Methotrexate revisited.
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Anti-Asthmatic Agents↗
Biomedical subjects
M F Mullarkey
Publications and source records attributed to M F Mullarkey.
Human cutaneous allergic late-phase response is inhibited by soluble IL-1 receptor.
The late-phase allergic reaction (LPR) occurs 4 to 8 h after allergen exposure and probably causes the symptoms of chronic allergic disease. To determine the effects of soluble IL-1 receptor on the cutaneous LPR, we performed a prospective, randomized, double-blind, placebo-controlled study on 15 allergic subjects. Intradermal injections of allergen were placed on subjects' forearms, followed by immediate subcutaneous injections at the same site of either 1, 10, 25, 50, or 100 micrograms of rhu IL-1R to three subjects in each dosage group. Placebo was given to matched allergen-injected sites on the contralateral arm. Erythema, induration, and itching were recorded for each site. Sites were biopsied at 8 h for immunohistologic evaluations. Rhu IL-1R significantly reduced the clinical reaction at all concentrations. At 1 and 10 micrograms, measurements of LPR were significantly less (p < 0.05) than at placebo sites at several time points from 2 to 8 h. At higher concentrations, LPR was suppressed at rhu IL-1R and placebo sites, suggesting a systemic effect of rhu IL-1R. Histologic evaluation and indirect immunofluorescence for eosinophil granule major basic protein, neutrophil elastase, and mast cell tryptase showed no statistical differences between rhu IL-1R and placebo sites or among doses. IL-1 plays an important role in the generation of allergic LPR. While microgram quantities of rhu IL-1R inhibited the clinical signs and symptoms of LPR, its effects on the allergic inflammatory infiltrate are yet to be defined. In this short term trial, rhu IL-1R was neither immunogenic nor toxic.
Adult↗
Methotrexate and asthma.
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Adrenal Cortex Hormones↗
Use of methotrexate in the treatment of steroid-dependent adolescent asthmatics.
Five children 10 to 16 years of age with steroid-dependent asthma were treated with methotrexate. All were able to reduce their doses of prednisone and all had improvement in their clinical status. No significant side effects were noted in patients treated 1 to 3 years. This open study suggests that methotrexate should be considered in the treatment of older children with severe asthma and morbidity from their steroid therapy.
Adolescent↗
Long-term methotrexate treatment in corticosteroid-dependent asthma.
STUDY OBJECTIVE: To study the long-term efficacy and toxicity of low-dose methotrexate as corticosteroid-sparing adjunctive therapy in patients with corticosteroid-dependent bronchial asthma. DESIGN: A prospectively evaluated case series. PATIENTS: We studied 31 cushingoid asthmatics who needed daily prednisone and were found to be unable to reduce their prednisone dosage. These patients had used maximal daily doses of bronchodilator and inhaled corticosteroid and, on average, had used prednisone, 26.8 mg/d, for 4.7 years (range, 1 to 11 years). Of these 31 patients, 25 completed 18 to 28 months of methotrexate therapy. INTERVENTION: Patients were treated for at least 18 months with low-dose methotrexate (range, 15 to 50 mg/wk). RESULTS: The mean prednisone dose was reduced from 26.9 mg/d to 6.3 mg/d (P = 0.0001) in the 25 patients treated with long-term methotrexate: Fifteen patients discontinued the regular use of prednisone, 9 patients reduced prednisone use by more than 50%, and 1 patient failed to respond. The forced expiratory volume in 1 second (FEV1) improved from 1.7 L/s to 1.9 L/s (P = 0.0513), and subjective symptom scores for breathing ability, cough, wheeze, and frequency of nocturnal awakenings all improved. Adverse drug reactions were noted in 15 patients. These reactions were mild and did not lead to discontinuation of drug therapy. CONCLUSION: Methotrexate is effective and safe when used as a long-term, corticosteroid sparing agent in patients with severe bronchial asthma.
Adult↗
Methotrexate in the treatment of corticosteroid-dependent asthma. A double-blind crossover study.
To test our previous observation that methotrexate reduces corticosteroid requirements of patients with severe asthma, we studied 14 patients with corticosteroid-dependent bronchial asthma in a 24-week randomized double-blind crossover trial comparing a low dosage of methotrexate (15 mg per week) with placebo. At base line the mean dosage of prednisone was 173.5 mg per week (range, 70 to 420). On the average, 36.5 percent less prednisone was required when patients received methotrexate than when they received placebo (P = 0.01). Measurement of forced vital capacity and forced expiratory volume in one second showed that there was no deterioration in the condition of patients in whom the dosage of prednisone was reduced. The patients' subjective assessment of breathing ability indicated significant improvement (P = 0.01). The adverse effects of methotrexate were limited to transient nausea in three patients and an evanescent rash in one patient. Nine patients are still receiving methotrexate 3 to 10 months after the study's conclusion. The dosages of steroids have been further reduced in each of these patients, and prednisone has been discontinued in four. We conclude from this preliminary study that the use of methotrexate allows a significant reduction in the use of corticosteroids in patients with severe asthma without deterioration of pulmonary function.
Adrenal Cortex Hormones↗
Eosinophilic nonallergic rhinitis.
Eosinophilic nonallergic rhinitis is one of the major forms of nonallergic rhinitis. It is characterized by the presence of many eosinophils in nasal secretions, a negative history for allergen exacerbation, and negative skin tests. It is often associated with nasal polyps and shares their exquisite sensitivity to corticosteroid therapy, both systemic with prednisone or topical with flunisolide. Patients with rhinitis can be separated into diagnostic categories and assigned scores on the basis of history of allergic reactions, status of nasal mucosa, response to skin tests, and IgE titer. Based on these criteria, in a study of 142 patients with rhinitis, those with allergic or probable allergic rhinitis could clearly be separated from those with nonallergic rhinitis. Thirty-four percent had allergic rhinitis (mean score 5.4), 15% had probable allergic rhinitis (mean score 3.8), 37% had vasomotor rhinitis (noneosinophilic, nonallergic rhinitis; mean score 0.75), and 15% had eosinophilic nonallergic rhinitis (mean score 0.71). Eighty-three percent of patients with eosinophilic nonallergic rhinitis responded to antihistamines and 93% responded to the topical corticosteroid flunisolide, making the total response 90%. The response of the latter patients to these medications was statistically better than the response of those patients with allergic rhinitis.
Eosinophilia↗
Propagation and characterization of human blood basophils.
Basophils were isolated and propagated in large numbers from the blood of patients with chronic myelogenous leukemia. Propagation over 4-6 weeks of culture was dependent upon a growth factor(s) other than interleukin-2 obtained from a lectin-stimulated clone of the Jurkat cell line. Evidence that these basophils were dividing during culture included an increase in both the number of basophils and the histamine content of the cultures over time, as well as ultrastructural studies that demonstrated basophil cell division. The cells also had the capacity to be stimulated in an IgE-dependent manner characteristic of basophils. Cultured basophils passively sensitized with IgE underwent noncytotoxic degranulation after stimulation with specific antigen. Antigen-stimulated basophils released histamine, leukotrienes B4 and C4 and other 5-lipoxygenase products of arachidonic acid metabolism. Culture models such as this may permit the propagation and purification of sufficient numbers of basophils to allow biochemical and immunological analyses of basophil physiology.
Arachidonic Acid↗
Association of aspirin-sensitive asthma with HLA-DQw2.
Patients with ASA-sensitive asthma form a clinically homogeneous subgroup of asthmatics characterized by nonatopic eosinophilia, sinusitis, nasal polyps, and frequent steroid dependency. Twenty-six Caucasian patients with ASA-sensitive asthma and 22 Caucasian patients with uncomplicated asthma were typed for HLA Class I and II antigens. A significant increase in HLA-DQw2 (relative risk, 4.06) was found in ASA-sensitive asthmatics. Asthmatic patients who were not ASA-sensitive had HLA frequencies that did not differ significantly from healthy Caucasian control subjects. These findings suggest that ASA-sensitive asthma represents a disease entity unique from other forms of asthma. Presumably, DQw2 or an associated genetic factor is involved in the pathogenesis of ASA-sensitive asthma.
Aspirin↗
Methotrexate in the treatment of steroid-dependent asthma.
A 63-year-old woman with refractory psoriatic arthritis and asthma, requiring intermittent steroid therapy, was treated with methotrexate (MTX). Her arthritis responded rapidly and it was noted that her asthma required no further steroid therapy. Six patients with established steroid-dependent asthma were then treated with 7.5 to 15.0 mg of MTX per week, after protocols used to treat psoriasis and rheumatoid arthritis. Five patients reduced their steroid usage while on MTX. Side effects were minimal while taking MTX. It was concluded that MTX may have a role in reducing cortisone requirements in steroid-dependent asthma.
Asthma↗
The classification of nasal disease: an opinion.
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Humans↗
A clinical approach to rhinitis.
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Ephedrine↗
Effects of corticosteroids on eosinophil chemotaxis and adherence.
Therapeutic doses of corticosteroids frequently induce eosinopenia; however, the mechanism(s) involved remain obscure. To investigate this question, we studied the effects of corticosteroids on eosinophil adherence and migration. Eosinophils from normal donors were prepared by dextran sedimentation and Hypaque gradient centrifugation to 45-96% purity. Adherence was measured by filtration of whole blood and isolated eosinophils through nylon wool columns. Before prednisone administration, adherence was 83.8+/-3.2% for eosinophils in heparinized blood and 82.1+/-3.2% for isolated eosinophils. 4 h after oral prednisone administration whole blood eosinophil adherence was reduced to 53.9+/-10.7%; at 24 and 48 h adherence was normal. In contrast, isolated eosinophils showed no decrease in adherence 4, 24, or 48 h after corticosteroid administration. Similarly, in vitro addition of hydrocortisone to isolated eosinophils at 0.01 and 2.0 mg/ml did not reduce adherence. Eosinophil migration was tested in modified Boyden chambers by "lower-surface" and "leading-front" methods, using zymosan-activated serum and buffered saline to assess chemotactic and random migration, respectively. In vitro incubation of eosinophils with hydrocortisone or methylprednisolone produced a dose-dependent inhibition of chemotaxis. Using lower-surface methods the minimal concentration effecting substantial inhibition was 0.01 mg/ml for both drugs. At 2.0 mg/ml hydrocortisone and methylprednisolone inhibited eosinophil chemotaxis 82.6+/-4.4% and 85.0+/-3.5%, respectively. Using leading-front chemotaxis techniques significant inhibition was detected at 0.001 mg/ml hydrocortisone. Eosinophils incubated and washed free of corticosteroids responded normally to chemoattractants, indicating that the inhibitory effect of these drugs was reversible. Hydrocortisone at 2 mg/ml inhibited random eosinophil migration, although this effect was not apparent at lower concentrations. Corticosteroids did not act as chemotactic factor inactivators and were not toxic as measured by trypan blue exclusion. Eosinophils obtained from donors who had received 40 mg of prednisone orally for four days showed normal chemotactic responses, probably reflecting the fact that the cells were washed free of plasma before testing. In contrast, incubation of eosinophils in plasma from donors who had received a 300-mg bolus of hydrocortisone induced 46.1+/-4.5% more inhibition of chemotaxis than did incubation in normal plasma. These results indicate that: (a) eosinophil adherence is transiently reduced following in vivo corticosteroid administration, (b) eosinophil chemotaxis is inhibited by both in vitro and in vivo administration of corticosteroids, and (c) the chemotaxis inhibiting effect is nontoxic, cell-directed, dose-dependent and reversible. Inhibition of eosinophil adherence and chemotaxis may in part explain how corticosteroids produce eosinopenia and decrease the local accumulation of eosinophils.
Cell Adhesion↗
Allergic and nonallergic rhinitis: their characterization with attention to the meaning of nasal eosinophilia.
We examined the differences between allergic and nonallergic rhinitis. One hundred forty-two patients were evaluated. Forty-eight patients were diagnosed as having allergic rhinitis (AR) on the basis of histories correlating with skin tests and markedly elevated total serum IgE levels. Forty-two percent of these patients had nasal eosinophilia (greater than or equal to 25%) and 58% had histories or findings consistent with asthma. Fifty-two individuals had no evidence for immunologic nasal disease, incriminated physical agents as precipitants, and demonstrated no associated respiratory pathology. These patients were classified as having vasomotor rhinitis (VMR). Twenty-one patients had symptoms similar to those of patients with VMR but they demonstrated nasal eosinophilia and were classified as having eosinophilic nonallergic rhinitis (ENR). These patients had a high prevalence of nasal polyps and were significantly more responsive to medical therapy than any group studied. It is concluded that nasal eosinophilia is of little value in the evaluation of AR but provides significant information regarding the therapy and prognosis in nonallergic rhinitis.
Adolescent↗
Adverse reactions to radiographic contrast material.
Major adverse reactions to radiographic contrast media will occur more often as contrast material is now also administered during computerized tomographic (CT) scanning. Differentiation of the two major contrast reactions, the vagus reaction and the anaphylactoid reaction, is essential. Bradycardia is the key finding for identifying the vagus reaction. The vagus reaction involving hypotension and bradycardia requires treatment with large doses of atropine given intravenously. The immediate generalized reaction or anaphylactoid reaction should be treated as anaphylaxis with administration of vasopressors, fluids, steroids and antihistamines. Steroids and antihistamines given before the examination may offer protection to those high-risk patients who have had previous anaphylactoid reactions to contrast material.
Atropine↗
Allergic and nonallergic rhinitis. Diagnosis and management.
The causes of rhinitis are many. Allergic rhinitis is mediated by IgE, and immunotherapy in selected patients is very effective. Immunoglobulins do not seem to play a role in nonallergic rhinitis, and immunotherapy is ineffective. Correct diagnosis spares the patient needless expense, inconvenience, and eventual disappointment.
Desensitization, Immunologic↗
Flunisolide in chronic bronchial asthma.
Sixteen steroid dependent and 13 steroid independent patients with bronchial asthma were treated for three months with flunisolide by aerosol. Asthma improved in these patients, other medication usage decreased and adverse side effects were minimal. A significant increase in morning plasma cortisol levels occurred in steroid dependent patients, whereas cortisol levels in steroid independent patients remained normal. An unexpected decline in response to metyrapone occurred in both groups of patients and suggests that this test is affected by flunisolide usage.
Adrenal Cortex Function Tests↗
Homology and relationship between the genomes of papovaviruses, BK virus and simian virus 40.
A number of hybridization techniques have been used to assess the homology between the genomes of BK virus (BKV) and simian virus 40 (SV40). A noncontiguous set of homologous sequences has been localized primarily within the late region of the SV40 genome, and these sequences presumably account for the cross-reaction between V-antigens of the two viruses. The reason for the relatively strong crossreaction between SV40 and BKV T-antigens is still unclear. The sequence homology and similarity in genomic organization suggest a close relationship between these papovaviruses.
BK Virus↗