Daily Dose Range Research Articles

Kinetic and clinical observations in cyanotic children on propranolol therapy.

The kinetics of propranolol and its metabolite 4-hydroxypropranolol were determined together with heart rate and blood pressure responses in five cyanotic children on long-term propranolol therapy and after abrupt withdrawal. The daily dose range of propranolol was 2.4 to 4.4 mg/kg. Mean steady-state plasma propranolol concentrations, 16.5 to 114 ng/ml, were linearly related to dose (r = 0.93; p < 0.02) above a threshold dose of 1.8 mg/kg/day. There was excellent correlation (r = 0.96; p = 0.01) between concentrations and reduction in heart rate (delta HR, 14 to 27.5 beats/min), which also suggested a maximum heart rate response at plasma propranolol concentrations of 80 to 100 ng/ml. There was an inverse relationship between the plasma concentrations of 4-hydroxypropranolol and dose. On abrupt withdrawal of long-term propranolol therapy, plasma levels declined with a propranolol half-life (t1/2) of 3.9 to 6.4 hr, which correlated with the hemoglobin value. The 4-hydroxypropranolol t1/2 was 5.2 to 7.5 hr. Heart rates returned to normal after approximately 36 hr. Changes in blood pressure were minimal.

Effects in Vivo of Vitamin D Metabolites and 17βEstradiol on Parathyroid Hormone-Dependent Formation of Adenosine 3′,5′-Monophosphate in Rat Bone*

We used an in vivo infusion technique to assess the hypothesis that vitamin D metabolites and estrogens modulate tissue responsiveness to parathyroid hormone via effects on the adenylate cyclase-cAMP system. After treatment with these agents for 3-4 days, rats were thyroparathyroidectomized. Twenty-four hours later, parathyroid extract (PTE) was infused, and cAMP in calvaria was measured. The response to PTE was achieved by 2 min and represented a 4-fold increase in the tissue concentration of cAMP at the highest dose of hormone tested. Treatment with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], did not affect cAMP levels in bone. However, 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3], either 0.25 or 1.25 micrograms daily, led to a major increase in PTE-stimulated cAMP formation, a result which persisted when carried out in chronically thyroparathyroidectomized animals. This effect did not reflect direct stimulation of adenylate cyclase or inhibition of cyclic nucleotide phosphodiesterase from bone by the vitamin metabolite, nor did it operate via the 1,25-(OH)2D3 receptor. 24,25-(OH)2D3 treatment also increased cAMP concentrations in renal cortical slices, but not in liver. Adenylate cyclase activity in kidneys from 24,25-(OH)2D3-treated rats was not different from that found in control tissue, but total cytosol phosphodiesterase activity was diminished. 17 beta-Estradiol, over a daily dose range of 2.5 micrograms to 5.0 mg, lowered basal cAMP levels but did not alter PTE-stimulated cAMP production. We conclude that modulation of PTH action in bone by estrogen does not involve modification of the acute cAMP response to PTH. Further, the results support the concept that there are unique actions of 24,25-(OH)2D3 on bone and kidney which are not duplicated by 1,25(OH)2D3.

Elimination of oral cimetidine in chronic renal failure and during haemodialysis.

1 The absorption and elimination of a single oral dose of 400 mg cimetidine was studied in fourteen fasting patients with impaired renal function. In addition, the dialysance of cimetidine was studied in five patients on haemodialysis. 2 The absorption was somewhat, but clinically insignificantly delayed. A second unexplained peak in the absorption curve was found. 3 First order elimination kinetics were confirmed and the length of time of a cimetidine concentration over 0.5 mg/l could be correlated with creatinine clearance. 4 The magnitude of extra renal elimination was estimated to be approximately one fourth of total cimetidine elimination in normal patients and seemed unaffected by impaired renal function. 5 A dose schedule based on AUC found in the patients in renal failure is suggested. The recommendations for daily oral dose range from 300 mg (at borderline dialysis) to 1000 mg in mild renal failure. The suggested doses will give an average plasma concentration of the same order as seen in patients with normal renal function.

Study of serum digoxin status in digitoxicity by radioimmunoassay

Forty-seven patients who were being treated with digoxin in a daily dose range of 0.25 mg. to 0.75 mg. were the study material. Thirty-two patients were toxic. Seven patients out of these 32 were in an under-digitalized state and 15 patients were nontoxic. All patients were clinically assessed and investigated for routine hematological value, serum protein, electrolytes, serum creatinine, blood urea, and serum calcium. Serum digoxin concentration was estimated in all cases by the radioimmunoassay method. The assay was repeated after the patients recovered from toxic manifestations on withdrawal of the digoxin. The mean serum digoxin level in toxic patients (2.64 ± 0.68 ng./ml.) was significantly higher (P < 0.001) than that in nontoxic patients (1.35 ± 0.45 ng./ml.). After recovery from toxicity, the mean serum digoxin level (1.43 ± 0.32 ng./ml.) was found to be significantly lower than the level in the toxic patients and was similar to the level in patients of the nontoxic group. Seven patients whose symptoms simulated digitoxicity were in fact in an under-digitalized state (0.74 ± 0.35 ng./ml.), and their symptoms were relieved with a higher dosage of digoxin. In this study an attempt has been made to show the importance of the estimation of serum digoxin in the assessment of therapeutic and toxic effects of the drug so as to modify the dosage schedule for the optimal therapeutic response.

Dopaminergic agonist nomifensine compared with amitriptyline: a double‐ blind clinical trial in acute primary depressions.

1. Nomifensine (8-amino-2-methyl-4-phenyl-1,2,3,4,-tetrahydroisoquinoline) is a new antidepressant which displays an interesting pharmacological profile and acts as a potent dopaminergic agonist. 2. In a double-blind clinical trialnomifensine was compared with a standard and widely tested antidepressant amitriptyline. A total of 24 patients with primary acute depressions, defined by research criteria, were treated for 8 weeks and their clinical condition and laboratory values monitored at regular intervals. The dosage schedule was a flexible one, with a daily dose range from 50-200 mg for nomifensine and 50-225 mg for amitriptyline. 3. Nomifensine and amitriptyline were found to be equivalent in their antidepressant efficacy. Nomifensine, however, showed a trend towards more rapid effect and was relatively free of side-effects. 4. As nomifensine combined antidepressant activity with low frequency of adverse effects, it would seem to be suitable for wider use in the treatment of primary depressions. The results of our study have to be generalized with caution because of the limited sample size.

Letters to the Editor

You are quite correct; the dose of dextroamphetamine was not included in the paper.1 The daily dose range for dextroamphetamine was 5 to 40 mg. The average daily dose was 12.4 mg. Fifty-four percent of the children received this medication during the summer, and 10% received the medication three times daily. There was no significant relationship between the dose of dextroamphetamine and growth suppression, a finding presented in Table IV of the paper. We do not know if doses less than 5 mg daily are nonsuppressive of growth.