F. Andreasen

Pharmacokinetics of amiodarone after intravenous and oral administration.

SummarySeven patients with cardiac arrhythmias were given amiodarone 400 mg intravenously over 2 min, and 2–4 days later the same dose was given orally. The serum concentration of amiodarone was determined by HPLC; the sensitivity of the analysis was 0.1 µg/ml. The time sequence of the measurements of drug concentration made conventional compartemental analysis impossible. There was large individual variation but some of the curves suggested enterohepatic circulation. The time from oral intake to the peak serum concentration was estimated to be 7.3±2.9 h (SD). The “amount of drug reaching the general circulation in 24 h after oral intake” averaged 42% (22–80%). After oral administration of amiodarone 200 mg 8 hourly the serum concentration before the morning dose averaged 0.61 µg/ml after 24 h, 0.76 after 48 h, 1.18 after 1 week and 1.56 µg/ml after 1 month. In one patient, who had been on amiodarone therapy for 8 months, the drug was discontinued and the serum concentration was followed over the next 3 months. The drug elimination curve suggested an elimination half life of 13.7 days. Because of instability in physiological saline protein binding could not be precisely quantitated, but only characterized as strong. No unchanged amiodarone was found in urine. The urinary excretion of iodine over 2 h after intravenous administration suggested that 5% of orally administered amiodarone was eliminated in the urine after biotransformation. No effect of the drug was observed during the first 10 days of treatment. In 2 patients with supraventricular arrhythmia, an excellent response was seen, and in one with ventricular arrhythmia there was a good response.

Effects of Simvastatin on Bone Turnover and BMD: A 1-Year Randomized Controlled Trial in Postmenopausal Osteopenic Women†

To study effects of statins on human bone, 82 postmenopausal women were randomized to 1‐year treatment with simvastatin 40 mg/day or placebo. The study showed no effect of simvastatin on biochemical bone markers or on BMD at the hip or spine. Thus, our results do not support a general beneficial effect of simvastatin on bone.

Loop Diuretics Increase Bone Turnover and Decrease BMD in Osteopenic Postmenopausal Women: Results From a Randomized Controlled Study With Bumetanide†

To study effects of loop diuretics on bone, 87 women were randomized to 1 year of treatment with bumetanide or placebo. Compared with placebo, bumetanide decreased BMD by 2% at the total hip and by 1.4% at the whole body. Levels of biochemical bone markers were lower in the placebo than in the bumetanide group. Thus, treatment with loop diuretics affects bone metabolism.

Role of Extracellular and Intracellular Acidosis for Hypercapnia-Induced Inhibition of Tension of Isolated Rat Cerebral Arteries

The importance of smooth muscle cell pHi and pHo for the hypercapnic vasodilation of rat cerebral arteries was evaluated in vitro. Vessel segments were mounted in a myograph for isometric tension recording; pHi was measured by loading the smooth muscle cells with the fluorescent dye BCECF, and pHo was measured with a glass electrode. In all studies, Ca(2+)-dependent basal tension (in the absence of any agonist) and tension in the presence of arginine vasopressin were investigated. Control solution was physiological saline bubbled with 5% CO2 and containing 25 mmol/L HCO3- (pH 7.45 to 7.50). Induction of hypercapnic acidosis (10% CO2) or normocapnic acidosis (15 mmol/L HCO3-) caused significant inhibition of smooth muscle tension, and both conditions reduced pHi as well as pHo. N-Nitro-L-arginine significantly inhibited the relaxation to hypercapnic acidosis but had no significant effect on relaxation to normocapnic acidosis. Predominant extracellular acidosis, induced by reducing [HCO3-] from 25 to 9 mmol/L and CO2 from 5% to 2.5%, also caused inhibition of tension in steady state. By contrast, predominant intracellular acidosis, induced by increasing [HCO3-] from 25 to 65 mmol/L and CO2 from 5% to 15%, induced a small increase of basal tension and a small decrease of tension in the presence of arginine vasopressin. The responses to predominant intracellular or extracellular acidosis were qualitatively similar in the presence and absence of endothelium and in the presence and absence of N-nitro-L-arginine. It is concluded that the extracellular acidosis and not smooth muscle intracellular acidosis is responsible for the relaxation to hypercapnic acidosis.

Statins decrease bone turnover in postmenopausal women: a cross-sectional study.

Background Statins have been suggested as potential agents in the management of osteoporosis. Reviews of medical records have shown an increased bone mass and some studies have shown a reduced occurrence of fractures in subjects on long‐term treatment with statins. We studied the effects of treatment with statins on calcium homeostasis, bone turnover and bone mineral density.

Effects of thiazide‐ and loop‐diuretics, alone or in combination, on calcitropic hormones and biochemical bone markers: a randomized controlled study

Abstract. Rejnmark L, Vestergaard P, Heickendorff L, Andreasen F, Mosekilde L (Aarhus University, Aarhus, Denmark). Effects of thiazide‐ and loop‐diuretics, alone or in combination, on calcitropic hormones and biochemical bone markers: a randomized controlled study (Original study). J Intern Med 2001; 250: 144–153.

Dose‐effect relations of loop‐ and thiazide‐diuretics on calcium homeostasis: a randomized, double‐blinded Latin‐square multiple cross‐over study in postmenopausal osteopenic women

Background Thiazide diuretics (TDs) reduce whereas loop diuretics (LDs) increase urinary calcium. We studied the effects of different doses of a TD and LD on electrolytes, calcitropic hormones and biochemical bone markers.

Individual Variation in Response to Thiopental

The anaesthetic records of 540 patients operated on during a 3‐week period were studied. The purpose was to elucidate the influence of age, sex, concentration of haemoglobin, creatinine concentration in serum, heart disease, and the premedication given on the size of the induction dose of thiopental. A statistically significant fall in dose with advancing age was seen after the age of 60 and the significance increased when a weight‐related dose was used for the calculations. A 6% difference, indicating a lower induction dose in women, was not statistically significant. When premedication with scopolamine and morphine had been used, significantly less thiopental was needed to induce anaesthesia than after atropine, diazepam and pethidine. When both sexes were considered, no correlation was found between haemoglobin concentration and induction dose of thiopental, but in two groups of women, weak negative correlations between these two variables were found. Thirty‐seven patients on long‐term treatment with digoxin and a diuretic required significantly less thiopental than 37 patients, otherwise comparable, not receiving this medication. About 60% of the dose used in 21 patients who were to have operations on their limbs was needed in 21 patients who were to be operated for valvular heart disease. Eleven patients with moderately elevated serum creatinine (average 2.1±1.0 mg/100 ml) required 11% (not statistically significant) less than 11 patients with normal serum creatinine (1.1±0.2 mg/100 ml). A considerable individual variation still exists for patients who are comparable with respect to all factors known to influence sensitivity to thiopental.

Effects of long‐term treatment with loop diuretics on bone mineral density, calcitropic hormones and bone turnover

Background.  Loop diuretics (LD) are widely used in the treatment of cardiovascular diseases and disorders with fluid accumulation. LD are known to increase renal calcium losses and may thereby affect calcium homeostasis and bone metabolism.

AMIODARONE INDUCED CORNEA VERTICILLATA

Among 30 patients (17 men, 46–76 years and 13 women, 15–70 years), treated with the antiarrhythmic drug amiodarone, 21 patients (11 men and 10 women) developed bilateral cornea verticillata. Total doses up to 494 g had been given and the duration of therapy was up to 113 weeks. In 14 patients samples of 50 μl tear fluid were analyzed for aminodarone. No amiodarone was present in the tears at low serum concentrations but a rapid increase in tear concentrations was seen at serum values above 1.2 μg/ml (P < 0.001). The grade of cornea verticillata was significantly correlated to total dose as well as to duration of treatment (P ≦ 0.001). On the day of examination at the eye clinic there was no significant correlation between se‐amiodarone, tear‐amiodarone concentration and the grade of cornea verticillata. One patient complained of coloured haloes. None had decreased visual acuity, fundus changes, cataract, exophthalmus, increased intraocular pressure, abnormal colour vision, or abnormal central corneal thickness, which could be attributed to the treatment of amiodarone.