1120
Dr Wittmann and Dr Wittmann suggest that our randomised trial was confounded by early mobilisation of patients allocated to fixed-dose LMWH. However, patients in both treatment groups were mobilised after 3 days and those treated with intravenous heparin received their medication via a portal device; it is unlikely that the observed differences in efficacy are due to differences in mobilisation. A third group, receiving LMWH by continuous infusion for the "true" assessment of efficacy, seems unnecessary. Of the 71 patients in the category "recent immobilisation or surgery" 18 were operated on in the 12 months preceding study entry; 15 received thromboprophylaxis. Academisch Ziekenhuis, University of Amsterdam, 1105 AZ Amsterdam, Netherlands
ANTHONIE W. A LENSING HARRY R. BÜLLER PAOLO PRANDONI
keratinocytes,s and since these cells and released cytokines presumably have an important role in the pathogenesis of these diseases, their inhibition by cyclosporin may explain the drug’s therapeutic action.
School of Medicine, Kawasaki 216, Japan
M. MIZOGUCHI K. KAWAGUCHI Y. OHSUGA Y. IKARI
Institute of Medical Science, St Marianna University
A. YANAGAWA Y. MIZUSHIMA
Department of Dermatology, St Marianna University
2. 3.
1. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-82.
Cyclosporin ointment for psoriasis and atopic dermatitis SIR,-Systemic cyclosporin is useful in the treatment of skin diseases such as psoriasis1 and atopic dermatitis.2 Unfortunately, when given by this route, adverse effects limit the drug’s clinical use. A topical cyclosporin preparation has not hitherto been successful because penetration enhancers are required to obtain absorption of the drug through the skin. We have devised an ointment base for cyclosporin containing olive oil, ethanol, Aerosil 200, and polyoxy5-glyceryl monostearate. The percutaneous absorption of 1 %, 5%, and 10% cyclosporin ointment has been confirmed in C3H/HeN mice after 14 h, with corresponding cyclosporin concentrations of 23, 840, and 150 ng/ml in whole blood and 610, 6000, and 23 000 ng/g in skin tissue. The topical application of these ointments was found to suppress dinitrofluorobenzene-induced contact dermatitis. An open study has been done with twice daily application of 5% cyclosporin ointment in ten patients (mean age 52, range 32-78) with psoriasis and twelve (mean age 27-3 years, range 14-44) with atopic dermatitis. Informed consent was obtained. The psoriasis patients were observed for 4-12 weeks and the efficacy of treatment was assessed by PASI (psoriasis area and severity index) score every two weeks. The atopic dermatitis patients were assessed on days 0, 14, and 28 for pruritus, erythema, and lichenification, on a 0-4 scale. Two psoriasis patients achieved complete remission and the rest had a good response. Mean PASI scores fell from 21 ’8 at baseline to 3-9 by the end of the study. In atopic dermatitis, mean total scores changed from 10-9 (day 0) to 6-9 (day 14) and to 7-8 (day 28); six patients showed good results for both eruptions and itching. Three other patients responded well on day 14, but showed exacerbation of the condition on day 28. Patch testing in these patients discounted an allergic reaction to cyclosporin. An in-vitro study has shown that cyclosporin inhibits histamine release.3 However, the three remaining patients stopped using the ointment on day 14 because of itching, despite a good response, so cyclosporin ointment cannot suppress severe itching in atopic dermatitis as other drugs which inhibit histamine release do. Good results took longer to obtain for patients with psoriasis than for those with atopic dermatitis; however, they were maintained for longer in psoriasis. Over 3 months after the therapy was discontinued, one psoriasis patient is still in remission. Laboratory results did not change significantly. Whole blood cyclosporin concentrations were undetectable (less than 20 ng/ml) in four patients and ranged from 22 to 29 ng/ml in eleven. The low blood concentrations resulting from percutaneous absorption were not associated with any adverse systemic effects. One psoriasis patient had a skin tissue concentration of 440 ng/g. The ointment seems more effective and with fewer side-effects than systematically administered cyclosporin. The mechanisms that improve these skin diseases are unknown. Proliferation and function of helper/inducer T cells are selectively inhibited.4 By suppressing the production of cytokines or growth factors, cyclosporin also inhibits the proliferation and function of
CN, Fradin MS, Messana JM, et al. Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind study. N Engl JMed 1991; 324: 277-84 van Joost T, Stolz E, Heule F. Efficacy of low dose cyclosporine in severe atopic skin disease. Arch Dermatol 1987; 123: 166-67. L’ubica D. Cyclosporine A inhibits rat mast cell activation. EurJ Immunol 1990; 20: 1469-73. Wagner H. Cyclosporine A. mechanisms of action. Transplant Proc 1983; 15: 523-26 Furure M, Gaspari AA, Katz SI. The effect of cyclosporine A on epidermal cells II: cyclosporine A inhibits proliferation of normal and transformed keratinocytes. J Invest Dermatol 1988; 90: 796-800.
1. Ellis
4. 5.
Immunisation against gastric helicobacter infection in a mouse/Helicobacter felis model SIR,-Long-term infection with Helicobacter pylori has been associated with gastric cancer.’ The hypothesis is that chronic gastritis caused by this bacterium progresses to atrophic gastritis, intestinal metaplasia, and hypochlorhydria; if other conditions are fulfilled (eg, particular dietary components), carcinoma is induced as a direct effect of H pylori or by action of other overgrowing bacteria. If H pylori infection is a prerequisite for the development of gastric cancer so intervention would become a possibility for a disease that carries a very high mortality in some developing countries. The most convenient intervention would be immunisation but the likely efficacy of this approach is uncertain because people remain infected for decades despite a striking immune response to this gastric organism. However, there is precedent for the suggestion that an immune response that is insufficient to dislodge an established parasite may prevent a new infection.2 Czinn and Nedrud3 have described experiments on oral immunisation against H pylori in mice and ferrets.3Cholera toxin, when given orally with whole-cell sonicates of H pylori, had a substantial adjuvant effect, resulting in increased concentrations of serum and gastrointestinal IgG and IgA. They speculated that oral immunisation with killed H pylori might protect against this infection and the accompanying gastroduodenal disease-but they could not confirm this hypothesis because H pylori will not infect mice or ferrets. We have developed an animal model of H pylori-associated gastroduodenal disease using the closely related organism H felis.4 This bacterium colonises the gastric mucosa of mice in very large numbers, and in the germ-free rodent it induces a gastritis mimicking that seen in man .5 In specific-pathogen-free (SPF) mice Hfelis behaves very like H pylori; it shows the same susceptibility to antimicrobial therapy and has been used to screen novel anti-H pylori agents. With this model we have used the Czinn and Nedrud immunising protocol to test the hypothesis that the enhanced mucosal immunity would be protective. SPF Balb C mice were immunised on days 1,3,6,30, and 54 with 0-5 ml phosphate-buffered saline, 1 mg H felis sonicate, or, I mg sonicate plus 10 Ilg cholera toxin (Sigma). 3 days after the last immunising dose, the mice were challenged with 10’ Hfelis. The mice were killed 3 weeks after challenge, and infection with H felis was assessed:6 Proportion of H felis infected Immunisation Saline Sonicate Sonicate plus cholera toxin
mice 3 wk post-challenge
19/19 (100%) 21/21 (100%)J 1/19 (5%) (p
Dr Wittmann and Dr Wittmann suggest that our randomised trial was confounded by early mobilisation of patients allocated to fixed-dose LMWH. However, patients in both treatment groups were mobilised after 3 days and those treated with intravenous heparin received their medication via a portal device; it is unlikely that the observed differences in efficacy are due to differences in mobilisation. A third group, receiving LMWH by continuous infusion for the "true" assessment of efficacy, seems unnecessary. Of the 71 patients in the category "recent immobilisation or surgery" 18 were operated on in the 12 months preceding study entry; 15 received thromboprophylaxis. Academisch Ziekenhuis, University of Amsterdam, 1105 AZ Amsterdam, Netherlands
ANTHONIE W. A LENSING HARRY R. BÜLLER PAOLO PRANDONI
keratinocytes,s and since these cells and released cytokines presumably have an important role in the pathogenesis of these diseases, their inhibition by cyclosporin may explain the drug’s therapeutic action.
School of Medicine, Kawasaki 216, Japan
M. MIZOGUCHI K. KAWAGUCHI Y. OHSUGA Y. IKARI
Institute of Medical Science, St Marianna University
A. YANAGAWA Y. MIZUSHIMA
Department of Dermatology, St Marianna University
2. 3.
1. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-82.
Cyclosporin ointment for psoriasis and atopic dermatitis SIR,-Systemic cyclosporin is useful in the treatment of skin diseases such as psoriasis1 and atopic dermatitis.2 Unfortunately, when given by this route, adverse effects limit the drug’s clinical use. A topical cyclosporin preparation has not hitherto been successful because penetration enhancers are required to obtain absorption of the drug through the skin. We have devised an ointment base for cyclosporin containing olive oil, ethanol, Aerosil 200, and polyoxy5-glyceryl monostearate. The percutaneous absorption of 1 %, 5%, and 10% cyclosporin ointment has been confirmed in C3H/HeN mice after 14 h, with corresponding cyclosporin concentrations of 23, 840, and 150 ng/ml in whole blood and 610, 6000, and 23 000 ng/g in skin tissue. The topical application of these ointments was found to suppress dinitrofluorobenzene-induced contact dermatitis. An open study has been done with twice daily application of 5% cyclosporin ointment in ten patients (mean age 52, range 32-78) with psoriasis and twelve (mean age 27-3 years, range 14-44) with atopic dermatitis. Informed consent was obtained. The psoriasis patients were observed for 4-12 weeks and the efficacy of treatment was assessed by PASI (psoriasis area and severity index) score every two weeks. The atopic dermatitis patients were assessed on days 0, 14, and 28 for pruritus, erythema, and lichenification, on a 0-4 scale. Two psoriasis patients achieved complete remission and the rest had a good response. Mean PASI scores fell from 21 ’8 at baseline to 3-9 by the end of the study. In atopic dermatitis, mean total scores changed from 10-9 (day 0) to 6-9 (day 14) and to 7-8 (day 28); six patients showed good results for both eruptions and itching. Three other patients responded well on day 14, but showed exacerbation of the condition on day 28. Patch testing in these patients discounted an allergic reaction to cyclosporin. An in-vitro study has shown that cyclosporin inhibits histamine release.3 However, the three remaining patients stopped using the ointment on day 14 because of itching, despite a good response, so cyclosporin ointment cannot suppress severe itching in atopic dermatitis as other drugs which inhibit histamine release do. Good results took longer to obtain for patients with psoriasis than for those with atopic dermatitis; however, they were maintained for longer in psoriasis. Over 3 months after the therapy was discontinued, one psoriasis patient is still in remission. Laboratory results did not change significantly. Whole blood cyclosporin concentrations were undetectable (less than 20 ng/ml) in four patients and ranged from 22 to 29 ng/ml in eleven. The low blood concentrations resulting from percutaneous absorption were not associated with any adverse systemic effects. One psoriasis patient had a skin tissue concentration of 440 ng/g. The ointment seems more effective and with fewer side-effects than systematically administered cyclosporin. The mechanisms that improve these skin diseases are unknown. Proliferation and function of helper/inducer T cells are selectively inhibited.4 By suppressing the production of cytokines or growth factors, cyclosporin also inhibits the proliferation and function of
CN, Fradin MS, Messana JM, et al. Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind study. N Engl JMed 1991; 324: 277-84 van Joost T, Stolz E, Heule F. Efficacy of low dose cyclosporine in severe atopic skin disease. Arch Dermatol 1987; 123: 166-67. L’ubica D. Cyclosporine A inhibits rat mast cell activation. EurJ Immunol 1990; 20: 1469-73. Wagner H. Cyclosporine A. mechanisms of action. Transplant Proc 1983; 15: 523-26 Furure M, Gaspari AA, Katz SI. The effect of cyclosporine A on epidermal cells II: cyclosporine A inhibits proliferation of normal and transformed keratinocytes. J Invest Dermatol 1988; 90: 796-800.
1. Ellis
4. 5.
Immunisation against gastric helicobacter infection in a mouse/Helicobacter felis model SIR,-Long-term infection with Helicobacter pylori has been associated with gastric cancer.’ The hypothesis is that chronic gastritis caused by this bacterium progresses to atrophic gastritis, intestinal metaplasia, and hypochlorhydria; if other conditions are fulfilled (eg, particular dietary components), carcinoma is induced as a direct effect of H pylori or by action of other overgrowing bacteria. If H pylori infection is a prerequisite for the development of gastric cancer so intervention would become a possibility for a disease that carries a very high mortality in some developing countries. The most convenient intervention would be immunisation but the likely efficacy of this approach is uncertain because people remain infected for decades despite a striking immune response to this gastric organism. However, there is precedent for the suggestion that an immune response that is insufficient to dislodge an established parasite may prevent a new infection.2 Czinn and Nedrud3 have described experiments on oral immunisation against H pylori in mice and ferrets.3Cholera toxin, when given orally with whole-cell sonicates of H pylori, had a substantial adjuvant effect, resulting in increased concentrations of serum and gastrointestinal IgG and IgA. They speculated that oral immunisation with killed H pylori might protect against this infection and the accompanying gastroduodenal disease-but they could not confirm this hypothesis because H pylori will not infect mice or ferrets. We have developed an animal model of H pylori-associated gastroduodenal disease using the closely related organism H felis.4 This bacterium colonises the gastric mucosa of mice in very large numbers, and in the germ-free rodent it induces a gastritis mimicking that seen in man .5 In specific-pathogen-free (SPF) mice Hfelis behaves very like H pylori; it shows the same susceptibility to antimicrobial therapy and has been used to screen novel anti-H pylori agents. With this model we have used the Czinn and Nedrud immunising protocol to test the hypothesis that the enhanced mucosal immunity would be protective. SPF Balb C mice were immunised on days 1,3,6,30, and 54 with 0-5 ml phosphate-buffered saline, 1 mg H felis sonicate, or, I mg sonicate plus 10 Ilg cholera toxin (Sigma). 3 days after the last immunising dose, the mice were challenged with 10’ Hfelis. The mice were killed 3 weeks after challenge, and infection with H felis was assessed:6 Proportion of H felis infected Immunisation Saline Sonicate Sonicate plus cholera toxin
mice 3 wk post-challenge
19/19 (100%) 21/21 (100%)J 1/19 (5%) (p
