Volume 40, No. 2/2002(February)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Original
Seminal plasma hormone concentration after oral application of progesterone
M. Feuring, T. Bertsch, B.M. Tran, K. Rossol-Haseroth, R. Losel, H.C. Tillmann, A. Schultz, M. Weigel and M. Wehling
Abstract
M. Feuring1, T. Bertsch2, B.M. Tran1, K. Rossol-Haseroth1, R. Losel1, H.C. Tillmann1, A. Schultz1, M. Weigel3 and M. Wehling1
1Institute of Clinical Pharmacology, 2Institute of Clinical Chemistry, and 3University Women’s Hospital, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany
Previous studies have revealed beneficial in vitro effects of progesterone on sperm function. The aim of this pilot study was to prove if orally given micronized progesterone leads to elevations in progesterone and/or 17a-hydroxyprogesterone levels in seminal plasma, since higher seminal plasma levels of these hormones could possibly have a beneficial effect on sperm function as seen in in vitro investigations. Multiple application of micronized progesterone given over 4 days (daily dose 400 mg) to 6 healthy subjects resulted in elevated seminal plasma levels of progesterone (10.90 ± 9.02 nmol/l vs. 1.43 ± 0.56 nmol/l, p = 0.04) and 17a-hydroxyprogesterone (3.09 ± 1.72 nmol/l vs. 1.62 ± 1.26 nmol/l, p = 0.04) whereas no significant difference could be found in testosterone levels (34.82 ± 13.00 vs. 30.91 ± 8.56 nmol/l, p = 0.43). In contrast, androstendione levels in seminal plasma were reduced (2.68 ± 1.28 nmol/l vs. 3.65 ± 1.36 nmol/l, p = 0.01). Although micronized progesterone is rapidly metabolized, oral application resulted in pronounced elevations of progesterone and 17a-hydroxyprogesterone in seminal plasma. Further studies will show if oral application of micronized progesterone can induce beneficial effects on sperm function such as those seen in in vitro investigations.Correspondence to:
Prof. Dr. M. Wehling; Institute of Clinical Pharmacology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, D-68135 Mannheim, Germany
Email: martin.wehling@kpha.ma.uni-heidelberg.de
Original
Comparison of different reduced sampling approaches for the estimation of pharmacokinetic parameters for long half-life drugs in patients with renal or hepatic impairment
I. Mahmood
Abstract
I. Mahmood
Division of Pharmaceutical Evaluation I, Office of Clinical Pharmacology and Biopharmaceutics (HFD-860) Food and Dru Administration, Woodmont Office Center II, Rockville, MD, USA
Objective: To compare 3 different reduced sampling approaches (truncated area, population and Bayesian; sampling schedule till 48 or 72 hours) with the extensive sampling for the estimation of pharmacokinetic parameters for long half-life drugs in healthy subjects and in patients with renal or hepatic impairment. Methods: Two drugs (extensively metabolized or extensively excreted) whose half-lives were greater than 30 hours were used in this analysis. Pharmacokinetic parameters such as maximum plasma concentration, clearance and half-life were estimated in healthy subjects and in patients using the above-mentioned 3 reduced sampling approaches and then compared with the extensive sampling. Results: The truncated area method failed to detect the same magnitude of difference in pharmacokinetic parameters between healthy subjects and patient populations that was determined using extensive sampling. On the other hand, the population or Bayesian approach provided the same magnitude of difference in pharmacokinetic parameters between the 2 populations that was observed with extensive sampling. Conclusion: This study indicates that the truncated area method may be a less suitable method to accurately characterize the pharmacokinetics of a long half-life drug either in healthy subjects or in patients with renal or hepatic impairment compared to a population or Bayesian approach.Correspondence to:
Dr. I. Mahmood; Division of Pharmaceutical Evaluation I, Office of Clinical Pharmacology and Biopharmaceutics (HFD-860), Woodmont Office Center II, Rockville Pike, Rockville, MD 20852, USA
Email: Mahmoodi@CDER.FDA.GOV
Original
One-compartment model for amino acids and other biological molecules in peritoneal dialysis
S. de la Motte, J. Plum, J. Passlick-Deetjen and B. Grabensee
Abstract
S. de la Motte1, J. Plum2, J. Passlick-Deetjen3 and B. Grabensee2
1Harrison Clinical Research, Munich, 2Department of Nephrology and Rheumatology, Heinrich Heine University, Düsseldorf, and 3Fresenius Medical Care Deutschland, Bad Homburg, Germany
Objectives: Investigation of the main factors determining the concentration-time course of amino acids and biological molecules in serum and dialysates. Methods: In a randomized, 3-period cross-over study, 11 patients were treated once with each of 3 peritoneal dialysis solutions, 1 containing amino acids and bicarbonate, 1 containing glucose and bicarbonate and 1 containing glucose and lactate. Nineteen amino acids, 3 proteins, 2 metabolites and 2 ions were measured in serum and dialysate. A standard compartment model was fitted to the data. Results: The amino acids differed significantly in their kinetic characteristics (p < 0.001), mainly volume of distribution and elimination rate. Differences in absorption were small compared to the interpatient variation. The average transport rate from serum to dialysate was 0.50 – 1.14 h–1, from dialysate to serum 0.33 – 0.41 h–1, for elimination from the central compartment 0.35 to 2.27 h–1, for volume of distribution 0.29 to 0.83 l/kg, for serum protein binding 19 – 47%, for amount in tissue 82 – 95%, for endogenous metabolic rate 16 – 151 mmol×kg–1×h–1. The volume of distribution correlated with the R group (polar positive < aliphatic < polar uncharged). For the various proteins, the 2 bicarbonate solutions had higher serum-to-dialysate transport rates than the lactate solution (p = 0.018 – 0.601). Conclusion: The compartment model demonstrated its usefulness. Accordance with literature data for healthy volunteers indicated the validity of the estimates.Correspondence to:
Dr. S. de la Motte; Hohenzollernstraße 10, D-85586 Poing, Germany
Email: sdelamotte@t-online.de
Original
Effects of acute and chronic alacepril treatment on exercise capacity and hemodynamics in patients with heart failure: a preliminary study
S. Osaki, T. Kinugawa, K. Ogino, M. Kato, Y. Furuse, Y. Tomikura, O. Igawa, I. Hisatome and C. Shigemasa
Abstract
S. Osaki, T. Kinugawa, K. Ogino, M. Kato, Y. Furuse, Y. Tomikura, O. Igawa, I. Hisatome and C. Shigemasa
Division of Cardiology, First Department of Internal Medicine, Tottori University Faculty of Medicine, Yonago, Japan
Objective: This study determined whether alacepril treatment improves exercise hemodynamics in patients with heart failure. Methods: Supine bicycle ergometer exercise was performed after administration of placebo and after acute and chronic (12 weeks) alacepril treatment in 4 patients with heart failure. Oxygen uptake (VO2), arterial oxygen saturation (SaO2), and mixed venous oxygen saturation (SvO2) were measured continuously using a pulse oxymeter and a fiber optic catheter. Cardiac index was calculated with Fick’s equation. Results: Acute alacepril treatment did not significantly alter the VO2 or hemodynamics. After chronic alacepril treatment, peak VO2 increased (placebo vs chronic alacepril treatment: 17.7 ± 2.8 vs 21.7 ± 2.8 ml/min/kg, p < 0.05). Arteriovenous oxygen difference (SaO2 – SvO2) at peak exercise was not altered, however, cardiac index at peak exercise (5.07 ± 0.67 vs 6.35 ± 0.48 l/min/m2, p = 0.02) increased and stroke volume index at peak exercise (37.3 ± 3.4 vs 46.5 ± 1.1 ml/m2, p = 0.07) tended to increase. Conclusions: Chronic treatment with alacepril improved maximal exercise capacity in patients with heart failure. The increased peak VO2 was primarily due to the increased cardiac index, but not due to the widening of arteriovenous oxygen difference. Therapy-induced increase in stroke volume index may contribute to the increased cardiac index at peak exercise in our patients with heart failure.Correspondence to:
Dr. T. Kinugawa; Division of Cardiology, First Department of Internal Medicine, Tottori University Faculty of Medicine, 36-1 Nishimachi, Yonago, 683-8504, Japan
Email: kinugawa@grape.med.tottori-u.ac.jp
Preface
Scripps-Bio Conference Accelerating Drug Development
A.W. Fox
Viewpoint
The revised Declaration of Helsinki – Is justice served?
J.C. Diamant
Abstract
J.C. Diamant
Scripps Clinic Department of Graduate Medical Education, Scripps Clinic, La Jolla, CA, USA
The World Medical Association revised the Declaration of Helsinki in October 2000. The Declaration is intended to provide a universal set of principles, which direct the ethical conduct of clinical medical research involving human subjects throughout the world. Previous research ethics codes emphasized the principles of informed consent and beneficence toward research subjects. The revised Helsinki Declaration places a premium not only upon these values but also the principle of distributive justice. The new Declaration demands that scientists see to it that the risks and benefits of scientific inquiry are distributed fairly to those that participate in research and to the communities from where participants are drawn. The authors of the Declaration have sought to establish justice by minimizing the use of placebo controls, insisting that populations from where research subjects are drawn stand to benefit from the research, and by requiring that therapeutic agents be made available to all trial participants long after a trial is completed. This paper argues that the aim of seeking a more just distribution of the risks and benefits of research may actually be undermined by the tools that the Declaration employs to enforce justice.Correspondence to:
J.C. Diamant, MD; Scripps Clinic Department of Graduate Medical Education, Scripps Clinic, 10666 N. Torrey Pines Road, La Jolla, CA, 92037 USA
Email: jdiamant@ scrippsclinic.com
Extended Abstract
Orphan drug product regulation – United States
M.E. Haffner
Abstract
M.E. Haffner
Office of Orphan Products Development (HF-35), Food and Drugs Administration, Rockville, MD, USA
The legislative history of the United States Orphan Drug Act began with rare, unanimous approval by the United States Congress. The Act, mid consequently the Regulations, have evolved since then. The two-stage process of Orphan Drug designation and approval is outlined, as well as the incentives that are offered to commercial companies for their implementation. Orphan Drugs are likely to be over-represented among drugs used under “Treatment” INDs. For patent- and “drug-difference” reasons, the benefits under the Orphan Drug Act are especially valuable to those who develop biologics. By any measure, this legislation, which requires only voluntary participation, has been a success; because the human genome is likely to lead to more biologicals than orthodox drugs, this success is likely to continue into the future. But even so, the 18-year experience with Orphan Drugs in the United States has led to some 225 Orphan Product approvals that benefit many millions of patients.Correspondence to:
M.E. Haffner, MD, MPH Director; Office of Orphan Products Development (HF-35), Food and Drugs Administration, 5600 Fishers Lane, Room 15A08, Rockville, MD 20857, USA
Email: mhaffner@oc.fda.gov
Abstracts
Scripps-BIO Conference “Accelerating Drug Development” / La Jolla, California, October 24 – 26, 2001
