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Volume 48, No. 3/2010(March)
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Original Research
Relation of the first hypertension-associated event with medication, compliance and persistence in naïve hypertensive patients after initiating monotherapy
J. Mathes, K. Kostev, A. Gabriel, O. Pirk and R.E. Schmieder
173
48$
Abstract
Objective: To analyze the relation of medication, compliance and persistence with the risk of the first hypertensionassociated event in naïve hypertensive patients after initiating monotherapy with any of the first-line antihypertensive drug classes. Methods: A retrospective cohort study in the IMS Disease Analyzer database was performed. The study cohort comprised all previously untreated hypertensive patients who were free from hypertension-associated comorbidities, in whom new monotherapy with angiotensin II receptor blockers (ARBs), ACE-inhibitors (ACEIs), beta-blockers (BBs), calcium channel blockers (CCBs) or diuretics was initiated. Compliance and persistence were determined within 2 years. The relation between medication, compliance, persistence and risk of the first hypertension-associated event was analyzed using a Cox regression model. Outcomes in the ARB cohort were compared with outcomes in each other drug class cohort separately and with outcomes in the group of non-ARBs (pooled data). Results: 7,661 patients were identified with a follow-up of at least 2 years (totaling 45,585 patient-years of follow-up). ARBs were associated with more favorable measures (all p < 0.05) of compliance (0.86 vs. 0.82 and 0.74, respectively) and persistence (509 days vs. 459 and 324 days) compared with the group of non-ARBs and diuretics, respectively. The risk of the first hypertension-associated event was higher (all p < 0.05) with diuretics (adjusted hazard ratio (aHR) 0.68), BBs (0.79), CCBs (0.78), and the group of non-ARBs (0.81) and was similar with ACEIs (aHR 0.93, p = 0.37) compared to ARBs. Overall, high compliance was associated with a reduced risk of the first event (p < 0.05). Conclusion: Our real-world data suggest that initiating a treatment with ARB monotherapy shows significant benefits in most outcomes including hypertension-related complications compared to other antihypertensive drug monotherapies. The documented impact of compliance on the risk of the first event should have clinical and policy implications.Correspondence to:
J. Mathes, MPharm
IMS HEALTH GmbH & Co. OHG
Health Economics & Outcomes Research
Hefnersplatz 10
90402 Nuremberg, Germany
Email: JMathes@de.imshealth.com
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 3/2010 (173-183)
Relation of the first hypertension-associated event with medication, compliance and persistence in naïve hypertensive patients after initiating monotherapy
J. Mathes1, K. Kostev2, A. Gabriel1, O. Pirk1 and R.E. Schmieder3
1IMS HEALTH GmbH & Co. OHG, Health Economics & Outcomes Research, Nuremberg, 2IMS HEALTH GmbH & Co. OHG, Centre of Excellence Patient Data, Frankfurt am Main and 3Friedrich-Alexander-University Erlangen-Nuremberg, Department of Nephrology and Hypertension, University Hospital, Erlangen, Germany Objective: To analyze the relation of medication, compliance and persistence with the risk of the first hypertensionassociated event in naïve hypertensive patients after initiating monotherapy with any of the first-line antihypertensive drug classes. Methods: A retrospective cohort study in the IMS Disease Analyzer database was performed. The study cohort comprised all previously untreated hypertensive patients who were free from hypertension-associated comorbidities, in whom new monotherapy with angiotensin II receptor blockers (ARBs), ACE-inhibitors (ACEIs), beta-blockers (BBs), calcium channel blockers (CCBs) or diuretics was initiated. Compliance and persistence were determined within 2 years. The relation between medication, compliance, persistence and risk of the first hypertension-associated event was analyzed using a Cox regression model. Outcomes in the ARB cohort were compared with outcomes in each other drug class cohort separately and with outcomes in the group of non-ARBs (pooled data). Results: 7,661 patients were identified with a follow-up of at least 2 years (totaling 45,585 patient-years of follow-up). ARBs were associated with more favorable measures (all p < 0.05) of compliance (0.86 vs. 0.82 and 0.74, respectively) and persistence (509 days vs. 459 and 324 days) compared with the group of non-ARBs and diuretics, respectively. The risk of the first hypertension-associated event was higher (all p < 0.05) with diuretics (adjusted hazard ratio (aHR) 0.68), BBs (0.79), CCBs (0.78), and the group of non-ARBs (0.81) and was similar with ACEIs (aHR 0.93, p = 0.37) compared to ARBs. Overall, high compliance was associated with a reduced risk of the first event (p < 0.05). Conclusion: Our real-world data suggest that initiating a treatment with ARB monotherapy shows significant benefits in most outcomes including hypertension-related complications compared to other antihypertensive drug monotherapies. The documented impact of compliance on the risk of the first event should have clinical and policy implications.Correspondence to:
J. Mathes, MPharm
IMS HEALTH GmbH & Co. OHG
Health Economics & Outcomes Research
Hefnersplatz 10
90402 Nuremberg, Germany
Email: JMathes@de.imshealth.com
Original Research
Efficacy and tolerability of EPs 7630 in children and adolescents with acute bronchitis – A randomized, double-blind, placebo-controlled multicenter trial with a herbal drug preparation from Pelargonium sidoides roots
W. Kamin, V. Maydannik, F.A. Malek and M. Kieser
184
0$
Abstract
Objective: The study aim was to demonstrate the efficacy and to investigate the tolerability of EPs 7630, a herbal drug preparation from Pelargonium sidoides roots, in the treatment of patients (1 – 18 years) with acute bronchitis outside the strict indication for antibiotics. Materials and methods: A total of 200 patients were randomized to receive either active drug containing EPs 7630 (1 – 6 years: 3 × 10 drops/d; > 6 – 12 years: 3 × 20 drops/d; > 12 – 18 years: 3 × 30 drops/d) or placebo for 7 consecutive days. Primary outcome measure: change in the total score of bronchitis-specific symptoms (BSS) from Day 0 to Day 7. Main secondary outcome measures: treatment outcome, patients’ satisfaction with treatment, onset of effect, bed rest. Results: From baseline to Day 7, the mean BSS score improved significantly more for EPs 7630 compared with placebo (3.4 ± 1.8 vs. 1.2 ± 1.8 points, p < 0.0001). On Day 7, treatment outcome was significantly better (p < 0.0001), satisfaction with treatment more pronounced (77.6% vs. 25.8%, p < 0.0001), onset of effect faster, and time of bed rest shorter as compared with placebo. Tolerability was similarly good in both groups. All adverse events were assessed as non-serious. Conclusion: EPs 7630 was shown to be efficacious and safe in the treatment of acute bronchitis in children and adolescents outside the strict indication for antibiotics with patients treated with EPs 7630 perceiving a more favorable course of the disease and a good tolerability as compared with placebo.Correspondence to:
W. Kamin, PD
University Hospital Pediatrics
Langenbeckstr. 1
55101 Mainz, Germany
Email: wkamin@evkhamm.de
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 3/2010 (184-191)
Efficacy and tolerability of EPs 7630 in children and adolescents with acute bronchitis – A randomized, double-blind, placebo-controlled multicenter trial with a herbal drug preparation from Pelargonium sidoides roots
W. Kamin1, V. Maydannik2, F.A. Malek3 and M. Kieser4
1University Hospital Pediatrics, Mainz, Germany, 2Pediatrics Faculty, National Medical University of Ukraine, Kiev, Ukraine, 3Dr. Willmar Schwabe GmbH & Co. KG Pharmaceuticals, Clinical Research Department, Karlsruhe and 4Institute of Medical Biometry and Informatics, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany Objective: The study aim was to demonstrate the efficacy and to investigate the tolerability of EPs 7630, a herbal drug preparation from Pelargonium sidoides roots, in the treatment of patients (1 – 18 years) with acute bronchitis outside the strict indication for antibiotics. Materials and methods: A total of 200 patients were randomized to receive either active drug containing EPs 7630 (1 – 6 years: 3 × 10 drops/d; > 6 – 12 years: 3 × 20 drops/d; > 12 – 18 years: 3 × 30 drops/d) or placebo for 7 consecutive days. Primary outcome measure: change in the total score of bronchitis-specific symptoms (BSS) from Day 0 to Day 7. Main secondary outcome measures: treatment outcome, patients’ satisfaction with treatment, onset of effect, bed rest. Results: From baseline to Day 7, the mean BSS score improved significantly more for EPs 7630 compared with placebo (3.4 ± 1.8 vs. 1.2 ± 1.8 points, p < 0.0001). On Day 7, treatment outcome was significantly better (p < 0.0001), satisfaction with treatment more pronounced (77.6% vs. 25.8%, p < 0.0001), onset of effect faster, and time of bed rest shorter as compared with placebo. Tolerability was similarly good in both groups. All adverse events were assessed as non-serious. Conclusion: EPs 7630 was shown to be efficacious and safe in the treatment of acute bronchitis in children and adolescents outside the strict indication for antibiotics with patients treated with EPs 7630 perceiving a more favorable course of the disease and a good tolerability as compared with placebo.Correspondence to:
W. Kamin, PD
University Hospital Pediatrics
Langenbeckstr. 1
55101 Mainz, Germany
Email: wkamin@evkhamm.de
Original Research
Effect of saquinavir/ritonavir on P-glycoprotein activity in healthy volunteers using digoxin as a probe
C. Schmitt, B. Kaeser, M. Riek, N. Bech and C. Kreuzer
192
36$
Abstract
Background: Saquinavir and ritonavir, both human immunodeficiency virus-1 protease inhibitors, also inhibit the adenosine triphosphate-dependent efflux pump P-glycoprotein (P-gp), which is located at a variety of anatomic sites, including the human intestine. P-gp plays an important role in the absorption, distribution and elimination of numerous drugs. This study investigated the inhibitory potential of multiple administrations of ritonavir-boosted saquinavir at the target therapeutic dose of 1,000 mg saquinavir/100 mg ritonavir twice daily on the pharmacokinetics of oral digoxin, a model P-gp substrate that is predominantly excreted as unchanged drug in the urine. Methods: In an open-label, 1-sequence, 2-period crossover study, a single digoxin dose of 0.5 mg was administered orally on Day 1. From Days 11 through 26, participants received oral administration of saquinavir/ritonavir 1,000/100 mg twice daily. A second dose of digoxin was administered on Day 24. Blood and urine sampling for pharmacokinetic analyses of digoxin was performed at scheduled time points on Days 1 – 4 and Days 24 – 27. Serial blood samples were drawn to determine plasma levels of saquinavir and ritonavir on Days 21 – 24. Adverse event reports were collected. Results: Of the 17 enrolled participants (9 males and 8 females) who received at least one dose of study medication, 16 completed the study. Two weeks of pretreatment with ritonavir and saquinavir resulted in a 1.27-fold increase in digoxin Cmax (90% confidence interval (1.05 – 1.54)) and a 1.49-fold increase in AUC0–72 (90% CI (1.32 – 1.69)). Renal clearance decreased by a factor 0.88 from 111 to 97.3 ml/min while digoxin half-life increased from 37.0 to 45.3 h. The unbound fraction of digoxin was almost unaffected. The changes in digoxin renal clearance and exposure (AUC0–72) following 2 weeks of treatment with saquinavir/ritonavir were found to be more pronounced among female participants compared with males. Plasma concentrations of saquinavir/ritonavir at trough and at 4 h postdose were within the expected ranges for each gender, with female participants showing higher concentrations than male participants. All three treatments were well tolerated, with no serious adverse events noted. Despite the higher digoxin exposure among females compared to males following saquinavir/ritonavir administration, overall safety profiles were similar. On electrocardiographic readings, a trend of a longer PR interval was noted with triple combination of agents. Conclusions: Pretreatment with saquinavir/ritonavir 1,000/100 mg twice daily increased digoxin exposure most likely via P-gp-inhibition. Given the relatively narrow therapeutic window of digoxin, caution should be exercised when these three drugs are administered together. It is recommended to reduce digoxin doses and to monitor digoxin serum concentrations.Correspondence to:
C. Schmitt, PharmD
F. Hoffmann-La Roche, Ltd.
Pharmaceutical Division, 663/2113
4070 Basel, Switzerland
Email: Christophe.schmitt@roche.com
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 3/2010 (192-199)
Effect of saquinavir/ritonavir on P-glycoprotein activity in healthy volunteers using digoxin as a probe
C. Schmitt1, B. Kaeser1, M. Riek1, N. Bech2 and C. Kreuzer1
1F. Hoffmann-La Roche, Ltd., Pharmaceutical Division, Basel, Switzerland, and 2Roche Products Ltd., Welwyn Garden City, UK Background: Saquinavir and ritonavir, both human immunodeficiency virus-1 protease inhibitors, also inhibit the adenosine triphosphate-dependent efflux pump P-glycoprotein (P-gp), which is located at a variety of anatomic sites, including the human intestine. P-gp plays an important role in the absorption, distribution and elimination of numerous drugs. This study investigated the inhibitory potential of multiple administrations of ritonavir-boosted saquinavir at the target therapeutic dose of 1,000 mg saquinavir/100 mg ritonavir twice daily on the pharmacokinetics of oral digoxin, a model P-gp substrate that is predominantly excreted as unchanged drug in the urine. Methods: In an open-label, 1-sequence, 2-period crossover study, a single digoxin dose of 0.5 mg was administered orally on Day 1. From Days 11 through 26, participants received oral administration of saquinavir/ritonavir 1,000/100 mg twice daily. A second dose of digoxin was administered on Day 24. Blood and urine sampling for pharmacokinetic analyses of digoxin was performed at scheduled time points on Days 1 – 4 and Days 24 – 27. Serial blood samples were drawn to determine plasma levels of saquinavir and ritonavir on Days 21 – 24. Adverse event reports were collected. Results: Of the 17 enrolled participants (9 males and 8 females) who received at least one dose of study medication, 16 completed the study. Two weeks of pretreatment with ritonavir and saquinavir resulted in a 1.27-fold increase in digoxin Cmax (90% confidence interval (1.05 – 1.54)) and a 1.49-fold increase in AUC0–72 (90% CI (1.32 – 1.69)). Renal clearance decreased by a factor 0.88 from 111 to 97.3 ml/min while digoxin half-life increased from 37.0 to 45.3 h. The unbound fraction of digoxin was almost unaffected. The changes in digoxin renal clearance and exposure (AUC0–72) following 2 weeks of treatment with saquinavir/ritonavir were found to be more pronounced among female participants compared with males. Plasma concentrations of saquinavir/ritonavir at trough and at 4 h postdose were within the expected ranges for each gender, with female participants showing higher concentrations than male participants. All three treatments were well tolerated, with no serious adverse events noted. Despite the higher digoxin exposure among females compared to males following saquinavir/ritonavir administration, overall safety profiles were similar. On electrocardiographic readings, a trend of a longer PR interval was noted with triple combination of agents. Conclusions: Pretreatment with saquinavir/ritonavir 1,000/100 mg twice daily increased digoxin exposure most likely via P-gp-inhibition. Given the relatively narrow therapeutic window of digoxin, caution should be exercised when these three drugs are administered together. It is recommended to reduce digoxin doses and to monitor digoxin serum concentrations.Correspondence to:
C. Schmitt, PharmD
F. Hoffmann-La Roche, Ltd.
Pharmaceutical Division, 663/2113
4070 Basel, Switzerland
Email: Christophe.schmitt@roche.com
Original Research
Pediatric iron preparations for infants in Bahrain: some therapeutic concerns
K.A.J. Al Khaja, R.P. Sequeira, T. Al-Ansari, A.H.H. Damanhori, H. James and S.S. Handu
200
28$
Abstract
Background: Infants and children are at a high risk for medication errors. Objectives: This retrospective study was conducted to determine the type and prevalence of prescribing errors related to pediatric iron preparations prescribed in primary care in Bahrain. Methods: Prescriptions issued for infants and collected at 20 health center pharmacies for 2 weeks were audited, specifically for errors. Results: Of 2,282 prescriptions dispensed for infants (mean age 9.14 ± 0.91 months), 159 (7.0%) included an iron preparation. Iron preparations were mostly prescribed (90.6%) with brand names, several of which were neither listed in the primary care drug list nor were available as pediatric dosage forms. 42 (26.4%) prescriptions were issued without specifying the dosage forms, 14 (8.8%) without the duration of therapy and 4 (2.5%) without dosage. Iron dosage was stated as metric volume (ml) and metric weight (mg elemental iron) units in 78.6% and 9.4% of the prescriptions, respectively. The mean elemental iron (± SD) prescribed for treating anemia was 4.5 ± 1.7 mg/kg body weight. A significant difference was observed between physicians and nurses regarding the amount of elemental iron prescribed for treating anemia. Conclusions: Prescribing of multiple brands of pediatric iron preparations unavailable in the primary care drug list and in pediatric dosage forms, prescribing iron as inconvenient decimal fractions (metric volume units), and omission errors in prescriptions, were common. This may be related to poor communications between the prescribers and the pharmacy services and a lack of information dissemination on newly introduced iron formulations. Moreover, frequent changes in brand availability in primary care may have created confusion for prescribers. The communication between pharmacy services and prescribers should be strengthened, and the procurement of multiple brands should be discouraged. A better management of drug supply and effective policies to minimize prescribing errors are needed in Bahrain.Correspondence to:
Prof. K.A.J. Al Khaja
Arabian Gulf University
Department of Pharmacology and Therapeutics
P.O. Box 22979, Kingdom of Bahrain
Email: khlidj@agu.edu.bh
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 3/2010 (200-205)
Pediatric iron preparations for infants in Bahrain: some therapeutic concerns
K.A.J. Al Khaja1, R.P. Sequeira1, T. Al-Ansari2, A.H.H. Damanhori2, H. James1 and S.S. Handu1
1Department of Pharmacology and Therapeutics, Arabian Gulf University, and 2Primary Care, Ministry of Health, Manama, Kingdom of Bahrain Background: Infants and children are at a high risk for medication errors. Objectives: This retrospective study was conducted to determine the type and prevalence of prescribing errors related to pediatric iron preparations prescribed in primary care in Bahrain. Methods: Prescriptions issued for infants and collected at 20 health center pharmacies for 2 weeks were audited, specifically for errors. Results: Of 2,282 prescriptions dispensed for infants (mean age 9.14 ± 0.91 months), 159 (7.0%) included an iron preparation. Iron preparations were mostly prescribed (90.6%) with brand names, several of which were neither listed in the primary care drug list nor were available as pediatric dosage forms. 42 (26.4%) prescriptions were issued without specifying the dosage forms, 14 (8.8%) without the duration of therapy and 4 (2.5%) without dosage. Iron dosage was stated as metric volume (ml) and metric weight (mg elemental iron) units in 78.6% and 9.4% of the prescriptions, respectively. The mean elemental iron (± SD) prescribed for treating anemia was 4.5 ± 1.7 mg/kg body weight. A significant difference was observed between physicians and nurses regarding the amount of elemental iron prescribed for treating anemia. Conclusions: Prescribing of multiple brands of pediatric iron preparations unavailable in the primary care drug list and in pediatric dosage forms, prescribing iron as inconvenient decimal fractions (metric volume units), and omission errors in prescriptions, were common. This may be related to poor communications between the prescribers and the pharmacy services and a lack of information dissemination on newly introduced iron formulations. Moreover, frequent changes in brand availability in primary care may have created confusion for prescribers. The communication between pharmacy services and prescribers should be strengthened, and the procurement of multiple brands should be discouraged. A better management of drug supply and effective policies to minimize prescribing errors are needed in Bahrain.Correspondence to:
Prof. K.A.J. Al Khaja
Arabian Gulf University
Department of Pharmacology and Therapeutics
P.O. Box 22979, Kingdom of Bahrain
Email: khlidj@agu.edu.bh
Original Research
Blood pressure-lowering and antiproteinuric effect of switching from high-dose angiotensin receptor blockers to normal-dose telmisartan and low-dose hydrochlorothiazide in hypertensive patients with chronic kidney disease
M. Abe, K. Okada, T. Maruyama, S. Matsumoto and K. Matsumoto
206
36$
Abstract
Objectives: We evaluated the changes in the blood pressure and urinary protein excretion in poorly controlled hypertensive and proteinuric patients with mild to moderate chronic kidney disease (CKD) after switching from the high-dose angiotensin receptor blockers (ARBs) to a combination of normal-dose telmisartan (40 mg) and low-dose hydrochlorothiazide (HCTZ; 12.5 mg). Methods: 60 adults with Stages 2 – 3 CKD who had been receiving high-dose ARBs and had not achieved their target blood pressure of 130/80 mmHg were switched to a combination of telmisartan (40 mg) and HCTZ (12.5 mg) once daily for a 12-week study period. We measured the blood pressure, pulse rate, urinary protein excretion, and total monthly drug costs before and after the switch. Results: The mean systolic blood pressure dropped from 153 to 133 mm Hg and the mean diastolic blood pressure, from 89 to 78 mmHg (p < 0.0001, for both). Further, the mean blood pressure decreased (p < 0.0001), without any significant change in the pulse rate. Urinary protein excretion adjusted for urinary creatinine was reduced from 3,749 to 2,474 mg/g creatinine (p < 0.0001). No significant change was detected in the estimated glomerular filtration rate and serum creatinine level. With the switching from high-dose ARBs to the combination of normal-dose telmisartan and low-dose HCTZ treatment, the blood pressure decreased in all the subjects, and 36% of all the subjects achieved optimal blood pressure levels. No adverse metabolic effects were noted even among the diabetic patients. The monthly drug costs were significantly reduced after the switch (13,614 ± 6,108 vs. 9,936 ± 5,571 yen/month, p < 0.0001). Conclusions: We concluded that the telmisartan and HCTZ combination may be more efficacious than monotherapy of the high-dose ARBs in reducing blood pressure and urinary protein excretion in hypertensive patients with CKD. Further investigation would be required to assess whether the combination of high-dose ARBs and low-dose HCTZ has a greater antiproteinuric effect than the combination of normal-dose telmisartan (40 mg) and low-dose HCTZ (12.5 mg).Correspondence to:
M. Abe, MD
Division of Nephrology, Hypertension and Endocrinology
Department of Medicine
Nihon University School of Medicine
30-1, Oyaguchi-Kamimachi, Itabashi-ku
Tokyo 173-8610, Japan
Email: mabe@med.nihon-u.ac.jp
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 3/2010 (206-213)
Blood pressure-lowering and antiproteinuric effect of switching from high-dose angiotensin receptor blockers to normal-dose telmisartan and low-dose hydrochlorothiazide in hypertensive patients with chronic kidney disease
M. Abe, K. Okada, T. Maruyama, S. Matsumoto and K. Matsumoto
Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan Objectives: We evaluated the changes in the blood pressure and urinary protein excretion in poorly controlled hypertensive and proteinuric patients with mild to moderate chronic kidney disease (CKD) after switching from the high-dose angiotensin receptor blockers (ARBs) to a combination of normal-dose telmisartan (40 mg) and low-dose hydrochlorothiazide (HCTZ; 12.5 mg). Methods: 60 adults with Stages 2 – 3 CKD who had been receiving high-dose ARBs and had not achieved their target blood pressure of 130/80 mmHg were switched to a combination of telmisartan (40 mg) and HCTZ (12.5 mg) once daily for a 12-week study period. We measured the blood pressure, pulse rate, urinary protein excretion, and total monthly drug costs before and after the switch. Results: The mean systolic blood pressure dropped from 153 to 133 mm Hg and the mean diastolic blood pressure, from 89 to 78 mmHg (p < 0.0001, for both). Further, the mean blood pressure decreased (p < 0.0001), without any significant change in the pulse rate. Urinary protein excretion adjusted for urinary creatinine was reduced from 3,749 to 2,474 mg/g creatinine (p < 0.0001). No significant change was detected in the estimated glomerular filtration rate and serum creatinine level. With the switching from high-dose ARBs to the combination of normal-dose telmisartan and low-dose HCTZ treatment, the blood pressure decreased in all the subjects, and 36% of all the subjects achieved optimal blood pressure levels. No adverse metabolic effects were noted even among the diabetic patients. The monthly drug costs were significantly reduced after the switch (13,614 ± 6,108 vs. 9,936 ± 5,571 yen/month, p < 0.0001). Conclusions: We concluded that the telmisartan and HCTZ combination may be more efficacious than monotherapy of the high-dose ARBs in reducing blood pressure and urinary protein excretion in hypertensive patients with CKD. Further investigation would be required to assess whether the combination of high-dose ARBs and low-dose HCTZ has a greater antiproteinuric effect than the combination of normal-dose telmisartan (40 mg) and low-dose HCTZ (12.5 mg).Correspondence to:
M. Abe, MD
Division of Nephrology, Hypertension and Endocrinology
Department of Medicine
Nihon University School of Medicine
30-1, Oyaguchi-Kamimachi, Itabashi-ku
Tokyo 173-8610, Japan
Email: mabe@med.nihon-u.ac.jp
Original Research
Pharmacokinetics and pharmacodynamics of basiliximab in Japanese pediatric renal transplant patients
T. Nagai, Y. Gotoh, Y. Watarai, T. Tajima, K. Arai and K. Uchida
214
44$
Abstract
Objectives: This study was aimed at evaluating the pharmacokinetics and pharmacodynamics of basiliximab in Japanese pediatric renal transplant patients. Materials and methods: This study was carried out with the approval of the Institutional Review Board of our institution. Written consent was obtained from the legal representative of each patient, as also from the patients themselves where possible. Eligible patients were Japanese pediatric patients weighing less than 35 kg and younger than 15 years of age who were scheduled to undergo renal transplantation. Each patient was given intravenous basiliximab at the total dose of 20 mg administered in two divided doses of 10 mg each on the day of transplantation and on the fourth day after transplantation. Cyclosporine and corticosteroids were also administered as the basic concomitant maintenance immunosuppressive therapy. The time course of changes in the serum basiliximab concentrations and the percentage of CD25+ T-lymphocytes in the peripheral blood were determined up to 26 weeks after the transplantation to calculate the period of suppression of the CD25+ T-lymphocytes. Serum basiliximab was measured by an ELISA technique, and the percentage of CD25+ T-lymphocytes in the peripheral blood was determined by flow cytometry. Results: 6 Japanese pediatric patients weighing less than 35 kg and aged over 1 year and less than 15 years who were scheduled to undergo renal transplantation were enrolled in this study. In regard to the time course of changes of the serum basiliximab concentration, after the peak serum concentration was reached, basiliximab was gradually eliminated from the blood with a mean half-life of 7.06 days. CD25+ T-lymphocytes in the peripheral blood were suppressed completely when the serum concentration of basiliximab was over 0.2 µg/ml, and the period of suppression of the CD25+ T cells was 40.3 – 51.7 days (mean ± SD; 45.8 ± 4.9). Conclusion: Changes in the serum concentration of basiliximab and the period of suppression of CD25+ peripheral blood T-lymphocytes in Japanese pediatric renal transplant patients were similar to those reported for non-Japanese pediatric transplant patients and Japanese adult renal transplant patients with a cyclosporine and corticosteroid regimen. This indicates that expected efficacy can be obtained in Japanese pediatric renal transplant patients using the recommended dosing regimens validated by non-Japanese studies.Correspondence to:
T. Nagai
Department of Pediatric Nephrology
Aichi Children’s Health and Medical Center
1-2, Osakada, Morioka-cho
Obu City, Aichi, Japan
Email: nagataku@cool.odn.ne.jp
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 3/2010 (214-223)
Pharmacokinetics and pharmacodynamics of basiliximab in Japanese pediatric renal transplant patients
T. Nagai1, Y. Gotoh2, Y. Watarai3, T. Tajima4, K. Arai5 and K. Uchida3
1Department of Pediatric Nephrology, Aichi Children’s Health and Medical Center, 2Department of Pediatrics, 3Department of Transplant Surgery, Nagoya Daini Red-Cross Hospital Kidney Center, Aichi, 4Development Division, Novartis Pharma K.K., and 5Department of Urology, Tokyo Rosai Hospital, Tokyo, Japan Objectives: This study was aimed at evaluating the pharmacokinetics and pharmacodynamics of basiliximab in Japanese pediatric renal transplant patients. Materials and methods: This study was carried out with the approval of the Institutional Review Board of our institution. Written consent was obtained from the legal representative of each patient, as also from the patients themselves where possible. Eligible patients were Japanese pediatric patients weighing less than 35 kg and younger than 15 years of age who were scheduled to undergo renal transplantation. Each patient was given intravenous basiliximab at the total dose of 20 mg administered in two divided doses of 10 mg each on the day of transplantation and on the fourth day after transplantation. Cyclosporine and corticosteroids were also administered as the basic concomitant maintenance immunosuppressive therapy. The time course of changes in the serum basiliximab concentrations and the percentage of CD25+ T-lymphocytes in the peripheral blood were determined up to 26 weeks after the transplantation to calculate the period of suppression of the CD25+ T-lymphocytes. Serum basiliximab was measured by an ELISA technique, and the percentage of CD25+ T-lymphocytes in the peripheral blood was determined by flow cytometry. Results: 6 Japanese pediatric patients weighing less than 35 kg and aged over 1 year and less than 15 years who were scheduled to undergo renal transplantation were enrolled in this study. In regard to the time course of changes of the serum basiliximab concentration, after the peak serum concentration was reached, basiliximab was gradually eliminated from the blood with a mean half-life of 7.06 days. CD25+ T-lymphocytes in the peripheral blood were suppressed completely when the serum concentration of basiliximab was over 0.2 µg/ml, and the period of suppression of the CD25+ T cells was 40.3 – 51.7 days (mean ± SD; 45.8 ± 4.9). Conclusion: Changes in the serum concentration of basiliximab and the period of suppression of CD25+ peripheral blood T-lymphocytes in Japanese pediatric renal transplant patients were similar to those reported for non-Japanese pediatric transplant patients and Japanese adult renal transplant patients with a cyclosporine and corticosteroid regimen. This indicates that expected efficacy can be obtained in Japanese pediatric renal transplant patients using the recommended dosing regimens validated by non-Japanese studies.Correspondence to:
T. Nagai
Department of Pediatric Nephrology
Aichi Children’s Health and Medical Center
1-2, Osakada, Morioka-cho
Obu City, Aichi, Japan
Email: nagataku@cool.odn.ne.jp
Original Research
Effect of Schisandra sphenanthera extract on the concentration of tacrolimus in the blood of liver transplant patients
W. Jiang, X. Wang, X. Xu and L. Kong
224
28$
Abstract
Background: Tacrolimus (Tac) is widely used to prevent allograft rejection after liver transplantation. We found that the concentration of Tac in blood was significantly increased in liver transplant patients who were receiving Schisandra sphenanthera extract (SchE). The objective of this study was to determine the effect of SchE on the concentration of Tac in the blood of liver transplant patients. Materials and methods: Patients were initially administered Tac (first phase) and then SchE was provided (second phase). During the first phase of treatment, 46 patients received the same oral dose of Tac. In the second phase of treatment, 21 patients (Group A) received the same dose of Tac and 25 patients (Group B) received a lower dose of Tac. The concentration of Tac in the blood and the biochemical indices of liver function, as well as symptoms of Tac-related toxicity, were determined, and 14 patients were selected for a pharmacokinetic study. Results: After co-administration of Tac and SchE, the average increase in the mean concentration of Tac in the blood was 339% and 262% in Groups A and B, respectively. The liver function indices were decreased significantly (p < 0.01); whereas the average increase of Cmax, AUC0-12 and AUMC0-12 of Tac was 183%, 212% and 227%, respectively. Tac-associated side-effects, such as diarrhoea and agitation, decreased significantly in all patients, but the incidence of other side-effects did not change significantly. Conclusions: SchE markedly increased the concentration of Tac in the blood of liver transplant patients, improved liver function and reduced the incidence of Tac-associated side-effects.Correspondence to:
L. Kong, PhD, MD
Nanjing Medical University
The First Affiliated Hospital
Department of Liver Transplantation Center
The National Institute of Living Donor Liver Transplantation
300 Guangzhou Road, Nanjing 210029, China
Email: lbkong@njmu.edu.cn
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 3/2010 (224-229)
Effect of Schisandra sphenanthera extract on the concentration of tacrolimus in the blood of liver transplant patients
W. Jiang1, X. Wang2, X. Xu1 and L. Kong2
1Department of Neonatal Surgery, Nanjing Children’s Hospital Affiliated to Nanjing Medical University and 2Nanjing Medical University, The First Affiliated Hospital, Department of Liver Transplantation Center, The National Institute of Living Donor Liver Transplantation, Nanjing, China Background: Tacrolimus (Tac) is widely used to prevent allograft rejection after liver transplantation. We found that the concentration of Tac in blood was significantly increased in liver transplant patients who were receiving Schisandra sphenanthera extract (SchE). The objective of this study was to determine the effect of SchE on the concentration of Tac in the blood of liver transplant patients. Materials and methods: Patients were initially administered Tac (first phase) and then SchE was provided (second phase). During the first phase of treatment, 46 patients received the same oral dose of Tac. In the second phase of treatment, 21 patients (Group A) received the same dose of Tac and 25 patients (Group B) received a lower dose of Tac. The concentration of Tac in the blood and the biochemical indices of liver function, as well as symptoms of Tac-related toxicity, were determined, and 14 patients were selected for a pharmacokinetic study. Results: After co-administration of Tac and SchE, the average increase in the mean concentration of Tac in the blood was 339% and 262% in Groups A and B, respectively. The liver function indices were decreased significantly (p < 0.01); whereas the average increase of Cmax, AUC0-12 and AUMC0-12 of Tac was 183%, 212% and 227%, respectively. Tac-associated side-effects, such as diarrhoea and agitation, decreased significantly in all patients, but the incidence of other side-effects did not change significantly. Conclusions: SchE markedly increased the concentration of Tac in the blood of liver transplant patients, improved liver function and reduced the incidence of Tac-associated side-effects.Correspondence to:
L. Kong, PhD, MD
Nanjing Medical University
The First Affiliated Hospital
Department of Liver Transplantation Center
The National Institute of Living Donor Liver Transplantation
300 Guangzhou Road, Nanjing 210029, China
Email: lbkong@njmu.edu.cn
Case Report
Celecoxib in a 12-year-old boy with familial adenomatous polyposis
P. Pérez-Segura, A. Bodas, M. Sereno, B. Martínez-Amores, H. Olivera, S. Díaz, J.A. López-Asenjo, J. Puente, C. Maluenda and E. Díaz-Rubio
230
16$
Abstract
Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder characterized by colonic polyps in early adult life. Children with this disease are at risk for colonic cancer, so prophylactic colectomy is the standard treatment to prevent this complication. Chemoprevention experience with NSAIDs in children is exceptional. This case report describes our experience with Celecoxib, a COX-2 inhibitor, in a 12-year-old boy.Correspondence to:
A. Bodas
Department of Pediatrics
Hospital Clínico San Carlos
Madrid, Spain
Email: andresbpinedo@yahoo.es
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 3/2010 (230-232)
Celecoxib in a 12-year-old boy with familial adenomatous polyposis
P. Pérez-Segura1, A. Bodas2, M. Sereno1, B. Martínez-Amores1, H. Olivera1, S. Díaz1, J.A. López-Asenjo3, J. Puente1, C. Maluenda2 and E. Díaz-Rubio1
1Department of Oncology, 2Department of Pediatrics and 3Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder characterized by colonic polyps in early adult life. Children with this disease are at risk for colonic cancer, so prophylactic colectomy is the standard treatment to prevent this complication. Chemoprevention experience with NSAIDs in children is exceptional. This case report describes our experience with Celecoxib, a COX-2 inhibitor, in a 12-year-old boy.Correspondence to:
A. Bodas
Department of Pediatrics
Hospital Clínico San Carlos
Madrid, Spain
Email: andresbpinedo@yahoo.es
Bioavailability Section
Bioavailability of two oral suspension and two oral tablet formulations of nimesulide 100 mg in healthy Brazilian adult subjects
H.M. Rigato, B.C. Borges, C.E. Sverdloff, R.A. Moreno, , E. Orpineli and N. Carter Borges
233
44$
Abstract
A specific, fast and sensitive high performance liquid chromatography coupled to an electro spray tandem triple quadrupole mass spectrometer (LC-MS/MS) assay was developed for the determination of nimesulide in human plasma using carbamazepine as the internal standard. The lower limit of quantification (LLOQ) was 50 ng/ml and the calibration curves were linear in the concentration range of 50 – 6,000 ng/ml. Method inter-batch precision and accuracy ranged from 2.78 to 10.80%, and 94.92 to 102.46%, respectively. Intra-batch precision ranged from 2.44 to 7.74%, while intra-batch accuracy ranged from 91.70 to 104.73%. The analytical method was applied to evaluate the pharmacokinetic and relative bioavailability of two different pharmaceutical formulations containing nimesulide, one tablet and one oral suspension, manufactured by the same pharmaceutical factory, comparing with two reference Nisulid® formulations in 52 volunteers of both sexes previously divided in two groups of 26 subjects (13 men and 13 females each group). The test tablet formulation was not bioequivalent to the Nisulid® 100 mg tablet with respect to the rate of absorption, but was bioequivalent according to the extent of drug absorption. On the other hand, since the 90% CI for Cmax, AUC0-t and AUCinf were within the 80 – 125% interval in the oral suspension study, it was concluded that test oral suspension were bioequivalent to Nisulid® 50 mg/ml with respect to both the rate and extent of absorption.Correspondence to:
N. Carter Borges, MD, PhD, FACC, FACP
24 Cesar Bierrenbach Street
Campinas, SP 13015-025, Brazil
Email: medney@synchrophar.com
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 3/2010 (233-242)
Bioavailability of two oral suspension and two oral tablet formulations of nimesulide 100 mg in healthy Brazilian adult subjects
H.M. Rigato1, B.C. Borges2, C.E. Sverdloff3, R.A. Moreno3, 4, E. Orpineli4 and N. Carter Borges1,4
1Department of Medical Clinic, State University of Campinas, Campinas, 2College of Medicine, Pontificia Universidade Católica, Sorocaba, 3Department of Pharmacology, State University of Campinas, and 4Synchrophar Assessoria e Desenvolvimento de Projetos Clínicos, Campinas, SP, Brazil A specific, fast and sensitive high performance liquid chromatography coupled to an electro spray tandem triple quadrupole mass spectrometer (LC-MS/MS) assay was developed for the determination of nimesulide in human plasma using carbamazepine as the internal standard. The lower limit of quantification (LLOQ) was 50 ng/ml and the calibration curves were linear in the concentration range of 50 – 6,000 ng/ml. Method inter-batch precision and accuracy ranged from 2.78 to 10.80%, and 94.92 to 102.46%, respectively. Intra-batch precision ranged from 2.44 to 7.74%, while intra-batch accuracy ranged from 91.70 to 104.73%. The analytical method was applied to evaluate the pharmacokinetic and relative bioavailability of two different pharmaceutical formulations containing nimesulide, one tablet and one oral suspension, manufactured by the same pharmaceutical factory, comparing with two reference Nisulid® formulations in 52 volunteers of both sexes previously divided in two groups of 26 subjects (13 men and 13 females each group). The test tablet formulation was not bioequivalent to the Nisulid® 100 mg tablet with respect to the rate of absorption, but was bioequivalent according to the extent of drug absorption. On the other hand, since the 90% CI for Cmax, AUC0-t and AUCinf were within the 80 – 125% interval in the oral suspension study, it was concluded that test oral suspension were bioequivalent to Nisulid® 50 mg/ml with respect to both the rate and extent of absorption.Correspondence to:
N. Carter Borges, MD, PhD, FACC, FACP
24 Cesar Bierrenbach Street
Campinas, SP 13015-025, Brazil
Email: medney@synchrophar.com
