Volume 41, No. 8/2003(August)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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PD-PD relationships
Book review
Review
Review on raloxifene: profile of a selective estrogen receptor modulator
Abstract
M. Heringa
Medical Department, Division of Nephrology, University of Ulm, Germany, and University of Utrecht, The Netherlands
Raloxifene is a selective estrogen receptor modulator approved for prevention and treatment of osteoporosis in postmenopausal women. Raloxifene has an estrogen-agonistic effect on bone, although it is unclear how this effect comes about. It has been proven that raloxifene decreases levels of both bone formation markers and bone resorption markers in postmenopausal women. Moreover, it preserves the bone mineral density at most skeletal sites in these women. Raloxifene decreases the serum levels of low-density lipoprotein cholesterol and total cholesterol. In breast tissue, raloxifene is an estrogen antagonist. It decreases the risk of breast cancer in postmenopausal women. In contrast to estrogen and tamoxifen, raloxifene does not increase the risk of uterine cancer and it does not cause endometrial proliferation. Raloxifene is rapidly absorbed after oral administration, but its bioavailability is only 2% because of an extensive first-past effect. The maximum plasma concentration of 0.5 ng/ml is reached after 6 hours. Raloxifene is more than 95% bound to plasma proteins and the apparent volume of distribution is 2,348 l/kg. The clearance is 40 – 60 l/kg×h and the half-life of raloxifene after multiple dosing is 32.5 h. Less than 0.2% of an oral dose is excreted unchanged in the urine and less than 6% is excreted in urine as glucuronide conjugates. Serious adverse event caused by raloxifene is a 3-fold increase in the risk of thromboembolic events.
Endothelial function
Effects of transdermal and oral estrogen supplementation on endothelial function, inflammation and cellular redox state
Abstract
H. Kawano, H. Yasue, N. Hirai, T. Yoshida, H. Fukushima, S. Miyamoto, S. Kojima, J. Hokamaki,H. Nakamura, J. Yodoi and H. Ogawa
1Department of Cardiovascular Medicine, Kumamoto University School of Medicine, 2Kumamoto Aging Research Institute, Kumamoto, and 3Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan
The incidence of ischemic heart disease shows a sharp rise after menopause. However, the effects of hormone replacement therapy (HRT) on cardiovascular disease are still controversial. Not only oxidative stress, but also inflammation has been suggested to play an important role in the pathogenesis of cardiovascular events. We compared the effects of HRT on endothelial function, cellular antioxidant system and inflammation between oral and transdermal administration in mild hypercholesterolemic postmenopausal women. Transdermal estradiol replacement was administrated to 12 patients (mean age 53 years) for 12 weeks, and oral conjugated equine estrogen was administrated to 12 patients (mean age 54 years) for 12 weeks. The flow-mediated endothelium-dependent dilation of the brachial artery, serum levels of thioredoxin as a marker of the cytoprotective antioxidant system, and high-sensitivity C-reactive protein (hs-CRP) were measured every 4 weeks. The flow-mediated vasodilation increased with HRT (oral, baseline 4.9 ± 0.5, 4-week 8.9 ± 0.7*, 8-week 9.9 ± 0.6*, 12-week 9.4 ± 0.7*; transdermal, 4.7 ± 0.6, 8.3 ± 0.7*, 9.1 ± 0.8*, 8.9 ± 0.9%*, * = p < 0.01 versus baseline). The thioredoxin levels decreased with HRT (oral, 26.1 ± 7.2, 24.1 ± 8.2, 22.1 ± 7.8, 19.1 ± 7.0*; transdermal, 26.9 ± 7.4, 23.4 ± 8.7, 21.1 ± 7.9, 19.2 ± 7.2 ng/ml*, * = p < 0.01 versus baseline). There were no differences in the variation of the flow-mediated vasodilation or thioredoxin concentrations between the 2 groups. The hs-CRP levels increased with oral HRT (0.32 ± 0.12, 0.72 ± 0.17*, 0.86 ± 0.23*, 0.88 ± 0.21 mg/dl*, * = p < 0.01 versus baseline), while transdermal HRT did not elicit any changes (0.35 ± 0.15, 0.34 ± 0.17, 0.38 ± 0.20, 0.36 ± 0.22 mg/dl). The differences of hs-CRP concentrations between the 2 groups analyzed by 2-way ANOVA were significant (p < 0.01). Oral HRT instigated inflammation, but transdermal did not. Both oral and transdermal HRT, however, improved endothelial function and decreased oxidative stress through affecting the cellular redox state. These differentials in the effects caused by the course of administration may affect the future cardiovascular events.
Herbal drug efficacy
Multiple n = 1 trials in the identification of responders and non-responders to the cognitive effects of Ginkgo biloba
Abstract
P.H. Canter and E. Ernst
Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, Exeter, UK
Objective: A pilot study to assess multiple crossover n=1 trials with verum/placebo discrimination as the outcome measure as a means of identifying responders and non-responders to the acute nootropic effect of Ginkgo biloba (G. biloba) among healthy volunteers. Method: Multiple double-blind, placebo-controlled n = 1 trials with 8 treatments in randomized order and separated by minimum washout periods of 7 days. Treatments were acute 120 mg doses of G. biloba extract (GK501) or undistinguishable placebo. The frequency distribution of correct scores for verum-placebo discrimination was compared with the binomial distribution to identify putative responders, who were then tested for consistency of performance over a further 8 treatments. Results: The frequency distribution of scores (n = 11) was bimodal and a discontinuity defined 3 putative responders and 2 putative negative responders for re-test. Two of the putative responders again performed at above chance level and the probability of achieving their scores or better by chance was 0.013 and 0.052. Conclusions: n = 1 trials with verum/placebo discrimination as outcome are a promising method for exploring response heterogeneity to treatments with a subjective effect. Preliminary evidence suggests that there are responders and non-responders to an acute G. biloba treatment among healthy subjects.
Adverse drug reaction
Betaxolol-induced deterioration of asthma and a pharmacodynamic analysis based on b-receptor occupancy
Abstract
A. Miki, Y. Tanaka, H. Ohtani and Y. Sawada
1Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka and
2Tanaka Clinic, Hyogo, Japan
Objective: To report a case of deterioration of asthma associated with continuous use of oral betaxolol, a b1-selective b-blocking agent. We also analyzed the pharmacokinetics in this case by applying a receptor occupancy model. Case summary: A 68-year-old woman taking 5 mg of betaxolol for hypertension occasionally experienced asthmatic coughing after upper respiratory tract infection. Two years after the start of betaxolol, her asthma gradually worsened. Although pharmacotherapy for asthma was introduced, betaxolol was continued. Finally, she was admitted to hospital with bronchospasm. When she was discharged after 2 months, betaxolol was discontinued and losartan potassium (25 mg/d) was initiated instead for her hypertension. Since then, she has been free from bronchospasm. Method: We calculated the mean receptor occupancy (Fss) of the b1- and b2-receptors after the usual oral dose of betaxolol by using pharmacokinetic-pharmacodynamic parameters obtained from the literature. We estimated the decrease in the exercise pulse rate or the forced expiratory volume in 1 second (FEV1) by applying the Fss values to the model previously reported by us. Results: Betaxolol seems less likely than other b1-blocking agents to cause pulmonary adverse effects. However, the estimated decrease in FEV1 after oral administration of betaxolol (5 mg) was close to that after oral bisoprolol (5 mg), which has been reported to induce asthma. Conclusions: Oral betaxolol may induce bronchospasm, although betaxolol is considered to be highly cardioselective and seems less likely than other b1-selective blocking agents to cause pulmonary adverse effects. Betaxolol should be administered with caution to patients with asthma or chronic pulmonary disease.
PD-PD relationships
Pharmacokinetic-pharmacodynamic interrelationships of intravenous and oral levosimendan in patients with severe congestive heart failure
Abstract
1Cardiovascular Projects, Research Centre, Orion Pharma, Espoo, Finland, 2Mustamäe Hospital, Tallinn, Estonia, and 3Department of Clinical Pharmacology, Helsinki University, Finland
1Cardiovascular Projects, Research Centre, Orion Pharma, Espoo, Finland, 2Mustamäe Hospital, Tallinn, Estonia, and 3Department of Clinical Pharmacology, Helsinki University, Finland
Objective: To assess the pharmacokinetic-pharmacodynamic (PK-PD) interrelations after a 6-hour continuous infusion and a 2 mg single oral dose of levosimendan in patients with congestive heart failure (CHF). Methods: This was an open-label, non-randomized Phase II trial in 29 patients with New York Heart Association (NYHA) class III – IV CHF, comprising 2 study days. On the first day, patients were given 6-hour levosimendan infusion with the dose 0.2 mg/kg/min. After a 1-week washout, the patients received a 2 mg single oral dose of levosimendan. Heart rate-corrected electromechanical systole QS2i was the primary variable. Secondary variables were heart rate (HR), systolic (sBP) and diastolic blood pressure (dBP) and 24-hour ambulatory ECG (Holter). Results: QS2i shortened from 515 ms at baseline to 506 ms at the end of 6-hour infusion (p = 0.007). After 2 mg single dose, QS2i shortened at 2 h after drug intake from 532 ms at baseline to 525 ms (p = 0.006). The effect was similar also at 8 h (532 ms vs 526 ms, p = 0.017). Mean of maximum shortening of QS2i observed during the infusion was 22 ms (p < 0.0001) and 17 ms after 2 mg single oral dose (p < 0.0001). The concentration-effect loops for QS2i showed a clear counter-clockwise hysteresis with both modes of administration. sBP and dBP decreased both during infusion and after 2 mg oral dose. HR remained unchanged during both modes of administration. Conclusions: Both 6-hour infusion and 2 mg single dose of levosimendan showed that levosimendan possesses moderate inotropic and vasodilatory effects in patients with severe congestive heart failure, which could be described as counter-clockwise hysteresis. It seemed that the vasodilatory effect appeared earlier than the inotropic effect.
