UREMIC PRURITUS is one of the most

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1 Therapeutic Effect of Topical Gamma-Linolenic Acid on Refractory Uremic Pruritus Yung-Chih Chen, MD, Wan-Ting Chiu, MD, and Mai-Szu Wu, MD Background: Pruritus is a bothersome symptom affecting up to 80% of dialysis patients. Lymphocyte and cytokine interaction has an important role in the pathogenesis of uremic pruritus. Gamma-linolenic acid (GLA) is associated with immune modulation of T lymphocytes and lymphokines. The aim of this study is to determine whether topical GLA can attenuate uremic pruritus. Methods: Seventeen dialysis patients with refractory uremic pruritus who passed the screening criteria entered a prospective, randomized, double-blind, placebo-controlled, crossover study. They stopped all antipruritic therapy at least 2 weeks before the study and were randomly assigned to treatment with either GLA 2.2% cream or placebo-based cream applied to the entire body after taking a bath once a day and to pruritic sites 3 times a day for 2 weeks, and then the reverse treatment after a 2-week washout period. Severity of pruritus was evaluated by using a traditional visual analogue scale (VAS) and a modified questionnaire method (pruritus score [PS]). Hemogram, aspartate and alanine aminotransferases, bilirubin, albumin, blood urea nitrogen, creatinine, calcium, phosphate, and intact parathyroid hormone were measured. Results: Sixteen patients completed the study; 1 patient was withdrawn because of an allergic skin reaction. There were no significant differences between groups except for sex distribution. Median VAS and PS values between groups did not differ significantly at baseline. There is a greater antipruritic effect of GLA based on evaluation with both the VAS and PS. There is persistence of a residual effect into the second treatment period after GLA treatment. Conclusion: GLA-rich cream is better than placebo-based cream for alleviating uremic pruritus. It is a useful adjuvant in the management of refractory uremic pruritus. Am J Kidney Dis 48: by the National Kidney Foundation, Inc. INDEX WORDS: Gamma-linolenic acid; uremic pruritus. UREMIC PRURITUS is one of the most bothersome symptoms for patients with chronic renal failure. The underlying mechanisms are not yet fully understood. Factors that have 1,2 been implicated include xerosis, elevated serum phosphate levels, elevated serum magnesium levels, 3 secondary hyperparathyroidism, 4 allergic sensitization, intradermal mast cell proliferation, 5 6 iron deficiency anemia, dialysis membrane material, increased plasma histamine levels, 7 8,9 and uremic neuropathy. None of these factors consistently was shown as the cause of pruritus. Some combinations of these factors are thought to be possible causes. Many therapies have been proposed for patients with uremic pruritus. Among these treatments 10 are intensive efficient dialysis, UV B phototherapy, 11,12 use of non complement-activating dialysis membranes, 12 electric-needle (acupuncture) therapy, 13 activated charcoal, 14 antihistam ines, 15 capsaicin, 16 cholestyramine, 17 emollients 18 and topical corticosteroids, 12 epoetin, 19 ketotifen, 20 and nicergoline. 12 They improved pruritus in some patients, but either had no effect or aggravated symptoms in others. It is reasonable to speculate that other important mediators may have a role in the development of uremic pruritus. Essential fatty acids and their derivatives have a protective function and influence skin structure and physiological characteristics. 21 Gammalinolenic acid (GLA) is an important essential fatty acid found naturally in the fatty acid fractions of some plant seed oils. Tamimi et al first found that GLA-rich evening primrose oil may be beneficial in alleviating uremic pruritus in some patients; the mechanism may be through reversal or modulation of the pathological change. It would be very interesting to know whether GLA itself could relieve uremic pruritus. To further evaluate the clinical efficacy of topical GLA for uremic pruritus, we conducted a From the Division of Nephrology, Chang Gung Memorial Hospital, Keelung; School of Medicine, Chang Gung University; and Department of Dermatology, Cathay General Hospital, Taipei, Taiwan. Received November 1, 2005; accepted in revised form March 31, Originally published online as doi: /j.ajkd on June 8, Support: None. Potential conflicts of interest: None. Address reprint requests to Mai-Szu Wu, MD, Division of Nephrology, Chang Gung Memorial Hospital, 222, Mai-Chin Rd, Keelung, Taiwan. maxwu1@adm.cgmh.org.tw 2006 by the National Kidney Foundation, Inc /06/ $32.00/0 doi: /j.ajkd American Journal of Kidney Diseases, Vol 48, No 1 (July), 2006: pp

2 70 CHEN, CHIU, AND WU Fig 1. Trial design: randomized, double-blind, placebo-controlled, crossover study. Abbreviations: GLA, GLA-containing cream; Pb, placebo cream; S, scoring. prospective, randomized, double-blind, placebocontrolled, crossover trial. METHODS Patient Selection Patients undergoing maintenance hemodialysis or peritoneal dialysis were enrolled. Patients with severe uremic pruritus that was refractory to such treatments as antihistamines, antipruritic lotions, and UV therapy were selected. All selected patients had Kt/V urea (amount of dialysis delivered; K clearance of urea, t time on dialysis, V estimated total body water) greater than 1.5 to ensure the adequacy of dialysis. Patients were excluded from the study if there were causes of pruritus other than renal failure. Informed consent was obtained from all participants. The study was approved by our ethics committee. Study Design The study was a 6-week, single-center, prospective, randomized, double-blind, placebo-controlled, crossover trial to evaluate the therapeutic effect of topical GLA 2.2% cream (Primordia, Chang Gung Biotechnology, Taiwan) on refractory uremic pruritus in dialysis patients Fig ( 1). Patients who entered the study discontinued all antipruritic therapy at least 2 weeks before the study. Baseline pruritus was assessed at the end of this 2-week period. At the end of the baseline day, patients were randomly assigned to group A or group B. Patients in group A were allocated to treatment with GLA and placebo cream in that sequence, and patients in group B, in the reverse sequence Fig ( 1). There was a 2-week washout period between each treatment period. During treatment periods, each of which lasted 2 weeks, patients applied topical GLA-rich cream or placebo cream in a double-blind fashion to their entire body after taking a bath once a day and additionally to pruritic sites 3 times a day. The amount of topical cream (GLA-rich cream or placebo cream) was standardized for each enrolled patient. The amount of topical cream initially was 30 ml/d and subsequently was adjusted according to the application area. Topical cream was stored in a plastic container for each patient s use. Placebo cream was composed mainly of the moisture-preserving substance urea. Patients were evaluated by using pruritus scoring before and after the treatment periods Fig ( 1). Assessment of Pruritus The severity of pruritus was evaluated by using 2 methods: a traditional visual analogue scale (VAS) and a modified questionnaire method (pruritus score [PS]) that has been described previously. 24 The VAS consisted of a 100-mm horizontal line marked 0 (no pruritus) to 100 (maximum intensity of pruritus). Patients marked or reported a number (score), rating their pruritus by themselves. The modified questionnaire method consisted of independent scores of the Table 1. Pruritus Score Evaluation Score Distribution Pruritus in single site 1 Scattered pruritus 2 Generalized pruritus 3 Frequency 4 short episodes ( 10 min; maximum, 5 points) 1 1 long episode ( 10 min; maximum, 5 points) 1 Continuous pruritus 5 Severity Pruritus without the need to scratch 1 Pruritus with the need to scratch, but without excoriations 2 Pruritus relieved by scratching, but with excoriations 3 Pruritus unrelieved by scratching accompanied by excoriations 4 Totally restless 5 Sleep disturbances Each episode of awakening due to pruritus (maximum, 6 points) 2 Minimal pruritus, 3 points, maximal pruritus, 19 points.

3 GAMMA-LINOLENIC ACID, UREMIC PRURITUS 71 distribution, frequency, and severity of pruritus and sleep disturbances caused by itching Table ( 1). Laboratory Assays Hemogram (automated cell count), aspartate aminotransferase (enzymatic method), alanine aminotransferase (enzymatic method), bilirubin (spectrophotometric method), albumin (colorimetric method), blood urea nitrogen (enzymatic method), creatinine (colorimetric method), calcium (spectrophotometric method), phosphate (spectrophotometric method), ferritin (chemiluminescence analyzer), and intact parathyroid hormone (ipth; chemiluminescence analyzer) were measured before and at the end of each treatment period. Statistical Analysis The pruritus evaluation by patients using a VAS and PS is expressed as median and interquartile range (IQR). Because our data do not follow a Gaussian bell-shaped distribution precisely, nonparametric analysis with Wilcoxon test was used to estimate treatment differences in paired patients receiving GLA or placebo cream. In head-to-head comparisons, treatment differences between the use of GLA and placebo cream in nonpaired patients in group A and group B during treatment period 1 or 2 were analyzed by using Mann-Whitney U test. Laboratory data were analyzed by means of paired Student t-test. A 2-tailed P less than 0.01 is considered statistically significant. All statistical tests were performed using GraphPad Prism, version 4.0 (GraphPad Software Inc, San Diego, CA). RESULTS Subjects Seventeen dialysis patients (14 patients, hemodialysis; 3 patients, peritoneal dialysis) fulfilled the screening criteria and consented to take part in the study. The 17 patients were randomly assigned, and 16 patients completed the study. Only 1 patient withdrew from the study. This patient had an allergic skin reaction during treatment period 2 while receiving GLA cream in group B. Table 2. Patient Characteristics After Randomization Group A (GLA pb) (n 8) Group B (pb GLA) (n 9) P (2-tailed) Age (y) NS Sex ratio (M/F) 3:5 5: Time on dialysis (mo) NS Underlying disease Diabetes mellitus 4 3 NS Chronic glomerulonephritis 2 1 NS Hypertension 0 1 NS Polycystic disease 1 0 NS Other 1 0 NS Laboratory data White blood cells ( 10 3 / L) NS Hemoglobin (g/dl) NS Aspartate aminotransferase (U/L) NS Alanine aminotransferase (U/L) NS Total bilirubin (mg/dl) NS Albumin (g/dl) NS Blood urea nitrogen (mg/dl) NS Creatinine (mg/dl) NS Calcium (mg/dl) NS Phosphate (mg/dl) NS ipth (pg/ml) NS Ferritin (ng/ml) NS Basal pruritus evaluation VAS / /80 NS PS by questionnaire / /9.0 NS NOTE. Values expressed as mean SD/median or number of patients. To convert white blood cells in 10 3 / L to10 9 /L, multiply by 1; hemoglobin and albumin in g/dl to g/l, multiply by 10; bilirubin in mg/dl to mol/l, multiply by 17.1; blood urea nitrogen in mg/dl to mmol/l, multiply by 0.357; creatinine in mg/dl to mol/l, multiply by 88.4; calcium in mg/dl to mmol/l, multiply by ; phosphate in mg/dl to mmol/l, multiply by ; ipth in pg/ml to ng/l, multiply by 1; ferritin in ng/ml to g/l, multiply by 1. Abbreviations: NS, not significant; GLA, GLA-containing cream; pb, placebo-containing cream.

4 72 Patient Characteristics After Randomization General and clinical characteristics of patients selected to enter this study are listed Table in 2. There were no significant differences between groups except for sex distribution, with a female and male preponderance in groups A and B, respectively. Average ipth levels were pg/ml (ng/l) in group A and pg/ml (ng/l) in group B. There was no significant difference in ipth levels between groups. Median or mean basal VAS and PS values between groups did not differ significantly at baseline. Antipruritic Effect of Treatment Pruritus evaluations by means of VAS and PS for each group in both treatment periods, presented as median and IQR, are shown Fig in 2 to see the trend of antipruritic effect. Median VAS and PS scores before GLA treatment in group A during treatment period 1 were 75 (IQR, 60 to 100) and 10.5 (IQR, 8.5 to 12.5), respectively. Median VAS and PS scores before placebo treatment in group B during treatment period 1 were 80 (IQR, 60 to 95) and 9 (IQR, 7 to 13.5), respectively. Median VAS and PS scores at the CHEN, CHIU, AND WU end of GLA treatment in group A during treatment period 1 were 30 (IQR, 10 to 35) and 6 (IQR, 4 to 7), respectively. Median VAS and PS scores at the end of placebo treatment in group B during treatment period 1 were 75 (IQR, 50 to 80) and 8 (IQR, 7 to 12), respectively. Median VAS and PS scores before placebo treatment in group A during treatment period 2 were 50 (IQR, 40 to 75) and 7.5 (IQR, 7 to 11), respectively. Median VAS and PS scores before GLA treatment in group B during treatment period 2 were 80 (IQR, 65 to 85) and 9 (IQR, 7 to 12.5), respectively. Median VAS and PS scores at the end of placebo treatment in group A during treatment period 2 were 50 (IQR, 40 to 70) and 7.5 (IQR, 6.5 to 10), respectively. Median VAS and PS scores at the end of GLA treatment in group B during treatment period 2 were 40 (IQR, 30 to 60) and 4 (IQR, 4 to 5), respectively. There was a greater antipruritic effect of GLA in group A during treatment period 1 and in group B during treatment period 2 than of placebo in group A during treatment period 2 and in group B during treatment period 1, shown by both VAS and PS evaluation. There was no significant placebo effect in the first treatment Fig 2. Trend in antipruritic effects. Median scores (horizontal lines) in both pruritus assessment methods obtained during each treatment period of the study shown in order of time. Abbreviations: GLA, GLA-containing cream; pb, placebo cream.

5 GAMMA-LINOLENIC ACID, UREMIC PRURITUS 73 Fig 3. Paired comparison of the treatment effect of either GLA cream (GLA) or placebo cream (pb). Median values shown as horizontal lines. There was a significant decrease in VAS and PS scores after GLA treatment. period in group B. There was persistence of a residual effect into the second treatment period after GLA treatment in group A. Differences in efficacy between treatments in treatment period 1 are similar to those in treatment period 2. However, differences in pruritus evaluation in the washout period were smaller than those in the first treatment period. According to the proposal of Lehmacher, 25 results showed a positive -re sidual effect in our study, which indicated the prolonged antipruritic effect of GLA cream. Results of paired analysis of treatment effect are shown in Fig 3. By VAS evaluation, median values before and after GLA treatment were 75 (IQR, 60 to 90) and 30 (IQR, 20 to 55; P ), respectively. Median values before and after placebo treatment were 72.5 (IQR, 50 to 80) and 67.5 (IQR, 40 to 77.5; P not significant), respectively. By PS evaluation, median values before and after GLA treatment were 9.5 (IQR, 7.5 to 12.5) and 4.5 (IQR, 4 to 6; P ), respectively. Median values before and after placebo treatment were 8.0 (IQR, 7 to 12.5) and 8.0 (IQR, 7 to 11.5; P not significant), respectively. In the head-to-head comparison in the first treatment period, mean changes in ratios of scores by means of VAS during GLA treatment were 51.23% 29.41% (SD) and 14.97% 14.73% during placebo treatment. Mean changes in ratios of scores by means of PS were 40.36% 21.34% during GLA treatment and 9.92% 11.62% during placebo treatment. In the head-to-head comparison in the second treatment period, mean changes in ratios of scores by means of VAS were 45.51% 22.41% during GLA treatment and 11.19% 42.02% during placebo treatment. Mean changes in ratios of scores by means of PS were 53.21% 11.28% during GLA treatment and 0.65% 21.07% during placebo treatment. There was a significantly greater antipruritic effect by GLA treatment in both pruritus evaluations in both treatment periods (P 0.01; Fig 4). Laboratory Assays There were no significant changes in hematologic or biochemical parameters during the study period. Calcium and phosphate levels were associated with uremic pruritus. There was no significant change in calcium, phosphate, or calciumphosphate product values before and after GLA and placebo treatment (data not shown). Adverse Effect of Treatment An erythematous skin reaction appeared in 1 patient when she applied GLA cream.

6 74 CHEN, CHIU, AND WU Fig 4. Head-to-head comparison of changes in ratios of either VAS or PS on GLAcontaining cream (GLA) versus placebo cream (pb) in treatment periods 1 and 2. Mean values shown as horizontal lines. There was a significant improvement in uremic pruritus by means of both pruritus evaluations. DISCUSSION Uremic pruritus continues to be an annoying problem for patients and nephrologists because therapies directed at the possible causes have not relieved pruritus consistently. The benefit of these treatments is controversial. Essential fatty acids and their derivatives have a protective function and influence skin structure and physiological characteristics. 21 GLA is an important essential fatty acid composed of 18 carbon atoms with 3 double bonds. 22 It is found naturally in fatty acid 22 fractions of some plant seed oils. Most notably, sources of GLA include evening primrose oil, borage oil, black currant oil, and hemp seed oil. GLA is present in evening primrose oil at a 22 concentration of 7% to 14% of total fatty acids. It is metabolized to dihomogammalinolenic acid, which is the immediate precursor of prostaglandin E 1, an eicosanoid with known anti-inflamma- 26,27 tory and immunoregulatory properties. Evening primrose oil was tested in controlled clinical trials for various disorders, including atopic dermatitis, rheumatoid arthritis, acute respiratory distress syndrome, asthma, ulcerative colitis, dry eye syndrome, diabetic neuropathy, multiple sclerosis, and premenstrual syndrome. 22,28,29 Fiocchi et al 30 found that oral GLA significantly reduced pruritus in children with atopic dermatitis. Our results show a significant antipruritic effect by topical GLA treatment in long-term dialysis patients. All patients obtained marked remission of pruritus in various degrees. A residual effect of GLA was shown during the study. We thought the possible reason for a residual effect into the second treatment period after GLA treatment was the short washout period. There was no serious treatment-related adverse event during the study. The only patient who withdrew from the study developed allergic cutaneous erythema. During hemodialysis, various cytokines are released secondary to the contact of blood and dialysis membranes. 31 Interleukin 2 causes itch - ing and erythema when administered intrave- 32 nously as a part of cancer therapy. Intradermal injection of interleukin 2 leads to intense pruritus. 33 Release of inflammatory and potentially pruritogenic substances may be induced by interleukin Thalidomide and tacrolimus allevi - ated refractory pruritus in hemodialysis patients. Wahlgren et al 35 also found the antipruritic effect of oral cyclosporine A in patients with atopic

7 GAMMA-LINOLENIC ACID, UREMIC PRURITUS 75 dermatitis. Increased tumor necrosis factor synthesis by monocytes also was thought to be a 36 cause of uremic pruritus. These results suggested the role of inflammatory cytokines 37,38 35 and the hypothesis of pruritogenic cytokines. Supplementation of GLA led to a significant increase in plasma levels of dihomogammalinolenic acid, known as a precursor of anti-inflammatory eicosanoids. 39 It is likely that systemic GLA might improve uremic pruritus through a decrease in inflammatory cytokine production and immunoregulation. 40 How this antipruritic effect of topical GLA-rich cream works is not well known. We speculate that this effect may come from a local anti-inflammatory and immunoregulatory effect by GLA or its metabolites absorbed through the transepidermal route. This hypothesis deserves more basic studies for further confirmation. In our study, mean ipth levels between groups A and B differed at baseline (320.7 pg/ml in group A versus pg/ml in group B). Mean basal ipth levels in both groups were greater than median basal ipth levels (161.5 pg/ml in group A versus 48.1 pg/ml in group B) in both groups because there is a positively skewed distribution. Therefore, mean ipth level in group A was affected more by extreme values (eg, 990 pg/ml in group A) in such extremely skewed distributions. However, there is no statistically significant difference in basal ipth levels between groups A and B. We used 2 scoring methods to evaluate pruritus. Because the variable of score is on an ordinal scale, we express the central tendency of these scores in groups by median rather than mean to avoid extreme values by individual subjective evaluation. In addition, the variable of score could not follow a Gaussian bell-shaped distribution. The median is more suitable for representing the central tendency than the mean. Therefore, we used a nonparametric test to evaluate P values between groups conservatively, and results should be more convincing than those of past studies. Dietary and supplemental sources of GLA were investigated reliably and found to be nontoxic. Limited cases of soft stool, belching, and 41 abdominal bloating were reported. Several longterm studies showed that up to 2.8 g/d of GLA is well tolerated. 42,43 Even in topical use, the pos - sible related side effects include nausea, diarrhea, and hot feeling of the skin in a few cases. 23 In our study, there were none of these side effects during the study period, except for skin rash in 1 woman. We conclude that GLA-rich cream is effective in alleviating uremic pruritus. It is a useful adjuvant in the management of patients with refractory uremic pruritus. Topical use of GLA is safe and effective in most cases. Additional study is necessary with regard to the suggestion of an anti-inflammatory effect of topical GLA in uremic patients. The development of topical GLA could be an adjuvant or alternative to existing therapy for dialysis-related pruritus. REFERENCES 1. Ponticelli C, Bencini PL: Uremic pruritus: A review. Nephron 60:1-5, Morton CA, Lafferty M, Hau C, Henderson I, Jones M, Lowe JG: Pruritus and skin hydration during dialysis. Nephrol Dial Transplant 11: , Carmichael AJ, McHugh MM, Martin AM, Farrow M: Serological markers of renal itch in patients receiving long term haemodialysis. Br Med J 296:1575, Katz AI, Hampers CL, Merrill JP: Secondary hyperparathyroidism and renal osteodystrophy in chronic renal failure. Analysis of 195 patients, with observations on the effects of chronic dialysis, kidney transplantation and subtotal parathyroidectomy. Medicine 48: , Dimkovic N, Djukanovic L, Radmilovic A, Bojic P, Juloski T: Uremic pruritus and skin mast cells. Nephron 61:5-9, Valsecchi R, Cainelli T: Generalized pruritus: A manifestation of iron deficiency. Arch Dermatol 119:630, Stockenhuber F, Sunder-Plassmann G, Balcke P: Increased plasma histamine levels in chronic renal failure. N Engl J Med 317:386, Stockenhuber F, Kurz RW, Sertl K, Grimm G, Balcke P: Increased plasma histamine levels in uraemic pruritus. Clin Sci (Lond) 79: , Jedras M, Zakrzewska-Pniewska B, Wardyn K, Switalski M: Uremic neuropathy Is uremic neuropathy related to patient age, duration of nephropathy and dialysis treatment? Pol Arch Med Wewn 99: , Hiroshige K, Kabashima N, Takasugi M, Kuroiwa A: Optimal dialysis improves uremic pruritus. Am J Kidney Dis 25: , Blachley JD, Blankenship DM, Menter A, Parker TF III, Knochel JP: Uremic pruritus: Skin divalent ion content and response to ultraviolet phototherapy. Am J Kidney Dis 5: , Robertson KE, Mueller BA: Uremic pruritus. Am J Health Syst Pharm 53: , Gao H, Zhang W, Wang Y: Acupuncture treatment for 34 cases of uremic cutaneous pruritus. J Tradit Chin Med 22:29-30, 2002

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