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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.

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.

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.

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.

Abstract

J.B. Schulze and B.G. Woodcock

Abstract

A.W. Fox

Abstract

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Abstract

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Volume 41, No. 3/2003(March)