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CHEMOTACTIC LEUKOTRIENES IN PSORIASIS
1464 PERCUTANEOUS DRAINAGE IN BILIARY OBSTRUCTION
SiR,—Recent discussion (Oct. 23, p. 896; Nov. 20, p. 1155) on the merits of alternative
treatments
of biliary obstruction has not, I
think, given sufficient attention to the fact, whatever the method used, of the loss of bile. Patients who have a T-tube for drainage of the bile duct rapidly improve once the tube is clamped or removed, and replacement of fluid and electrolytes, especially if done by the usual method of serum level and assay of the bile drain, does not completely resolve the problems. Some time ago, with this in mind, I endeavoured to fmd means of returning the bile itself. It is almost impossible for the patient to drink it, and rectal instillation produces such an intense proctitis that the patient develops other problems. Although, therefore, the use of a nasogastric tube is a drawback, we tried returning the bile in this way. This also, we found, produced problems with intense gastritis in some cases, and the only method which was satisfactory was to use a tube which was passed right into the duodenum. Might I suggest therefore that, whatever method of external drainage is used, intraduodenal instillation of the bile drained is well worthwhile. We prefer an alternative technique with an internal
diversion. General Hospital,
Birmingham B4 6NH
GEORGE T. WATTS
CHEMOTACTIC LEUKOTRIENES IN PSORIASIS
SiR,—Dr Brain and her colleagues’ data (Oct. 2, p. 762) fit in well with our findings of increased levels of chemotactic leukotrienes in the scales of patients with psoriasis. 1,2 This finding was met with scepticism by the Institute of Dermatology team when we presented it at the International Congress of Dermatology in Tokyo, May, 1982.2Our experimental approach differed from theirs. Instead of extracting leukotrienes from stripped, in situ skin, we collected scales from skin lesions of more than twenty patients with psoriasis and callus from two healthy controls. We also took punch biopsy specimens from skin lesions and from unaffected skin often patients with psoriasis before and after 3 weeks of anthralin therapy and from five healthy controls. Aqueous extracts of scales as well as tissue from normal and psoriatic skin contained variably increased levels of neutrophil chemotactic activity, measured in vitro in modified Boyden chemotaxis chambers. The material was of low molecular weight (<500) and was heat stable (100°C, 10 min); it was not demonstrable in skin from normal controls. The chemotactic activity in 1 mg of scales corresponded, on average, to the biological activity of 0 -1 nmol/l synthetic leukotriene B4. On reverse-phase high-pressure liquid chromatography, leukotriene B4 and 5-HETE were found to be the major chemotactic leukotrienes extracted from the scales. These substances are potent neutrophil, eosinophil, and macrophage chemotactic factors 34 and they can therefore cause not only the non-directed5,6 but also the directed migration of leucocytes into psoriatic dermis and epidermis. As would be expected with any biological system, there is also a means to down-regulate the inflammatory process initiated by the leukotrienes. We found a potent, heat-labile inhibitor of leukotriene B4 induced chemotaxis in the aqueous extracts of psoriatic scales. This inhibitor was also detectable at much lower levels in normal human callus. The findings of Brain et al. and those described here suggest that cells in the cutaneous inflammatory infiltrate and also,
possibly, epidermal cells in the skin of patients with psoriasis, produce increased quantities of chemotactic leukotrienes, which then accumulate in the scales overlying the lesional dermis to maintain the continuous influx of inflammatory cells. Since increased levels of leukotrienes were found by us in unaffected psoriatic skin as well, one must assume that products of the lipoxygenase pathway do indeed play an important role early on in the pathogenesis of the psoriatic lesion. Whether a defect in lipoxygenase-dependent leukotriene synthesis is the primary defect in psoriasis or whether the increased generation of these substances is only a secondary event, will have to await further studies. This work Cz 22/3-4.
was
supported by the Deutsche Forschungsgemeinschaft, grant
Antoni van Leeuwehhockhuis, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
JÜRGEN GRABBE BEATE M. CZARNETZKI MITHAT MARDIN
KETOCONAZOLE, CYCLOSPORIN, AND THE KIDNEY SiR.—Dr Ferguson and colleagues (Oct. 16. p. 882) and Dr Dieperink and Dr Miller (Nov. 27, p. 1217) have shown that increased blood trough levels of cyclosporin (CyA) in renal transplant recipients treated concomitantly with ketoconazole are followed by rises in serum creatinine levels. Both sets of workers have attributed the increases in circulating cyclosporin levels and resulting nephrotoxicity to a decrease in the hepatic metabolism of the immunosuppressant, due to the ketoconazole. Our studies of hepatic drug metabolising enzymes support these conclusions. Hepatic enzymes, including cytochrome P 450’ play an important metabolic role in transforming drugs into often less toxic and usually more readily excretable products. This process may be especially important for cyclosporin which is hydrophobic. We have investigated the effect of inducing cytochrome P 450 on cyclosporin-related nephrotoxicity in the normal Sprague-Dawley rat. Hepatic cytochrome P 450 levels were decreased by 33% and serum urea and creatinine increased (table) in rats treated with the drug (50 mg/kg daily) for 14 days. When ’Aroclor 1254’, a known inducer of cytochrome ?45o’, was administered (25 mg/kg/24h) along with CyA, hepatic levels of cytochrome P 450 were increased by 100%, compared to the untreated animal, and the nephrotoxic effects of the CyA were prevented without affecting the immunosuppressive properties of the CyA. The fact that increasing the levels of cytochrome P 450 prevented the CyA-related nephrotoxicity indicates that CyA is probably detoxified through metabolism by this enzyme. Since at the same time the immunosuppressive properties of CyA were unaffected by aroclor 1254, it may be that inducing cytochrome P450 clinically, for example with phenobarbitone, would provide a regimen for cyclosporin therapy with both diminished side-effects and improved efficacy. Conversely, the decrease in cytochrome P 450 caused by cyclosporin increases the danger of adverse interactions with drugs which are detoxified by this enzyme (e.g., warfarin). C. CUNNINGHAM M. D. BURKE P. H. WHITING J. G. SIMPSON D. N. WHEATLEY
Departments of Pathology, Chemical Pathology, and Pharmacology, University of Aberdeen, Aberdeen AB9 2ZD
AP, Kappas A. The inducing properties of polychlorinated biphenyls hepatic monoxygenases. Clin Pharmacol Ther 1977; 22: 809-16.
1. Alvares
on
CREATININE AND UREA LEVELS IN RATS GIVEN CYCLOSPORIN WITH 1. Grabbe J,
2. 3. 4.
5.
6.
Czarnetzki BM. Studies on ECF-production in human skin. Arch Dermatol Res 1982; 273: 192-93. Czarnetzki BM, Tagami H Chemotaxis, fundamental aspects and clinical applications. Proc XVIth Int Congr Dermatol (in press). Czarnetzki BM, Grabbe J Biological and chemical characterization of eosinophil chemotactic factors from human leukocytes Agents Actions (in press). Czarnetzki BM, Frosch PJ, Mardin M, Macher E Leukotriene B4 and neutrophilderived eosinophil chemotactic factor (ECLPMN) Comparison of their biological characteristics. Proc XIVth Symp Coll Int Allergy. Basle: Karger (in press) Ford-Hutchinson AW, Bray MA, Doig MV, Shipley ME, Smith MJH. Leukotriene B4, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature 1980; 268: 264-65. Smith MJH. Biological aspects of leukotriene B4. Colloq Inst Pasteur/INSERM 1981; 100: 129-45.
OR WITHOUT AROCLOR
Results
1254
as mean ± SD (n=no. of animals). Groups were compared by Student’s t test for paired samples (*p<0’05). Treatment with aroclor 1254 alone did not affect creatmine or
urea
levels.
SiR,—Recent discussion (Oct. 23, p. 896; Nov. 20, p. 1155) on the merits of alternative
treatments
of biliary obstruction has not, I
think, given sufficient attention to the fact, whatever the method used, of the loss of bile. Patients who have a T-tube for drainage of the bile duct rapidly improve once the tube is clamped or removed, and replacement of fluid and electrolytes, especially if done by the usual method of serum level and assay of the bile drain, does not completely resolve the problems. Some time ago, with this in mind, I endeavoured to fmd means of returning the bile itself. It is almost impossible for the patient to drink it, and rectal instillation produces such an intense proctitis that the patient develops other problems. Although, therefore, the use of a nasogastric tube is a drawback, we tried returning the bile in this way. This also, we found, produced problems with intense gastritis in some cases, and the only method which was satisfactory was to use a tube which was passed right into the duodenum. Might I suggest therefore that, whatever method of external drainage is used, intraduodenal instillation of the bile drained is well worthwhile. We prefer an alternative technique with an internal
diversion. General Hospital,
Birmingham B4 6NH
GEORGE T. WATTS
CHEMOTACTIC LEUKOTRIENES IN PSORIASIS
SiR,—Dr Brain and her colleagues’ data (Oct. 2, p. 762) fit in well with our findings of increased levels of chemotactic leukotrienes in the scales of patients with psoriasis. 1,2 This finding was met with scepticism by the Institute of Dermatology team when we presented it at the International Congress of Dermatology in Tokyo, May, 1982.2Our experimental approach differed from theirs. Instead of extracting leukotrienes from stripped, in situ skin, we collected scales from skin lesions of more than twenty patients with psoriasis and callus from two healthy controls. We also took punch biopsy specimens from skin lesions and from unaffected skin often patients with psoriasis before and after 3 weeks of anthralin therapy and from five healthy controls. Aqueous extracts of scales as well as tissue from normal and psoriatic skin contained variably increased levels of neutrophil chemotactic activity, measured in vitro in modified Boyden chemotaxis chambers. The material was of low molecular weight (<500) and was heat stable (100°C, 10 min); it was not demonstrable in skin from normal controls. The chemotactic activity in 1 mg of scales corresponded, on average, to the biological activity of 0 -1 nmol/l synthetic leukotriene B4. On reverse-phase high-pressure liquid chromatography, leukotriene B4 and 5-HETE were found to be the major chemotactic leukotrienes extracted from the scales. These substances are potent neutrophil, eosinophil, and macrophage chemotactic factors 34 and they can therefore cause not only the non-directed5,6 but also the directed migration of leucocytes into psoriatic dermis and epidermis. As would be expected with any biological system, there is also a means to down-regulate the inflammatory process initiated by the leukotrienes. We found a potent, heat-labile inhibitor of leukotriene B4 induced chemotaxis in the aqueous extracts of psoriatic scales. This inhibitor was also detectable at much lower levels in normal human callus. The findings of Brain et al. and those described here suggest that cells in the cutaneous inflammatory infiltrate and also,
possibly, epidermal cells in the skin of patients with psoriasis, produce increased quantities of chemotactic leukotrienes, which then accumulate in the scales overlying the lesional dermis to maintain the continuous influx of inflammatory cells. Since increased levels of leukotrienes were found by us in unaffected psoriatic skin as well, one must assume that products of the lipoxygenase pathway do indeed play an important role early on in the pathogenesis of the psoriatic lesion. Whether a defect in lipoxygenase-dependent leukotriene synthesis is the primary defect in psoriasis or whether the increased generation of these substances is only a secondary event, will have to await further studies. This work Cz 22/3-4.
was
supported by the Deutsche Forschungsgemeinschaft, grant
Antoni van Leeuwehhockhuis, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
JÜRGEN GRABBE BEATE M. CZARNETZKI MITHAT MARDIN
KETOCONAZOLE, CYCLOSPORIN, AND THE KIDNEY SiR.—Dr Ferguson and colleagues (Oct. 16. p. 882) and Dr Dieperink and Dr Miller (Nov. 27, p. 1217) have shown that increased blood trough levels of cyclosporin (CyA) in renal transplant recipients treated concomitantly with ketoconazole are followed by rises in serum creatinine levels. Both sets of workers have attributed the increases in circulating cyclosporin levels and resulting nephrotoxicity to a decrease in the hepatic metabolism of the immunosuppressant, due to the ketoconazole. Our studies of hepatic drug metabolising enzymes support these conclusions. Hepatic enzymes, including cytochrome P 450’ play an important metabolic role in transforming drugs into often less toxic and usually more readily excretable products. This process may be especially important for cyclosporin which is hydrophobic. We have investigated the effect of inducing cytochrome P 450 on cyclosporin-related nephrotoxicity in the normal Sprague-Dawley rat. Hepatic cytochrome P 450 levels were decreased by 33% and serum urea and creatinine increased (table) in rats treated with the drug (50 mg/kg daily) for 14 days. When ’Aroclor 1254’, a known inducer of cytochrome ?45o’, was administered (25 mg/kg/24h) along with CyA, hepatic levels of cytochrome P 450 were increased by 100%, compared to the untreated animal, and the nephrotoxic effects of the CyA were prevented without affecting the immunosuppressive properties of the CyA. The fact that increasing the levels of cytochrome P 450 prevented the CyA-related nephrotoxicity indicates that CyA is probably detoxified through metabolism by this enzyme. Since at the same time the immunosuppressive properties of CyA were unaffected by aroclor 1254, it may be that inducing cytochrome P450 clinically, for example with phenobarbitone, would provide a regimen for cyclosporin therapy with both diminished side-effects and improved efficacy. Conversely, the decrease in cytochrome P 450 caused by cyclosporin increases the danger of adverse interactions with drugs which are detoxified by this enzyme (e.g., warfarin). C. CUNNINGHAM M. D. BURKE P. H. WHITING J. G. SIMPSON D. N. WHEATLEY
Departments of Pathology, Chemical Pathology, and Pharmacology, University of Aberdeen, Aberdeen AB9 2ZD
AP, Kappas A. The inducing properties of polychlorinated biphenyls hepatic monoxygenases. Clin Pharmacol Ther 1977; 22: 809-16.
1. Alvares
on
CREATININE AND UREA LEVELS IN RATS GIVEN CYCLOSPORIN WITH 1. Grabbe J,
2. 3. 4.
5.
6.
Czarnetzki BM. Studies on ECF-production in human skin. Arch Dermatol Res 1982; 273: 192-93. Czarnetzki BM, Tagami H Chemotaxis, fundamental aspects and clinical applications. Proc XVIth Int Congr Dermatol (in press). Czarnetzki BM, Grabbe J Biological and chemical characterization of eosinophil chemotactic factors from human leukocytes Agents Actions (in press). Czarnetzki BM, Frosch PJ, Mardin M, Macher E Leukotriene B4 and neutrophilderived eosinophil chemotactic factor (ECLPMN) Comparison of their biological characteristics. Proc XIVth Symp Coll Int Allergy. Basle: Karger (in press) Ford-Hutchinson AW, Bray MA, Doig MV, Shipley ME, Smith MJH. Leukotriene B4, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature 1980; 268: 264-65. Smith MJH. Biological aspects of leukotriene B4. Colloq Inst Pasteur/INSERM 1981; 100: 129-45.
OR WITHOUT AROCLOR
Results
1254
as mean ± SD (n=no. of animals). Groups were compared by Student’s t test for paired samples (*p<0’05). Treatment with aroclor 1254 alone did not affect creatmine or
urea
levels.