Cordray.indd

Comparison of intranasal hypertonic
Dead Sea saline spray and intranasal
aqueous triamcinolone spray in
seasonal allergic rhinitis
Scott Cordray, DO, FAOCO; Jim B. Harjo, DO; Linda Miner, PhD Abstract
Introduction
Intranasal corticosteroids are well known to be effica- Symptoms of seasonal allergic rhinitis are usually caused cious in the treatment of allergic rhinitis. Nasal irrigation by tree, grass, and weed pollens. An important place to with saline, including hypertonic saline, has long been consider seasonal allergic rhinitis is Tulsa, Okla., which recommended for the treatment of sinonasal disease, is located in the northeast region of the state and is known and it has been shown to have a positive effect on the as “Green Country.” The city lies at the threshold of two physiology of the nasal mucosa. Until now, no study of distinct zones––a deciduous forest area and a grasslands the clinical efficacy of intranasal hypertonic Dead Sea area––in which the population is exposed to a diversity saline as a monotherapy for seasonal allergic rhinitis has of allergenic vegetation.1 These two zones are populated been reported. We conducted a prospective, randomized, by vegetation that accounts for 70% (127 of 181) of all single-blind, placebo-controlled comparison of intranasal allergenic species and by 79% (26 of 33) of the most al- hypertonic Dead Sea saline spray and intranasal aqueous lergenic species.1 triamcinolone spray in 15 patients with seasonal allergic The highest concentrations of airborne tree pollens are rhinitis. Results were based on a 7-day regimen. Based typically seen in the early spring. Genera include Quercus on Rhinoconjunctivitis Quality of Life Questionnaire (oak), Juniperus (cedar), and Ulmus (elm). Quercus releases scores, clinically and statistically significant (p < 0.0001) the most abundant pollen during any season.2,3 Juniperus improvements were seen in both active-treatment groups; ashei (mountain cedar) pollen is carried upwind into the as expected, the corticosteroid spray was the more effec- Tulsa area from southwest Oklahoma and west Texas dur- tive of the two treatments. No significant improvement ing the fall and through the winter.3,4 occurred in the control group. Our preliminary results In the late spring and early summer, pollens are released not only confirm the efficacy of intranasal corticosteroid by other allergenic trees, such as Juglans regia (walnut) therapy in moderate-to-severe allergic rhinitis, they also and Carya illinoensis (pecan). Also, a number of grasses suggest that the Dead Sea saline solution can be an ef- pollinate from late spring through the summer; among fective alternative in mild-to-moderate allergic rhinitis, the most allergenic are Cynodon dactylon (bermuda) and particularly with respect to nasal and eye symptoms. The Phleum pratense (timothy). Fall is typically the season hypertonicity of the Dead Sea solution may have a positive for Ambrosia trifida (giant ragweed), which is the second effect on the physiology of the nasal mucosa by improving most abundant pollen in the Tulsa area; pollination usually mucociliary clearance. In addition, the dominant cation peaks in mid-September and ends in early October. in the Dead Sea solution––magnesium––probably exerts In addition to allergen avoidance, proven treatments for anti-inflammatory effects on the nasal mucosa and on the seasonal allergic rhinitis include intranasal corticosteroids, oral and topical H receptor antagonists (antihistamines), in- tranasal saline solutions, and occasionally immunotherapy; Dr. Cordray is an otolaryngologist in private practice. Dr. Harjo is a recently, treatment with leukotriene receptor antagonists family physician in private practice. Dr. Miner is director of aca- has also been suggested. The superior effects of intranasal demic programs at Southern Nazarene University. All are located corticosteroids in sinonasal diseases have been established with respect to symptom resolution and quality of life.5-12 Reprint requests: Scott Cordray, DO, Hillcrest Physicians Bldg., 1145 S. Utica Ave., #513, Tulsa, OK 74104. Phone: (918) 582-8217; fax: Intranasal corticosteroids also have a significant effect on (918) 582-8219; e-mail: scordray@cfaith.com inflammatory mediators in allergic rhinitis.13,14 In fact, when ENT-Ear, Nose & Throat Journal ■ July 2005
COMPARISON OF INTRANASAL HYPERTONIC DEAD SEA SALINE SPRAY AND INTRANASAL AQUEOUS TRIAMCINOLONE SPRAY IN SEASONAL ALLERGIC RHINITIS compared with oral antihistamines and with leukotriene neck cancer, human immunodeficiency virus-related nasal receptor antagonists (with intranasal saline typically used disease, cystic fibrosis, and renal, hepatic, pulmonary, and as a control) for the treatment of seasonal allergic rhinitis, cardiovascular disease. corticosteroids have been shown to be superior.5,7,9,11,12 During the study, 6 of the 21 patients withdrew. Two The effects of intranasal hypertonic saline solutions patients withdrew because of adverse reactions, 2 did are less clear. Some studies have shown that they exert not return for the second of two scheduled visits, 1 was beneficial effects on nasal physiology, mucociliary clear- disqualified for antihistamine use during the study period, ance in particular,15-18 and that they help relieve symptoms and 1 had stopped treatment prematurely. The final data and improve quality of life in patients with sinonasal analysis, therefore, was based on findings in the 15 pa- disease.19-21 Other studies, however, have shown that they tients––3 men and 12 women, aged 20 to 74 years (mean: have a negative effect on nasal physiology and no effect 35.2 ± 16.05)––who completed both visits. Written informed consent was obtained from all patients. One such hypertonic saline solution is made from Dead The research protocol and the informed consent form were Sea salts. The Dead Sea is the world’s most saline lake approved by the Institutional Review Board of Family body, and it contains proportionately more magnesium, Medical Care of Tulsa, Inc. calcium, bromine, and potassium and less sodium, sulfate, Study design. This randomized, single-blind, placebo-
and carbonate than any ocean.25 Magnesium is the dominant controlled study was conducted during 6 weeks of the cation, accounting for approximately 35% of the composi- spring allergy season in Tulsa, Okla. All patients were tion of Dead Sea salts. This chemical composition makes required to comply with the study protocol at two office Dead Sea salt unlike any other sea salt in the world.26 visits. The treatment protocol was explained to them with Treatment with Dead Sea salts has been shown to have both oral and written instructions. positive effects on skin conditions such as psoriasis27 and Patients were randomized into 3 groups of 5 each to contact eczema.28 The magnesium ion is believed to be receive either intranasal hypertonic Dead Sea saline spray primarily responsible for these positive effects.27-30 Also, (2 sprays into each nostril 3 times daily), aqueous triam- it is well established that magnesium in its intravenous,31,32 cinolone spray (110 µg into each nostril once daily), or inhaled and nebulized,33-35 and dietary36,37 forms plays a a placebo nasal saline spray (2 sprays into each nostril 3 role in treating acute asthma, which is known to cause a times daily) for 7 days. At the first visit, each patient underwent skin-prick A report from Italy revealed that intranasal hypertonic allergen testing for tree pollen (American elm, post oak, saline was beneficial in reducing the amount of as-needed and mountain cedar), grass pollen (bermuda and timothy), antihistamines in a pediatric population with seasonal al- short ragweed pollen, and Alternaria mold extract. Patients lergic rhinitis.38 Until now, no study has been published also completed the standardized version of the Rhinocon- regarding the effects of hypertonic saline as a monotherapy junctivitis Quality of Life Questionnaire (RQLQ), once for seasonal allergic rhinitis. In this article, we describe at the first visit and again at the completion of treatment. what we believe is the first such preliminary study. The RQLQ is a reliable, validated instrument with strong discriminative properties.39,40 The survey contains 28 Patients and methods
questions regarding 7 domains: activities, sleep, practical Patient population. Our study population was originally problems, nasal symptoms, eye symptoms, other symp-
made up of 21 patients who had presented to the family toms, and emotional status. For each domain, patients rate practice office of one of the authors (J.B.H.) seeking treat- themselves as to how much their symptoms have affected ment for symptoms of seasonal allergic rhinitis. In order them during the previous week on a scale of 0 (no effect) to be eligible for this study, patients had to be at least 18 to 6 (great effect). years of age, had to have experienced at least two of six Statistical analysis. Statistical analysis was performed
symptoms (nasal stuffiness, watery/itchy eyes, rhinorrhea, with the assistance of the Excel statistical package (Mi- sneezing, postnasal drainage, and itchy throat/cough) at crosoft; Redmond, Wash.) and confirmed by the Statistica presentation, and had to have had a positive skin puncture 2003 package (StatSoft; Tulsa). Values analyzed were the test for seasonal allergens. Exclusion criteria included the mean RQLQ scores in each of the 7 domains and the overall presence of chronic sinusitis, nasal polyposis, a deviated composite scores. The Student’s t test was figured from nasal septum or history of nasal septal perforation, and the composite scores. A one-sided hypothesis was used in recent nasal or sinus surgery; the use of an antihistamine, anticipation of an expected reduction in composite scores cromolyn, decongestant, or a topical or systemic corti- after treatment; this helped obviate a type II error, which costeroid within the preceding 2 weeks or an immuno- likely would have occurred in view of the small number therapeutic agent within the preceding 2 years; pregnancy of patients in this study. and/or lactation; and chronic conditions such as head and Volume 84, Number 7
on any RQLQ domain. Juniper et al, who developed the Following treatment, clinically and statistically significant RQLQ, defined a clinically significant difference as “the improvements in mean composite RQLQ scores were seen smallest difference in score in the domain of interest which in both the Dead Sea saline group and the corticosteroid patients perceive as beneficial and would mandate a change group; no significant improvement occurred in the control in management,” and they provided evidence that this dif- ference is 0.5.40 Based on this interpretation, the placebo in The Dead Sea saline group experienced a significant our study did lead to a clinically significant difference in reduction in the mean composite RQLQ score, which fell three domains: sleep, eye symptoms, and emotional status. from 3.38 to 2.02, a difference of 1.36 (p < 0.0001). This finding supports the idea that although nasal saline is As expected, the corticosteroid group experienced the typically used as a control in studies of allergic rhinitis, it most marked overall improvement, as its mean composite is not a genuine placebo. Ratner et al have suggested that RQLQ score declined from 3.24 to 1.03, a difference of oral nonsedative antihistamines have been shown to be no more effective than placebo aqueous nasal sprays in In the control group, the mean composite RQLQ score placebo-controlled studies in which the active comparator was 2.60 prior to treatment and 2.44 afterward, a difference was an intranasal corticosteroid, but they have been shown of 0.16. The difference was not statistically significant to be superior to placebo tablets when the active comparator (p = 0.6483). Likewise, there was no significant difference was another oral antihistamine.11 In light of the findings by in any of the 7 domain scores pre- and posttreatment. Ratner et al and their belief that intranasal saline washes In both active-treatment groups, improvements were seen the nasal mucosa of allergens and mucus, we suggest that in all 7 individual domains. The greatest improvements in the efficacy of intranasal saline might be equal to that of the Dead Sea saline group involved nasal symptoms (from oral H receptor antagonists for some patients with mild 3.83 to 2.17, a difference of 1.66) and eye symptoms (from symptoms. Nasal saline may indeed play a role in the 3.00 to 2.04, a difference of 0.96). In the corticosteroid treatment of allergic rhinitis when it is delivered as a true group, the greatest improvements involved eye symptoms irrigation agent rather than as just a simple moisturizer. One (from 3.75 to 0.85, a difference of 2.90) and nasal symptoms Tulsa allergist, Jane Purser, MD, recommends nasal saline (from 3.65 to 1.40, a difference of 2.25). irrigation with a minimum of 5 sprays in each nostril every morning, and she has observed some clinically significant Discussion
improvements among her patients with chronic sinonasal Corticosteroids. Our expected finding that triamcinolone disease (oral communication, February 2001). We believe
resulted in a statistically significant alleviation of severe that nasal saline spray as a placebo is probably adequate symptoms and improvement in quality of life is consistent for research purposes, but it does provide some actual with the large body of evidence that intranasal corticoste- clinical benefit as an irrigant in some patients. roids are not only efficacious but superior for the treatment Dead Sea saline. The use of the intranasal hypertonic
of seasonal allergic rhinitis.5,7,9,11,12 It is interesting that of Dead Sea saline solution in our study resulted in some the 7 RQLQ domains, intranasal triamcinolone’s greatest moderate but clinically and statistically significant improve- effect was on reducing eye symptoms (i.e., conjunctivitis). ment in posttreatment RQLQ scores. It was most effective This suggests that allergic rhinitis is a disease of systemic in treating nasal symptoms. It was also significantly more immunologic response and that intranasal corticosteroids effective than the placebo in all 7 domains. We believe ours have a global effect rather than just a local effect. is the first study to demonstrate the possible efficacy of Saline control. According to our analysis, nasal saline as intranasal hypertonic Dead Sea saline solution in alleviating
the control preparation had no statistically significant effect symptoms and improving overall quality of life in patients Table. Mean composite RQLQ scores pre- and posttreatment in the
action is unclear, but we can offer some possible explanations. Like the nasal saline placebo, it may act as a mild irrigant and physically clear mucus and inflammatory cells. It may also have positive effects on mucociliary clearance.15,16 Finally, in view of its beneficial effect on eye symptoms, it may have global anti-inflammatory proper- ties and affect the systemic immunologic ENT-Ear, Nose & Throat Journal ■ July 2005
COMPARISON OF INTRANASAL HYPERTONIC DEAD SEA SALINE SPRAY AND INTRANASAL AQUEOUS TRIAMCINOLONE SPRAY IN SEASONAL ALLERGIC RHINITIS Magnesium. Regarding the latter explanation, magne- cell degranulation and histamine release. Through a number
sium is the dominant cation in the Dead Sea saline solution, of mechanisms, this activity causes symptoms of sneezing, and it is reasonable to postulate that magnesium exerts some rhinorrhea, nasal and ocular itchiness, eye watering, and effect on inflammatory cells or inflammatory mediators. cough. Chemotactic factors presumably modulate the influx Asthma is known to be associated with increased amounts of eosinophils, one of which is histamine. Magnesium of eosinophils and has long been believed to cause a reac- administered intranasally via Dead Sea saline solution tion similar to an allergy. Intravenous magnesium has been may inhibit eosinophil release of major basic protein and shown to be beneficial in the treatment of acute asthma,31,32 mast cell release of histamine, thereby inhibiting the local and nebulized magnesium in combination with albuterol immune response and probably creating the anti-inflam- was shown to exert beneficial effects in a pediatric popula- matory effect of the systemic response. tion in an emergency department in Detroit.35 In another Our data suggest that the use of intranasal hypertonic study, 36.8% of asthma patients who were treated for 4 Dead Sea saline solution in a spray form results in a moder- weeks at the Dead Sea itself were able to discontinue their ate reduction of symptoms and a moderate improvement medications; even those who continued inhalation treat- in overall quality of life in patients with seasonal allergic ment were able to reduce the frequency of their puffs by rhinitis, and that it is probably useful in patients with 43%.34 Dietary magnesium has positive effects, as well. mild-to-moderate symptoms. The Dead Sea solution also Researchers in the United Kingdom found that a dietary appears to be significantly better than nasal saline placebo regimen high in magnesium significantly improved lung in reducing symptoms and improving quality of life, and function and lowered asthma symptom scores.36,37 The role it probably exerts antiinflammatory effects on the nasal of magnesium in lung function is probably twofold: (1) mucosa and the systemic inflammatory response. Patients Magnesium relaxes bronchial smooth muscle and thereby with moderate-to-severe symptoms should probably be dilates airways, and (2) it may exert some influence on treated with an intranasal corticosteroid, with or without inflammatory cells and their subsequent release of inflam- a nasal wash with Dead Sea saline solution. It is possible that a different delivery system––namely irrigation––may Evidence of the positive effect that magnesium in enhance the positive effects of the Dead Sea solution, and Dead Sea salts has on some skin diseases was reported we hope that such a study can be undertaken. by Greiner and Diezel in Germany.30 They administered In conclusion, it appears that the intranasal hypertonic water with a high concentration of magnesium ions to mice Dead Sea saline solution is superior to plain saline solution with allergenic contact dermatitis that had been induced in the treatment of seasonal allergic rhinitis. However, in by 1-chloro-2, 4-dinitrobenzene (DNCB). Mice that were view of the small number of patients in our study, these challenged by DNCB plus magnesium chloride experienced results are only preliminary. Fortunately, several studies significantly less inflammation than did mice that were are under way to help confirm or refute our conclusion. challenged by DNCB alone and by DNCB plus sodium chloride. Greiner and Diezel confirmed these findings in References
5 humans who had a known allergy to nickel; magnesium 1. Levetin E, Buck P. Hay fever plants in Oklahoma. Ann Allergy chloride suppressed nickel sulfate-induced contact derma- titis, and sodium chloride did not.30 Another study from 2. Levetin E, Larsen-Purvis M. Tulsa Pollen Calendar. The University Germany by Ludwig et al revealed that high concentrations 3. Levetin E. A long-term study of winter and early spring tree pollen of magnesium ions inhibited the release of arachidonic in the Tulsa, Oklahoma atmosphere. Aerobiologia 1998;14:21-8. acid (an important precursor of inflammatory mediators) 4. Levetin E, Buck P. Evidence of mountain cedar pollen in Tulsa. and leukotriene B4 (a potent regulator in inflammatory reactions) in polymorphonuclear leukocytes.41 Ludwig et 5. Kaszuba SM, Baroody FM, deTineo M, et al. Superiority of an intranasal corticosteroid compared with an oral antihistamine in al concluded that high concentrations of magnesium inhibit the as-needed treatment of seasonal allergic rhinitis. Arch Intern eicosanoid metabolism during the release of arachidonic acid by directly inhibiting the 5-lipoxygenase enzyme. 6. Parikh A, Scadding GK, Darby Y, Baker RC. Topical corticosteroids Magnesium probably stabilizes eosinophils (which under in chronic rhinosinusitis: A randomized, double-blind, placebo- certain conditions degranulate major basic protein) and mast controlled trial using fluticasone propionate aqueous nasal spray. cells (which degranulate histamine). It has been demon- 7. Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus strated that when magnesium levels in the blood decrease, oral H1 receptor antagonists in allergic rhinitis: Systematic review eosinophil and histamine levels subsequently increase.42 It of randomized controlled trials. BMJ 1998;317(7173):1624-9. has also been shown that magnesium inhibits eosinophils 8. Mabry RL. Pharmacotherapy of allergic rhinitis: Corticosteroids. from undergoing exocytosis and degranulation.43 Allergic Otolaryngol Head Neck Surg 1995;113:120-5. 9. Jen A, Baroody F, deTineo M, et al. As-needed use of fluticasone rhinitis typically begins with the exposure of IgE-bound propionate nasal spray reduces symptoms of seasonal allergic mast cells to an allergen and progresses to subsequent mast rhinitis. J Allergy Clin Immunol 2000;105:732-8. Volume 84, Number 7
10. Juniper EF, Kline PA, Hargreave FE, Dolovich J. Comparison of 30. Greiner J, Diezel W. [Inflammation-inhibiting effect of magnesium beclomethasone dipropionate aqueous nasal spray, astemizole, and ions in contact eczema reactions]. Hautarzt 1990;41:602-5. the combination in the prophylactic treatment of ragweed pollen- 31. Keen JH. Intravenous magnesium sulfate for acute asthma. J Emerg induced rhinoconjunctivitis. J Allergy Clin Immunol 1989;83: 32. Ciarallo L, Sauer AH, Shannon MW. Intravenous magnesium therapy 11. Ratner PH, van Bavel JH, Martin BG, et al. A comparison of the for moderate to severe pediatric asthma: Results of a randomized, efficacy of fluticasone propionate aqueous nasal spray and loratadine, placebo-controlled trial. J Pediatr 1996;129:809-14. alone and in combination, for the treatment of seasonal allergic 33. Rolla G, Bucca C, Bugiani M, et al. Reduction of histamine-induced bronchoconstriction by magnesium in asthmatic subjects. Allergy 12. Pullerits T, Praks L, Skoogh BE, et al. Randomized placebo-con- trolled study comparing a leukotriene receptor antagonist and a 34. Harari M, Barzillai R, Shani J. Magnesium in the management nasal glucocorticoid in seasonal allergic rhinitis. Am J Respir Crit of asthma: Critical review of acute and chronic treatments, and Deutches Medizinisches Zentrum’s (DMZ’s) clinical experience 13. Benson M, Strannegard IL, Strannegard O, Wennergren G. Topi- at the Dead Sea. J Asthma 1998;35:525-36. cal steroid treatment of allergic rhinitis decreases nasal fluid TH2 35. Mahajan PV, Rosenberg N, Sethuraman U, Dimitri H. Comparison cytokines, eosinophils, eosinophil cationic protein, and IgE but of nebulized magnesium plus albuterol to nebulized albuterol alone has no significant effect on IFN-gamma, IL-1beta, TNF-alpha, or in children with mild to moderate asthma. Presented at the annual neutrophils. J Allergy Clin Immunol 2000;106:307-12. meeting of the American Academy of Pediatrics; Oct. 19-23, 2002; 14. Nielsen LP, Bjerke T, Christensen MB, et al. Eosinophil markers in seasonal allergic rhinitis. Intranasal fluticasone propionate inhibits 36. Hill J, Micklewright A, Lewis S, Britton J. Investigation of the ef- local and systemic increases during the pollen season. Allergy fect of short-term change in dietary magnesium intake in asthma. 15. Talbot AR, Herr TM, Parsons DS. Mucociliary clearance and buff- 37. Britton J, Pavord I, Richards K, et al. Dietary magnesium, lung ered hypertonic saline solution. Laryngoscope 1997;107:500-3. function, wheezing, and airway hyperreactivity in a random adult 16. Homer JJ, England RJ, Wilde AD, et al. The effect of pH of douch- population sample. Lancet 1994;344:357-62. ing solutions on mucociliary clearance. Clin Otolaryngol 1999;24: 38. Garavello W, Romagnoli M, Sordo L, et al. Hypersaline nasal ir- rigation in children with symptomatic seasonal allergic rhinitis: A 17. Tomooka LT, Murphy C, Davidson TM. Clinical study and literature randomized study. Pediatr Allergy Immunol 2003;14:140-3. review of nasal irrigation. Laryngoscope 2000;110:1189-93. 39. Juniper EF, Thompson AK, Ferrie PJ, Roberts JN. Validation of 18. Homer JJ, Dowley AC, Condon L, et al. The effect of hypertonicity the standardized version of the Rhinoconjunctivitis Quality of Life on nasal mucociliary clearance. Clin Otolaryngol 2000;25:558- Questionnaire. J Allergy Clin Immunol 1999;104(2 Pt 1):364-9. 40. Juniper EF, Guyatt GH, Griffith LE, Ferrie PJ. Interpretation of 19. Shoseyov D, Bibi H, Shai P, et al. Treatment with hypertonic saline rhinoconjunctivitis quality of life questionnaire data. J Allergy versus normal saline nasal wash of pediatric chronic sinusitis. J 41. Ludwig P, Petrich K, Schewe T, Diezel W. Inhibition of eico- 20. Heatley DG, McConnell KE, Kille TL, Leverson GE. Nasal irriga- sanoid formation in human polymorphonuclear leukocytes by tion for the alleviation of sinonasal symptoms. Otolaryngol Head high concentrations of magnesium ions. Biol Chem Hoppe Seyler 21. Rabago D, Zgierska A, Mundt M, et al. Efficacy of daily hypertonic 42. Chyrek-Borowska S, Obrzut D, Hofman J. The relation between saline nasal irrigation among patients with sinusitis: A randomized magnesium, blood histamine level and eosinophilia in the acute controlled trial. J Fam Pract 2002;51:1049-55. stage of the allergic reactions in humans. Arch Immunol Ther Exp 22. Min YG, Lee KS, Yun JB, et al. Hypertonic saline decreases ciliary movement in human nasal epithelium in vitro. Otolaryngol Head 43. Larbi KY, Gomperts BD. Complex pattern of inhibition by magne- sium of exocytosis from permeabilised eosinophils. Cell Calcium 23. Boek WM, Keles N, Graamans K, Huizing EH. Physiologic and hypertonic saline solutions impair ciliary activity in vitro. Laryn- 24. Adam P, Stiffman M, Blake RL, Jr. A clinical trial of hypertonic saline nasal spray in subjects with the common cold or rhinosinusitis. 25. Even-Paz Z, Shani J. The Dead Sea and psoriasis. Historical and geographic background. Int J Dermatol 1989;28:1-9. 26. Nissenbaum A. Minor and trace elements in Dead Sea water. Chem 27. Goldberg LH, Sagher F. Psoriasis treatment at the Dead Sea. Cutis 28. Schiffner R, Schiffner-Rohe J, Gerstenhauer M, et al. Dead Sea treatment––Principle for outpatient use in atopic dermatitis: Safety and efficacy of synchronous balneophototherapy using narrow- band UVB and bathing in Dead Sea salt solution. Eur J Dermatol 29. Levi-Schaffer F, Shani J, Politi Y, et al. Inhibition of proliferation of psoriatic and healthy fibroblasts in cell culture by selected Dead ENT-Ear, Nose & Throat Journal ■ July 2005

Source: http://www.breathethesea.com/DeadSeaStudy.pdf