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Meclofenamate (Meclomen) therapy of psoriasis
Volume 8 Number 5 May, 1983
Correspondence
Iu ad&tton, Reference 6 was incorrectly Identified We were led to beheve that the monograph would appear m the Federal Register, and it has not as of this date Therefore, tt should have been hsted as a personal communication
Brent M Schdhnger, M D Mmdy Berstem, M D 450 Clarkson Ave Brooklyn, NY 11203
Meclofenamate (Meclomen) therapy of psoriasis* To the Edttor Recent developments m&cate that 5-hpoxygcnase and its distal leukotnene (LT) mctabohtcs play a key role m the pathophyslology of psonasls 12 In psonatlc plaques 5-hpoxygcnasc actlvttya and LTB4 levels are increased 4~ Indomcthacln can exacerbate psoriasis, perhaps by its known ablhty to increase LTB4 levels in cells 6 7 Conversely, mhtbmon of 5-hpoxygenase actlwty would be expected to lower cellular LTB4 levels In fact, a doublc-bhnd study of benoxaprofen, a known anhlbxtor of 5-hpoxygenase, 8 demonstrated remarkable anUpsonatlc actlwty 9 Benoxaprofen may ~mprove psoriasis by its antfllpoxygenase activity, although an unknown and enttrely unrelated action of the drug could bc rcsponslble For these reasons we were unpressed by the recent report that mcclofcnamate (Meclomcn, Parke-Davls) amproved psonasls in an open study m three patients ~o Meclofcnamate is known to antagonize slow-reacting substance of anaphylaxis (SRS-A) 1~ SRS-A is now known to be a mixture of LTC4 and LTD4 We theorized that perhaps meclofcnamate might be exertlng antlpsonatlc action by mhthltlng 5-hpoxygenase Inhthmon of this enzyme would reduce the formation of all LTs within lesions Therefore, we have done an open evaluation of oral meclofenamate, 100 mg three times a day, m over 100 psoriatic patients Many were outpatients treated only w~th meclofenamate and cmolhents Others were lnpatxents, receiving concomitant maxtmal GocckermanIngrain, m whom wc looked for hastemng of the usual slow response Meclofenamate therapy was extremely well tolerated by most patxcnts, however, approximately 10% &scont~nued the drug because of gasmc &stress or &arrhea *Repnnt requests should be sent to Dr John J Voorhees
759
Patients were treated with meclofenamate for 1 to 2 months The majority of patients had severe psonasm Approxtmately 10% cleared or almost cleared Another 50% exhibited modest to good improvement or had an accelerated response to tra&taonal therapy The remaining 40% obtained nunmaal or no benefit Therefore, detectable anttpsonattc activity was seen m only 60% of the pataents In the patxents who responded, cleanng usually began w~thm 1 to 2 weeks, with maxunum benefit observed by 4 weeks In several patients, impressive responses were seen m less than 1 week Characteristically, lesion color changed from red to pink, with rapid reductxon m scahng The change m color was usually accompanied by an approxamate 50% reductaon m les~on thickness Cleanng usually occurred from the center toward the edge of the lesions In those patients who had benefit but whose psonasls did not clear completely, the drug seemed to improve the lesions to a point beyond which no further advantage was seen However, such parttal ~mprovement was valuable, since tt was then easier to clear the patient w~th other treatments Acute, xnflammatory widespread psonasls, as well as chromc, thick plaque psonasls, xmproved dunng meclofenamate admamstrataon However, we have the lmpress~on that the acute inflammatory form may be shghtly more responswe to meclofenamate therapy than plaque psonasls Therefore, future studies of this drug in psonasls should include both types Several patients had concomitant psoriatic arthritis which responded very well to meclofenamate In general, the response of the arthritis to this drug was comparable to, or better than, nonsteroldal anti-inflammatory agents that the pauents had prewously taken In fact, meclofenamate m a y be the drug of choice for psonattc arthntas and coexastent cutaneous psoriasis, since ~t has the capactty to improve both condmons In summary, meclofenamate is one of the easiest systermc therapies that we have employed We beheve that a double-bhnd placebo-controlled trial should be done to confirm or refute the chmcal anecdotes and testtmomals that we report here However, since at most 60% of the patients showed a response, it is questionable whether ~mprovement can be detected m a conventaonal double-bhnd experiment Clearly, a large sample size and a careful experimental desagn will be reqmred Further stuches will be necessary to assess the wmdom of using more or less than 300 mg per day Also, it may be productwe to examine the actw~ty of topical meclofenamate Finally, ~t is possible that at least some of the other
760
Journal of the American Academy of Dermatology
Correspondence
nonsteroidal anti-inflammatory drugs may exert their anti-inflammatory and antiarthritic action by inhibiting LTB4 formation rather than by reducing the synthesis of prostaglandins. Nonsteroidal anti-inflammatory drugs that are actually weak inhibitors o f prostaglandin formation should be the first candidates to be evaluated for possible utility in the treatment of psoriasis.
Charles N. Ellis, M.D. John J. Voorhees, M.D. Department of Dermatology University of Michigan Medical School C2064 Outpatient Bldg. A n n Arbor, MI 48109 REFERENCES 1. Voorhees J J: Leukotrienes and other lipoxygenase products in the pathogenesis and therapy of psoriasis and other dermatoses. Arch Dermatol (In press.) 2. Greaves MW: Prostaglandins and dermatology. J R Coil Physicians (Lond) 16:219-225, 1982. 3. Ziboh VA, Casebolt T, Marcelo CL, Voorhees J J: Enhancement of 5-1ipoxygenase activity in soluble preparations of human psoriatic plaque preparation. J Invest Dermatol (In press.) 4. Brain SD, Camp RDR, Dowd PM, et al: Psoriasis and leukotriene B4. Lancet 2:762-763, 1982. 5. Grabbe J, Czarnetzki BM, Mardin M: Chemotactic leukotrienes in psoriasis. Lancet 2: 1464, 1982. 6. Katayama H, Kawada A: Exacerbation of psoriasis induced by indomethacin. J Derrnatol (Tokyo) 8:323-327, 1981. 7. Ellis CN, Fallon JD, Heezen JL, Voorhees J J: Topical indomethacin exacerbates lesions of psoriasis. J Invest Dermatol (In press.) 8. Harvey J, Parish H, Ho PPK, et aI: The preferential inhibition of 5-lipoxygenase product formation by benoxaprofen. I Pharm Pharmacol 35:44-45, 1983. 9. Kragballe K, Herlin T: Benoxaprofen improves psoriasis: A double blind study. Arch Derrnatol (In press.) 10. Winthrop GJ: Does meclofenamate help psoriasis and arthritis? N Engl J Med 307:1528, 1982. 1i. Berry PA, Collier HOJ: Bronchoconstrictor action and antagonism of a slow-reacting substance from anaphylaxis of guinea pig isolated lung. Br J Pharmaeol 23:201-216, 1964.
U V B is a d d i t i v e w h e n r e p e a t e d w i t h i n an 8-hour interval
To the Editor: In a recent report, Petrozzi and Reyes 1 concluded that once-a-day exposure to ultraviolet radiation (UVR) is as efficacious in clearing psoriasis lesions as is a schedule in which the U V R dose is split into two daily
T a b l e I. Erythematous r e s p o n s e s to repeat s u b - M E D U V B
Repeat dose given Immediately after initial UVB 8 hr after initial UVB 10 hr after initial UVB 12 hr after initial UVB
24 hr after initial UVB (No. positive)
48 hr after initial UVB (No. positive)
4
4
4 2* 0
4 0* 0
N~4.
*N=2. exposures. They stated that U V R appeared to be directly additive within a 12-hour period. We conducted a study in which we tested on normal skin the erythematous response induced by a repeated application of subminimal erythema dose (IVIED) exposure to UVB. We found UVB to be directly additive when the exposure was repeated within an 8-hour interval. The buttocks of four volunteers with normal skin were irradiated with a Burdick UVB light source over a cardboard template consisting of 6 columns of five 2 x 2-cm squares. Rows represented increasing doses of UVB irradiation, and increasing time intervals were followed from left to right. Patients received an initial exposure of UVB over the entire grid. The first row across the grid received a 5-second exposure of UVB, with subsequent rows exposed for 10, 15, 20, and 30 seconds. Each column subsequently received a second dose of exposure equal to the initial dose, but intervals of time between the two doses increased across the columns. The first column was kept as a control and was not exposed for a second dose. The second column received the second exposure immediately following the initial dose. The third, fourth, fifth, and sixth columns received the second exposure at 8, 10, 12, and 24 hours, respectively. The MED was determined by the control column, and erythematous responses were checked at 12, 24, and 48 hours after the initial exposure. Sub-MED doses of UVB were shown to be additive when given within an 8-hour period; i.e., any combination of exposures of UVB equaling the IVIED of the patient when given within an 8-hour interval produced an erythematous response by 24 hours after the first irradiation. All four subjects demonstrated this response at 8 hours, and in none of the subjects was this reponse evident when the UVB was repeated 12 hours after the initial dose. However, in two subjects we gave
Correspondence
Iu ad&tton, Reference 6 was incorrectly Identified We were led to beheve that the monograph would appear m the Federal Register, and it has not as of this date Therefore, tt should have been hsted as a personal communication
Brent M Schdhnger, M D Mmdy Berstem, M D 450 Clarkson Ave Brooklyn, NY 11203
Meclofenamate (Meclomen) therapy of psoriasis* To the Edttor Recent developments m&cate that 5-hpoxygcnase and its distal leukotnene (LT) mctabohtcs play a key role m the pathophyslology of psonasls 12 In psonatlc plaques 5-hpoxygcnasc actlvttya and LTB4 levels are increased 4~ Indomcthacln can exacerbate psoriasis, perhaps by its known ablhty to increase LTB4 levels in cells 6 7 Conversely, mhtbmon of 5-hpoxygenase actlwty would be expected to lower cellular LTB4 levels In fact, a doublc-bhnd study of benoxaprofen, a known anhlbxtor of 5-hpoxygenase, 8 demonstrated remarkable anUpsonatlc actlwty 9 Benoxaprofen may ~mprove psoriasis by its antfllpoxygenase activity, although an unknown and enttrely unrelated action of the drug could bc rcsponslble For these reasons we were unpressed by the recent report that mcclofcnamate (Meclomcn, Parke-Davls) amproved psonasls in an open study m three patients ~o Meclofcnamate is known to antagonize slow-reacting substance of anaphylaxis (SRS-A) 1~ SRS-A is now known to be a mixture of LTC4 and LTD4 We theorized that perhaps meclofcnamate might be exertlng antlpsonatlc action by mhthltlng 5-hpoxygenase Inhthmon of this enzyme would reduce the formation of all LTs within lesions Therefore, we have done an open evaluation of oral meclofenamate, 100 mg three times a day, m over 100 psoriatic patients Many were outpatients treated only w~th meclofenamate and cmolhents Others were lnpatxents, receiving concomitant maxtmal GocckermanIngrain, m whom wc looked for hastemng of the usual slow response Meclofenamate therapy was extremely well tolerated by most patxcnts, however, approximately 10% &scont~nued the drug because of gasmc &stress or &arrhea *Repnnt requests should be sent to Dr John J Voorhees
759
Patients were treated with meclofenamate for 1 to 2 months The majority of patients had severe psonasm Approxtmately 10% cleared or almost cleared Another 50% exhibited modest to good improvement or had an accelerated response to tra&taonal therapy The remaining 40% obtained nunmaal or no benefit Therefore, detectable anttpsonattc activity was seen m only 60% of the pataents In the patxents who responded, cleanng usually began w~thm 1 to 2 weeks, with maxunum benefit observed by 4 weeks In several patients, impressive responses were seen m less than 1 week Characteristically, lesion color changed from red to pink, with rapid reductxon m scahng The change m color was usually accompanied by an approxamate 50% reductaon m les~on thickness Cleanng usually occurred from the center toward the edge of the lesions In those patients who had benefit but whose psonasls did not clear completely, the drug seemed to improve the lesions to a point beyond which no further advantage was seen However, such parttal ~mprovement was valuable, since tt was then easier to clear the patient w~th other treatments Acute, xnflammatory widespread psonasls, as well as chromc, thick plaque psonasls, xmproved dunng meclofenamate admamstrataon However, we have the lmpress~on that the acute inflammatory form may be shghtly more responswe to meclofenamate therapy than plaque psonasls Therefore, future studies of this drug in psonasls should include both types Several patients had concomitant psoriatic arthritis which responded very well to meclofenamate In general, the response of the arthritis to this drug was comparable to, or better than, nonsteroldal anti-inflammatory agents that the pauents had prewously taken In fact, meclofenamate m a y be the drug of choice for psonattc arthntas and coexastent cutaneous psoriasis, since ~t has the capactty to improve both condmons In summary, meclofenamate is one of the easiest systermc therapies that we have employed We beheve that a double-bhnd placebo-controlled trial should be done to confirm or refute the chmcal anecdotes and testtmomals that we report here However, since at most 60% of the patients showed a response, it is questionable whether ~mprovement can be detected m a conventaonal double-bhnd experiment Clearly, a large sample size and a careful experimental desagn will be reqmred Further stuches will be necessary to assess the wmdom of using more or less than 300 mg per day Also, it may be productwe to examine the actw~ty of topical meclofenamate Finally, ~t is possible that at least some of the other
760
Journal of the American Academy of Dermatology
Correspondence
nonsteroidal anti-inflammatory drugs may exert their anti-inflammatory and antiarthritic action by inhibiting LTB4 formation rather than by reducing the synthesis of prostaglandins. Nonsteroidal anti-inflammatory drugs that are actually weak inhibitors o f prostaglandin formation should be the first candidates to be evaluated for possible utility in the treatment of psoriasis.
Charles N. Ellis, M.D. John J. Voorhees, M.D. Department of Dermatology University of Michigan Medical School C2064 Outpatient Bldg. A n n Arbor, MI 48109 REFERENCES 1. Voorhees J J: Leukotrienes and other lipoxygenase products in the pathogenesis and therapy of psoriasis and other dermatoses. Arch Dermatol (In press.) 2. Greaves MW: Prostaglandins and dermatology. J R Coil Physicians (Lond) 16:219-225, 1982. 3. Ziboh VA, Casebolt T, Marcelo CL, Voorhees J J: Enhancement of 5-1ipoxygenase activity in soluble preparations of human psoriatic plaque preparation. J Invest Dermatol (In press.) 4. Brain SD, Camp RDR, Dowd PM, et al: Psoriasis and leukotriene B4. Lancet 2:762-763, 1982. 5. Grabbe J, Czarnetzki BM, Mardin M: Chemotactic leukotrienes in psoriasis. Lancet 2: 1464, 1982. 6. Katayama H, Kawada A: Exacerbation of psoriasis induced by indomethacin. J Derrnatol (Tokyo) 8:323-327, 1981. 7. Ellis CN, Fallon JD, Heezen JL, Voorhees J J: Topical indomethacin exacerbates lesions of psoriasis. J Invest Dermatol (In press.) 8. Harvey J, Parish H, Ho PPK, et aI: The preferential inhibition of 5-lipoxygenase product formation by benoxaprofen. I Pharm Pharmacol 35:44-45, 1983. 9. Kragballe K, Herlin T: Benoxaprofen improves psoriasis: A double blind study. Arch Derrnatol (In press.) 10. Winthrop GJ: Does meclofenamate help psoriasis and arthritis? N Engl J Med 307:1528, 1982. 1i. Berry PA, Collier HOJ: Bronchoconstrictor action and antagonism of a slow-reacting substance from anaphylaxis of guinea pig isolated lung. Br J Pharmaeol 23:201-216, 1964.
U V B is a d d i t i v e w h e n r e p e a t e d w i t h i n an 8-hour interval
To the Editor: In a recent report, Petrozzi and Reyes 1 concluded that once-a-day exposure to ultraviolet radiation (UVR) is as efficacious in clearing psoriasis lesions as is a schedule in which the U V R dose is split into two daily
T a b l e I. Erythematous r e s p o n s e s to repeat s u b - M E D U V B
Repeat dose given Immediately after initial UVB 8 hr after initial UVB 10 hr after initial UVB 12 hr after initial UVB
24 hr after initial UVB (No. positive)
48 hr after initial UVB (No. positive)
4
4
4 2* 0
4 0* 0
N~4.
*N=2. exposures. They stated that U V R appeared to be directly additive within a 12-hour period. We conducted a study in which we tested on normal skin the erythematous response induced by a repeated application of subminimal erythema dose (IVIED) exposure to UVB. We found UVB to be directly additive when the exposure was repeated within an 8-hour interval. The buttocks of four volunteers with normal skin were irradiated with a Burdick UVB light source over a cardboard template consisting of 6 columns of five 2 x 2-cm squares. Rows represented increasing doses of UVB irradiation, and increasing time intervals were followed from left to right. Patients received an initial exposure of UVB over the entire grid. The first row across the grid received a 5-second exposure of UVB, with subsequent rows exposed for 10, 15, 20, and 30 seconds. Each column subsequently received a second dose of exposure equal to the initial dose, but intervals of time between the two doses increased across the columns. The first column was kept as a control and was not exposed for a second dose. The second column received the second exposure immediately following the initial dose. The third, fourth, fifth, and sixth columns received the second exposure at 8, 10, 12, and 24 hours, respectively. The MED was determined by the control column, and erythematous responses were checked at 12, 24, and 48 hours after the initial exposure. Sub-MED doses of UVB were shown to be additive when given within an 8-hour period; i.e., any combination of exposures of UVB equaling the IVIED of the patient when given within an 8-hour interval produced an erythematous response by 24 hours after the first irradiation. All four subjects demonstrated this response at 8 hours, and in none of the subjects was this reponse evident when the UVB was repeated 12 hours after the initial dose. However, in two subjects we gave