Volume 41, No. 3/2003(March)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Therapeutics
The role of active metabolites in dihydrocodeine effects
Abstract
H. Schmidt, S.V. Vormfelde, M. Walchner-Bonjean, K. Klinder, S. Freudenthaler, C.H. Gleiter, U. Gundert-Remy, G. Skopp, R. Aderjan and U. Fuhr
1pharmazentrum frankfurt, Clinical Pharmacology, University of Frankfurt, 2Institute of Clinical Pharmacology, University of Göttingen, 3Institute of Pharmacology, Clinical Pharmacology, University of Köln, 4Institute of Forensic Medicine, University of Heidelberg, 5Department of Clinical Pharmacology, University of Tübingen, and 6BgVV, Berlin, Germany
Objective: The metabolism of dihydrocodeine to dihydromorphine, a high affinity m-opioid receptor ligand in membrane homogenates, is catalyzed by CYP2D6. However, it is not clear whether an active CYP2D6 enzyme is required for opioid receptor-mediated effects in man after standard dihydrocodeine doses. Methods: Whole cell opioid-receptor affinity and effects on cAMP accumulation of dihydrocodeine and its metabolites were determined in differentiated SH-SY5Y neuroblastoma cells. In a double-blind, 2-period, placebo-controlled randomized crossover pilot study the pharmacokinetics of dihydrocodeine (60 mg single dose) and its metabolites were examined in 5 phenotyped extensive (EMs) and 4 poor metabolizers (PMs) for CYP2D6, and pharmacodynamics were evaluated using a pain threshold model and dynamic pupillometry. Results: Displacement binding and cAMP accumulation experiments showed clearly higher affinities (100- and 50-fold) and activities (180- and 250-fold) of dihydromorphine and dihydromorphine-6-glucuronide, respectively, whereas the other metabolites had similar or lower affinities and activities as compared to dihydrocodeine. The clinical study revealed no significant difference in plasma or urine pharmacokinetics between EMs and PMs for dihydrocodeine and its glucuronide. Dihydromorphine and its glucuronides were detectable in EMs only. A clear reduction of initial pupil diameters was observed up to 6 hours postdose in both PMs and EMs, with no obvious differences between CYP2D6 phenotypes. In the pain threshold model no effects were observed in either group. Conclusion: CYP2D6 phenotype has no major impact on opioid receptor-mediated effects of a single 60 mg dihydrocodeine dose, despite the essential role of CYP2D6 in formation of highly active metabolites.
Therapeutics
Steady state bupivacaine plasma concentrations and safety of a femoral “3-in-1” nerve block with bupivacaine in patients over 80 years of age
Abstract
M.M.J. Snoeck, T.B. Vree, M.J.M. Gielen and A.J. Lagerwerf
1Department of Anesthesiology, Canisius Wilhelmina Hospital, and
2Institute for Anesthesiology, University Medical Center St. Radboud, Nijmegen, NL
Objectives: Fracture of the upper femur is a common injury in the elderly. Several anesthetic techniques exist for surgery of traumatic hip fracture. The aim of this investigation was to study plasma concentrations and safety of 2 mg/kg bupivacaine in a femoral “3-in-1” nerve block in patients older than 80 years of age. Subjects and methods: A 3-in-1 femoral nerve block, combined with a general anesthetic was used in 10 elderly patients aged over 80 years. They were undergoing emergency surgery for stabilization of their fractured femur. Bupivacaine plasma concentrations of radial artery blood samples were assessed over a 6-hour period after a femoral 3-in-1 injection of 2 mg/kg bupivacaine 0.375% with epinephrine (1 : 400,000). Results: No toxic reactions to bupivacaine were seen. In 8 of the 10 patients per- and postoperative analgesia were adequate as a result of the nerve block. Patients experienced loss of sensation and analgesia for 26.6 ± 4.6 hours (mean ± SD). This was inversely related to the apparent steady state concentration of bupivacaine. The mean of the individual peak plasma concentrations of bupivacaine (Cmax) was 0.74 ± 0.64 mg/ml. The highest plasma concentration was 1.83 mg/ml. Large variations in plasma concentrations were detected in these patients. Bupivacaine metabolites were not detected. Conclusions: A femoral 3-in-1 nerve block, using 2 mg/kg bupivacaine with epinephrine, provides prolonged pain relief without local anesthetic toxicity in elderly patients. It is a satisfactory supplementary analgesic technique for hip and knee surgery in the elderly.
Therapeutics
Evaluation of the efficacy of a combined formulation (Grippostad®-C) in the therapy of symptoms of common cold: a randomized, double-blind, multicenter trial
Abstract
R. Koytchev, V. Vlahov, N. Bacratcheva, B. Giesel, B. Gawronska-Szklarz, J. Wojcicki, A. Mrozikiewicz, M. van der Meer and R.-G. Alken
1CCDRD AG, Neuenhagen, Germany, 2Chair of Clinical Pharmacology, Multidisciplinary Hospital for Active Treatment Queen Giovanna, Sofia, Bulgaria, 3STADA R&D GmbH, Bad Vilbel, Germany, 4Chair of Pharmacology, Pomeranian Academy of Medicine, Szczecin, Poland, 5Institute of Clinical Pharmacology, Poznan, Poland, and 6Trident Bioanalytics Ltd., Carrigtwohill Co., Cork, Republic of Ireland
Background: The aim of the present trial was to evaluate the efficacy of a combined product in the treatment of common cold and to examine the contribution of the separate components. In the published literature there is conflicting data on the efficacy of agents used in the treatment of common cold, especially when given in drug combinations. Methods: A prospective, randomized, double-blind, multicenter, 4-arm, controlled trial was carried out in 1,167 patients with common cold treated with one of the following medications: Grippostad®-C, a combination of acetaminophen, caffeine, chlorpheniramine and ascorbic acid (verum), ascorbic acid (control), chlorpheniramine and ascorbic acid (reference 1), as well as acetaminophen, caffeine, and ascorbic acid (reference 2). A score of common cold symptoms (headache, throat pain, extremities and joint pain, cough, blocked nose, and disturbances of sleep quality) was the primary outcome. The test drug was first compared with the control using a hierarchic test strategy, then with reference 1, followed by reference 2 with the aim of proving superiority. Findings: A clinically relevant and statistically significant difference was demonstrated at each level of the hierarchy. Grippostad®-C was significantly superior to all other treatment groups, the combination of acetaminophen, caffeine, and ascorbic acid was significantly superior to the control, and the combination of chlorpheniramine and ascorbic acid was not statistically different from the control. Interpretation: The efficacy of Grippostad®-C for the treatment of common cold was proven. The findings demonstrate that the combination is superior to each of its separate components and each of the components has its own distinctive contribution to the efficacy of the combination product.
Therapeutic drug monitoring
Evaluation of therapeutic drug monitoring of antiepileptic drugs
Abstract
Y.M. Irshaid, A.A. Hamdi and M. Al Homrany
1Department of Clinical Pharmacology and 2Department of Internal Medicine, College of Medicine and Medical Sciences, King Khalid University, Abha, Saudi Arabia
Results of the therapeutic drug monitoring (TDM) of the concentration of antiepileptic drugs (AEDs), performed at Aseer Central Hospital over a 1-year period were evaluated. Most of the requests were for phenytoin (PHT) determination followed by carbamazepine (CBZ), valproic acid (VPA) and phenobarbital (PB). Serum concentrations of PB, CBZ, VPA and PHT within the presumed therapeutic range constituted 87%, 73%, 45% and 33%, respectively. Valproic acid exhibited age differences in the proportion of concentrations below the presumed therapeutic range, such that subtherapeutic concentrations increased while therapeutic concentrations decreased with age. When the requests were related to particular patients, 71% of patients were on monotherapy with PHT as the most commonly used single drug and PB the least. Patients using 2 AEDs were found to constitute 23.5% of all patients with “PHT + CBZ” and “CBZ + VPA” being the most commonly prescribed 2 drugs combination. The frequency of concentrations within the therapeutic ranges decreased when 1 or 2 more drugs were used with either PHT or VPA. In addition, combination with PHT was associated with a reduction in mean CBZ concentration, while combination with CBZ was associated with a reduction in mean VPA concentration.
Viewpoint
Teaching pharmacology – what should be taught, what results can be expected?what results can be expected?
Abstract
J.B. Schulze and B.G. Woodcock
Letter to the Editor
Clinical pharmacology today: light at the end of the tunnel?
Letter to the Editor
Book review
Letter to the Editor
Announcements
