecalciferol. It is suggested that analogues of cholecalciferol will be biologically active if they possess a hydroxyl group in the same steric position as that at C-1 of cholecalciferol, with the greatest activity shown by those that also have a C-25 hydroxyl group. The implication of these findings for the chemical features necessary for binding to receptor proteins are briefly discussed.

Animals↗
PubMed1972

Dihydrotachysterol: a calcium active steroid not dependent upon kidney metabolism.

The activity of dihydrotachysterol and cholecalciferol was determined in nephrectomized or sham-operated vitamin D-depleted rats using in vitro transport of calcium and phosphate by everted intestinal preparations as the index of physiologic response. The activity of dihydrotachysterol was not reduced by absence of the kidneys whereas that of cholecalciferol was markedly inhibited so that at least a 10-fold greater dose of the latter was necessary to produce an equivalent effect in the nephrectomized rat as in the control. Dihydrotachysterol is therefore equipotent with cholecalciferol in the anephric rat although much less active in the intact animal.

Animals↗
PubMed1984

Vitamin D replacement therapy and renal function. Calcitriol v dihydrotachysterol.

We treated 24 patients who had chronic renal insufficiency and renal osteodystrophy with either calcitriol (1,25-dihydroxyvitamin D3) or dihydrotachysterol. Renal function was evaluated before and during treatment to determine if these vitamin D analogues caused an accelerated rate of renal function deterioration. An accelerated rate of increase in the serum creatinine level was found in three of 12 patients in each treatment group after therapy was started, but the mean rate of increase during treatment did not differ significantly from the rate during the pretreatment control period in either group. The occurrence of hypercalcemia or an excessive serum calcium x phosphorus-product did not correlate with the rate of change in renal function during treatment with either drug. We concluded that children receiving calcitriol are not at greater risk for an accelerated rate of renal function deterioration than are children treated with dihydrotachysterol. Furthermore, neither vitamin D analogue could be directly implicated as a cause of an accelerated rate of renal function deterioration when episodes of hypercalcemia were transient and occurred infrequently.

Adolescent↗
PubMed1975

Comparison of the effects of vitamin D3, dihydrotachysterol, and parathormone on calcium kinetics in the rat.

Rats were treated with 100 I.U. (= 2.5 mcg) Vit. D3/day during 14 days and submitted to a radio-Calcium assay of Calcium kinetics. The results were compared with those obtained in weight-matched pair-fed controls, and with those obtained in former experiments applying dihydrotachysterol and parathormone. Vit. D3, which is transformed to a hormone, increased the fast exchange compartment, the exchange rate between the compartments, the endogenous fecal Calcium excretion rate, and the bone uptake and release rates. These findings indicate that the Vit. D-hormone is more similar in its action to the other hormone, parathormone, than to its close chemical relative dihydrotachysterol.

Animals↗
PubMed1979

The response to 1,25-dihydroxycholecalciferol and to dihydrotachysterol in adult-onset hypophosphataemic osteomalacia.

The biochemical changes observed in a patient with adult-onset hypophosphataemic osteomalacia after three weeks treatment with 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) followed by dihydrotachysterol (DHT) are reported. The treatment with 1,25-(OH)2D3 resulted in restoration of intestinal phosphate absorption to normal with a small rise in plasma phosphate concentration; there was no significant change in tubular reabsorption of phosphate. The tubular reabsorption of bicarbonate, which was initially low, returned almost into the normal range with normalisation of plasma bicarbonate concentration. Aminoaciduria decreased. There were no changes in plasma or urinary calcium but immunoreactive parathyroid hormone (i-PTH) which was initially elevated fell but still remained above the normal range. These changes were maintained after replacing the 1,25-(OH)2D3 treatment with dihydrotachysterol (DHT).

Amino Acids↗
PubMed1999

Unaccountable severe hypercalcemia in a patient treated for hypoparathyroidism with dihydrotachysterol.

This report describes a forty-seven-year-old female patient with a complex medical history. She was suffering from an unspecified interstitial lung disease, papillary thyroid carcinoma which had been treated, hypoparathyroidism after thyroidectomy for which she was receiving dihydrotachysterol and calcium, and atrial fibrillation and congestive heart failure as a result of mitral stenosis. Shortly after mitral valve replacement she developed a severe hypercalcemia (serum calcium 5.95 mmol/l) during a febrile illness. At that time anti-tuberculous agents were also being administered for presumed tuberculosis. The possible mechanisms for this severe elevation of the calcium level are discussed. Immobilization, while Paget's bone disease was present, and perhaps enhanced activation of dihydrotachysterol by rifampicin, could have led to increased calcium-release into the circulation. Continuous supplecation of calcium and vitamin D, provoked dehydration and the mechanism of the milk-alkali syndrome also contributed to this extremely high calcium level. It is concluded that hypoparathyroid patients being treated with vitamin D and calcium should be carefully monitored in the case of an intercurrent illness or a change in medication.

Calcium↗
PubMed1987

A comparative study of cholecalciferol, dihydrotachysterol and alfacalcidol in the treatment of elderly patients with hypocalcaemia.

Fifty elderly patients with hypocalcaemia were randomly treated for 8 weeks with either oral dihydrotachysterol, parenteral cholecalciferol or oral alfacalcidol. All three treatments were successful in normalizing the serum calcium levels in most patients within 2 weeks. Hypercalcaemia was seen only with alfacalcidol but was rapidly reversed once treatment was discontinued. Hypercalcaemia was not observed with either dihydrotachysterol or cholecalciferol. These therefore, require less frequent biochemical monitoring. A single cholecalciferol injection eliminates the problems of compliance.

Aged↗
PubMed1982

Serum concentrations of dihydrotachysterol-2 in the treatment of osteoporosis and hypoparathyroidism.

A method for the quantitative estimation of dihydrotachysterol-2 is described using high performance liquid chromatography coupled to an UV monitor. Since radioactive labelled DHT2 is not available, recovery is based on the assumption that dihydrotachysterol-2 and cholecalciferol behave identically during chromatic procedures. Evidence is presented to support this assumption. In patients treated with DHT2 the serum concentrations of DHT2 rose in proportion to the administered dose.

Chromatography, High Pressure Liquid↗
PubMed1988

Aluminum metabolism in rats: effects of vitamin D, dihydrotachysterol, 1,25-dihydroxyvitamin D and phosphate binders.

In order to study the effects of vitamin D on aluminium balance when different forms of vitamin D and phosphate binders are used simultaneously for therapeutic purposes, 30 Sprague-Dawley weanling rats, weighing 44-66 g, were randomly assigned to 5 groups: (A) control, (B) aluminum hydroxide, (C) dihydrotachysterol at 16 micrograms/kg/day, (D) 1,25-dihydroxyvitamin D at 16 ng/kg/day and (E) vitamin D at 2,000 IU/kg/day. Aluminum hydroxide (60 mg/kg/day) in the feed was provided to all except the control group. The vitamin D or metabolites were fed by stomach tube daily for a period of 10 days. At the end of the study, the mean (+/- SEM) serum aluminum concentration, as determined by flameless atomic absorption spectrophotometry, was 5.0 +/- 2.4 micrograms/l; there were no significant differences in these results between groups. During the last three days of the study, 24-hour urine and stool collections were made with the usual precautions against trace mineral contamination. The means (+/- SEM) of aluminum balances for groups A, B, C, D and E were -388 +/- 261, 1,121 +/- 331; 2,316 +/- 304; 2,387 +/- 245, and 1,968 +/- 337 micrograms/day, respectively. We conclude that at therapeutic doses of aluminum hydroxide and vitamin D or its metabolites, hyperaluminemia was not observed. However, the positive aluminum balances imply retention, and the use of vitamin D, especially its potent metabolites dihydrotachysterol and 1,25-dihydroxyvitamin D, intensified this risk.

Aluminum↗
PubMed1990

[Effect of dihydrotachysterol on the periodontal tissues in rats].

The purpose of the present study was to investigate the histological changes of the periodontal tissues in rats produced by oral administration of dihydrotachysterol (DHT). Forty-five rats, 6 weeks old, were divided equally into 9 groups (Groups A-I). Groups A, D and G, control groups, received an administration of corn oil (0.5 ml) once a day for 1, 2 and 4 weeks, respectively. Groups B, E and H received an administration of DHT (25 micrograms) once a day for 1, 2 and 4 weeks, respectively. Groups C, F and I had an administration of DHT (50 micrograms) once a day for 1, 2 and 4 weeks, respectively. The animals of all groups were killed 24 hours after the last administration. The periodontal tissues of the maxillary first molar of all animals were examined histologically and histometrically. Histological and histometrical findings: 1. In Groups A, D and G, control groups, the periodontal ligament, alveolar bone and cementum appeared normal during the entire experimental period. 2. In Group B, the peridontal tissues were almost similar to those of the control group. 3. In Groups C and E, osteoid tissue was observed in the alveolar bone surface. The thickness of the periodontal ligament decreased and the bone marrow spaces were slightly enlarged. The volmetric density of the alveolar bone decreased compared with that of the control groups. 4. In Groups F, H and I, the thickness of the periodontal ligament decreased significantly. In the periodontal ligament, destruction of collagen fibers was observed, and fibroblasts, collagen fibers and oxytalan fibers decreased in number. Dental ankylosis was also found. An abnormal darkly-stained layes (using the PAS staining method) was observed in the cementum surface. The alveolar bone marrow spaces were enlarged and replaced by fibrous tissue. In the histometrical findings, the thickness of the periodontal ligament and the volumetric density of the alveolar bone had decreased, and the volume of the cementum had increased significantly. The result of the present study suggested that oral administration of dihydrotachysterol to the rats induced the changes of the periodontal tissues similar to those seen in aging humans.

Alveolar Bone Loss↗