Calcitonin dosing

FIGURE 2.2 Binding and dose-response curves for human calcitonin on human calcitonin receptors type 2. (a) Dose-response curves for microphysiometry responses to human calcitonin in HEK cells (open circles) and binding in membranes from HEK cells (displacement of [,25I]-human calcitonin). Data from [1]. (b) Regression of microphysiometry responses to human calcitonin (ordinates) upon human calcitonin fractional receptor occupancy (abscissae). Dotted line shows a direct correlation between receptor occupancy and cellular response. 

FIGURE 5.4 Microphysiometry responses of HEK 293 cells transfected with human calcitonin receptor, (a) Use of microphysiometry to detect receptor expression. Before transfection with human calcitonin receptor cDNA, HEK cells do not respond to human calcitonin. After transfection, calcitonin produces a metabolic response, thereby indicating successful membrane expression of receptors, (b) Cumulative concentration-response curve to human calcitonin shown in real time. Calcitonin added at the arrows in concentrations of 0.01, 0.1, 1.10, and lOOnM. Dose-response curve for the effects seen in panel B. 

FIGURE 5.6 Calcitonin receptor responses, (a) Real-time melanin dispersion (reduced light transmittance) caused by agonist activation (with human calcitonin) of transfected human calcitonin receptors type II in melanophores. Responses to 0.1 nM (filled circles) and lOnM (open circles) human calcitonin, (c) Dose-response curves to calcitonin in melanophores (open circles) and HEK 293 cells, indicating calcium transient responses (filled circles). 

Calcitonin 4-8 lU/kg SQ or IM q6-12 hours 2-4 hours 1-3 days 2-3 mg/dL Salmon-derived formulation preferred 1-unit test dose recommended can be given in renal failure may cause flushing, nausea. 

The answer is c. (Hardman, p 15230 Administration of intravenous CaG would immediately correct the tetany that might occur in a patient in whom a thyroidectomy was recently performed. Parathyroid hormone would act more slowly but could be given for its future stabilizing effect. Long-term control of a patient after a thyroidectomy can be obtained with vitamin D and dietary therapy Calcitonin is a hypocalcemic antagonist of parathyroid hormone. Plicamycin (mithramycin) is used to treat Paget s disease and hypercalcemia. The dose employed is about one-tenth the amount used for plicamycin s cytotoxic action. 

The benzyl ester of hyaluronic acid (HYAFF 11) is a highly mucoadhesive polymer which can be processed into microspheres. Such microspheres containing salmon calcitonin were intravaginally administered to rats as a dosage form for the prevention of ovariectomy osteopenia [65]. In recent studies, HYAFF 11-salmon calcitonin microspheres were formulated as single-dose pessaries, resulting in sustained plasma concentrations of calcitonin [67]. 

Calcitonin gene-related peptide (CGRP) induces a dose-related increase in penile arterial inflow, cavernous smooth muscle relaxation, cavernous outflow occlusion, and an erectile response. CGRP plus PGEj may be an alternative to penile implants in selected patients. 

With the exception of the possible development of a hypervitaminosis associated with high-dose administration of vitamin D2 or D3, the compounds discussed in this chapter are relatively safe. Allergic reactions to the injection of calcitonin and PTH have occurred and chronic use of some bisphosphonates has been associated with the development of osteomalacia. The principal side effects of intravenous bisphosphonates are mild and include low-grade fever and transient increases in serum creatinine and phosphate levels. Oral bisphosphonates are poorly absorbed and can cause esophageal and gastric ulceration. They should be taken on an empty stomach the individual must remain upright for 30 minutes after ingestion. 

Nasal absorption. Sucrose ester of coconut fatty acid in aqueous ethanol solution (sucrose cocoate SL-40) administered intrana-sally to anesthetized male Sprague-Dawley rats at a dose of 0.5% sucrose cocoate with insulin, produced a rapid and significant increase in plasma insulin level with a concomitant decrease in blood glucose levels. Administration of a dose of 0.5% sucrose cocoate with calcitonin produced a rapid increase in plasma calcitonin levels and a concomitant decrease in plasma calcium levels . 

Calcitonin has proved useful as ancillary treatment in a large number of patients. Calcitonin by itself seldom restores serum calcium to normal, and refractoriness frequently develops. However, its lack of toxicity permits frequent administration at high doses (200 MRC units or more). An effect on serum calcium is observed within 4-6 hours and lasts for 6-10 hours. Calcimar (salmon calcitonin) is available for parenteral and nasal administration. 

The goal of treatment is to reduce bone pain and stabilize or prevent other problems such as progressive deformity, hearing loss, high-output cardiac failure, and immobilization hypercalcemia. Calcitonin and bisphosphonates are the first-line agents for this disease. Treatment failures may respond to plicamycin. Calcitonin is administered subcutaneously or intramuscularly in doses of 50-100 MRC (Medical Research Council) units every day or every other day. Nasal inhalation at 200-400 units per day is also effective. Higher or more frequent doses have been advocated when this initial regimen is ineffective. Improvement in bone pain and reduction in serum alkaline phosphatase and urine hydroxyproline levels require weeks to months. Often a patient who responds well initially loses the response to calcitonin. This refractoriness is not correlated with the development of antibodies. 

The changes in calvarial phosphatase activities observed in animals treated with 25-(OH)D3 are totally different from those obtained with either 1.25-(OH)2D3 or 24.25—(OH)2D3. This fact indicates that physiological doses of 25-(OH)D3 may have an effect on cellular activity, independent of the conversion of this metabolite into these dihydroxyderivatives. The various effects of these vitamin D3 metabolites cannot be correlated with changes in serum calcium and/or phosphate concentrations. Among those factors other than serum calcium and phosphate concentrations that may be involved in the mechanism of action of vitamin D3 metabolites on bone phosphatase activities, the parathyroid hormone is of importance. This hormone is known to be a potent activator of bone phosphatases223,224,228. Parathormone increases the content of alkaline, neutral and acid phosphatases in mouse calvaria in vitro. Calcitonin does not prevent the increase of those enzymes while dichloromethylene diphosphonate causes a decrease in acid phosphatase and pyrophosphatase226. ... 

Nausea is common with calcitonin, and vomiting or diarrhea occur more rarely. These symptoms usually settle without treatment if the drug is continued and may also be reduced by giving the dose at bedtime. 

Kaskani E, Lyritis GP, Kosmidis C, et al. Effect of intermittent administration of 200 IU intranasal salmon calcitonin and low doses of 1 alpha(OH) vitamin D3 on bone mineral density of the lumbar spine and hip region and biochemical bone markers in women with postmenopausal osteoporosis a pilot study. Clin Rheumatol. 2005 24 232-238. 

Other Systemic Effects. Other systemic effects have been observed. Barium sulfate was observed to act as an appendocolith in two cases following barium enema procedures (Palder and Dalessandri 1988). This is a rare occurrence and probably not significant in cases of human barium toxicity. Intravenous injection of barium sulfate into pigs increased calcitonin secretion from the thyroid (Pento 1979). This is probably not a significant effect for humans since intravenous exposure is not a common route and the dose required was so high (1.7 mg/kg/minute for 20 minutes) it caused cardiotoxicity. 

Carrier proteins should be incorporated in calcitonin formulations for intravenous infusions, since this protein may be adsorbed to administration sets. Care must be exercised for dose adjustment when mixing with cardiac glycosides. 

---