High-dose Oral Vitamin Research Articles

Chronotherapy of high-dose 1,25-dihydroxyvitamin D in hemodialysis patients with secondary hyperparathyroidism: A single-dose study

A high-dose oral intermittent vitamin D (pulse therapy) is widely used for the treatment of secondary hyperparathyroidism associated with kidney failure. However, hypercalcemia by vitamin D sometimes interrupts this treatment. Because serum calcium concentration possesses a circadian rhythm, a chronopharmacologic approach of vitamin D may have merit for avoidance of adverse reactions. Six female secondary hyperparathyroidism patients receiving maintenance hemodialysis received a single oral dose of 2 microg 1,25-dihydroxyvitamin D3 at either 8 AM or 8 PM in a crossover design. Serum concentrations of ionized and total calcium, phosphate, and vitamin D3 were determined for a 48-hour period after administration. We also measured serum intact parathyroid hormone before and 48 hours after dosing as an index for efficacy. A single oral administration of the drug caused an increase in concentration of ionized calcium, serum calcium, and phosphate. However, the area under concentration-time curve from zero to 48 hours [AUC(0-48)] and peak concentration of these variables were markedly lower after dosing at 8 PM. Pre-dose concentrations of these variables were lower at night. The AUC(0-48) of serum vitamin D3 of the morning and night trials did not differ significantly. Reduction of intact parathyroid hormone concentration was also similar between the two trials. The administration of vitamin D3 at night may reduce the occurrence of hypercalcemia and hyperphosphatemia in patients with secondary hyperparathyroidism, whereas the pharmacokinetics and intact parathyroid hormone-lowering effect of the drug does not vary with dosing time.

Chronotherapy of high-dose 1,25-dihydroxyvitamin D in hemodialysis patients with secondary hyperparathyroidism: A single-dose study

Background A high-dose oral intermittent vitamin D (pulse therapy) is widely used for the treatment of secondary hyperparathyroidism associated with kidney failure. However, hypercalcemia by vitamin D sometimes interrupts this treatment. Because serum calcium concentration possesses a circadian rhythm, a chronopharmacologic approach of vitamin D may have merit for avoidance of adverse reactions. Methods Six female secondary hyperparathyroidism patients receiving maintenance hemodialysis received a single oral dose of 2 μg 1,25-dihydroxyvitamin D3 at either 8 AM or 8 PM in a crossover design. Serum concentrations of ionized and total calcium, phosphate, and vitamin D3 were determined for a 48-hour period after administration. We also measured serum intact parathyroid hormone before and 48 hours after dosing as an index for efficacy. Results A single oral administration of the drug caused an increase in concentration of ionized calcium, serum calcium, and phosphate. However, the area under concentration–time curve from zero to 48 hours [AUC(0-48)] and peak concentration of these variables were markedly lower after dosing at 8 PM. Predose concentrations of these variables were lower at night. The AUC(0-48) of serum vitamin D3 of the morning and night trials did not differ significantly. Reduction of intact parathyroid hormone concentration was also similar between the two trials. Conclusion The administration of vitamin D3 at night may reduce the occurrence of hypercalcemia and hyperphosphatemia in patients with secondary hyperparathyroidism, whereas the pharmacokinetics and intact parathyroid hormone–lowering effect of the drug does not vary with dosing time. Clinical Pharmacology & Therapeutics (1999) 66, 609–616; doi: 10.1053/cp.1999.v66.103169001

Parathyroid allotransplantation without immunosuppression

The hypocalcaemia of permanent hypoparathyroidism is a severe and sometimes fatal complication after thyroid and parathyroid surgery. Due to the multiple metabolic functions of parathyroid hormone, the symptoms and associated diseases of hypoparathyroidism cannot always be controlled sufficiently with oral calcium and vitamin D supplements. We report the successful treatment of two patients with postoperative hypoparathyroidism by allotransplantation of cultivated parathyroid tissue particles that were encapsulated with a semipermeable membrane (microencapsulation). A 52-year-old woman and a 55-year-old woman had postoperative hypoparathyroidism after subtotal bilateral thyroid resection for multinodular goitre. To relieve symptoms the hypocalcaemia was treated with intravenous calcium (8 g and 4 g calcium per day, respectively) and high-dose oral vitamin D. Intact parathyroid hormone was not detectable in the serum of the two patients. Parathyroid allotransplantation was considered because both patients suffered from tetany, bone pain, depression, and impaired vision. Previous studies showed that MHC class I and II antigens are expressed on parathyroid tissue and their concentrations might determine graft outcome. Reduction of MHC expression can be achieved by depletion of immunogenic MHC-bearing cells with magnetic microspheres or tissueculture passages. The combination of microencapsulation and tissue-culture passage provides the key for successful isotransplantation, allotransplantation, and xenotransplantation of parathyroids as shown in long-term animal studies. The donor for both patients was an ABO compatible, HLA-mismatched patient with parathyroid hyperplasia due to secondary hyperparathyroidism. After parathyroidectomy, the tissue was cut into pieces of 1 mm. These particles were immersed in amitogenic degassed 2% sodium-alginate. The alginate was configured to allow nutritive substances as well as parathyroid hormone to pass through the membrane, while excluding immunogens and mediators of the cellular immune response. The suspension was passed through a spray nozzle (inner diameter 2 mm) for encapsulation with a constant flow of 6·5 L/min. The resulting spheres (microcapsules) were hardened by a 7-min incubation in 10 mmol/L barium chloride. Following multiple washes, microcapsules were cultured (RPMI 1640 with glutamine, 10 000 μg/mL streptomycin and penicillin, 10% fetal calf serum, and 2·4 mmol calcium chloride) for 2 days. 20 microcapsules were then transplanted into the brachioradial muscle of the non-dominant forearm. The study protocol was approved by the ethics committee of the Philipps-University of Marburg and written informed consent was given by both patients. The serum concentrations of total calcium and intact parathyroid hormone (iPTH) in one of the patients before and after allotransplantation are presented in the figure. The serum values of calcium and iPTH of the other case showed similar increases. For both patients calcium and vitamin D replacement therapy was reduced by half daily, beginning the first day after allotransplantation. They were discharged from the hospital without any hypocalcaemic symptoms and with no immunosuppressive therapy. The oral calcium and vitamin D replacement therapy was 0·6 g and 0·25 μg daily, in both patients, respectively. The combination of tissue-culture passage and microencapsulation could make parathyroid allotransplantation a practical option for successful treatment completely (table). No side effects were observed. Palpation showed softening of sclerotic lesions. Histopathological analysis of skin biopsy specimens taken 18 h after the last UVA-1 irradiation of this treatment course revealed dermal collagen with a thickness close to that of normal skin. ISH was done on formalin-fixed and paraffin-embedded tissue specimens with human interstitial collagenase-specific mRNA transcript. The probe sequence (5'dGGA AGC CAA AGG AGC TGT AGA TGT CCT-3') was unique when compared with all primate nucleic-acid sequences registered in the Entrez database. For IHC a monoclonal mouse serum (antibody 41-IE5, Oncogene Research Products, Cambridge, MA, USA) specific for human MMP-1 protein was used and immunohistochemically labelled. Both assays produced colorimetric reactions of variable intensity (table). In pretreatment specimens, a specific colorimetric signal was either absent (–) or weak (+) in fibroblastic cells. After UVA-1 treatment, an increase of interstitial collagenase m-RNA and protein expression was detected separately in most dermal fibroblastic cells. Here, a moderate (++) to strong (+++) signal was identified either by ISH, IHC, or both in all tissue specimens. In two of the lesions, signal intensity was greatest in fibroblasts of the upper papillary dermis. In both assays, UVA-1 phototherapy induced an increased signal for interstitial collagenase, weaker than that seen in fibroblasts, mainly in the upper layer of keratinocytes, melanocytes, and endothelial cells. Our results show that UVA-1 irradiation indeed induces expression of interstitial collagenase in fibroblasts of sclerotic morphea plaques. Together with the clinical and histological improvement of skin lesions, this is evidence that UVA-1 phototherapy acts by induction of interstitial collagenase in the clearance of morphea. In other studies, UVA-1 phototherapy has been shown to induce a variety of cytokines and soluble factors thereby causing profound immunomodulation. Our results also suggest that UVA-1 irradiation may also be of therapeutic benefit in other conditions characterised by excessive collagen production including keloid scars and a variety of rheumatological diseases.

Effects of high-dose oral vitamin A on diarrheal episodes among children with persistent diarrhea in a northeast Brazilian community.

The mean +/- SEM duration of diarrheal episodes decreased from 7.1 +/- 2.2 days to 4.3 +/- 0.9 days (P < 0.05) while the incidence of diarrheal episodes remained steady (2.2 +/- 0.3 versus 2.4 +/- 0.5 episodes; P = not significant) between two three-month periods before and after the oral administration of a single large age-adjusted dose of vitamin A among children at historical risk for persistent diarrhea in an impoverished Brazilian community.

The role of vitamin A in child growth, development and survival.

Vitamin A is essential for growth, development and survival. For children in deprived settings an adequate vitamin A status may be more critical to survival protection than to growth and development. During infancy breast milk from malnourished mothers is protective against the development of xerophthalmia; it needs to be complemented after six months by other dietary sources of vitamin A to provide full health protection. Correcting the low vitamin A content of breast milk from malnourished mothers within the first four weeks of delivery by a high dose oral vitamin A supplement can be an effective short-term preventive strategy while efforts are made to improve the dietary intake for the long-term solution.

Routine High-dose Vitamin A Therapy for Children Hospitalized with Measles

Measles is without specific therapy and remains important globally as a cause of childhood death. In controlled studies, high-dose vitamin A therapy (Hi-VAT)--with 400,000 IU vitamin A--has been demonstrated to markedly reduce measles-associated morbidity and mortality. We performed a retrospective study of the hospital records of 1720 children < 15 years of age who were hospitalized for measles, to determine the extent to which these findings, in research settings, are applicable to the case management of measles under conditions of routine hospital practice. The outcomes were studied of children hospitalized during two non-consecutive 2 year periods (1985-6 and 1989-90). A policy of Hi-VAT for all children hospitalized with measles was started during the intervening period. As compared with the group of children on standard therapy (n = 1061), children receiving Hi-VAT (n = 651) had a shorter hospital stay (mean 10 versus 13 days; P < 0.001), a lower requirement for intensive care (4.3 versus 10.5 per cent; P < 0.001), and a lower death rate (1.6 versus 5 per cent; P < 0.001). No adverse effects of Hi-VAT therapy were observed. We conclude that a policy of high dose oral vitamin A (400,000 IU) supplementation in measles provides benefits which are equivalent to those previously observed only in controlled research trials, that it is highly cost effective, and that it should form part of the routine case management of all children hospitalized with measles.

Quantitative plasma disposition of retinol and retinyl esters after high-dose oral vitamin A administration in the cynomolgus monkey

A solid-phase extraction technique followed by automated high-performance liquid chromatography sample elution was successfully used to evaluate the effect of three pharmaceutical parameters on the plasma profile of various forms of vitamin A after an oral dose to cynomolgus monkeys. The three parameters evaluated were the chemical form of vitamin A (retinol versus retinyl acetate), the vehicle (acetone/Tween 20/water versus acetone/soybean oil), and the retinol dose (2, 10, and 50 × 10 3 retinol equivalents/kg). The form of the administered compound, retinol or retinyl acetate, appeared to have no major effect on the formation of nonpolar retinoids. The ester profile in plasma differed depending on whether the dose was administered in the water-based or the oil-based vehicle. Irrespective of the vehicle type the predominant retinoid formed was retinyl palmitate/oleate. However, retinol doses in the water-based vehicle formed relatively high concentrations of retinyl laurate and retinyl myristate but no retinyl linolenate. The retinol dose in the oil-based vehicle formed consistent, but relatively minor, concentrations of retinyl linolenate, higher relative concentrations of retinyl linoleate, and no retinyl laurate or myristate. The dose of retinol administered had an impact on the diversity of the nonpolar retinoid profile. The low dose led to the presence of almost exclusively retinyl palmitate/oleate and retinyl stearate, whereas at higher doses the other retinyl esters became major retinol constituents. These findings are consistent with the hypothesis that, at low doses, the principle esterification pathway is via lecithin:retinol acyltransferase (LRAT) which produces retinyl palmitate, but at higher doses acyl-CoA:retinol acyltransferase is a prominent esterification enzyme, due to the saturation of the LRAT pathway, producing a more diverse profile of retinyl esters.

Quantitative Plasma Disposition of Retinol and Retinyl Esters after High-Dose Oral Vitamin A Administration in the Cynomolgus Monkey

A solid-phase extraction technique followed by automated high-performance liquid chromatography sample elution was successfully used to evaluate the effect of three pharmaceutical parameters on the plasma profile of various forms of vitamin A after an oral dose to cynomolgus monkeys. The three parameters evaluated were the chemical form of vitamin A (retinol versus retinyl acetate), the vehicle (acetone/Tween 20/water versus acetone/soybean oil), and the retinol dose (2, 10, and 50 × 103 retinol equivalents/kg). The form of the administered compound, retinol or retinyl acetate, appeared to have no major effect on the formation of nonpolar retinoids. The ester profile in plasma differed depending on whether the dose was administered in the water-based or the oil-based vehicle. Irrespective of the vehicle type the predominant retinoid formed was retinyl palmitate/ oleate. However, retinol doses in the water-based vehicle formed relatively high concentrations of retinyl laurate and retinyl my-ristate but no retinyl linolenate. The retinol dose in the oil-based vehicle formed consistent, but relatively minor, concentrations of retinyl linolenate, higher relative concentrations of retinyl linoleate, and no retinyl laurate or myristate. The dose of retinol administered had an impact on the diversity of the nonpolar retinoid profile. The low dose led to the presence of almost exclusively retinyl palmitate/oleate and retinyl stearate, whereas at higher doses the other retinyl esters became major retinol constituents. These findings are consistent with the hypothesis that, at low doses, the principle esterification pathway is via lecithin:retinol acyltransferase (LRAT) which produces retinyl palmitate, but at higher doses acyl-CoA:retinol acyltransferase is a prominent esterification enzyme, due to the saturation of the LRAT pathway, producing a more diverse profile of retinyl esters.

Reduced chronic hemolysis during high-dose vitamin E administration in Mediterranean-type glucose-6-phosphate dehydrogenase deficiency.

The observation that high-dose oral vitamin E supplementation (800 IU per day) improved red-cell survival in two rare disorders associated with increased red-cell susceptibility to oxidative stress prompted a similar trial in 23 patients with Mediterranean glucose-6-phosphate dehydrogenase (G6PD) deficiency. Three months of vitamin E administration resulted in decreased chronic hemolysis as evidenced by improved red-cell life span (P less than 0.025), with an improvement in red-cell half-life from 22.9 +/- 0.7 days to 25.1 +/- 0.6 days (mean +/- S.E.M.), increased hemoglobin concentration (P less than 0.001), and decreased reticulocytosis (P less than 0.001) as compared with base-line values. Evaluation after one year of vitamin E administration demonstrated sustained improvement in all these indexes. Controlled clinical trials of vitamin E supplementation may be warranted to examine its efficacy in ameliorating acute hemolytic crises or in reducing morbidity from neonatal jaundice in this relatively common genetic disorder.