A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. Pediatric Tacrolimus Study Group.

BACKGROUND: A topical formulation of tacrolimus, an immunosuppressant currently marketed for the prevention of rejection after solid organ transplant, is a potential therapeutic agent for atopic dermatitis. OBJECTIVE: We sought to determine the safety and efficacy of tacrolimus ointment in pediatric patients with moderate-to-severe atopic dermatitis. METHODS: In this double-blind, vehicle-controlled multicenter trial, children ages 7 to 16 years were treated with twice daily application of tacrolimus ointment at 1 of 3 concentrations (0.03% [n = 43], 0.1% [n = 49], or 0.3% [n = 44]) or vehicle (n = 44) for up to 22 days, with a 2-week follow-up period. RESULTS: The Physician's Global Evaluation of clinical response showed that 69% (95% confidence interval: 53-82) of patients in the 0.03% tacrolimus ointment group, 67% (95% confidence interval: 52-81) in the 0.1% tacrolimus ointment group, and 70% (95% confidence interval: 54-83) in the 0.3% tacrolimus ointment group, compared with 38% (95% confidence interval: 24-54) in the vehicle group, had a marked to excellent (> or =75%) improvement or clearing of their atopic dermatitis (P =.005, .007, and .004, respectively for the 3 tacrolimus groups compared with the vehicle group). The mean percent improvement for a modified Eczema Area and Severity Index at end of treatment for each of the 3 tacrolimus groups (0.03%, 72%; 0.1%, 77%: and 0.3%, 81%) was significantly better than that of the vehicle group (26%; P <.001). The median percent reduction in pruritus was significantly greater for tacrolimus-treated patients (74% to 89%) than for vehicle-treated patients (51%, P = .027). No serious systemic adverse events were noted, and systemic absorption was minimal. CONCLUSION: Tacrolimus ointment appears to be safe and effective in children with atopic dermatitis.

High strength capsaicin cream for osteoarthritis pain: rapid onset of action and improved efficacy with twice daily dosing.

In a randomized, single-blind, 28-day study, a new high strength capsaicin cream (0.25%) applied twice daily (n = 31) was compared with four-times-daily application of low strength capsaicin cream (0.025%; n = 29) for the treatment of pain associated with osteoarthritis. High strength capsaicin provided greater pain relief with a more rapid onset of action when compared with lower strength capsaicin. After 2 days of treatment, pain severity was reduced by 48.0 +/- 7.7% in the 0.25% capsaicin treatment group (p < 0.001 vs. baseline and p = 0.009 vs. low strength capsaicin) compared with a 17.7 +/- 8.1% reduction in the 0.025% capsaicin treatment group (p = 0.038 vs. baseline). Fifty-five percent of the patients using 0.25% capsaicin b.i.d. experienced at least a 50% reduction in pain severity after 2 days of treatment.By contrast, it was day 14 before one-half of the patients applying 0.025% capsaicin cream q.i.d. experienced a 50% reduction in pain severity. The most commonly reported adverse experience was a transient burning sensation after application of the cream. The incidence of burning with 0.25% capsaicin cream was greater than 0.025% capsaicin cream only on day 2 (69% vs. 31%, p = 0.006). Thereafter, daily reports of burning sensations after drug application declined rapidly in both treatment groups. The results demonstrate that 0.25% capsaicin cream applied b.i.d. is highly effective and well tolerated therapy for osteoarthritis pain.

Clinical correlation of the venom-specific IgG antibody level during maintenance venom immunotherapy.

Allergen immunotherapy is associated with a significant increase of specific IgG antibodies that have been suggested as a mechanism of action and as a marker of efficacy for immunotherapy. The value of venom-specific IgG antibody determinations as a measure of clinical protection against sting anaphylaxis has been difficult to prove in individual patients. We performed 211 insect sting challenges in 109 patients over a 4-year period to determine the significance of venom IgG levels 3 micrograms/ml or lower. Systemic symptoms occurred in only 1.6% of those with venom IgG more than 3 micrograms/ml, but in 16% of those with less than 3 micrograms/ml IgG, and notably in 26% of patients with low venom IgG who had received less than 4 years of treatment. The venom IgG level had no predictive value in patients who had received more than 4 years of therapy. Honeybee sting data were inconclusive because of the small number of subjects. We conclude that low venom-specific IgG levels are associated with an elevated risk of treatment failure during the first 4 years of immunotherapy with yellow jacket or mixed vespid venoms.

Stevens-Johnson syndrome (SJS): effectiveness of corticosteroids in management and recurrent SJS.

To confirm that corticosteroids are beneficial in the treatment of Stevens-Johnson syndrome (SJS), 15 patients with the syndrome were evaluated by the same group of physicians over 2 years. All patients had cutaneous and most had mucosal lesions. Patients were treated with corticosteroids ranging from prednisone 40 mg daily to methylprednisolone 750 mg daily. The same group of physicians participated in the management of these patients until recovery. No deaths occurred among the 15 patients. Recovery was complete in all cases, and there was no residual skin, mucosal, or visceral damage except for minimal scarring in one patient. In some cases, reversal of disease after onset of corticosteroid therapy was sufficiently dramatic to demonstrate a benefit. The use of corticosteroids in the treatment of SJS remains controversial. We conclude that corticosteroids are beneficial in treatment of the syndrome. They may be lifesaving in some patients and should be the standard of therapy. SJS should be considered to be erythema multiforme with either bullous lesions or visceral involvement or both.

Systemic cold urticaria in a five-year-old boy.

A 5-year-old white boy had a history of generalized urticaria on total body exposure to a cold environment. Standard ice cube testing was negative. Plasma analysis revealed the presence of cryofibrinogen. Systemic cold challenge with serial plasma assays for complement, histamine, and prostaglandin D2 disclosed an elevation and peak of plasma histamine and prostaglandin D2 levels after the onset of generalized urticaria with no change in serum complement levels.

The mast cell: a comprehensive, updated review.

The mast cell has been suspected of playing an important clinical role for over a century. Improved techniques to isolate and purify homogeneous mast cell populations have made it easier to study mast cell activation, secretion, heterogeneity, and differentiation in several animal models including man. Despite the many laboratory accomplishments made which better characterize the mast cell, there is still a paucity of information that can be practically applied to clinical situations. This review will concentrate on events leading up to the recent advances made in specific areas of mast cell research.

IgG antibody against formaldehyde human serum proteins: a comparison with other IgG antibodies against inhalant proteins and reactive chemicals.

Immune responses to formaldehyde (F) have been recorded for seven decades. More recently, sensitive assays for antibody against F-human serum albumin (HSA) have been reported. IgG antibody against F-HSA has been said to correlate with symptoms against F-HSA. We report on 61 serum samples analyzed for IgG antibodies against F-HSA. IgG antibodies against F-HSA were most prevalent in subjects who had received intravenous F. In no case (either presumed symptomatic to F or with IgG antibody against F-HSA) was there a correlation of serologic results with symptoms. We also reviewed inhalation disease caused by chemicals and proteins acting as immunogens and report that at this time there is no evidence that gaseous F meets the criteria for causation of inhalational IgG-mediated lung disease by clinical or serologic studies. Very high IgG antibody levels occur in respiratory immunologic inhalational disease, and the absence of these high IgG levels against F is strong evidence against F or F proteins being an inhalational antigen of significance.

Induction of histamine release from human skin mast cells by bradykinin analogs.

Kinins are potent proinflammatory peptides that induce histamine release from rodent mast cells. We examined the ability of bradykinin, lysylbradykinin and a series of kinin analogs to cause histamine release from human basophils, human lung mast cells and human skin mast cells. At concentrations ranging from 0.1 microM to 1 mM, bradykinin failed to cause histamine release from any of the human histamine-containing cells studied. Lysylbradykinin was also without effect on basophils and lung mast cells, but was a weak secretagogue for human skin mast cells, inducing 5.5 +/- 3% (mean +/- SD) of total cellular histamine release at a concentration of 10(-5) M. Similarly, when sixteen recently developed bradykinin antagonists were examined, these compounds had no effect on basophils or lung mast cells but all sixteen induced dose-dependent histamine release from skin mast cells. The release process was temperature dependent and, at a concentration of 10(-5) M, the antagonists induced 8-27% histamine release. Although preincubation of cells with 10(-3) M bradykinin or des(Arg9) bradykinin significantly inhibited antagonist-induced histamine release, the requirement for such high concentrations of these peptides to cause inhibition suggested that histamine release is not mediated by either B1 or B2 kinin receptors. To understand further the mechanism of histamine release, we examined a series of bradykinin analogs with single amino acid substitutions in the bradykinin sequence. Replacement of proline7 in the bradykinin sequence with D-phenylalanine is the essential change used to convert kinin analogs into antagonists, and 10(-5) M [DPhe7]-bradykinin induced 8-10% histamine release. Other analogs, devoid of antagonist activity, however, such as [DPhe6]-bradykinin and [LPhe7]-bradykinin were able to induce equivalent levels of histamine release. The ability to induce histamine release appears to be related, at least in part, to aromaticity, since [DTrp6]-bradykinin and [DTrp7]-bradykinin induced greater amounts of histamine release than equivalent [DPhe]-analogs, causing approximately 20% histamine release at 10(-5) M. By contrast, [DAla7]-bradykinin was an ineffective stimulus. In summary, a single amino acid substitution can convert bradykinin into a secretagogue for human skin mast cells. The ability of kinin analogs to induce histamine release from skin mast cells, but not lung mast cells or basophils, emphasizes the heterogeneity of human histamine-containing cells.

Basophil-mast cell response syndromes: a unified clinical approach.

Allergic antibodies, now known to be of the IgE class, have been associated with basophil and mast cell activation and thus with histamine release since these cells contain histamine. Common allergen induced diseases such as allergic rhinitis have been correlated with IgE antibody, basophils, mast cells and histamine release and partial control with pharmacologic use of histamine receptor blockade. This report now classifies all immediate-type reactions in reference to basophils and mast cells and activation of these cells. This approach appears particularly important in relation to those immediate-type reactions which simulate IgE mediated responses but in which no allergenic stimulus is present. The mechanisms of pharmacologic control of these basophil-mast cell response syndromes and potential research approaches are emphasized.

Purification and characterization of human skin mast cells. Evidence for human mast cell heterogeneity.

Our previous studies of human lung and intestinal mast cells failed to show the heterogeneity found among mast cells in murine species. Recently, we and others have developed techniques for the enzymatic dispersion of human neonatal skin mast cells. In addition, we are now able to make single cell suspensions of mast cells from adult skin and to purify these cells to near homogeneity. Comparative studies of mast cells from these several sources have uncovered several major differences among them. Adult and neonatal skin mast cells themselves differ in that the former are 10-fold less sensitive to goat anti-human IgE, with maximal release occurring at 3.0 and 0.3 microgram/ml, respectively. Skin mast cells also differ in optimal temperature for release: adult mast cells respond maximally at 23 to 30 degrees C and neonatal cells at 37 degrees C. Skin mast cells from both sources are dramatically different from lung and intestinal mast cells in two aspects. First, skin mast cells are quite responsive to several stimuli--morphine sulfate (10(-4) to 10(-6) M), substance P (10(-5) to 10(-7) M), compound 48/80 (10 to 0.1 microgram/ml), f-Met peptide (10(-6) M), and C5a (10(-8) M)--to which the other mast cells fail to respond. Second, although stimulated skin mast cells produce prostaglandin D2, little leikotriene C4, if any, is generated, unlike lung or intestinal mast cells. These differences in inflammatory potential among human mast cells from various sites have important implications for the management of allergic and inflammatory responses.