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Off-Label Dermatologic Therapies
Usage, Risks, and Mechanisms
Vincent W. Li, MD;
Michael P. Jaffe;
William W. Li, MD;
Harley A. Haynes, MD
Arch Dermatol. 1998;134:1449-1454.
ABSTRACT
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Off-label refers to the prescribing of Food and Drug Administration–approved drugs for a use not indicated on the package insert. The prescribing of off-label drugs may benefit patients with many dermatologic diseases including angiogenesis-related conditions. We surveyed 55 dermatologists from a single large academic program to assess their use of particular drugs for specific skin conditions, their perception of such use as being for Food and Drug Administration–approved or for off-label indications, and their attitudes towards off-label therapies. The practice of prescribing off-label drugs was common among the respondents, many of whom had misperceptions about which conditions are Food and Drug Administration–approved indications and about the legal ramifications of off-label therapies. We suggest that understanding the principles of off-label prescribing in conjunction with the mechanisms of drug action in diseases may help clinicians exercise their judgment in finding innovative therapies for their patients.
INTRODUCTION
A prescription is considered off-label when the condition being treated is not listed on the package insert or in the Physicians' Desk Reference1 as an indication for the drug being used. Off-label prescribing is sometimes referred to as unconventional medicine because it does not conform to convention as established under the rigid standards of the Food and Drug Administration (FDA), or as innovative therapy, the term used by a congressionally appointed commission to describe a clinician's departure "in a significant way from standard or accepted practice."2 While many clinicians are aware of anecdotes or case studies regarding the off-label use of medicines and while off-label prescribing is being increasingly acknowledged,3 the scope and significance of this phenomenon is only now beginning to receive systematic study. A representative national survey was taken of oncologists on off-label prescribing and FDA policies toward information dissemination (J. E. Calfee, L. McGinness, unpublished data, September 1997). We postulate that off-label prescribing is common in the field of dermatology in which therapeutic options are often numerous and relatively benign. Of special interest is the application of this practice in angiotherapies (angiogenesis-based therapies), a group of treatment modalities that modulate the generation of new blood vessels. According to a recent market study by the Angiogenesis Foundation, Cambridge, Mass, a nonprofit information clearinghouse and think tank, up to 110 million people in the United States have some type of angiogenesis-dependent skin disease.4
To study the perception and practice of off-label prescribing, we surveyed the affiliated dermatologists at a large medical center encompassing 12 hospitals (academic attending dermatologists, private practitioners, and residents and fellows-in-training). Our objectives were to determine the frequency, sources, and motivation of prescribing off-label medicines and to identify the perceived role of the FDA in restricting off-label uses. In addition, we considered whether a knowledge of drug mechanisms might affect off-label prescribing. The subjects completed an anonymous questionnaire addressing their use of specific drugs for specific diseases and were asked their opinion about whether the indications were approved or off-label.
PARTICIPANTS, MATERIALS, AND METHODS
A close-ended questionnaire was developed to evaluate the use and perception of FDA-approved drugs for approved and off-label indications.
SURVEY TOOL
Respondents were instructed to refrain from consulting references, to indicate whether they had prescribed a particular drug for a particular condition during the past 3 years, and to evaluate only the drug's use, not its efficacy. In addition, the respondents were asked whether they perceived the drug's use in treating the condition for which it was prescribed to be approved by the FDA or off-label. If the disease was not seen in a given respondent's practice, the question was left unanswered. Fifteen systemic therapies and 7 topical therapies representing treatments for a range of dermatologic conditions were listed. Of the 21 drugs, 10 had angiogenesis-modulating activity.
Other questions addressed the importance that respondents placed on a physician's responsibility to use a drug only for its approved indications, their perception of the legal risk of prescribing off-label, the sources from which they learned about FDA-approved disease indications, and their reasons for prescribing drugs off-label. All questions were yes/no or multiple choice.
STUDY SAMPLE
Fifty-nine questionnaires were distributed to affiliated dermatologists in Harvard Medical School's Department of Dermatology, that includes faculty and house officers from Massachusetts General Hospital, Brigham and Women's Hospital, Beth Israel-Deaconess Medical Center, Boston Children's Hospital, Dana-Farber Cancer Institute, Joslin Diabetes Center, Cambridge City Hospital, Cambridge, Mass, Lahey-Hitchcock Clinic, Burlington, Mass, Harvard Pilgrim Health Plan, and the Brockton/West Veterans Administration Medical Centers in Brockton and West Roxbury, Mass (all places are located in Boston, Mass, except where noted). No attempt was made to identify persons completing the questionnaire, but respondents were queried about their type of practice (academic, private, in-training). Forty-two of the 55 respondents were board-certified dermatologists. Only 4 had less than 1 year (9 months) of residency training in dermatology.
RESULTS
The 55 surveys completed represented a 93% response rate. Of the respondents, 21 (38%) were in academic practice, 15 (27%) were in private practice, and 19 (35%) were in-training (dermatology residents and fellows). A comparative analysis revealed little behavioral discrepancy among these subgroups.
OFF-LABEL USE
All 55 respondents used drugs for off-label indications. All 15 systemic therapies and all 7 topical therapies listed in the questionnaire were used by at least some of the dermatologists. Table 1 shows data on the use of all drugs listed. For some questions, certain respondents left answers blank, indicating that they did not see the disease or were unsure of the answer; in such cases, their answer was not coded.
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Table 1. Data of Prescription Drug Use and Perception of FDA Approval*
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PERCEPTION OF DRUG APPROVAL
Twenty-one of the 22 drug/indication pairs listed represented off-label use but were incorrectly believed by some dermatologists to be FDA approved. Nine off-label treatments were believed by more than 25% of respondents to be approved and 5 were believed by at least half of respondents to be approved: azathioprine (Imuran, Glaxo-Welcome Inc, Research Triangle Park, NC), for bullous pemphigoid; cyclosporine (Sandimmune, not Neoral, Novartis Pharmaceuticals Corp, East Hanover, NJ), for psoriasis; itraconazole, (Sporanox, Janssen Pharmaceutica, Titusville, NJ), for onychomycosis in human immunodeficiency virus (HIV); psoralen for vitiligo; and betamethasone dipropionate (Diprolene, Schering Corp, Kenilworth, NJ) under occlusion for palmar-plantar psoriasis. The only drug listed for an approved purpose was hydroxychloroquine sulfate (Plaquenil, Sanofi Pharmaceuticals Inc, New York, NY) for lupus erythematosus; 12 (22%) of 55 respondents incorrectly believed that this was an off-label indication.
PERCEPTION OF LEGAL RISK FROM THE FDA IN OFF-LABEL USE
Twenty-eight (53%) of 53 respondents believed that when they prescribed a drug for off-label use they were placing themselves "at risk for legal action by the FDA" (Figure 1). This figure was slightly lower (9 [41%] of 22 respondents) among academic dermatologists than among private practitioners or physicians-in-training.
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Figure 1. Perception of legal risk from the Food and Drug Administration (FDA). Respondents were queried if they perceived that prescribing in an off-label fashion placed them at risk for legal action from the FDA.
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PHYSICIAN'S RESPONSIBILITY FOR RESTRICTING DRUG USE TO APPROVED INDICATIONS
Only 8 (15%) of 55 respondents believed that it was important to use a drug only within its FDA-approved indications; these respondents answered 1 or 2 on a scale of 1 to 5. Half of respondents (27 [49%]) did not feel it was important, answering 4 or 5 on a scale of 1 to 5, while the remainder were undecided (Figure 2).
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Figure 2. Importance placed on following Food and Drug Administration-approved indications. Important is defined as number of respondents answering 1 or 2 on a scale of 1 to 5; not important, number answering 4 or 5. Not shown are the respondents who answered 3 (undecided).
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SOURCES OF INFORMATION ON APPROVED AND OFF-LABEL USE
When respondents were asked to name the single source from which they learned most about FDA-approved uses for drugs, 27 (49%) identified the Physicians' Desk Reference, 11 (20%) identified drug representatives, and 8 (15%) cited package label inserts.
Of the 4 options listed, case reports in the literature were the most frequently cited information source on the prescribing of drugs for off-label uses, selected by 40% of respondents. The other 3 options were personal experience, anecdotal experience of colleagues, and frustration with approved alternatives.
COMMENT
Understanding the practice of off-label prescribing is important for several reasons. First, physicians are increasingly concerned about minimizing their perceived risk. Second, the lay media have recently focused on the possible risks associated with off-label use of high-profile drugs, such as sildenafil citrate (Viagra, Pfizer Pharmaceuticals, New York, NY), to increase sexual performance in men and fenfluramine hydrochloride and and phentermine hydrochloride, a combination drug product also known as fen-phen, to combat obesity. The cover story for the May 11, 1998 issue of Business Week, whose headline reads "Danger: Read the Label. . . . Doctors Are Prescribing Drugs for Unapproved Uses and Patients Are at Risk," further catapulted this issue into the mainstream. A third concern is that as physicians become restricted by managed-care formularies treatments that are not approved by the FDA may fall by the wayside. Any of these factors can have a negative impact on patients by limiting their access to potentially effective off-label therapies.
Our study suggests that the practice of prescribing drugs for off-label uses is common in dermatology. In fact, 100% of the dermatologists surveyed prescribed one or more of the topical and systemic therapies listed in our questionnaire for off-label use.
Our analysis reveals a positive correlation (R=0.69) between use and belief in FDA approval for systemic drugs (Figure 3). In practical terms, the importance of this relationship is not clear because belief in FDA approval is often different than actual approval. Dermatologists in this study misidentified many of the off-label therapy/disease pairs as approved by the FDA.
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Figure 3. Prescription use plotted against perception of Food and Drug Administration (FDA)-approved status for a particular indication. Data points in the lower right quadrant represent drugs perceived most often to be FDA approved. Data points in the lower right quadrant represent drugs perceived to have been used in an off-label fashion. As might be expected, most dermatologists did not use drugs for conditions that they did not believe to be FDA-approved indications (data points in lower left quadrant).
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THE ROLE OF THE FDA IN DRUG APPROVAL
What is the FDA's role in guiding a physician's use of drugs? The FDA has jurisdiction over pharmaceutical manufacturers but cannot regulate how and to whom physicians prescribe drugs after their approval. For the physician, the legal implications of using FDA-approved medications for unlabeled uses are clear.5 The concept of off-label prescribing was first described to the FDA in 1972 and was regarded as being in line with laws passed by Congress to guide the FDA, principally the 1938 Federal Food, Drug, and Cosmetic Act and its 1962 amendments. According to these laws, physicians make the final judgment about the appropriate use of any FDA-approved drug by weighing the available scientific and clinical information, the facts presented in the package insert, and their own experience (and that of their colleagues) in prescribing the drug. As long as neither the manufacturer nor the pharmacy to which a drug is shipped intends for the drug to be used for an unlabeled purpose when it is shipped, federal laws governing interstate commerce are fulfilled. A physician may lawfully prescribe a drug at a different dosage or for conditions not described in the package insert without informing or obtaining the consent of the FDA. Federal courts have continued to uphold this autonomy, stating that Congress does not want to interfere with physicians' treatment of their patients.6 Although a patient has a right to seek civil damages in court if there is evidence of malpractice, off-label prescribing does not itself constitute liability. If a physician uses a drug for an off-label indication to benefit a patient while simultaneously using it as part of a research investigation, they are subject to appropriate internal review board and informed consent requirements. On the other hand, if innovative therapy is used solely to benefit a patient, no specific type of consent is required although the risks should be disclosed to the patient.5
Drug development and regulatory issues are not understood by all clinicians. There is a perception among some that if a therapy were truly effective and safe for a particular indication, it would have received FDA approval for that condition. In reality, the lack of mention of an indication on the package insert does not imply that a drug is unapproved for that indication. In fact, there is no legal definition of the term unapproved use. A disease indication is simply a condition that the manufacturer has submitted to the FDA to consider for approval. The US Pharmacopoeia Drug Information, the PDR Companion Guide, and the American Medical Association's Drug Evaluations books are annually published resources that describe uses of drugs in accepted and common clinical practice, regardless of their official labeling status. It is unclear how many physicians actually use this resource and whether they understand the implications and risks associated with applying such information to patients.
The approved indications for a drug can be driven as much by politics and business as by medicine. The average duration and cost of drug development are more than 15 years and more than $300 million, respectively.7 Drug developers want their indications to encompass the largest possible market so that they can at least recoup their initial investment. Once a drug is approved, its approval for another indication is a costly and lengthy process that few pharmaceutical firms can justify as the clock on their patent protection winds down. A few dermatologic drugs have undergone this capital-intensive process. As an example, cyclosporine under the trade name Neoral, (Novartis Pharmaceuticals Corp, East Hanover, NJ) was recently approved for the treatment of psoriasis. Some drug manufacturers may never choose to apply for certain indications if there is no clear financial gain. For example, diflorasone diacetate (Psorcon, Dermik Laboratories Inc, Collegeville, Pa) is the only class I topical steroid approved for use under occlusion, but dermatologists already routinely prescribe other non–diflorasone steroids for use in this fashion. In addition, the use of itraconazole (Sporanox) is indicated for use in patients with onychomycosis who do not have HIV but many dermatologists already routinely prescribe this drug for their patients infected with HIV.
DRUG MECHANISMS AND OFF-LABEL PRESCRIBING
In the current environment of competing therapies, what motivates dermatologists to choose one therapy over another? Clearly, belief in efficacy is an important factor. But how do physicians conclude that a drug works when no clinical trial results are available? Our survey indicates that case reports of efficacy in the literature often influence situations in which drugs are prescribed. Nevertheless, half the responding dermatologists felt uncomfortable about prescribing off-label drugs, even though they believed such drugs might benefit their patients.
Another factor that may influence prescribing of drugs is an understanding of the scientific basis for a drug's activity in a given disease. This point is well illustrated in evolving angiogenesis-based therapies. Although the field of angiogenesis has recently received intense media attention in terms of a "cure" for cancer, angiotherapies have tremendous potential to treat diseases in many other fields including dermatology.8 Angiogenesis, or neovascularization, underlies many conditions in which either excessive or insufficient blood vessel growth leads to disease development or progression.9-10 Certain skin diseases are characterized by excessive vascularity; in psoriasis, for example, the tortuous vessels in the papillary dermis support the proliferation of the diseased epidermis. In other diseases, such as chronic ulcer diseases, there is insufficient vascularity to provide the appropriate granulation tissue for wound healing.Therefore, the pharmacological manipulation of angiogenesis may be useful in treating many dermatologic diseases. More than 100 drug candidates are being developed for the control of angiogenesis, but most are not expected to be on the market for another 2 to 5 years. Only 1 drug has obtained FDA approval for an angiogenic skin condition: recombinant human platelet–derived growth factor, becaplermin, (Regranex, Ortho-McNeil Pharmaceutical Inc, Raritan, NJ) for the treatment of diabetic foot ulcers .11 In the meantime, dermatologists are learning from the scientific literature that a number of existing formulary medicines have been rediscovered by researchers as agents possessing angiogenesis-modulating properties. Table 2 lists common angiogenic skin disorders and therapies that have been used to treat them. The inhibition or stimulation of angiogenesis may contribute to the efficacy of these drugs.10, 12-24
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Table 2. Dermatologic Therapies With an Angiogenesis-Based Mechanism
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Modulating angiogenesis is only one of many mechanisms by which drugs may affect the dermatologic diseases listed in our survey. For example, topical mupirocin (Bactroban, SmithKline Beecham Pharmaceuticals, Philadelphia, Pa), and oral antibiotics may alleviate atopic dermatitis by suppressing staphylococcal superantigen on the skin of colonized patients.11 Although the general use of antihistamines in eczema is controversial, cetirizine hydrochloride (Zyrtec, Pfizer Pharmaceuticals Inc, New York, NY) may relieve inflammation by inhibiting eosinophil chemotaxis.25 Niacinamide, also known as nicotinamide, may constitute a useful steroid-sparing therapy for certain inflammatory disorders because it can inhibit nitric oxide synthesis in macrophages and suppress the antigen-presenting function of the class II major histocompatibility complex on endothelial cells and fibroblasts at sites of tissue inflammation.26-27 The antimalarial chloroquine may be effective in lupus partly because of its action on endothelial cell apoptosis.28 Azelaic acid cream, although indicated for acne, may be helpful in pigmentary disorders since it inhibits tyrosinase and disrupts melanin biosynthesis.29 Lastly, antibiotics of the tetracycline class are well known to have anti-inflammatory as well as antimicrobial activity, possibly because of the inhibition of complement-driven neutrophil migration and suppression of matrix metalloproteinases associated with inflammation.30-31
In summary, this study underscores 3 important points. First, FDA-approved drugs are frequently prescribed for off-label dermatologic indications, but misunderstanding exists about the indications for which drugs are approved. Second, physicians appear to be inadequately informed about the FDA's regulatory role and the perceived legal risks involved in the prescribing of drugs. Third, knowledge of mechanisms of action of drugs used in dermatology (eg, modulation of angiogenesis) is an important factor in the choice of therapy.
Although clinical trials remain the criterion standard for FDA approval of a drug, a knowledge of off-label drug use broadens the clinician's ability to relieve the symptoms of patients with diseases that are refractory to standard therapy or for which there is no effective standard therapy. Fortunately, the accessing of information about off-label use is becoming easier for the clinician. The federal government recently eased its restrictions barring drug manufacturers from telling physicians about off-label uses for their products. The FDA Modernization Act passed by Congress in 1997 allows companies to distribute published studies about their products for off-label indications, although manufacturers still cannot market their drugs for off-label use. Under these new guidelines, manufacturers must still submit a copy of the information to the FDA 60 days before distributing it; after a review, the agency can regulate this distribution of information.
AUTHOR INFORMATION
Accepted for publication August 31, 1998.
We thank Andrew Jay Lee, MHS, and the staff of the Angiogenesis Foundation, Cambridge, Mass, an international nonprofit clearinghouse for information, research, and education in angiogenesis, for their assistance with regulatory documents and database reviews.
Reprints: Dermatology Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
From the Division of Dermatology, Department of Medicine, Brigham and Women's Hospital, and the Department of Dermatology, Harvard Medical School, (Drs V. W. Li and Haynes) Boston, Mass; and the Angiogenesis Foundation Inc, Cambridge, Mass (Drs V. W. Li, and W. W. Li and Mr Jaffe). Information presented herein is intended for educational purposes and does not constitute medical or legal advice.
REFERENCES
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1. Physicians' Desk Reference. 52nd ed. Montvale, NJ: Medical Economics Co; 1998.
2. Cowan D. Innovative therapy: the responsibility of hospitals. J Leg Med. 1984;5:219-231.
PUBMED
3. Thakkar S. Oncologists judge themselves the best judges of cancer treatments. J Natl Cancer Inst. 1997;89:1188-1189.
ISI
| PUBMED
4. Market Study of Angiogenesis-Dependent Diseases: Classification and Sizing of the Potential Market for the Pharmaceutical Industry in the U.S and the European Union. Vol 1. Cambridge, Mass: The Angiogenesis Foundation; 1998:77-92.
5. Torres A. The use of Food and Drug Administration–approved medications for unlabeled (off-label) uses. Arch Dermatol. 1994;130:32-36.
ABSTRACT
6. Chaney v Heckler. 7128 F2d 1174 (1983).
7. The Angiogenesis Foundation Industry Database, 1998.
8. Gorman C. Curing cancer: how to tell the hype from the hope. Time. May 18, 1998;151:38-44.
9. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27-31.
FULL TEXT
|
ISI
| PUBMED
10. Li WW, Li VW, Casey R, et al. Clinical trials of angiogenesis-based therapies: overview and new guiding principles. In: Maragoudakis M, ed. Angiogenesis: Models, Modulators, and Clinical Applications. New York, NY: Plenum Publishing Corp, 1998:476-492.
11. Campbell DE, Kemp AS. Proliferation and production of interferon-gamma (IFN-gamma) and IL-4 in response to Staphylococcus aureus and staphylococcal superantigen in childhood atopic dermatitis. Clin Exp Immunol. 1997;107:392-397.
FULL TEXT
|
ISI
| PUBMED
12. Tsuchida T, Tsukamoto Y, Segawa K, et al. Effects of cimetidine and omeprazole on angiogenesis in granulation tissue of acetic acid-induced gastric ulcers in rats. Digestion. 1990;47:8-14.
ISI
| PUBMED
13. Oikawa T, Hirotani K, Nakamura O, et al. A highly potent antiangiogenic activity of retinoids. Cancer Lett. 1989;48:157-162.
FULL TEXT
|
ISI
| PUBMED
14. Testerman TL, Gerster JF, Imbertson LM, et al. Cytokine induction by the immunomodulators imiquimod and S-27609. J Leukoc Biol. 1995;58:365-372.
ABSTRACT
15. Majewski S, Szmurlo A, Marczak M, et al. Synergistic effect of retinoids and interferon alpha on tumor-induced angiogenesis: anti-angiogenic effects on HPV-harboring tumor cell-lines. Intl J Cancer. 1994;57:81-85.
ISI
| PUBMED
16. Oikawa T, Hirotani K, Ogasawar H, et al. Inhibition of angiogenesis by vitamin D analogues. Eur J Pharmacol. 1990;178:247-250.
FULL TEXT
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ISI
| PUBMED
17. Li VW, Li WW. Cyclosporine and angiogenesis in psoriasis. J Am Acad Dermatol. 1996;35:1019-1020.
ISI
| PUBMED
18. Rudnicka L, Marczak M, Szmurlo A, et al. Acitretin decreases tumor cell-induced angiogenesis. Skin Pharmacol. 1991;4:150-153.
ISI
| PUBMED
19. Tamargo RJ, Bok RA, Brem H. Angiogenesis inhibition by minocycline. Cancer Res. 1991;51:672-675.
FREE FULL TEXT
20. D'Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994;91:4082-4085.
FREE FULL TEXT
21. Vogt B, Frey FJ. Inhibition of angiogenesis in Kaposi's sarcoma by captopril. Lancet. 1997;349:1149.
FULL TEXT
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ISI
| PUBMED
22. Hori Y, Du DE, Yasui K, et al. Differential effects of angiostatic steroids and dexamethasone on angiogenesis and cytokine levels in rat sponge implants. Br J Pharmacol. 1996;118:1584-1591.
ISI
23. Ezekowitz RBA, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med. 1992;326:1456-1463.
ABSTRACT
24. Folkman J, Szabo S, Stovroff M, et al. Duodenal ulcer: discovery of a new mechanism and development of angiogenic therapy that accelerates healing. Ann Surg. 1991;214:414-427.
ISI
| PUBMED
25. Kontou-Fili K, Maniatakou G, Demaka P, et al. Therapeutic effects of cetirizine in delayed pressure urticaria: clinicopathological findings. J Am Acad Dermatol. 1991;24:1090-1093.
ISI
| PUBMED
26. Pellat-Deceunynck C, Wietzerbin J, Drapier JC. Nicotinamide inhibits nitric oxide synthase mRNA induction in activated macrophages. Biochem J. 1994;297:53-58.
PUBMED
27. Otsuka A, Hanafusa T, Miyagawa J, et al. Nicotinamide and 3-aminobenzamide reduce interferon-gamma-induced class II MHC (HLA-DR, and -DP) molecule expression on cultured human endothelial cells and fibroblasts. Immunopharmacol Immunotoxicol. 1991;13:263-280.
ISI
| PUBMED
28. Potvin F, Petitclerc E, Marcaeu F, et al. Mechanism of action of antimalarials in inflammation: induction of apoptosis in human endothelial cells. J Immunol. 1997;158:1872-1879.
ABSTRACT
29. Nazzaro-Porro M, Passi S. Identification of tyrosinase inhibitors in cultures of Pityrosporum. J Invest Dermatol. 1978;71:205-208.
FULL TEXT
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ISI
| PUBMED
30. Esterly NB, Furey NL, Flanagen LE. The effect of antimicrobial agents on leukocyte chemotaxis. J Invest Dermatol. 1978;70:51-55.
FULL TEXT
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ISI
| PUBMED
31. Golub LM, Lee HM, Greenwald RA, et al. A matrix metalloproteinase inhibitor reduces bone-type collagen degradation fragments and specific collagenases in gingival crevicular fluid during adult periodontitis. Inflamm Res. 1997;46:310-319.
FULL TEXT
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ISI
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