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DRUG INTERACTIONS |
From the Clinical Pharmacology Unit, Institute of Experimental and Clinical Toxicology and Pharmacology, University Hospital Hamburg-Eppendorf, Germany (Bajcetic, Benndorf, Appel, Schwedhelm, Schulze, Riekhof, Maas, Böger) and the Department of Pharmacology, Clinical Pharmacology and Toxicology, School of Medicine, University of Belgrade, Serbia and Montenegro (Bajcetic).
Address for reprints: Address for correspondence: Dr Ralf A. Benndorf, Institute of Experimental and Clinical Pharmacology and Toxicology, Clinical Pharmacology Unit, University Hospital Hamburg-Eppendorf, Martinistrasse 521, D-20246 Hamburg; e-mail: benndorf{at}uke.uni-hamburg.de.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: telmisartan • nisoldipine • hypertension • pharmacokinetic • interaction • calcium channel blockers • angiotensin receptor antagonists
In many cases, failure to achieve blood pressure targets may be attributed to the use of antihypertensive monotherapy.1,2 To attain blood pressure goals, many patients require combination therapy with 2 or more agents.3 Combinations of drugs from different classes with different mechanisms of action may have additive or even synergistic effects on blood pressure.3 Furthermore, submaximal doses of 2 antihypertensive agents may provide enhanced efficacy while minimizing the risk of dose-dependent adverse events that may compromise compliance. However, concomitant application of 2 or more antihypertensive medications may lead to pharmacokinetic drug interactions, ultimately resulting in an increased occurrence of adverse events.
Calcium channel blockers are one of the most popular classes of drugs used in the treatment of arterial hypertension. Nisoldipine is a potent vaso-selective second-generation dihydropiridine calcium blocker. It causes neither reflex tachycardia nor symptomatic bradycardia at therapeutic doses and has no significant negative inotropic effect.4,5 Nisoldipine as an extended-release formulation provides drug delivery over the 24-hour dosing period.6,7
Telmisartan belongs to a new class of orally active and highly selective non-peptide-substituted benzimidazole AT1-receptor antagonists.8-10 The efficacy of telmisartan has been shown to be at least equivalent to that of many other commonly prescribed antihypertensive agents, such as losartan,11 lisinopril,12 enalapril,13 atenolol,14 and amlodipine.15 Telmisartan has a pharmacokinetic profile that allows differentiating it from other angiotensin receptor blockers: long duration of action (mean terminal half-life of 24 hours, the longest in its class) and high tissue penetration (illustrated by the highest volume of distribution in its class).8,16
A recent study by Stangier and Su17 showed that telmisartan and amlodipine may be safely administered concomitantly as there is no clinically significant variation in primary pharmacokinetic parameters of amlodipine in the presence of telmisartan, and the safety of the combination is comparable to that of amlodipine alone.
Due to possible concomitant use of nisoldipine and telmisartan, it was of interest to investigate whether there is any pharmacokinetic interaction between those 2 drugs.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Patients were eligible for the study if they had been diagnosed with essential hypertension, were between 20 and 80 years old, and had signed the informed consent form. Main exclusion criteria were liver or renal dysfunction, severe heart failure, diabetes mellitus, acute or unstable coronary artery disease, or previously experienced hyperreactivity against AT1 receptor antagonists or calcium channel blockers. Patients who were on stable antihypertensive treatment underwent a washout phase of all antihypertensive and vasoactive medication during 2 weeks before the beginning of the study. During this period, clonidine and hydrochlorothiazide were available as rescue medication if blood pressure rose to levels of 180/110 mm Hg or above.
Patients came to the clinic on the morning of day 1 for blood sampling (standard clinical laboratory parameters), physical examination, and to have 24-hour blood pressure monitors mounted. After 24 hours, patients returned the blood pressure recorders and received study medication. Medication was once-daily telmisartan (40 mg), nisoldipine (10 mg), or a combination of telmisartan and nisoldipine (40/10 mg) for 3 weeks. After 3 weeks, patients returned to the clinic for blood sampling and physical examination as well as for 24-hour blood pressure recording. In this context, the occurrence of adverse events related to or independent of the study medication was closely monitored. Subsequently, fasting patients randomized to the nisoldipine monotherapy group received a dose of 10 mg of nisoldipine, which had to be taken under supervision with 200 mL of tap water. For pharmacokinetic analyses, blood samples were collected in EDTA tubes (9 mL) before nisoldipine intake and 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12, 24, and 48 hours after nisoldipine intake. Afterward, dosage of antihypertensive treatment was increased to once-daily telmisartan (80 mg), nisoldipine (20 mg), and telmisartan/nisoldipin (80/10 mg) in the combination group for the last 3 weeks. After 6 weeks, patients returned to the clinic to have their last blood sampling and 24-hour blood pressure recording done. Eventually, pharmacokinetic assessment of nisoldipine and telmisartan plasma concentrations in fasting patients randomized to receive telmisartan or the combination of telmisartan and nisoldipine was performed as described above following a dose of 80 mg telmisartan (telmisartan group) or of 80 mg telmisartan and 10 mg nisoldipine (combination group).
Analysis of Telmisartan and Nisoldipine Plasma Concentrations
Plasma was extracted from blood samples by centrifugation and was stored at -80°C until assay. Telmisartan plasma levels were measured using an automated high-performance liquid chromatography (HPLC) system from Dionex with fluorescence detection (Dionex, Germering, Germany). The HPLC system was equipped with a C18 column of the dimension 450 x 4.6 mm ID (Macharey & Nagel, Düren, Germany) with a C18 guard column. Eluent A consisted of 10 µM citrate buffer (pH 3.5) with 10% acetonitrile, whereas eluent B was made up of acetonitrile and water (60/40). We used a gradient program from 0 to 20 minutes (0% B to 100% B). Then the column was washed for 5 minutes with 100% B, and the gradient was set back to 0% B. Then, 100 µL of the plasma samples was mixed with 100 µL acetonitrile to precipitate the plasma proteins, and after centrifugation, 20 µL of supernatant was injected into the HPLC system. Telmisartan was detected by fluorescence measurement (excitation wavelength: 305 nm, emission wave-length: 380 nm). The validation of the method for measurement of telmisartan concentrations was done according to the International Conference on Harmonization guidelines for the validation of analytical procedures.18
Linearity of the method was determined with telmisartan concentrations of 5.0, 10.0, 50.0, 100.0, and 500.0 nM, respectively. The slope of the regression line was 1.0322, and the y intercept was -0.001. The correlation coefficient was 0.99.
Accuracy was determined by measurement of the recovery of 4 individual samples at 4 telmisartan concentrations (10.0, 50.0, 100.0, and 500.0 nM). The recovery of the 4 concentrations was 92.66%, 98.53%, 97.40%, and 99.25%, respectively. The mean recovery was 96.96% ± 2.97%.
Precision was determined by measurement of the variability of the measurement of the telmisartan concentrations in 4 individual samples at 4 concentrations (10.0, 50.0, 100.0, and 500.0 nM). The coefficient of variation was 12.90%, 5.15%, 2.74%, and 17.17% respectively. The mean coefficient of variation was 9.49% ± 6.71%. The limit of detection (LOD) was determined with 0.2 nM, and the limit of quantitation (LOQ) was 0.7 nM. The LOD and LOQ were determined based on the standard deviation of the response and the slope of the calibration curve.
Nisoldipine concentrations were determined using gas chromatography/mass spectrometry (GC/MS), a method previously described by Marques et al19 and slightly modified in our laboratory. As both nisoldipine and nifedipine are photosensitive compounds, the sample preparation and instrumental analysis were performed in a darkroom using yellow light, and for all the procedures, light-impervious tubes were used. Internal standard nifedipine (10 nM), 60-µL solutions of NaOH (12.5 M), and 600 µL of toluene were added to the aliquots (600 µL) of plasma taken from the patients receiving nisoldipine or the combination of telmisartan and nisoldipine. After shaking for 1 hour at 37°C (horizontal shaker, 300 rpm) and centrifugation for 10 minutes at 4°C (7000 rpm), the organic phases (500 µL) were separated and subsequently evaporated (Savant, Speed Vac, SC 110) to dryness. The residues, reconstituted in 60 µL of toluene and shaken for 15 minutes at 37°C (horizontal shaker, 600 rpm), were used for GC/MS.
The isolated enantiomers of nisoldipine were quantified with a gas chromatograph coupled to a model GC-MS Varian 1200 mass spectrometer. The detector operated at 300°C in the single ion monitoring (SIM) mode with electron-impact ionization. The m/z signal used for the quantification of nisoldipine was 386, whereas it was 344 for internal standard nifedipine. The identity of the peak in the mass chromatograms was confirmed by visual and computerized comparison of the peaks underlying mass spectra, with reference spectra recorded during this study. Calibration curves were generated from 0.05 pmol/L to 50 nmol/L (y = 0.99x + 0.05; r2 = 0.99), with the lowest concentration being the LOQ. Recovery was 99% ± 2%, and imprecision was 12% at the LOQ (n = 4). Intraday and interday variability were 2.6% and 3.3%, respectively (n = 6).
Pharmacokinetic Parameters
The measured plasma concentrations of telmisartan and nisoldipine served to calculate the following pharmacokinetic parameters: AUC at steady state (AUCss), which was calculated using the linear trapezoidal rule; Cmax at steady state (Cmax ss), defined as the maximum concentration observed after 1 dose at steady state; tmax at steady state (tmax ss), defined as the time of maximum observed concentration after 1 dose at steady state; terminal elimination half-life at steady state (t
ss), calculated using the formula t = ln 2/
z, with z being the first-order rate constant associated with the terminal (log-linear) portion of the concentration-time curve; and the mean residence time at steady state extrapolated to infinity (MRTss). All pharmacokinetic calculations were performed using WinNonlin 5.0.1 software (Pharsight, Mountain View, Calif; noncompartmental analysis).
Sample Size Calculation and Statistical Analysis
Given the known stable clinical efficacy and tolerability despite a considerable interindividual variance of telmisartan bioavailability, only a significant deviation from the current range (ie, ±75%-100%) of AUCs would be of clinical relevance. Based on a predescribed coefficient of variation of 0.55 of the geometric mean of the AUC, we estimated a relative within-group standard deviation of 0.4 to 0.6.20 We assumed relative differences of the means of at least 0.75 to be clinically significant. For a power of 80% and an alpha of 5%, this corresponds to a minimal sample size of 6 to 11 patients per group.
Distribution of data was tested using the Kolmogorov-Smirnov test. Continuous variables were expressed as appropriate as arithmetic mean ± standard deviation (SD), as geometric mean ± coefficients of variation of the geometric mean (pharmacokinetic parameters), or as median with 25% and 75% percentiles (interquartile range; nonparametric data). Differences in baseline characteristics among groups were tested with 1-way analysis of variance (ANOVA) if normally distributed, whereas baseline differences of variables with skewed distribution were tested with the Kruskal-Wallis H or Mann-Whitney U test. All pharmacokinetic parameters except for tmax ss were log-transformed prior to data analysis. Differences in pharmacokinetic parameters between monotherapy and combination groups were subsequently determined using the unpaired Student t test (log-transformed variables) or Mann-Whitney U test (tmax ss). Probability values less than 0.05 were considered significant. For all statistical analyses, SPSS version 13.0 was used.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics of Telmisartan and Nisoldipine
All below-mentioned pharmacokinetic values are summarized in Tables III and IV. Application at steady state of a single dose of telmisartan (80 mg) in patients with essential hypertension resulted in a geometric mean of AUCss (2.91 µmol·h/L), CL/fss (766 mL/min), and Vz/fss (1204 L), as well as a geometric mean Cmax ss of 1.18 µmol/L and a geometric mean tmax ss of 0.78 hours. The geometric mean half-life and mean residence time at steady state in this group were 17.1 and 10.4 hours, respectively. Coapplication at steady state of 80 mg telmisartan and 10 mg nisoldipine (combination group) led to significantly higher AUCss values of telmisartan (6.76 µmol·h/L; P < .01) and significantly lower CL/fss (351 mL/min) and Vz/fss values (455 L) as compared to those observed in the monotherapy group. In contrast, none of the other pharmacokinetic parameters investigated significantly differed between the combination and monotherapy group (Table III).
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As for nisoldipine pharmacokinetic parameters, a nonsignificant trend toward higher Cmax ss and AUCss values and a trend toward lower tmax ss were observed in patients receiving the combination of nisoldipine and telmisartan as compared to those receiving nisoldipine alone (Table IV). Interestingly, nisoldipine plasma concentrations measured 4 hours after tablet intake in patients of the combination group were significantly higher than those measured in patients randomized to receive nisoldipine alone (Figure 1B).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The main finding of this study is that the AUCss of telmisartan was significantly higher (132% increase); consequently, CL/fss and Vz/fss were significantly reduced in patients receiving both telmisartan and nisoldipine as compared to those receiving telmisartan alone. In this regard, it has to be mentioned that from a regulatory point of view (Food and Drug Administration and European Agency for the Evaluation of Medicinal Products [EMEA] guidelines for the conductance of drug interaction trials), drug interaction trials need to adhere to the crossover format. Hence, in light of the chosen parallel group design, our data will have to be confirmed in larger crossover trials. Nonetheless, our results strongly suggest that concomitant treatment with nisoldipine increases telmisartan bioavailability in patients with essential hypertension.
The reason for the increased bioavailability of telmisartan—in combined treatment with nisoldipine—remains speculative. In humans, telmisartan is almost exclusively subject to hepatic metabolism, primarily involving direct glucuronidation followed by biliary elimination.8 Importantly, telmisartan is not a substrate of any of the CYP isoenzymes, particularly CYP3A4, which have been described to play a major role in the metabolism of dihydropyridines, such as nisoldipine.21 In addition, a variety of dihydropyridines have been shown to inhibit P-glycoprotein (P-gp) activity in vitro, a transporter molecule that is involved in reducing intestinal and/or hepatic efflux elimination of various drugs.22 Whether nisoldipine modifies P-gp expression or activity is still unknown, but structural similarities of P-gp-inhibiting dihydropyridines and nisoldipine may indicate that nisoldipine has indeed the potential to modify P-gp function.22 Although P-gp dependency of telmisartan has not been demonstrated so far, telmisartan has been shown to induce bioavailability of the known P-gp substrate digoxin, suggesting a possible affinity of telmisartan to this transporter molecule.23 Thus, nisoldipine-induced inhibition of P-gp represents 1 potential mechanism that may contribute to increased oral telmisartan bioavailability in concomitant use with nisoldipine. Nevertheless, further in vitro and in vivo studies are needed to clarify whether nisoldipine and telmisartan indeed modify P-gp activity. By contrast, renal elimination appears not to play an important role in nisoldipine or telmisartan excretion (eg, bioavailability and pharmacokinetics of nisoldipine were not significantly different in patients with various degree of renal impairment).5,8 Hence, interaction of both drugs on the renal level is rather unlikely.
Furthermore, bioavailability of telmisartan has been reported to be significantly higher in women as compared to men (up to 3-fold higher AUC), a phenomenon that was not apparent in our study cohort (Table V).8 Moreover, gender ratios of the combination and telmisartan group were similar. Thus, a gender-specific bias apparently does not contribute to the observed nisoldipine-induced increase in telmisartan AUCss.
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As far as nisoldipine pharmacokinetics are concerned, patients randomized to the combination group displayed a trend toward higher nisoldipine Cmax ss and AUCss values as compared to those randomized to receive nisoldipine alone. In this regard, it seems plausible that mutual interaction of telmisartan and nisoldipine metabolism or excretion may equally affect telmisartan and nisoldipine pharmacokinetics, thereby inducing nisoldipine bioavailability. On the other hand, we cannot exclude that differences in treatment duration prior to plasma analyses (3 weeks [nisodipine monotherapy group] vs 6 weeks [combination group]) are responsible for these observations. Moreover, the telmisartan-induced increase in nisoldipine AUCss was rather minor—approximately 30%—and failed to reach statistical significance, presumably due to the small effect and the rather high level of data variability, which may be caused by a low and extremely variable bioavailability (4%-10%) of nisoldipine after oral application.6 Thus, the impact of telmisartan on nisoldipine pharmacokinetics remains to be determined in larger crossover trials.
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Telmisartan alone or in combination with nisoldipine significantly reduced blood pressure in our trial, whereas patients treated with nisoldipine alone merely showed a nonsignificant trend toward decreased blood pressure. The reason for this minor effect of nisoldipine monotherapy on blood pressure remains obscure but may be attributable to the small number of patients included in the study. Nevertheless, efficacy of nisoldipine in lowering blood pressure has been convincingly demonstrated in other clinical trials.26,27
Telmisartan, whether given alone or in combination with nisoldipine, was well tolerated, with no adverse events in the telmisartan monotherapy group and only few minor transient adverse events in the combination group, supposedly attributable to the nisoldipine component of the medication. Previous clinical studies with telmisartan and nisoldipine, respectively, had shown similar levels of tolerance.5,8,10,25-27 The most often recorded adverse events in our study were tibial edema, headache, and dizziness—the most common side effects of nisoldipine—which occurred with a similar frequency in the nisoldipine monotherapy and the combination groups. These data suggest that the observed increase in telmisartan AUCss in the combination group was not associated with a significantly reduced tolerability as compared to telmisartan monotherapy. Further comparative trials indicate that telmisartan has a tolerability profile similar to amlodipine or atenolol (with or without hydrochlorothiazide), other angiotensin II receptor antagonists (valsartan and losartan), and hydrochlorothiazide alone or telmisartan in combination with hydrochlorothiazide (including telmisartan 40 or 80 mg with hydrochlorothiazide as a fixed-dose combination), although edema was more common with amlodipine than telmisartan.28-31
In conclusion, the results of this study strongly suggest that concomitant administration of telmisartan and nisoldipine significantly increases telmisartan AUCss. In contrast, we observed a rather minor trend toward higher nisoldipine AUCss in the combination group. All treatments were well tolerated, and there was no clinical evidence that nisoldipine-mediated induction of telmisartan AUCss was associated with a higher incidence of adverse events in this group. However, larger clinical trials in the crossover format will have to confirm whether pharmacokinetic interaction of nisoldipine and telmisartan may enhance antihypertensive efficacy with unchanged tolerability.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This study was supported by Bayer Vital GmbH, Wuppertal, Germany.
* Both Bajcetic and Benndorf contributed equally to this work. 
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REFERENCES |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med. 1993; 328: 914-921.
2. Materson BJ. Variability in response to antihypertensive drug treatment. Hypertension. 2004;43: 1166-1167.
3. Chobanian AV, Bakris GL, Black HR, et al and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42: 1206-1252.
4. Zannad F. Nisoldipine coat-core and heart rate response during treatment of hypertension. Int J Clin Pract. 1999;53: 65-71.[Web of Science][Medline] [Order article via Infotrieve]
5. Nisoldipine (Sular®). In Physicians' Desk Reference. 60th ed. Montvale, NJ: Medical Economics; 2005: 1260-1262.
6. Heinig R. Clinical pharmacokinetics of nisoldipine coat-core. Clin Pharmacokinet. 1998;35: 191-208.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
7. White WB, Saunders E, Noveck RJ, Ferdinand K. Comparative efficacy and safety of nisoldipine extended-release (ER) and amlodipine (CESNA-III study) in African American patients with hypertension. Am J Hypertens. 2003;16(pt 1): 739-745.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Battershill AJ, Scott LJ. Telmisartan: a review of its use in the management of hypertension. Drugs. 2006;66: 51-83.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
9. Sharpe M, Jarvis B, Goa KL. Telmisartan: a review of its use in hypertension. Drugs. 2001;61: 1501-1529.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Telmisartan (Micardis®). In Physicians' Desk Reference. 60th ed. Montvale, NJ: Medical Economics; 2005: 997-999.
11. Zhu JR, Bai J, Cai NS, et al. Efficacy and safety of telmisartan vs. losartan in control of mild-to-moderate hypertension: a multi-centre, randomised, double-blind study. Int J Clin Pract Suppl. 2004;145: 46-49.
12. Neutel JM, Frishman WH, Oparil S, Papademitriou V, Guthrie G. Comparison of telmisartan with lisinopril in patients with mild-to-moderate hypertension. Am J Ther. 1999;6: 161-166.[Medline] [Order article via Infotrieve]
13. Smith DH. Treatment of hypertension with an angiotensin II-receptor antagonist compared with an angiotensin-converting enzyme inhibitor: a review of clinical studies of telmisartan and enalapril. Clin Ther. 2002;24: 1484-1501.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Alcocer L, Fernandez-Bonetti P, Campos E, et al. Clinical efficacy and safety of telmisartan 80 mg once daily vs. atenolol 50 mg once daily in patients with mild-to-moderate hypertension. Int J Clin Pract Suppl. 2004;145: 35-39.
15. Lacourciere Y, Lenis J, Orchard R, et al. A comparison of the efficacies and duration of action of the angiotensin II receptor blockers telmisartan and amlodipine. Blood Press Monit. 1998; 3: 295-302.[Medline] [Order article via Infotrieve]
16. Darbishire PL, Shepler B, Sutton JM. Differences among angiotensin II receptor blockers. US Pharm. 2004;10: HS19-HS25.
17. Stangier J, Su CA. Pharmacokinetics of repeated oral doses of amlodipine and amlodipine plus telmisartan in healthy volunteers. J Clin Pharmacol. 2000;40(pt 1): 1347-1354.[Abstract]
18. EMEA Guideline CPMP/ICH/381/95; Q 2 (R1) Validation of Analytical Procedures: Text and Methodology; June 1995.
19. Marques MP, Santos NA, Coelho EB, Bonato PS, Lanchote VL. Enantioselective assay of nisoldipine in human plasma by chiral high-performance liquid chromatography combined with gas chromatographic-mass spectrometry: applications to pharmacokinetics. J Chromatogr B Biomed Sci Appl. 2001;762: 87-95.[CrossRef][Medline] [Order article via Infotrieve]
20. Stangier J, Su CA, Brickl R, Franke H. Pharmacokinetics of single-dose telmisartan 120 mg given during and between hemodialysis in subjects with severe renal insufficiency: comparison with healthy volunteers. J Clin Pharmacol. 2000;40(pt 1): 1365-1372.[Abstract]
21. Unger T, Kaschina E. Drug interactions with angiotensin receptor blockers: a comparison with other antihypertensives. Drug Saf. 2003;26: 707-720.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
22. Klotz U. Interaction potential of lercanidipine, a new vasoselective dihydropyridine calcium antagonist. Arzneimittelforschung. 2002;52: 155-161.[Medline] [Order article via Infotrieve]
23. Stangier J, Su CA, Hendriks MG, et al. The effect of telmisartan on the steady-state pharmacokinetics of digoxin in healthy male volunteers. J Clin Pharmacol. 2000;40(pt 1): 1373-1379.[Abstract]
24. Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther. 2006;112: 71-105.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
25. Stangier J, Su CA, Fraunhofer A, Tetzloff W. Pharmacokinetics of acetaminophen and ibuprofen when coadministered with telmisartan in healthy volunteers. J Clin Pharmacol. 2000;40(pt 1): 1338-1346.[Abstract]
26. Rosenfeld JB, Zabludowski J. The efficacy and tolerability of nifedipine (NIF) and nisoldipine (NIS) both alone and combined with a beta-blocker in patients with essential hypertension: a multi-center, parallel-group study. J Clin Pharmacol. 1989;29: 1013-1016.[Abstract]
27. White WB, Saunders E, Noveck RJ, Ferdinand K. Comparative efficacy and safety of nisoldipine extended-release (ER) and amlodipine (CESNA-III study) in African American patients with hypertension. Am J Hypertens. 2003;16(pt 1): 739-745.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
28. Lacourciere Y, Lenis J, Orchard R, et al. A comparison of the efficacies and duration of action of the angiotensin II receptor blockers telmisartan and amlodipine. Blood Press Monit. 1998; 3: 295-302.[Medline] [Order article via Infotrieve]
29. Poirier L, de Champlain J, Larochelle P, Lamarre-Cliche M, Lacourciere Y. A comparison of the efficacy and duration of action of telmisartan, amlodipine and ramipril in patients with confirmed ambulatory hypertension. Blood Press Monit. 2004;9: 231-236.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
30. Freytag F, Schelling A, Meinicke T, Deichsel G, and the Telmisartan Hypertension Experience in a Randomized European Study Versus Atenolol Study Group. Comparison of 26-week efficacy and tolerability of telmisartan and atenolol, in combination with hydrochlorothiazide as required, in the treatment of mild to moderate hypertension: a randomized, multicenter study. Clin Ther. 2001;23: 108-123.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
31. Lacourciere Y, Neutel JM, Schumacher H. Comparison of fixed-dose combinations of telmisartan/hydrochlorothiazide 40/12.5 mg and 80/12.5 mg and a fixed-dose combination of losartan/hydrochlorothiazide 50/12.5 mg in mild to moderate essential hypertension: pooled analysis of two multicenter, prospective, randomized, open-label, blinded-end point (PROBE) trials. Clin Ther. 2005;27: 1795-1805.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
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