Skeletal deposition of clodronate is related to parathyroid function and bone turnover in dialysis patients.

AIMS: Bisphosphonates inhibit osteoclastic bone resorption, and in the future, they may also have a role in the therapy of renal osteodystrophy. Our aim was to study whether the severity of hyperparathyroidism has an effect on the clearance of clodronate via routes other than dialysis or kidneys (nonrenal, non-dialysis clearance, CL(NRD)), which most likely represents the deposition of the drug in the skeleton. METHODS: We studied 31 dialysis patients (9 female/22 male, aged 28 - 79, median 58 years), 18 on hemodialyis (HD) and 13 on peritoneal dialysis (PD). HD patients were studied on a non-dialysis day. An intravenous infusion of 300 mg clodronate was given during 60 min at 8:00 a.m. Blood, urine and PD fluid samples were collected for 1 + 24 h, and pharmacokinetic parameters were calculated. RESULTS: In PD patients, 7% of the infused drug was excreted into PD fluid within 24 h, and in those HD or PD patients with residual diuresis 11% was excreted via the kidneys. The highest CL(NRD) was seen in patients with the most severe hyperparathyroidism. There was a positive correlation between CL(NRD) and plasma intact PTH (r = 0.79, p < 0.001). CL(NRD) was also related to the serum levels of bone markers PINP (procollagen type I N-terminal propeptide, r = 0.81, p < 0.001), osteocalcin (r = 0.65, p < 0.001) and ICTP (type I collagen cross-linked telopeptide, r = 0.68, p < 0.001). However, even in the patients with normal PTH, more than one-third of the infused drug was taken up by bone. CONCLUSION: In dialysis patients, the skeletal deposition of clodronate is related to bone turnover being highest in severe hyperparathyroidism. However, even in the case of low turnover, the uptake of the drug in bone takes place in amounts that might be clinically significant.

Timing of food intake has a marked effect on the bioavailability of clodronate.

Because of the low and variable bioavailability of bisphosphonates and the huge effect of food on their gastrointestinal absorption, it is of utmost importance to know the optimal timing of drug intake in relation to food intake. We investigated the effect of time on the bioavailability of clodronate when the drug was administered 2, 1, or 0.5 h before breakfast, with breakfast, or 2 h after breakfast (in the middle of a 4-h fast). The study was conducted as a single-center, open, balanced, randomized, crossover pharmacokinetic study in 31 healthy subjects aged 21 to 34 years. The volunteers participated in five different sessions with 800 mg of oral clodronate, and these sessions were separated by washout phases, each for at least 1 week. The primary pharmacokinetic variables were the area under the serum concentration time curve in 24 h (AUC(0-24)) for clodronate and the maximal concentration of clodronate in serum (C(max)). Clodronate was absorbed rather similarly when taken in the morning on an empty stomach 2, 1, or 0.5 h before breakfast, but because the best absorption occurred (as expected) when the drug was taken 2 h before breakfast, this scheme served as the reference treatment. As evaluated by area under the serum concentration time curves, the dose-breakfast interval of 1 h scarcely reduced absorption from the reference treatment level (relative absorption 91%, p = 1.0). Compared with the reference treatment, clodronate was absorbed with 69% efficacy (p = 0.65) when breakfast followed only 0.5 h later. The dose-breakfast intervals of 0.5 and 1 h did not differ significantly from each other (p = 0.85). Absorption was, however, only 34% (p < 0.0001) of the optimum when the drug was taken 2 h after breakfast, and only 10% of optimal when clodronate was taken with breakfast (p < 0.0001). In conclusion, it can be recommended to take Bonefos capsules in the morning on an empty stomach at least 0.5 h before breakfast.

Comparative molecular field analysis of some clodronic acid esters.

Comparative molecular field analysis (CoMFA) has been used as a three-dimensional quantitative structure-activity relationship (QSAR) method to correlate three different types of biological activity data with physicochemical properties of some clodronate ester analogues, which act as bone-resorption regulators in cell cultures and rats. The QSAR studies show the importance of the steric properties of these new bisphosphonate derivatives for the inhibition of bone resorption in bone cell cultures and for their bioavailability in rats. This information will be used in predicting the structure of new more potent bisphosphonic compounds.

The steady-state pharmacokinetics of tamoxifen and its metabolites in breast cancer patients.

The steady-state pharmacokinetics of tamoxifen and its metabolites was studied in sixteen patients with advanced mammary cancer. Patients were randomized to receive tamoxifen given as Tamofen, Leiras, or as Nolvadex, ICI, 20 mg twice daily for 16 weeks in a cross-over study. Plasma and urine samples were analyzed during one dose interval (12 h) after treatment for 8 and 16 weeks. The concentrations of tamoxifen, N-desmethyltamoxifen, N,N-desdimethyltamoxifen, and metabolite Y were determined in plasma and the areas under the plasma level curves were calculated. 4-Hydroxytamoxifen was not found in plasma. In urine samples only tamoxifen and N-desmethyltamoxifen were above the detection limits even though metabolite Y was also analyzed after acid hydrolysis. There were no statistically significant differences in the concentrations of tamoxifen and its metabolites between the two preparations. The results of nonresponders did not differ from those of responders. Liver metastases had no effect on the metabolism of tamoxifen.

Serum salbutamol concentrations during oral and intravenous treatment in pregnant women.

The serum concentration of salbutamol was determined in 29 pregnant women during oral treatment (4 mg five times per day) and in seven during intravenous infusion (6-30 micrograms/min) because of premature labour. The concentration of salbutamol was determined by combined gas-liquid chromatography mass spectrometry. The mean concentration of serum salbutamol was twice as high during intravenous treatment (24; SD 9 ng/ml), than during oral treatment (12; SD 3 mg/ml). During oral treatment, the salbutamol levels were not correlated to maternal height, weight or the incidence or severity of side-effects. The serum concentrations of salbutamol in patients with twin pregnancies did not differ from those with singleton pregnancies. After stopping intravenous treatment, serum salbutamol levels remained high for several hours and oral treatment can be started 4-6 h after stopping intravenous infusion.

Electrolyte intake and excretion and blood pressure in young students with and without family history of hypertension.

Blood pressure and sodium, potassium, calcium and magnesium intake and excretion were investigated in 2 groups of young students, 1 with and 1 without a family history of hypertension. No differences in systolic or diastolic blood pressure were found between the two groups. Mean potassium excretion of male offsprings of hypertensive parents was 26% higher (p less than 0.05) than the mean potassium excretion of male controls. Sodium-potassium ratio was lower (1.7) in male offsprings of hypertensive patients than in male controls (2.3). There were no significant differences in intake or excretion of other electrolytes between controls and offsprings of hypertensive parents.

Antimuscarinic activity of oxybutynin in the human plasma quantitated by a radioreceptor assay.

The antimuscarinic activity of oxybutynin was measured as oxybutynin equivalents by a radioreceptor assay (RRA). The activity was studied in plasma samples of five volunteers after a single oral dose (10 mg) or after a single intravenous dose (28 micrograms/kg) of oxybutynin hydrochloride. The results were compared to the concentrations of the drug measured by gas liquid chromatography (GLC). Following oral administration, the maximum concentration measured by RRA was significantly higher (706 nmol/l) than that by GLC (38 nmol/l). In contrast, equal concentrations were measured after intravenous administration by both methods. Metabolites with antimuscarinic activity are possibly formed through first-pass metabolism after orally administered oxybutynin. The total antimuscarinic activity of oxybutynin and its metabolites are measured by RRA, but only the parent drug by GLC.

Bioavailability of a combination preparation of trimethoprim and folic acid.

The bioavailability of folic acid and trimethoprim was investigated from a combination preparation of folic acid (0.25 mg) and trimethoprim (100 mg) in ten healthy adult volunteers. Peroral administration of the preparation resulted in a mean peak plasma concentration of trimethoprim 1.09 mg/l (SEM 0.06). The AUC values for trimethoprim were 12.42 mg.h/l and 12.77 mg.h/l corresponding to combination preparation and plain trimethoprim, p greater than 0.1. After administration 0.25 mg folic acid in the combination preparation, there was a significant rise in serum folic acid concentrations. The AUC from 0-8 hours was 199.8 nmol.h/l (SEM 8.1) and 166.3 nmol.h/l (SEM 14.2) corresponding to combination preparation and plain trimethoprim, p less than 0.001. A loading dose of folic acid 10 mg was given intramuscularly 24 hours before drug intake. This new type of formulation of trimethoprim and folic acid has been developed in order to prevent in long-term use the adverse haematological effects induced by trimethoprim alone.

Aminophylline in ureterolithiasis: preliminary report.

Aminophylline (3 mg/kg i.v.) was injected in six patients with colicky pain caused by a ureter stone. In all but one this theophylline derivative caused a prompt and subjectively clear decrease in pain lasting from 30 min to 2 h. Serum levels over 12 microgram/ml were associated with good pain relief. A controlled study with an intravenous aminophylline infusion is warranted, because the pain-decreasing effect was too short-lasting after a single injection.

Pharmacokinetics of dihydroergotamine in healthy volunteers and in neurological patients after a single intravenous injection.

The pharmacokinetics of dihydroergotamine (DHE) was studied in healthy volunteers (n = 6) and in neurological patients (n = 12). After a single 1.0 mg intravenous injection (n = 5) DHE quickly disappeared (T 1/2 beta = 32.9 min, Vdss = 0.33 liter/kg, Cltot = 1055.7 ml/min). In saliva (dose 1.0 mg, n =6) and cerebrospinal fluid (dose 0.5 mg, n =12) there were no measurable amounts of DHE after a single i.v. dose. The 32-h cumulative urinary excretion was 0.02-0.04% of the 1.0 mg intravenous dose. In one subject renal (0.18 ml/min) and extrarenal (692.9 ml/min) clearance of DHE was calculated. According to our results DHe is probably eliminated mainly by hepatic metabolism. The pharmacokinetic properties of DHE indicate a fast clinical response without a cumulative action.

Pharmacokinetics of labetalol in healthy volunteers.

The pharmacokinetics of labetalol, a combined alpha- and beta-receptor blocking agent, were studied in eight healthy volunteers. After intravenous injections (n = 4) of 1.5 mg/kg, the drug was rapidly distributed (mean T 1/2 = 4.9 min) and quite rapidly eliminated (mean T 1/2 = 4.9 hrs). The mean total plasma clearance value was 24.80 ml/min/kg. The values for Vdc (mean 1.1 l/kg) and Vdss (mean 9.41 l/kg) indicate extensive extravascular distribution of labetalol. The systemic availability was about 18%. There was a significant correlation between the calculated drug concentrations in the hypothetical compartment 2 and the percentage decreases in blood pressure after the intravenous injection. After a single 200 mg oral dose (solution, non-coated and coated tablets), the tablet formulation had no significant effect on the gastrointestinal absorption. After repeated oral doses of 200 mg twice daily (n = 4), no accumulation in plasma was observed.

The pharmacokinetics of dihydroergotamine in the beagle dog after a single intravenous injection and after a continuous intravenous infusion.

The pharmacokinetics of dihydroergotamine (DHE) was studied in 6 beagles after a single 2.0 mg intravenous dose and after a continuous intravenous infusion (dose 2.0 mg, infusion time 51 min.=2.8-3.5 micrograms/min./kg). The concentrations of DHE in the plasma during 6 hours were determined by a radioimmunoassay. The mean alpha-phase T1/2 was 0.92 min. and 5.93 min., the mean beta-phase T1/2 was 104.42 min. and 115.79 min., and the mean plasma clearance value 202.88 ml/min. and 234.79 ml/min. after a single intravenous injection a continuous infusion administration, respectively. Similarly, the Vdc - values were 0.121/kg and significantly from each other. The simulated concentrations of DHE in the peripheral compartment increased rapidly explaining its fast effect on the vasculature in clinical use.

Plasma and tissue concentrations of methylergometrine (methylergonovine) in the rabbit.

The concentrations of methylergometrine (M) (methylergonovine) in the plasma, uterus, liver, and kidneys of the rabbit were determined by a radioimmunoassay after a single 0.2 mg/kg intravenous injection and the drug response was studied in the uterus in situ. M disappeared quickly from the plasma with a mean distribution phase half-life of 0.91 min. According to the fast uterine tissue uptake of M the drug response in this effector organ began quickly. The stimulated concentrations in the peripheral compartment of the two-compartment open model can be useful in the understanding of the rapid drug effect, but they do not describe the real situation in any particular tissue.

The use of labetalol as a moderate hypotensive agent in otological operations--plasma concentrations after intravenous administration.

The usefulness of labetalol, a combined alpha and beta adrenoceptor antagonist, as a moderate hypotensive agent during combination anaesthesia in otological operations was studied. These preliminary results show that an intravenous dose of 2.0 mg/kg of body weight of labetalol causes a moderate decrease in blood pressure without a concomitant increase in heart rate or excessive hypotension. The half-life of the elimination phase of labetalol in plasma varied between 3.9 and 6.3 hours. A direct relationship between the intravenous dose of the drug (0.5, 1.0 and 2.0 mg/kg i.v.) and the increase in the AUC value was observed. No correlation was found between the decrease in either the systolic or diastolic blood pressure and the plasma level of labetalol. This new type of antagonist may possess advantages over other current hypotensive drugs, i.e lack of tachycardia and excessive hypotension.

Antihypertensive effect and plasma levels of labetalol. A comparison with propranolol and dihydrallazine.

Seventeen outpatients suffering from essential hypertension were treated in a double-blind cross-over study with labetalol or with a combination of propranolol and dihydrallazine. The doses were increased depending on the response during the six week treatment periods. Both treatments reduced the blood pressure significantly as compared to the placebo, and the combination more than labetalol with the doses used, apparently because of a higher degree of the beta-blockade. Positive linear correlations were found between the dose of labetalol and the concentration in plasma as well as the concentration of labetalol in plasma and the decrease of standing blood pressures.

Excretion of methylergometrine (methylergonovine) into the human breast milk.

Methylergometrine concentrations in the maternal plasma and breast milk were determined by a radioimmunoassay during continuous treatment with 0.125 mg of methylergometrine 3 times daily. On the fifth postpartum day at 8:00 a.m. the patients (n=8) took 2 tablets of Myomergin (0.250 mg of methylergometrine) orally, and the levels in the plasma and milk were determined at 1 and 8 hr after the drug administration. Measurable amounts of the drug were found only in 5 out of 16 milk samples. It was concluded that this oxytocic drug does not appear in the breast milk in quantities sufficient to affect the infant. No cumulation in the plasma or in the breast milk was found.

The effect of intravenously administered proxyphylline and Baralgin on the contraction of the human gallbladder.

In subsequent studies 300 mg of proxyphylline (Group 1) and 1 amp Baralgin (Group 2) were administered intravenously to 20 patients in order to study the relaxing effect of proxyphylline and Baralgin on the contracted gallbladder in connection with routine oral cholecystography. After the standard contraction meal (200 ml cream) the intravenously administered proxyphylline had no relaxing effect on the human gallbladder, whereas Baralgin caused a significant dilation. The dilation effect lasted throughout the whole study period (60 min). Proxyphylline concentrations in the serum, determined by gas-liquid chromatography, proved to be on the therapeutic level which is said to be effective in the treatment of obstructive pulmonary disease. Because with proxyphylline no dilation effect on the gallbladder was found, the clinical spasmolytic response to proxyphylline during an acute attack of pain in a patient suffering from gallstones seems to be questionable. Baralgin caused a significant dilation effect on the gallbladder, and it seems to be a useful agent in an acute gallstone attack.

Quantitative determination of ergot alkaloids in biological fluids by radioimmunoassay.

1 Cross-reactivity of ergot alkaloids with an antiserum produced against lysergic acid conjugated with human serum, albumin was utilized to develop a radioimmunoassay for ergotamine, dihydroergotamine, dihydroergotoxine, ergometrine and methylergometrine in biological fluids. The antisera showed no cross-reactivity with simpler indole structures. 2 A procedure for extraction and concentration of alkaloids in biological fluids was developed. 3 The assay is sensitive for 1.8 ng/ml ergotamine, 1.5 ng/ml dihydroergotamine, 2.2 ng/ml dihydroergotoxine, 0.7 ng/ml ergotmetrine and 0.5 ng/ml methylergometrine. 4 The assay is sufficiently sensitive to permit the measurement of urine and plasma ergot alkaloid levels and it is suitable for determination in cases where a known ergot alkaloid is used.

Methylergometrine: comparison of plasma concentrations and clinical response of two brands.

There were no significant differences between the two brands of methylergometrine (methylergonovine), Methergin and Myomergin, in the radioimmunologically measured serum concentrations nor in the AUC after an oral 0.250 mg dose determined on the third or sixth postpartum day during a continuous treatment with methylergometrine 0.125 mg t.i.d., nor were there significant differences in the clinical response to this oxytocic drug. Peak serum concentrations were obtained at 3 hours (Methergin 6.3 nmol/1 and Myomergin 6.0 nmol/1), indicating a delayed gastrointestinal absorption in postpartum females in comparison with healthy male volunteers [6]. Spontaneous complaints of side-effects were rare and mild.