Steady state pharmacokinetics and dose equivalents of oral clodronate in renal failure.

OBJECTIVE: Clodronate is used in the treatment of osteoporosis, and malignancy-associated bone disease. The steady state pharmacokinetics and the dose equivalents of oral clodronate were assessed in subjects with various degrees of renal failure. MATERIALS AND METHODS: 1,600 mg of clodronate was given orally mornings for 11 days to 14 healthy volunteers (creatinine clearance, CLCr, > 80 ml/min), and 18, 12 and 16 subjects with mild (50 - 80 ml/min), moderate (30 - 50 ml/min) and severe (< 30 ml/min) renal failure, respectively. Trough drug levels at 4, 7 and 11 days, and concentration-time curves for 72 h after the last dose were followed. RESULTS: In all study groups, the trough drug levels achieved the kinetic steady state within 11 days. The area under the 24-h concentration-time curve (AUC0-24) enlarged and the elimination half-life (t1/2elim) prolonged progressively when the renal function was impaired. The maximum drug level and the time to maximum were not changed significantly in the renal failure. In the steady state phase, the diurnal drug excretion (E0-24) was not changed by the kidney function, but the renal drug clearance (CLD) decreased in close correlation with CLCr. The normal-to-failed AUC0-24 ratios in mild, moderate, and severe renal failure were 0.53, 0.43 and 0.31, respectively, when the ideally-matched counterpart was assumed as the normal reference to each renal failure group. CONCLUSIONS: In mild, moderate and severe renal failure, 53%, 43% and 31% oral clodronate doses, respectively, resulted in drug AUCs similar to those in controls with normal (> 80 ml/min) CLCR.

The effect of CYP2C19 substrate on the metabolism of melatonin in the elderly: A randomized, double-blind, placebo-controlled study.

The metabolism of melatonin to 6-sulphatoxymelatonin (aMT6S) and N-acetylserotonin (NAS) is catalyzed by cytochrome-P450 (CYP) isozymes CYP1A2 and CYP2C19 respectively. We studied the in vivo effect of CYP2C19 substrate (citalopram, omepratzole, or lansopratzole) on the metabolism of endogenous and exogenous melatonin by measuring the excretion of urinary aMT6S, the main metabolite of melatonin, and a reliable estimate of plasma melatonin in 15 insomniac psychogeriatric inpatients. The effect of melatonin treatment on sleep parameters was also assessed. The patients with or without CYP2C19 substrate were treated for 21 days randomly in a double-blind manner with placebo or 2 mg exogenous melatonin orally. aMT6S excretions were measured radioimmunologically from night urine at baseline (day 0), on day 21, and one day after the treatment was discontinued (day 22). Sleep parameters were assessed using the Sleep Assessment Scale and the Sleep Quality Scale. In the control patients receiving only melatonin, aMT6S excretion increased 72-fold and returned to baseline on day 22. In the patients receiving melatonin + CYP2C19 substrate, aMT6S excretion increased 156-fold and was, on day 22, still 6.4-fold higher than at baseline (p = 0.04). The 22/0 day aMT6S excretion ratio was 10-fold higher in the patients treated with melatonin + CYP2C19 substrate when compared with that in the subjects treated with placebo + CYP2C19 substrate (p = 0.02). CYP2C19 substrate did not affect the metabolism of endogenous melatonin. The sleep parameters in the patients on melatonin treatment did not differ from those in the patients treated with placebo. In conclusion, it may be inferred that CYP2C19 substrate slows the metabolism of exogenous melatonin and increases its bioavailability, as shown by the augmented excretion of aMT6S, probably by inhibiting the conversion of melatonin to NAS via CYP2C19 isozyme. Melatonin therapy may not affect the sleep parameters in our psychogeriatric inpatients.

Effects of bisphosphonates on prostaglandin E2 and thromboxane B2 production in human whole blood and monocytes stimulated by lipopolysaccharide and A23187.

Bisphosphonates are antiatherosclerotic, suppress monocyte-macrophages, and modulate proinflammatory mediators. Prostaglandin (PG) E(2), thromboxane (TX) A(2), and cyclooxygenase-2 (COX-2) enzyme are involved in inflammation and atherosclerosis. We studied the effects of four bisphosphonates (etidronate, clodronate, tiludronate, and alendronate) on PGE(2) and TXB(2) production in human whole blood and monocytes. PGE(2) and TXB(2) were determined by direct radioimmunoassay and COX-2 expression by Western blot. In whole blood, the bisphosphonates did not modulate the increase in PGE(2) and TXB(2) concentrations induced by calcium ionophore A23187 or lipopolysaccharide (LPS). None of the bisphosphonates did change PGE(2) and TXB(2) concentration after spontaneous clotting. A23187- and spontaneous clotting-induced PGE(2) and TXB(2) productions were inhibited over 90% by acetylsalicylic acid (ASA), and LPS-induced PGE(2) and TXB(2) formations were inhibited over 90% by nimesulide. None of the bisphosphonates altered these inhibitions. In monocytes, etidronate and clodronate augmented A23187-stimulated PGE(2) production 2.5- to 3.2-fold (p < 0.05). LPS- or A2318-induced elevations in TXB(2) were not influenced by the bisphosphonates. The tested bisphosphonates neither induced COX-2 expression nor modulated LPS-induced COX-2 expression in monocytes. The results suggest that the antiatherosclerotic effects of bisphosphonates are not mediated via PGE(2), TXA(2), or COX-2, and the bisphosphonates do not interfere with the suppression of platelet COX-1 activity by ASA and COX-2 activity by nimesulide.

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.

Laparoscopically assisted vaginal and abdominal hysterectomy: comparison of postoperative pain, fatigue and systemic response. A case-control study.

BACKGROUND AND OBJECTIVE: Laparoscopic and open surgery have been compared with conflicting results regarding their systemic responses. The sensitivity of biochemical markers that are used to discriminate between the stress responses to different types of surgery varies from study to study. We wanted to evaluate the stress response and the sensitivity of clinical and biochemical stress markers in patients undergoing laparoscopically assisted vaginal or abdominal hysterectomy. METHODS: We performed a case-control study with patients undergoing laparoscopically assisted vaginal hysterectomy (n=20) or abdominal hysterectomy (n=20). Pain scores were assessed at rest and during coughing, and active leg elevation and fatigue scores using a visual analogue scale. In 10 patients of each group, haematocrit, white cell count, C-reactive protein, glucose, cortisol, adrenocorticotrophic hormone, beta-endorphin immunoreactivity, interleukin-6 and urine excretion of epinephrine and norepinephrine were measured preoperatively and during the first 44 postoperative hours. RESULTS: The most sensitive symptoms and markers of the systemic response were pain scores during mobilization, fatigue scores, C-reactive protein and interleukin-6 (P < 0.01 in all comparisons). Pain scores at rest, and all other laboratory markers of the systemic response, did not discriminate between the two types of surgery. CONCLUSION: Follow-up of postoperative pain scores during mobilization and fatigue levels might be an easy tool for the evaluation of postoperative recovery. Using an identical anaesthetic technique, the neuroendocrine response was of the same magnitude after both types of surgery.

Effects of smoking cessation and nicotine substitution on systemic eicosanoid production in man.

This study investigated the effects of smoking cessation with and without nicotine substitution on the excretion of major urinary metabolites of thromboxane A2 and prostacyclin, 11-dehydrothromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1alpha, respectively, as well as on the excretion of leukotriene E4 in man. Urine samples were obtained from 20 healthy non-smoking controls and from 60 healthy smoking volunteers before, and 3, 7 and 14 days after smoking cessation. Fifteen smokers quit smoking without nicotine substitution, 15 used nicotine chewing gum and 30 used nicotine patches as a substitution therapy. Urinary thiocyanate as well as cotinine and trans-3'-hydroxycotinine excretions were used as compliance and nicotine substitution indicators. 11-Dehydrothromboxane B2, 2,3-dinor-6-ketoprostaglandin F1alpha and leukotriene E4 excretion was about two, three and five times higher in smokers than in controls, respectively. Three days after smoking cessation without nicotine substitution, 11-dehydrothromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1alpha levels were lowered to 75% (P<0.01) and 80% (P<0.05) of the initial values, and after 14 days to 50% (P<0.01) and 60% (P<0.05), respectively. In 3 days leukotriene E4 excretion was dropped to 70% of the initial value (P<0.05), but no further decrease was observed during the study. In individuals using nicotine chewing gum or nicotine patches no significant changes were observed in the analytes during the 2-week follow-up. The increased systemic eicosanoid synthesis observed in smokers may be involved in the harmful cardiovascular effects of smoking. The fact that eicosanoid production remains at pre-cessation level in volunteers who quit smoking but use nicotine substitution may be involved in the risk of cardiovascular complications reported during nicotine replacement therapy.

Acceptability and profile of the clinical drug trials underway in Finnish university hospitals in the 1990s: applications reviewed by ethics committees.

There is scarce information in literature about the decisions made by ethics committees concerning the clinical studies they have reviewed. A retrospective, detailed review of 666 applications, their amendments and the ethics committees' statements was undertaken. All protrocols of clinical studies on medicinal products submitted to and reviewed by the ethics committees of two university hospitals during the years 1992, 1994, 1996 and 1998 were investigated. Most of the studies were international (50%), multicenter (71%), phase III trials (41%) on a new clinical entity, (38%). Validity of the clinical drug study applications was acceptable in more than half of the cases (364; 55%), while 91 (14%) were approved with advisory comments, 153 (23%) had to be amended, 35 (5%) were left pending and 23 (3%) were rejected. Most of the questions pertained to informed consent and the study protcol. In accordance with precious results, our findings support the opinion that the submitted documents need to be improved, especially with regard to informed consent and study protocols, in order to gain better Good Clinical Practice (GCP) compliance. Well-defined, documented operating procedures of the ethics committees would have facilitated the practical issues in the review process.

Effects of short-term lamotrigine treatment on pharmacokinetics of carbamazepine.

AIM AND METHOD: The effects of short-term treatment with lamotrigine (LTG) (100 mg twice daily for one week) on single dose pharmacokinetics of carbamazepine (CBZ, 200 mg) were investigated in a randomized, double-blinded, placebo-controlled cross-over study with 10 healthy volunteers. RESULTS: Pharmacokinetic parameters for CBZ or for CBZ-10,11-epoxide, the main metabolite of CBZ, were not significantly affected by LTG pretreatment. The mean (+/- SEM) elimination half-life of CBZ was 33.0+/-1.8 h after pretreatment with placebo and 30.1+/-2.0 h after a one-week-pretreatment with LTG (NS). The area under the serum concentration curve to infinity (AUC) of CBZ was 638+/-45 micromol/l after placebo and 624+/-53 micromol/l after LTG (NS). Changes in the peak serum concentration, from 9.0+/-0.3 micromol/l to 9.2+/-0.4 micromol/l (LTG), and in the time to peak serum concentration, from 9.3+/-1.1 h to 9.1+/-1.2 h (LTG), were also not significant. CONCLUSION: These data support the earlier findings that LTG does not significantly affect the rate or extent of absorption, or elimination of CBZ.

Arterial responses in vitro and plasma digoxin immunoreactivity after losartan and enalapril treatments in experimental hypertension.

Treatment with the angiotensin-converting enzyme inhibitor, quinapril, has been shown to normalize increased dihydropyridine sensitivity and impaired potassium relaxation, characteristic features of arterial smooth muscle in spontaneously hypertensive rats, and also reduce the concentration of plasma digoxin-like immunoreactivity in these animals. However, whether angiotensin II receptor blocker therapy can beneficially influence these variables is not known. Therefore, we compared the effects of 10-week losartan and enalapril treatments (15 and 4 mg/kg/day, respectively) on functional responses of mesenteric arterial rings in spontaneously hypertensive rats and Wistar-Kyoto rats. Both losartan and enalapril normalized blood pressure, cardiac mass, and media to lumen ratio without significantly changing the media cross-sectional area in the mesenteric artery of spontaneously hypertensive rats (i.e. induced outward remodelling). The inhibitory effect of the calcium entry blocker nifedipine on calcium-evoked contractions was similar and less marked in arterial preparations from Wistar-Kyoto rats and losartan- and enalapril-treated spontaneously hypertensive rats than in those from untreated spontaneously hypertensive rats. Furthermore, the relaxations of arterial rings induced by the return of potassium to the organ bath (upon precontractions elicited by potassium-free solution) were used to evaluate the function of vascular Na+,K+-ATPase. The rate of potassium relaxation was faster in losartan- and enalapril-treated spontaneously hypertensive rats and all Wistar-Kyoto groups than in untreated spontaneously hypertensive rats, and the response was effectively inhibited by the sodium pump inhibitor ouabain. Both treatments especially augmented the ouabain-sensitive part of the potassium-relaxation in spontaneously hypertensive rats, indicating the involvement of the sodium pump in this response. However, no significant changes in plasma digoxin-like immunoreactivity were observed. In conclusion, the outward remodelling following long-term AT1-receptor blockade and angiotensin-converting enzyme inhibition in spontaneously hypertensive rats was associated with normalization of the increased dihydropyridine sensitivity of arteries. Both losartan and enalapril treatments also augmented arterial potassium relaxation in spontaneously hypertensive rats, suggesting enhanced function of Na+,K+-ATPase, but this effect could not be attributed to changes in circulating sodium pump inhibitor concentration.

Clinical pharmacology of eicosanoids, nicotine induced changes in man.

Smoking is an important risk factor for respiratory and cardiovascular diseases. The role of numerous chemical, partly uncharacterised compounds existing in tobacco smoke is not known. (-)-Nicotine, its stereoisomer (+)-nicotine and main metabolite cotinine are biologically active compounds influencing e.g. catecholamine and eicosanoid systems. The precise mechanisms are not well known. The purpose of the present study consisting of a PhD thesis (11) and five original papers was to investigate the in vitro effects of nicotine isomers and cotinine on eicosanoid production in polymorphonuclear leukocytes, platelets and whole blood in vitro, and to clarify the effects of smoking without and with nicotine substitution on eicosanoid production in vivo and ex vivo. It was found that all the tested compounds modulated blood cell eicosanoid synthesis. Nicotine isomers and cotinine increased PGE2 but decreased TXB2, LTB4 and LTE4 synthesis in vitro. Eicosanoid synthesis in vivo and ex vivo was higher in smokers (n = 60) than in non-smoking controls (n = 20). This may contribute to the harmful cardiovascular effects of smoking. Cessation of smoking without, but not with, nicotine substitution reduced eicosanoid synthesis measured ex vivo as whole blood production or in vivo as urinary excretion of eicosanoid metabolites after 3, 7 and 14 days. Thus long-term nicotine substitution diminishes the beneficial effects of smoking cessation.

Influences of nonselective, beta(1)-selective and vasodilatory beta(1)-selective beta-blockers on arterial pulse wave velocity in normotensive subjects.

beta-Adrenoceptor blockers with disparate properties may have differential influences on arterial pulse wave velocity (PWV). Therefore, influences of single medium doses of bisoprolol, propranolol and celiprolol on PWV were compared in healthy subjects. Arterial PWV was obtained from the time delay between flow pulses measured from the root of the aorta and the popliteal artery. Bisoprolol and propranolol decreased arterial PWV more than placebo (P less-than-or-equal to .002) and celiprolol (P<.0001). In conclusion, the acute effects of bisoprolol and propranolol on arterial PWV in normotensive subjects seem to differ from that of celiprolol.

Decrease in serum LDL cholesterol with microcrystalline chitosan.

Peroral microcrystalline chitosan (MCCh; 3 capsules, each 400 mg b.i.d.) or placebo was given for 8 weeks in a double-blind manner to 51 healthy obese women just before routine hospital and home meals. Weight records, serum lipids (total, LDL and HDL cholesterol, triglycerides) and safety laboratory parameters were monitored before the trial and at 4, 6 and 8 weeks of treatment. In a subgroup of subjects with a body mass index > or = 30 who had not changed their eating habits, serum LDL cholesterol decreased 0.57 +/- 0.72 mmol/l (n = ll) at 4 weeks in the MCCh group and 0.10 +/- 0.60 mmol/l (n = 14) in the placebo group (p < 0.05). At 8 weeks, LDL cholesterol reduction was 0.48 +/- 0.91 mmol/l in the MCCh group and 0.26 +/- 0.57 mmol/l in the placebo group (p > 0.1). In all subjects, the reduction in LDL cholesterol at 4 weeks was 0.48 +/- 0.72 mmol/l (n = 24) in MCCh subjects and 0.18 +/- 0.58 mmol/l (n = 27) in placebo subjects (p = 0.057), and 0.52 +/- 0.69 mmol/l and 0.31 +/- 0.63 mmol/l, respectively, at 8 weeks (p > 0.1). MCCh did not significantly alter serum total and HDL cholesterol (p > 0.1), but slightly increased serum triglycerides compared to placebo (p = 0.015-0.06). No reductions in weight were observed in any treatment group. Chitosan was well tolerated and no serious adverse events or changes in safety laboratory parameters were noted including serum fat-soluble vitamins A and E, and serum Fe++ and transferrin.

Comparison of pharmacokinetics of clodronate after single and repeated doses.

OBJECTIVE: Pharmacokinetics of orally given clodronate disodium, a drug for the treatment of hypercalcemia and bone resorption, were studied after a single dose of 400, 800 and 1600 mg given randomly to 11 healthy volunteers in a crossover manner, in 7-14 hospitalized cancer patients given 400, 800 and 1600 mg twice daily, each dosage for one week, and during the customary therapy in 15 additional cancer patients treated in hospital with 400 mg thrice daily for > or = 2 weeks. METHODS: Clodronate concentrations in serum and urine were measured by capillary gaschromatography with mass-selective detection. Pharmacokinetic parameters were calculated with a three-compartmental model. RESULTS: After a single oral dose to healthy volunteers the absolute clodronate concentrations increased almost dose-dependently. The mean cumulative excretion in urine was 1.72-2.77% of the dose, an interindividual range being from 0.92% to 5.52%. With 800 and 1600 mg twice daily for one week to cancer patients the serum drug concentrations increased almost progressively with increasing the dose. In cancer patients serum drug concentrations were clearly higher and renal drug clearances (mean 25-62 ml/min) lower than in healthy volunteers (mean 123-149 ml/min). The mean urinary excretions were 2.24-3.14% of the dose and interindividual ranges from 0.18% to 19.0%. During the routine cancer therapy with 400 mg thrice daily, the clodronate excretions in urine on two successive days were on an average 3.26% (range 0.0-10.5%). CONCLUSIONS: Absolute concentrations in serum and excretions in urine of orally given clodronate increase dose-dependently, but during the maintenance therapy in hospitalized cancer patients the renal drug clearances seem to be lower than in healthy volunteers. This and the large interindividual variation in kinetics propose therapeutic monitoring of clodronate for optimizing the oral dose of the drug.

Control of mesenteric arterial tone in vitro in humans and rats.

The majority of the findings concerning arterial physiology and pathophysiology originate from studies with experimental animals, while only limited information exists about the functional characteristics of human arteries. Therefore, the aim of the present work was to compare the control of vascular tone in vitro in mesenteric arterial rings of corresponding size (outer diameter 0.75-1 mm) from humans and Wistar-Kyoto rats. The relaxations to acetylcholine (ACh) were clearly less marked in the mesenteric arteries of humans when compared with rats. However, when calcium ionophore A23187 was used as the vasodilator, the endothelium-mediated relaxations did not significantly differ between these species. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) attenuated the relaxations to ACh and A23187 in both groups. The endothelium-independent relaxations to the beta-adrenoceptor agonist isoprenaline and the nitric oxide (NO)-donor nitroprusside were somewhat lower in human arteries, while vasodilation induced by the K+ channel opener cromakalim was similar between humans and rats. Arterial contractile sensitivity to noradrenaline and serotonin was slightly lower in human vessels, whereas contractile sensitivity to KCl was similar between these species. The contractions induced by cumulative addition of Ca2+ with noradrenaline as the agonist were effectively inhibited in both groups by the calcium channel blocker nifedipine, the effect of which was clearly more pronounced in human arteries. In conclusion, the control of vascular tone of isolated arteries of corresponding size from humans and rats appeared to be rather similar. The most marked differences between these species were the impaired endothelium-mediated dilation to ACh and the more pronounced effect of nifedipine on the Ca2(+)-induced contractions in human arteries.

Pharmacokinetics of clodronate in haemodialysis patients.

BACKGROUND: Clodronate is a bisphosphonate used in the treatment of hypercalcaemia of various aetiologies. The major route of elimination of clodronate is renal excretion. The aim of the study was to derive data for the adjustment of dosage in haemodialysis patients. METHODS: The pharmacokinetic parameters describing the fate of an intravenous infusion of 300 mg clodronate disodium were studied in 10 haemodialysis patients. Clodronate disodium in serum, urine and dialysate samples was analysed by capillary gas chromatography with mass-selective detection. RESULTS: Of the 300 mg clodronate infused, 159 mg (53%) was excreted into dialysate within 4 h. Clearance by haemodialysis (CLD) was 87.8+/-16.2 ml/min, accounting for 84% of total serum clearance (CLtot). Non-renal, non-dialysis clearance (CL(NRD)) represents the removal of the drug via other routes than dialysis or kidneys. The greatest CL(NRD) was observed in patients with most severe hyperparathyroidism. There was a positive correlation between CL(NRD) and plasma intact PTH concentration. CONCLUSIONS: According to the present findings, standard haemodialysis removes clodronate effectively from the circulation, and total clearance in haemodialysis patients on a dialysis day is not very different from that in healthy subjects. The regimen of dosing intravenous clodronate in hypercalcaemia can also be used in haemodialysis patients. The portion of clodronate eliminated by routes other than via dialysate or kidneys, i.e. predominantly via skeletal deposition, was related to the severity of hyperparathyroidism.

In the dose range of 0.5-2.0 mg/kg, acetylsalicylic acid does not affect prostacyclin production in hypertensive pregnancies.

OBJECTIVE: To determine the dose of acetylsalicylic acid (ASA), that inhibits the production of the vasoconstrictive, aggregatory thromboxane A2 while sparing the production of the vasodilatory antiaggregatory prostacyclin. DESIGN: A controlled study comparing the effects of three doses of ASA on the production of thromboxane A2 and prostacyclin. METHODS: Seven pregnant hypertensive patients and five non-pregnant healthy women received 0.5, 1.0 and 2.0 mg/kg/day of ASA, each dose for 10-12 days, the treatment periods following each other immediately. Seven normotensive pregnant women served as controls and were given no ASA. Blood and urine samples were taken at baseline and after the treatment periods to determine serum thromboxane B2 and the urinary 2.3-dinor-6-ketoprostaglandin F1alpha and 11-dehydrothromboxaneB2, the major stable metabolites of prostacyclin and thromboxane A2, respectively. RESULTS: The urinary excretion of 11-dehydrothromboxaneB2 was significantly higher in both hypertensive (34.9+/-18.3 pg/micromol creatinine) and normotensive (39.3+/-14.4 pg/micromol creatinine) pregnant women than in non-pregnant women (14.8+/-6.4 pg/micromol creatinine). The urinary excretion of 2.3-dinor-6-ketoprostaglandinF1alpha was also higher in normotensive pregnant women (93.9+/-50.9 pg/micromol creatinine) than in non-pregnant women (18.2+/-11.3 pg/micromol creatinine). The excretion rate of 2.3-dinor-6-ketoprostaglandinF1alpha in hypertensive patients was lower than in normotensive pregnant women (44.7+/-24.2 pg/micromol creatinine). At baseline the urinary 2.3-dinor-6-ketoprostaglandin F1alpha/11-dehydrothromboxaneB2 ratio was almost the same in the hypertensive patients (1.6) and in the non-pregnant women (1.2). The ratio was 2.6 in normotensive pregnant women. In the hypertensive group, already the lowest dose of ASA inhibited urinary 11-dehydrothromboxaneB2 excretion significantly. Because none of the doses of ASA inhibited 2.3-dinor-6-ketoprostaglandinF1alpha production, the 2.3-dinor-6-ketoprostaglandinF1alpha/11-dehydrothromboxaneB2 ratio was shifted in the favor of prostacyclin at all dose levels. In the non-pregnant women, even the highest dose level of ASA failed to affect the ratio. CONCLUSION: In the dose range of 0.5-2.0 mg/kg/day, ASA has a favorable effect on the ratio of prostacyclin to thromboxane A2 in hypertensive pregnancies.

Pharmacokinetics of bisphosphonates in rabbits.

Clodronate, pamidronate and etidronate are commonly used bisphosphonates, which accumulate extensively in arteries and some other tissues. We compared their pharmacokinetics in rabbits with those of tiludronate, the drug newly introduced to clinical use. The 14C-labelled drugs were given intravenously and plasma drug levels were monitored for up to 24 hr. The dose-related plasma concentrations of tiludronate and etidronate were clearly higher and decreased more slowly than those of clodronate and pamidronate (P < 0.001). Already at 5 min., the concentrations of tiludronate and etidronate were higher than those of clodronate and pamidronate (P = 0.016). At 24 hr, plasma concentration of tiludronate was 12 +/- 6.6%, of etidronate 18 +/- 2.5%, of clodronate 0.8 +/- 0.2%, and of pamidronate 1.4 +/- 0.4% of the dose per body weight. With the same dose (25 mg/kg), absolute AUC0-24 hr for tiludronate and etidronate was 9-11 times larger than for clodronate. AUC0-24 hr for pamidronate (2.5 mg/kg) was 11% of that for clodronate. Plasma clearance of tiludronate and etidronate was 9-15 times slower than that of clodronate and pamidronate. At 24 hr, the mean tissue-to-plasma ratio of tiludronate for aorta was 1.2-1.6. For bone, spleen, liver and kidneys the ratio varied from 5.4 to 52.6. The results suggest that 1) tiludronate and etidronate are removed from plasma much slower than clodronate and pamidronate, and 2) the potential of tiludronate to concentrate in arteries and bone is generally smaller than previously found with the other bisphosphonates.

Accumulation of bisphosphonates in human artery and their effects on human and rat arterial function in vitro.

Clodronate, etidronate and pamidronate are bisphosphonates introduced in the treatment of hypercalcaemia and osteoporosis. Interestingly, they also inhibit development of experimental atherosclerosis and affect smooth muscle tone of isolated rat tail artery. We have studied in vitro whether these hydrophilic compounds 1) accumulate in the wall of the human artery, 2) influence human arterial tone, and 3) interfere with the vascular action of L-type Ca2+ antagonists. Human internal mammary artery rings were incubated with 14C-labelled bisphosphonates. After a 2-hr incubation, the ratios of artery-to-incubate concentrations with 4 and 40 mumol/l of clodronate were, respectively, 3.0 +/- 0.5 (mean +/- S.E.M.) and 1.3 +/- 0.2, with 4 and 40 mumol/l of etidronate 7.4 +/- 0.9, and 3.2 +/- 0.4, and with 0.4 and 4 mumol/l of pamidronate 4.7 +/- 0.7 and 3.9 +/- 0.8. Both tested bisphosphonates, clodronate and pamidronate, reduced the arterial contractile force induced by alpha-adrenergic stimulation with noradrenaline and membrane depolarization with high concentration of KCl. Clodronate also decreased the arterial contraction induced by cumulative addition of Ca2+ with KCl as the agonist, and had an additive inhibitory effect on this response with the L-type Ca2(+)-channel blocker nifedipine. The results demonstrate that 1) bisphosphonates accumulate markedly in human artery, 2) clodronate and pamidronate reduce human arterial contactile force to alpha-adrenergic and depolarizing stimuli, and 3) as shown with clodronate, bisphosphonates may exert an additive inhibitory effect on human arterial contractions with an L-type Ca2(+)-channel blocker.

Influence of captopril, propranolol, and verapamil on arterial pulse wave velocity and other cardiovascular parameters in healthy volunteers.

OBJECTIVE: The effects of antihypertensive agents on cardiovascular parameters, especially on arterial pulse wave velocity, remain largely unknown in normotensive subjects. Therefore, the present investigation was designed to evaluate acute effects of ACE inhibitor captopril,beta-adrenoceptor blocker propranolol and calcium entry blocker verapamil on cardiovascular and ventilatory function in healthy volunteers. MATERIAL: The influence of single doses of captopril (25 mg), propranolol (40 mg), and verapamil (80 mg) on cardiovascular function and exercise capacity were compared in healthy volunteers in a randomized, double-blind, placebo-controlled fashion. METHODS: Cardiac output and beat-by-beat blood pressure were estimated non-invasively before and after the drug administrations by whole-body impedance cardiography and Finapres finger blood pressure monitoring, respectively. Arterial pulse wave velocity was obtained from the time delay between flow pulses measured from the root of the aorta and the popliteal artery, and systemic vascular resistance was calculated from cardiac output and mean arterial pressure. In addition, a progressive maximal exercise test was performed after the treatments. RESULTS: Propranolol reduced heart rate, cardiac output and arterial pulse wave velocity, and increased systemic vascular resistance clearly more effectively than placebo. In addition, captopril effectively decreased arterial resistance and pulse wave velocity. However, the influence of verapamil on cardiovascular parameters did not significantly differ from those observed in placebo-treated subjects. Exercise peak heart rate, peak blood pressure, and minute ventilation were reduced in subjects treated with propranolol, but not in those treated with captopril and verapamil, when compared to placebo. CONCLUSIONS: Acute administration of captopril and propranolol but not verapamil clearly modulated cardiovascular parameters in rest, suggesting differential effects of these compounds on cardiovascular function in healthy volunteers. These drugs seem to have disparate effects on arterial pulse wave propagation as an indicator of arterial compliance after short-term administration in healthy subjects. Captopril and verapamil had no effect on cardiovascular and ventilatory function during maximal exercise, while propranolol markedly altered also these variables in the present study.