1383
glass vials containing 0-9 ml 20 mmol/I "tris"-HCI buffer (pH 9-0). The whole procedure was done under yellow light because of the photosensitivity of nifedipine.6 The tubes were shaken gently for at 4°C to ensure maximum drug extraction into buffer, the collection strips were removed, and internal standard (0-1ml
48 h
nisoldipine, 260 u.g/1) was added. GCF eluates were analysed by capillary gas chromatography6 after solid-phase aqueous
extraction. The maximum plasma concentrations of nifedipine and its M-I metabolite (see table) and their respective areas under the concentration time curve (139-1121 and 88-623 flg.h.l-1) were unremarkable.However, in seven patients nifedipine concentrations were much higher in GCF than in plasma (table). The figure shows a typical time course
GCF nifedipine concentrations at site were above 1000 ug/1. This patient had a maximum GCF concentration of 7080 ug/1 (table). The two patients with undetectable GCF nifedipine were non-responders. The M-I metabolite of nifedipine was not detected ( < 40 g/1) in GCF, in contrast to plasma. Biological concentrations of nifedipine in the range 103-105 p.g/1 are unprecedented, even in overdose,’ and approach the maximum aqueous solubility of the drug.The very high concentrations in GCF make toxic effects highly likely. It is interesting that the two patients with undetectable GCF nifedipine did not have gingival overgrowth and it remains to be seen whether the gingival overgrowth develops in the two non-responders with high GCF concentrations. Our finding that the M-1 metabolite was undetectable in GCF suggests that the process by which nifedipine is sequestered in gingival tissues is dependent on the drug, and perhaps is even calcium-channel specific, since the metabolite is 1000 times less active than the parent drug.’ It seems highly likely that this sequestration predisposes the patient to the toxic effects of nifedipine seen in the gingivae. This mechanism may well be common to other calcium antagonists and to phenytoin and cyclosporin, since all these drugs affect calcium homoeostasis.3,9,10 Fuller understanding of this concentrating mechanism may lead to strategies for the prevention of gingival overgrowth, especially in transplant recipients.
(patient 3); steady-state one
10. Narahashi T. Drugs acting on calcium channels. In: Baker PF, ed. Calcium drugs in action: handbook of experimental pharmacology, vol 83. Berlin: Springer Verlag, 1988: 255-74. ADDRESSES: Department of Operative Dentistry, Dental School (J S. Ellis, FDSRSCEd, R. A. Seymour, PhD), and of Research Unit, Department Pharmacogenetics Pharmacological Sciences, Medical School (S. C. Monkman, BSc, Prof J. R. Idle, PhD), University of Newcastle upon Tyne, UK. Correspondence to Prof J. R. Idle, Department of Pharmacological Sciences, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Central-nervous-system dysfunction after warm or hypothermic cardiopulmonary bypass
The increasing popularity of warm heart surgery led us to assess the effect of temperature
during cardiopulmonary bypass (CPB) on neuropsychological function after coronary surgery. 34 patients enrolled in a randomised trial of normothermic versus hypothermic CPB were subjected to a battery of psychomotor and memory tests before and after their operations. The mean nasopharyngeal temperature for warm CPB was 34·7 (SD 0·5)°C and that for hypothermic CPB was 27·8 (2·0)°C. In all seven neuropsychological tests the postoperative scores were better in the warm CPB than in the hypothermic group, although only one difference achieved significance (trial-making test A; p
glass vials containing 0-9 ml 20 mmol/I "tris"-HCI buffer (pH 9-0). The whole procedure was done under yellow light because of the photosensitivity of nifedipine.6 The tubes were shaken gently for at 4°C to ensure maximum drug extraction into buffer, the collection strips were removed, and internal standard (0-1ml
48 h
nisoldipine, 260 u.g/1) was added. GCF eluates were analysed by capillary gas chromatography6 after solid-phase aqueous
extraction. The maximum plasma concentrations of nifedipine and its M-I metabolite (see table) and their respective areas under the concentration time curve (139-1121 and 88-623 flg.h.l-1) were unremarkable.However, in seven patients nifedipine concentrations were much higher in GCF than in plasma (table). The figure shows a typical time course
GCF nifedipine concentrations at site were above 1000 ug/1. This patient had a maximum GCF concentration of 7080 ug/1 (table). The two patients with undetectable GCF nifedipine were non-responders. The M-I metabolite of nifedipine was not detected ( < 40 g/1) in GCF, in contrast to plasma. Biological concentrations of nifedipine in the range 103-105 p.g/1 are unprecedented, even in overdose,’ and approach the maximum aqueous solubility of the drug.The very high concentrations in GCF make toxic effects highly likely. It is interesting that the two patients with undetectable GCF nifedipine did not have gingival overgrowth and it remains to be seen whether the gingival overgrowth develops in the two non-responders with high GCF concentrations. Our finding that the M-1 metabolite was undetectable in GCF suggests that the process by which nifedipine is sequestered in gingival tissues is dependent on the drug, and perhaps is even calcium-channel specific, since the metabolite is 1000 times less active than the parent drug.’ It seems highly likely that this sequestration predisposes the patient to the toxic effects of nifedipine seen in the gingivae. This mechanism may well be common to other calcium antagonists and to phenytoin and cyclosporin, since all these drugs affect calcium homoeostasis.3,9,10 Fuller understanding of this concentrating mechanism may lead to strategies for the prevention of gingival overgrowth, especially in transplant recipients.
(patient 3); steady-state one
10. Narahashi T. Drugs acting on calcium channels. In: Baker PF, ed. Calcium drugs in action: handbook of experimental pharmacology, vol 83. Berlin: Springer Verlag, 1988: 255-74. ADDRESSES: Department of Operative Dentistry, Dental School (J S. Ellis, FDSRSCEd, R. A. Seymour, PhD), and of Research Unit, Department Pharmacogenetics Pharmacological Sciences, Medical School (S. C. Monkman, BSc, Prof J. R. Idle, PhD), University of Newcastle upon Tyne, UK. Correspondence to Prof J. R. Idle, Department of Pharmacological Sciences, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Central-nervous-system dysfunction after warm or hypothermic cardiopulmonary bypass
The increasing popularity of warm heart surgery led us to assess the effect of temperature
during cardiopulmonary bypass (CPB) on neuropsychological function after coronary surgery. 34 patients enrolled in a randomised trial of normothermic versus hypothermic CPB were subjected to a battery of psychomotor and memory tests before and after their operations. The mean nasopharyngeal temperature for warm CPB was 34·7 (SD 0·5)°C and that for hypothermic CPB was 27·8 (2·0)°C. In all seven neuropsychological tests the postoperative scores were better in the warm CPB than in the hypothermic group, although only one difference achieved significance (trial-making test A; p
