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Volume 41, No. 5/2003(May)
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Obituary
Prof. Emeritus N.H. Rietbrock
Barry G. Woodcock
185
12$
Abstract
Institute of Clinical Pharmacology
Johann Wolfgang Goethe University Hospital
Frankfurt am Main
Germany
On the 16th February 2003, Professor Emeritus Norbert H. Rietbrock, one of the most prominent of German and European clinical pharmacologists, died after a short but severe illness, in Lemgo, North-Rhine-Westphalia, Germany. Norbert Rietbrock will be remembered for his contribution to the development of Clinical Pharmacology in Europe as a separate medical discipline and for the support he gave to clinical pharmacologists in eastern European countries. He will go down in history as a founder of the German Society of Clinical Pharmacology and Therapeutics (GKPharm) and as a co-founder of the European Association for Clinical Pharmacology and Therapeutics (EACPT). He was Honorary President of the 2nd Congress of the EACPT, 1997 in Berlin and was subsequently named as an honorary president of the EACPT.
Norbert Rietbrock was born on 9th June 1931 in Borken and obtained a degree in medicine from the University of Hamburg in 1959. His first appointment was at the Pharmacological Institute, University of Hamburg, with Professor G. Malorny. After moving to the Institute of Pharmacology and Toxicology, University of Würzburg, in 1966, he obtained the German habilitation (venia legendi) in 1968 under Professor D. Henschler, for a dissertation on “Kinetik und Mechanismen des Methanolumsatzes als Grundlage einer rationalen Therapie der Methanolvergiftung”. He later moved to the Institute of Clinical Pharmacology at the Free University of Berlin under Professor Emeritus Helmut Kewitz who was to have a major effect on his scientific and academic career. In 1977 he was appointed to the Chair of Clinical Pharmacology at the Johann Wolfgang Goethe University. Within a relatively short period, the Department of Clinical Pharmacology under his leadership became a center of excellence with more than 40 scientific and academic staff. He held this position until his retirement and becoming Professor Emeritus in 1999.
Norbert Rietbrock was a man of considerable courage, dynamism and conviction. He showed no hesitation in confronting opposition (from both industrial and academic fronts), and if necessary alone, when this impinged on his efforts as an independent researcher or on clinical pharmacology as an independent discipline. His direct approach received respect from many quarters even when opinions differed. A quotation that he often used and which typifies one aspect of his character is “Quam multa fieri non posse, priusquam sint facta, judicantur? How many things were once thought impossible before they were achieved?”
His founding with others of the Deutsche Gesellschaft für Klinische Pharmakologie und Therapie e.V. (GKPharm) in Vienna in September 1990 was followed with his election as the first chairman and the first scientific meeting of the society took place in Arnsburg/Lich in 1991. As Chairman of the GKPharm he was instrumental in setting up the Friedrich-Hartmut Dost memoral prize in memory of the pioneer pharmacokineticist, the late Professor Dr. med. Helmut Dost, University of Gießen. In recognition of his work for the Society he was made Honorary Member in 1999.
The material and non-material support he gave to the departments of clinical pharmacology in eastern Europe struggling to achieve union and parity with those in western Europe can be matched by few other European clinical pharmacologists. He visited and taught frequently in Bulgaria, Poland, Rumania and Hungary, arranged workshops and symposia in these countries and in 2001 this work was honored when he became Member of the Bulgarian Academy of Medicine. Up to his death he was making plans with others for the continuation of these efforts.
Norbert Rietbrock’s main area of research activity in clinical pharmacology on taking up the chair in Frankfurt was dose management, bioavailability and adverse reactions of cardiovascular drugs. He had a major influence on the prescribing practicies in Germany and indeed Europe because of work on non-renal-dependent cardiac glycosides which formed the subject of scientific symposia, numerous research publications and a handbook. His pioneering studies on fast-reaction rates in protein binding of warfarin and benzodiazepines were stimulated by the work of the physicist and Nobel Laureate Manfred Eigen, and were supported by research grants from the Deutsche Forschungsgemeinschaft over many years. Other main areas of research included studies on the pharmacokinetic first-pass effects especially with regard to calcium antagonists and the special therapeutic problems asociated with nitrates. Norbert Rietbrock was the main initiator of an International Symposium Series on “Methods in Clinical Pharmacology” with 10 or more symposia between 1980 and 1990 alone. In 1991 the first edition of the clinical pharmacology textbook “Klinische Pharmakologie – ein Leitfaden für die Praxis” (Clinical Pharmacology – a guide to practice) was published, which is now in its 4th edition and used by German speaking students and clinicians throughout Europe. In 1996 he was awarded the Dr. Richard Hammer-Medal by the Chamber of Medicine, Hessen, for his exceptional contribution to the practice of medicine.
Norbert Rietbrock never tired in giving encouragement and active support to his undergraduate students and younger research colleagues, who he regarded as a most important field of investment. He encouraged them to take responsibility and helped them to benefit from criticism. Much of his free time was also taken up with work in Berlin for governmental medical agencies. Despite all these duties, he was a dedicated father who held his family dear and who spoke about them often.
Norbert Rietbrock was a fan of classical music, especially the music of Georg Friedrich Händel, and played the organ occasionally in church. A main “hobby” in retirement was restoration of his 17th century residence in Lemgo where he had lived since his retirement from academic life in 1999. These “extracurricular” activities, however, did not withhold him from being active in clinical pharmacology. A book for the lay public, with the title “Ask your doctor or chemist” (Fragen Sie Ihren Arzt oder Apotheker), was published in 2000 as was the occasional editorial on medical education and the role of clinical pharmacology.
Norbert Rietbrock is survived by his two sons, Stephan and Andreas, and his wife Regina. His loss to clinical pharmacology is much too early since he was a man who was always active, with far-seeing vision and who could not be ignored. He will be long-remembered throughout Europe and afar as a champion of his chosen discipline and a tireless worker for fellow clinical pharmacologists. He will be remembered for his role as a teacher, for bringing scientific knowledge into practice and for increasing the impact of clinical pharmacology in our medicine and our daily lives. German clinical pharmacologists can be proud that he was one of them and will honor his memory.
Barry G. Woodcock
“pharmazentrum Frankfurt”
Institute of Clinical Pharmacology
Johann Wolfgang Goethe University Hospital
Frankfurt am Main
Germany
Barry G. Woodcock
“pharmazentrum Frankfurt”Institute of Clinical Pharmacology
Johann Wolfgang Goethe University Hospital
Frankfurt am Main
Germany
On the 16th February 2003, Professor Emeritus Norbert H. Rietbrock, one of the most prominent of German and European clinical pharmacologists, died after a short but severe illness, in Lemgo, North-Rhine-Westphalia, Germany. Norbert Rietbrock will be remembered for his contribution to the development of Clinical Pharmacology in Europe as a separate medical discipline and for the support he gave to clinical pharmacologists in eastern European countries. He will go down in history as a founder of the German Society of Clinical Pharmacology and Therapeutics (GKPharm) and as a co-founder of the European Association for Clinical Pharmacology and Therapeutics (EACPT). He was Honorary President of the 2nd Congress of the EACPT, 1997 in Berlin and was subsequently named as an honorary president of the EACPT.
Norbert Rietbrock was born on 9th June 1931 in Borken and obtained a degree in medicine from the University of Hamburg in 1959. His first appointment was at the Pharmacological Institute, University of Hamburg, with Professor G. Malorny. After moving to the Institute of Pharmacology and Toxicology, University of Würzburg, in 1966, he obtained the German habilitation (venia legendi) in 1968 under Professor D. Henschler, for a dissertation on “Kinetik und Mechanismen des Methanolumsatzes als Grundlage einer rationalen Therapie der Methanolvergiftung”. He later moved to the Institute of Clinical Pharmacology at the Free University of Berlin under Professor Emeritus Helmut Kewitz who was to have a major effect on his scientific and academic career. In 1977 he was appointed to the Chair of Clinical Pharmacology at the Johann Wolfgang Goethe University. Within a relatively short period, the Department of Clinical Pharmacology under his leadership became a center of excellence with more than 40 scientific and academic staff. He held this position until his retirement and becoming Professor Emeritus in 1999.
Norbert Rietbrock was a man of considerable courage, dynamism and conviction. He showed no hesitation in confronting opposition (from both industrial and academic fronts), and if necessary alone, when this impinged on his efforts as an independent researcher or on clinical pharmacology as an independent discipline. His direct approach received respect from many quarters even when opinions differed. A quotation that he often used and which typifies one aspect of his character is “Quam multa fieri non posse, priusquam sint facta, judicantur? How many things were once thought impossible before they were achieved?”
His founding with others of the Deutsche Gesellschaft für Klinische Pharmakologie und Therapie e.V. (GKPharm) in Vienna in September 1990 was followed with his election as the first chairman and the first scientific meeting of the society took place in Arnsburg/Lich in 1991. As Chairman of the GKPharm he was instrumental in setting up the Friedrich-Hartmut Dost memoral prize in memory of the pioneer pharmacokineticist, the late Professor Dr. med. Helmut Dost, University of Gießen. In recognition of his work for the Society he was made Honorary Member in 1999.
The material and non-material support he gave to the departments of clinical pharmacology in eastern Europe struggling to achieve union and parity with those in western Europe can be matched by few other European clinical pharmacologists. He visited and taught frequently in Bulgaria, Poland, Rumania and Hungary, arranged workshops and symposia in these countries and in 2001 this work was honored when he became Member of the Bulgarian Academy of Medicine. Up to his death he was making plans with others for the continuation of these efforts.
Norbert Rietbrock’s main area of research activity in clinical pharmacology on taking up the chair in Frankfurt was dose management, bioavailability and adverse reactions of cardiovascular drugs. He had a major influence on the prescribing practicies in Germany and indeed Europe because of work on non-renal-dependent cardiac glycosides which formed the subject of scientific symposia, numerous research publications and a handbook. His pioneering studies on fast-reaction rates in protein binding of warfarin and benzodiazepines were stimulated by the work of the physicist and Nobel Laureate Manfred Eigen, and were supported by research grants from the Deutsche Forschungsgemeinschaft over many years. Other main areas of research included studies on the pharmacokinetic first-pass effects especially with regard to calcium antagonists and the special therapeutic problems asociated with nitrates. Norbert Rietbrock was the main initiator of an International Symposium Series on “Methods in Clinical Pharmacology” with 10 or more symposia between 1980 and 1990 alone. In 1991 the first edition of the clinical pharmacology textbook “Klinische Pharmakologie – ein Leitfaden für die Praxis” (Clinical Pharmacology – a guide to practice) was published, which is now in its 4th edition and used by German speaking students and clinicians throughout Europe. In 1996 he was awarded the Dr. Richard Hammer-Medal by the Chamber of Medicine, Hessen, for his exceptional contribution to the practice of medicine.
Norbert Rietbrock never tired in giving encouragement and active support to his undergraduate students and younger research colleagues, who he regarded as a most important field of investment. He encouraged them to take responsibility and helped them to benefit from criticism. Much of his free time was also taken up with work in Berlin for governmental medical agencies. Despite all these duties, he was a dedicated father who held his family dear and who spoke about them often.
Norbert Rietbrock was a fan of classical music, especially the music of Georg Friedrich Händel, and played the organ occasionally in church. A main “hobby” in retirement was restoration of his 17th century residence in Lemgo where he had lived since his retirement from academic life in 1999. These “extracurricular” activities, however, did not withhold him from being active in clinical pharmacology. A book for the lay public, with the title “Ask your doctor or chemist” (Fragen Sie Ihren Arzt oder Apotheker), was published in 2000 as was the occasional editorial on medical education and the role of clinical pharmacology.
Norbert Rietbrock is survived by his two sons, Stephan and Andreas, and his wife Regina. His loss to clinical pharmacology is much too early since he was a man who was always active, with far-seeing vision and who could not be ignored. He will be long-remembered throughout Europe and afar as a champion of his chosen discipline and a tireless worker for fellow clinical pharmacologists. He will be remembered for his role as a teacher, for bringing scientific knowledge into practice and for increasing the impact of clinical pharmacology in our medicine and our daily lives. German clinical pharmacologists can be proud that he was one of them and will honor his memory.
Barry G. Woodcock
“pharmazentrum Frankfurt”
Institute of Clinical Pharmacology
Johann Wolfgang Goethe University Hospital
Frankfurt am Main
Germany
Therapeutics
Effect of epoetin on HO-1 mRNA level and plasma antioxidants in hemodialysis patients
L.A. Calò, L. Stanic, P.A. Davis, E. Pagnin, G. Munaretto, M. Fusaro, S. Landini, A. Semplicini and A. Piccoli
187
28$
Abstract
Objective: Patients with renal failure and undergoing hemo- (HD) or peritoneal dialysis are under oxidative stress which is thought to contribute to the long-term complications noted in this patient population. One effect of HD-induced oxidative stress is via red blood cell (RBC) membrane lipid peroxidation leading to RBC destruction and anemia. Interaction of this oxidative stress with epoetin (EPO) treatment to increase RBC number and Hb concentration remains unexplored. Patients and methods: This preliminary study used RT-PCR as well as colorimetric based assay approaches to evaluate the effect of EPO-a treatment on markers of oxidative stress in hemodialysis patients. Eighteen patients (12 males, 6 females, age range 45 – 68), were treated with EPO-a (Eprex) 50 UI/kg thrice weekly over an 8-month study period. Monocytes were isolated at baseline, then monthly thereafter, monocyte heme-oxygenase-1 (HO-1) and plasma Hb and antioxidant power (AOP) were determined. Results and conclusions: Treatment with EPO increased Hb (9.4 ± 0.7 g/dl to 10.9 ± 0.5, mean ± SD p < 0.001). In addition, both monocyte HO-1 mRNA (0.34 ± 0.08 vs. 0.59 ± 0.02 d.u. p < 0.001) and plasma AOP (1,379.8 ± 175 mmol/l to 1,624 ± 170, p < 0.04) increased. While AOP changes showed no correlation with other indices, increases in HO-1 and Hb were positively correlated using 2 different measures: D Hb (peak Hb – baseline Hb) vs. D HO-1 (peak HO-1 mRNA – baseline HO-1 mRNA) as well as D Hb (5 months – baseline) vs. D HO-1 (5 months – baseline) mRNA (r = 0.81, p < 0.001 and r = 0.76, p < 0.001; respectively). In conclusion, the increases upon EPO treatment of both HO-1 gene expression and plasma AOP as well as the significant correlation between D Hb and D HO-1 mRNA suggest that EPO treatment reduces oxidative stress via a combination of effects. These could potentially include effects on oxidative stress directly as well as effects on the levels and types of antioxidants present in plasma.
L.A. Calò1, L. Stanic2, P.A. Davis3, E. Pagnin1, G. Munaretto4, M. Fusaro4, S. Landini5, A. Semplicini1 and A. Piccoli6
1Department of Clinical and Experimental Medicine, Clinica Medica 4 and 6Division of Nephrology, University of Padova, Divisions of Nephrology and Dialysis, Hospitals of 2Camposampiero, 5Mestre-Venezia and 4Piove di Sacco, Italy, and 3Department of Internal Medicine, Clinical Nutrition, University of California, Davis, California, USA Objective: Patients with renal failure and undergoing hemo- (HD) or peritoneal dialysis are under oxidative stress which is thought to contribute to the long-term complications noted in this patient population. One effect of HD-induced oxidative stress is via red blood cell (RBC) membrane lipid peroxidation leading to RBC destruction and anemia. Interaction of this oxidative stress with epoetin (EPO) treatment to increase RBC number and Hb concentration remains unexplored. Patients and methods: This preliminary study used RT-PCR as well as colorimetric based assay approaches to evaluate the effect of EPO-a treatment on markers of oxidative stress in hemodialysis patients. Eighteen patients (12 males, 6 females, age range 45 – 68), were treated with EPO-a (Eprex) 50 UI/kg thrice weekly over an 8-month study period. Monocytes were isolated at baseline, then monthly thereafter, monocyte heme-oxygenase-1 (HO-1) and plasma Hb and antioxidant power (AOP) were determined. Results and conclusions: Treatment with EPO increased Hb (9.4 ± 0.7 g/dl to 10.9 ± 0.5, mean ± SD p < 0.001). In addition, both monocyte HO-1 mRNA (0.34 ± 0.08 vs. 0.59 ± 0.02 d.u. p < 0.001) and plasma AOP (1,379.8 ± 175 mmol/l to 1,624 ± 170, p < 0.04) increased. While AOP changes showed no correlation with other indices, increases in HO-1 and Hb were positively correlated using 2 different measures: D Hb (peak Hb – baseline Hb) vs. D HO-1 (peak HO-1 mRNA – baseline HO-1 mRNA) as well as D Hb (5 months – baseline) vs. D HO-1 (5 months – baseline) mRNA (r = 0.81, p < 0.001 and r = 0.76, p < 0.001; respectively). In conclusion, the increases upon EPO treatment of both HO-1 gene expression and plasma AOP as well as the significant correlation between D Hb and D HO-1 mRNA suggest that EPO treatment reduces oxidative stress via a combination of effects. These could potentially include effects on oxidative stress directly as well as effects on the levels and types of antioxidants present in plasma.
Therapeutics
Safety aspects of a coumarin-troxerutin combination regarding liver function in a double-blind placebo-controlled study
H.J. Schmeck-Lindenau, B. Naser-Hijazi, W. Becker, H.H. Henneicke-von Zepelin and J. Schnitker
193
32$
Abstract
Objective: Coumarin is reported to elevate liver function tests (LFT) values. In a prospective, placebo-controlled, clinical trial, efficacy and safety of a coumarin-containing combination (SB-LOT) were evaluated in the treatment of chronic venous insufficiency. Here, we report on the drug safety of coumarin with special respect to liver reaction. Methods: 114 patients were treated with SB-LOT (30 mg coumarin and 180 mg troxerutin t.i.d.) and 117 with placebo during a period of 16 weeks. LFT values (ALT, AST, AP and g-GT) were monitored at baseline, 4, 6, 8, 12 and 16 weeks of therapy. Adverse drug reactions were assessed regarding causality. Additionally, lymphocyte proliferation test was used to identify allergic reactions. Logistic regression analysis was performed to identify possible risk factors. Results: No serious adverse drug reactions occurred. Elevations of LFT were assessed as biochemical abnormality. Specific clinical symptoms such as jaundice did not occur. Only 1 patient reported fatigue and exhaustion. Logistic regression estimated a basic risk for elevation of LFT of 4.9% under SB-LOT and 2.1% under placebo. Hepatitis in the history and diseases of the liver were identified as risk factors. Conclusion: This evaluation contributes to safety data of SB-LOT in man. LFT elevation is transient and the low risk of the SB-LOT therapy to increase LFT value can be limited when risk factors are considered.
H.J. Schmeck-Lindenau, B. Naser-Hijazi, W. Becker, H.H. Henneicke-von Zepelin and J. Schnitker
1Zentralkrankenhaus Reikenheide, Akademisches Lehrkrankenhaus University of Göttingen, Bremerhaven, 2Schaper and Brümmer GmbH und Co. KG, Salzgitter, 3Department II, Medical Clinic, University of Tübingen, and 4Institute for Applied Statistics IAS, Bielefeld, Germany Objective: Coumarin is reported to elevate liver function tests (LFT) values. In a prospective, placebo-controlled, clinical trial, efficacy and safety of a coumarin-containing combination (SB-LOT) were evaluated in the treatment of chronic venous insufficiency. Here, we report on the drug safety of coumarin with special respect to liver reaction. Methods: 114 patients were treated with SB-LOT (30 mg coumarin and 180 mg troxerutin t.i.d.) and 117 with placebo during a period of 16 weeks. LFT values (ALT, AST, AP and g-GT) were monitored at baseline, 4, 6, 8, 12 and 16 weeks of therapy. Adverse drug reactions were assessed regarding causality. Additionally, lymphocyte proliferation test was used to identify allergic reactions. Logistic regression analysis was performed to identify possible risk factors. Results: No serious adverse drug reactions occurred. Elevations of LFT were assessed as biochemical abnormality. Specific clinical symptoms such as jaundice did not occur. Only 1 patient reported fatigue and exhaustion. Logistic regression estimated a basic risk for elevation of LFT of 4.9% under SB-LOT and 2.1% under placebo. Hepatitis in the history and diseases of the liver were identified as risk factors. Conclusion: This evaluation contributes to safety data of SB-LOT in man. LFT elevation is transient and the low risk of the SB-LOT therapy to increase LFT value can be limited when risk factors are considered.
Pharmacokinetics
Pharmacokinetics of lithium in healthy volunteers after exposure to high altitude
A. Arancibia, C. Paulos, J. Chávez and W.A. Ritschel
200
32$
Abstract
Introduction: Exposure of the human body to high altitude causes a number of physiological changes. In previous studies, we observed that these changes may alter the pharmacokinetics of drugs. The number of erythrocytes/mm3 increases both, after acute exposure to high altitude (HA), i.e. within 12 – 24 h after reaching high altitude (H), as well as in chronic exposure (HC) (> 10 months) to H. Also binding of drugs to biologic material may change with exposure to HA and/or HC. Objective: Since lithium is transported into and out of erythrocytes and binds strongly to erythrocytes, but is not plasma protein-bound, we selected this drug as candidate for the present study. Subjects, material and methods: Lithium carbonate 300 mg were administered orally to young healthy volunteers. One group residing at low altitude (Santiago, Chile, 600 m, group L), these same volunteers after 15 hours of exposure to high altitude (4,360 m, group HA), and volunteers living at high altitude for at least 10 months (group HC). Results: We found a significant increase of both hematocrit and red blood cell count (RBC) after exposure to H, both, acute or chronic. Elimination half-life increased 64.1% in group HA and 111.4% in group HC in comparison to group L. We also found an increase in volume of distribution: + 18.9% in group HA, and + 35.8% in group HC when measured in plasma, and + 16.9% in group HA and + 18.8% in group HC when measured in whole blood. Lithium uptake by the erythrocytes increases: the value of 36.7 ± 22.7% in Group L rose to 54.8 ± 21.1% and to 54.6 ± 24.2% in groups HA and HC, respectively. Total clearance decreases at high altitude, though the differences were significant only in group HC (37%). Conclusion: Results indicate that exposure to H produces alterations in the pharmacokinetics of lithium and that these variations may be clinically relevant.
A. Arancibia1, C. Paulos1, J. Chávez1 and W.A. Ritschel2
1Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile, and 2Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Ohio, USA Introduction: Exposure of the human body to high altitude causes a number of physiological changes. In previous studies, we observed that these changes may alter the pharmacokinetics of drugs. The number of erythrocytes/mm3 increases both, after acute exposure to high altitude (HA), i.e. within 12 – 24 h after reaching high altitude (H), as well as in chronic exposure (HC) (> 10 months) to H. Also binding of drugs to biologic material may change with exposure to HA and/or HC. Objective: Since lithium is transported into and out of erythrocytes and binds strongly to erythrocytes, but is not plasma protein-bound, we selected this drug as candidate for the present study. Subjects, material and methods: Lithium carbonate 300 mg were administered orally to young healthy volunteers. One group residing at low altitude (Santiago, Chile, 600 m, group L), these same volunteers after 15 hours of exposure to high altitude (4,360 m, group HA), and volunteers living at high altitude for at least 10 months (group HC). Results: We found a significant increase of both hematocrit and red blood cell count (RBC) after exposure to H, both, acute or chronic. Elimination half-life increased 64.1% in group HA and 111.4% in group HC in comparison to group L. We also found an increase in volume of distribution: + 18.9% in group HA, and + 35.8% in group HC when measured in plasma, and + 16.9% in group HA and + 18.8% in group HC when measured in whole blood. Lithium uptake by the erythrocytes increases: the value of 36.7 ± 22.7% in Group L rose to 54.8 ± 21.1% and to 54.6 ± 24.2% in groups HA and HC, respectively. Total clearance decreases at high altitude, though the differences were significant only in group HC (37%). Conclusion: Results indicate that exposure to H produces alterations in the pharmacokinetics of lithium and that these variations may be clinically relevant.
Drug Utilization
Trends in prescribing proton pump inhibitors in Taiwan: 1997 – 2000
T.-J. Chen, L.-F. Chou and S.-J. Hwang
207
28$
Abstract
2Department of Public Finance, National Chengchi University, Taipei, Taiwan
Objective: The prescribing of proton pump inhibitors (PPIs) had increased greatly in recent years worldwide. Aim of our study was to analyze the utilization patterns of PPIs within the National Health Insurance program in Taiwan from 1997 – 2000. Material and method: The systemic sampling datasets from the National Health Insurance Research Database served as data sources. Units of measurement for PPIs were numbers of prescription items and defined daily doses (DDDs). To estimate the proportion of the population treated daily with PPIs, numbers of DDDs per 1,000 inhabitants per day were calculated. In order to realize the role of PPIs in treating Helicobacter pylori-related disorders, we also analyzed various combined prescriptions of PPIs with amoxicillin, clarithromycin, metronidazole, tetracycline and bismuth. Results: In the study period, PPI prescriptions increased nearly 2-fold at the outpatient sector and more than 3-fold at the inpatient sector. Men received more PPI prescriptions, as a whole, than women. Most PPIs were prescribed at the outpatient sector: 93.9% in 1997, 92.3% in 1998, 90.4% in 1999 and 87.3% in 2000. The numbers of DDDs per 1,000 inhabitants per day for all kinds of PPIs were 0.59, 0.78, 1.07, and 1.13 from 1997 – 2000, respectively. While the percentage of monotherapy increased from 63.6% in 1997 to 75.5% in 2000, the combination therapies did not experience a rapid and sustained growth. Among the combination therapies, PPI + amoxicillin + metronidazole and PPI + amoxicillin were popular in 1997 and 1998, but triple therapy with PPI + amoxicillin + clarithromycin predominated in 1999 and 2000. Conclusions: Despite increasing use, prescribing volumes of PPIs in Taiwan were far fewer than those in other developed countries. Treatment of Helicobacter pylori-related disorders in Taiwan followed universal standard.
T.-J. Chen, L.-F. Chou and S.-J. Hwang
1Department of Family Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, and2Department of Public Finance, National Chengchi University, Taipei, Taiwan
Objective: The prescribing of proton pump inhibitors (PPIs) had increased greatly in recent years worldwide. Aim of our study was to analyze the utilization patterns of PPIs within the National Health Insurance program in Taiwan from 1997 – 2000. Material and method: The systemic sampling datasets from the National Health Insurance Research Database served as data sources. Units of measurement for PPIs were numbers of prescription items and defined daily doses (DDDs). To estimate the proportion of the population treated daily with PPIs, numbers of DDDs per 1,000 inhabitants per day were calculated. In order to realize the role of PPIs in treating Helicobacter pylori-related disorders, we also analyzed various combined prescriptions of PPIs with amoxicillin, clarithromycin, metronidazole, tetracycline and bismuth. Results: In the study period, PPI prescriptions increased nearly 2-fold at the outpatient sector and more than 3-fold at the inpatient sector. Men received more PPI prescriptions, as a whole, than women. Most PPIs were prescribed at the outpatient sector: 93.9% in 1997, 92.3% in 1998, 90.4% in 1999 and 87.3% in 2000. The numbers of DDDs per 1,000 inhabitants per day for all kinds of PPIs were 0.59, 0.78, 1.07, and 1.13 from 1997 – 2000, respectively. While the percentage of monotherapy increased from 63.6% in 1997 to 75.5% in 2000, the combination therapies did not experience a rapid and sustained growth. Among the combination therapies, PPI + amoxicillin + metronidazole and PPI + amoxicillin were popular in 1997 and 1998, but triple therapy with PPI + amoxicillin + clarithromycin predominated in 1999 and 2000. Conclusions: Despite increasing use, prescribing volumes of PPIs in Taiwan were far fewer than those in other developed countries. Treatment of Helicobacter pylori-related disorders in Taiwan followed universal standard.
Case Report
Henoch-Schönlein purpura associated with clarithromycin. Case report and review of literature clarithromycin. Case report and review of literature
J. Borrás-Blasco, R. Enriquez, F. Amoros, J.B. Cabezuelo, A. Navarro-Ruiz, M. Pérez and J. Fernández
213
20$
Abstract
4Allergy Service, Hospital General Universitario de Elche, Elche, Spain
Objective: To report a case of Henoch-Schönlein purpura that appears to be related to the intake of clarithromycin for pharyngitis/tonsillitis. Case summary: We describe a case of Henoch-Schönlein associated with clarithromycin therapy in a 48-year-old white man with no history of allergic drug reactions. Four days after starting therapy, he came to our hospital emergency room because of a non-pruritic palpable purpuric rash on the trunk and extremities and arthralgias involving elbows and knees. Administration of clarithromycin was suspended, in a few days, arthralgias and skin lesions quickly resolved. Three weeks later, the patient presented again with abdominal pain, dark-red urine and swelling of the legs. Urinalysis revealed proteinuria of 11 g/24 h and hematuria. A percutaneous renal biopsy showed a diffuse endocapillary proliferative glomerulonephritis with segmental areas of fibrinoid necrosis within glomeruli, on inmunofluorescence study granular deposits of IgA and C3 were present in the mesangium and capillary walls. A diagnosis of HSP was made. We suspected that the causative agent might be clarithromycin since this was the only drug added before the cutaneous and renal condition appeared. Conclusions: Our case and the previous case suggest that HSP may represent a potential adverse effect of clarithromycin, clinicians should be alerted to this potentially severe side effect of such a widely used drug. In accordance with the data obtained and based on the Naranjo algorithm, the adverse reaction could be considered possible.
J. Borrás-Blasco1, R. Enriquez2, F. Amoros2, J.B. Cabezuelo2, A. Navarro-Ruiz1, M. Pérez3 and J. Fernández4
1Pharmacy Service, 2Nephrology Section, 3Pathology Service, and4Allergy Service, Hospital General Universitario de Elche, Elche, Spain
Objective: To report a case of Henoch-Schönlein purpura that appears to be related to the intake of clarithromycin for pharyngitis/tonsillitis. Case summary: We describe a case of Henoch-Schönlein associated with clarithromycin therapy in a 48-year-old white man with no history of allergic drug reactions. Four days after starting therapy, he came to our hospital emergency room because of a non-pruritic palpable purpuric rash on the trunk and extremities and arthralgias involving elbows and knees. Administration of clarithromycin was suspended, in a few days, arthralgias and skin lesions quickly resolved. Three weeks later, the patient presented again with abdominal pain, dark-red urine and swelling of the legs. Urinalysis revealed proteinuria of 11 g/24 h and hematuria. A percutaneous renal biopsy showed a diffuse endocapillary proliferative glomerulonephritis with segmental areas of fibrinoid necrosis within glomeruli, on inmunofluorescence study granular deposits of IgA and C3 were present in the mesangium and capillary walls. A diagnosis of HSP was made. We suspected that the causative agent might be clarithromycin since this was the only drug added before the cutaneous and renal condition appeared. Conclusions: Our case and the previous case suggest that HSP may represent a potential adverse effect of clarithromycin, clinicians should be alerted to this potentially severe side effect of such a widely used drug. In accordance with the data obtained and based on the Naranjo algorithm, the adverse reaction could be considered possible.
Bioavailability Section
Scaling or wider bioequivalence limits for highly variable drugs and for the special case of Cmax
L. Tothfalusi, L. Endrenyi and K.K. Midha
217
40$
Abstract
Objective: To illustrate that bioequivalence (BE) can be effectively evaluated for highly variable (HV) drugs and drug products and for the special case of Cmax by using average BE. To demonstrate that either scaling or wider regulatory limits need not result in large observed ratios of the geometric means (GMR) of the 2 drug products. Methods: Two- and 4-period crossover BE investigations with 24 subjects were simulated. Variabilities of 15, 25 or 35% were assumed in special studies of Cmax and 40% in the general investigations of HV drugs. Acceptance of BE was analyzed in each study by various procedures and regulatory criteria. Under each condition, the percentage of simulated investigations accepting BE was recorded as the simulated GMR was gradually raised from 1.00. Results: Scaled average BE for HV drugs (in both 2- and 4-period studies) and expanding limits for Cmax increased substantially, as expected, the proportion of investigations accepting BE. An additional secondary regulatory criterion constrained the simulated GMR to 1.25 and limited the possibility of large deviations between the mean metrics of the 2 formulations. Acceptance of BE by the composite regulatory expectation never exceeded the acceptances by the separate component criteria. Conclusions: The sample size required for the evaluation of BE for HV drugs and drug products can be substantially reduced by applying the approach of scaled average BE. The same conclusion is reached from the determination of BE for the Cmax metric by expanding the regulatory limits to 0.75 – 1.33 or even to 0.70 – 1.43. Concerns for observations of high GMR values can be eased by imposing constraints with a secondary regulatory criterion.
L. Tothfalusi, L. Endrenyi and K.K. Midha
1Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary, 2Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada, and 3PharmaLytics Inc., University of Saskatchewan, Saskatoon, Canada Objective: To illustrate that bioequivalence (BE) can be effectively evaluated for highly variable (HV) drugs and drug products and for the special case of Cmax by using average BE. To demonstrate that either scaling or wider regulatory limits need not result in large observed ratios of the geometric means (GMR) of the 2 drug products. Methods: Two- and 4-period crossover BE investigations with 24 subjects were simulated. Variabilities of 15, 25 or 35% were assumed in special studies of Cmax and 40% in the general investigations of HV drugs. Acceptance of BE was analyzed in each study by various procedures and regulatory criteria. Under each condition, the percentage of simulated investigations accepting BE was recorded as the simulated GMR was gradually raised from 1.00. Results: Scaled average BE for HV drugs (in both 2- and 4-period studies) and expanding limits for Cmax increased substantially, as expected, the proportion of investigations accepting BE. An additional secondary regulatory criterion constrained the simulated GMR to 1.25 and limited the possibility of large deviations between the mean metrics of the 2 formulations. Acceptance of BE by the composite regulatory expectation never exceeded the acceptances by the separate component criteria. Conclusions: The sample size required for the evaluation of BE for HV drugs and drug products can be substantially reduced by applying the approach of scaled average BE. The same conclusion is reached from the determination of BE for the Cmax metric by expanding the regulatory limits to 0.75 – 1.33 or even to 0.70 – 1.43. Concerns for observations of high GMR values can be eased by imposing constraints with a secondary regulatory criterion.
Bioavailability Section
Bioequivalence study of two brands of enalapril tablets after single oral administration to healthy volunteers
I. Niopas, A.C. Daftsios and N. Nikolaidis
226
24$
Abstract
Objective: To compare the relative bioavailability and bioequivalence of 2 enalapril tablet formulations in healthy volunteers under fasting conditions. Methods: An open-label, single-dose, randomized, two-period, crossover trial with a 1-week washout period in 24 healthy volunteers. The 2 enalapril 20 mg tablet formulations used were Antiprex® (Elpen, Greece) as test and Renitec® (Vianex, Greece) as reference preparation. Serial blood samples were collected at 19 points for 36 h. Plasma samples were analyzed for enalaprilat, the pharmacologically active metabolite of enalapril, by a validated GC/MS assay. Pharmacokinetic parameters, such as AUC0-¥, AUC0-t, Cmax, Tmax, t1/2 and MRT were calculated from plasma concentrations for both formulations. Statistical comparisons (ANOVA and 90% confidence intervals) of AUC0-¥, AUC0-t and Cmax data were evaluated after logarithmic transformation, and differences of Tmax were tested non-parametrically. Results: The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios were 88.0 – 117.6% (point estimate: 101.8%) for AUC0-¥, 88.7 – 118.9% (point estimate: 102.7%) for AUC0-t, and 91.0% – 123.4% (point estimate: 106.0%) for Cmax. No statistically significant differences were found between the 2 preparations for Tmax, t1/2 and MRT values. Conclusions: From the results of the present study, it is concluded that the test and reference tablet formulations of enalapril are bioequivalent for both the extent and the rate of absorption and therefore the 2 products can be considered to be interchangeable in clinical practice.
I. Niopas, A.C. Daftsios and N. Nikolaidis
1Department of Pharmacy, School of Health Sciences, Aristotle University of Thessaloniki, and 2Analyses of Pharmaco-Chemical Products, American Farm School of Thessaloniki, Thessaloniki, Greece Objective: To compare the relative bioavailability and bioequivalence of 2 enalapril tablet formulations in healthy volunteers under fasting conditions. Methods: An open-label, single-dose, randomized, two-period, crossover trial with a 1-week washout period in 24 healthy volunteers. The 2 enalapril 20 mg tablet formulations used were Antiprex® (Elpen, Greece) as test and Renitec® (Vianex, Greece) as reference preparation. Serial blood samples were collected at 19 points for 36 h. Plasma samples were analyzed for enalaprilat, the pharmacologically active metabolite of enalapril, by a validated GC/MS assay. Pharmacokinetic parameters, such as AUC0-¥, AUC0-t, Cmax, Tmax, t1/2 and MRT were calculated from plasma concentrations for both formulations. Statistical comparisons (ANOVA and 90% confidence intervals) of AUC0-¥, AUC0-t and Cmax data were evaluated after logarithmic transformation, and differences of Tmax were tested non-parametrically. Results: The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios were 88.0 – 117.6% (point estimate: 101.8%) for AUC0-¥, 88.7 – 118.9% (point estimate: 102.7%) for AUC0-t, and 91.0% – 123.4% (point estimate: 106.0%) for Cmax. No statistically significant differences were found between the 2 preparations for Tmax, t1/2 and MRT values. Conclusions: From the results of the present study, it is concluded that the test and reference tablet formulations of enalapril are bioequivalent for both the extent and the rate of absorption and therefore the 2 products can be considered to be interchangeable in clinical practice.
