The inhibitory effect of antiallergy drugs on allergen and histamine induced wheal and flare response

The influence of antiallergy drugs on the allergy skin test has not previously been clearly defined. This study demonstrates that hydroxyzine can significantly inhibit the allergen and histamine induced wheal and flare response. The inhibition is significant one hour after drug administration and remains inhibitory for at least 24 hours. Aminophylline, ephedrine, and prednisone do not cause significant inhibition. Discontinuation of hydroxyzine for 24 hours prior to skin testing is not adequate to avoid wheal and flare inhibition.     

A case of eperisone hydrochloride (myonal)--induced drug eruption leading to erythema and angioedema]

Here we report a case of eperisone hydrochloride-induced drug eruption. A twenty-three-year-old female suffering from the common cold, headache and arthralgia was administered eperisone hydrochloride with several drugs including loxoprofen sodium. Two hours after receiving the medications, she noticed erythema and edema in the hands, and then the eruption spread across the whole body. The patient was hospitalized and treated with a corticosteroid intravenously. An oral challenge test showed that eperisone hydrochloride was responsible for this drug eruption. There have been eighteen cases of drug eruption caused by eperisone hydrochloride in the literature and eight cases have shown urticaria/anaphylaxis types. Some cases took several hours to exhibit symptoms even for urticaria/anaphylaxis types that were confirmed to induce an immediate allergic reaction.     

Hypersensitivity angiitis with granulomatous glomerulitis in a patient with preexisting IgA nephropathy

Following a 6-year history of asymptomatic proteinuria and microhematuria, a 51-year-old man suffered from acute systemic eruption, liver dysfunction and acute renal failure immediately after developing a cold and taking drugs including piroxicam, aspirin and bristocycline. Renal biopsy revealed progressive IgA nephropathy associated with acute tubulointerstitial nephritis and granulomatous glomerulitis. Although the drug actually responsible for this condition was not defined, it is likely that drug-induced hypersensitivity angiitis with granulomatous glomerulitis was superimposed on preexisting IgA nephropathy in this patient.     

HYPERSENSITIVITY ANGIITIS WITH GRANULOMATOUS GLOMERULITIS IN A PATIENT WITH PREEXISTING IgA NEPHROPATHY

Following a 6-year history of asymptomatic proteinuria and microhematuria, a 51-year-old man suffered from acute systemic eruption, liver dysfunction and acute renal failure immediately after developing a cold and taking drugs including piroxicam, aspirin and bristocycline. Renal biopsy revealed progressive IgA nephropathy associated with acute tubulointerstitial nephritis and granulomatous glomerulitis. Although the drug actually responsible for this condition was not defined, it is likely that drug-induced hypersensitivity angiitis with granulomatous glomerulitis was superimposed on preexisting IgA nephropathy in this patient. ACTA PATHOL JPN 38: 209–216, 1988.     

Prolongation of simple and choice reaction times in a double-blind comparison of twice-daily hydroxyzine versus terfenadine

Newer, nonsedating antihistamines provide a therapeutic alternative for the patient with allergy whose work is impaired by the side effects of traditional H1 antihistamines. To assess the differential effect of these antihistamines on reaction times and subjective symptoms, we compared terfenadine, 60 mg twice daily, to hydroxyzine, 25 mg twice daily, in a double-blind, placebo-controlled, crossover study of 16 healthy, asymptomatic adults. Simple reaction time and choice reaction time were measured with a computer-based, eye-hand, reaction-time testing apparatus. Reaction times and symptom scores were assessed 90 minutes after the fourth and tenth doses of each drug. Hydroxyzine, but not terfenadine, significantly prolonged both simple and choice reaction time (p less than or equal to 0.0001). However, decision time, the time to process one bit of spatial information, was not prolonged by either antihistamine. Therefore, hydroxyzine prolonged the interpretation and response to stimuli of the central nervous system without increasing single-bit processing time. Although terfenadine was not different from placebo for any symptom assessed, hydroxyzine produced significant drowsiness (p = 0.001), dry mouth (p = 0.022), and irritability (p = 0.021). During the 5 days of hydroxyzine administration, neither objective nor subjective symptoms demonstrated the development of tolerance. No correlation was found between subjective symptoms and prolongation of reaction times by hydroxyzine, suggesting that side effect symptoms of traditional antihistamines are unreliable predictors of objective performance. Terfenadine provides a promising therapeutic alternative to traditional antihistamines for individuals performing critical tasks.     

A case of eosinophilic cellulitis (Wells' syndrome)]

A 67-year-old man sustained a minor injury on the right hand after touching a potted plant. Several days later, he noted erythema and marked swelling on the right hand and forearm. The same lesions developed on the left hand and forearm. He also had pruritic erythema on the neck, trunk, and thighs. The initial clinical diagnosis was bacterial cellulitis and contact dermatitis. However, oral antibiotic and topical steroid therapy were not effective. Laboratory investigations revealed peripheral blood eosinophilia, elevated serum IgE level, and positive antinuclear antibody. Histopathological examination of a skin biopsy specimen showed an excessive infiltration of eosinophils and flame figures in the dermis. We diagnosed this case as eosinophilic cellulitis (Wells' syndrome). The skin lesions responded rapidly to the systemic oral steroid therapy. There has been no recurrence of eruption in 1 year of follow-up. The condition of the disease was correlated to peripheral blood eosinophil counts, and serum eosinophil cationic protein levels. However, serum interleukin-5 levels were within normal limits.     

Controlled trial of H1 antagonists in the treatment of chronic idiopathic urticaria.

The efficacy of astemizole, diphenhydramine, and hydroxyzine hydrochloride in the treatment of chronic idiopathic urticaria was evaluated in this 3-month double-blind, randomized, parallel group study. Thirty-six adult patients were randomly assigned, 13 to the astemizole group (10 mg daily), 12 to the diphenhydramine group (25 mg t.i.d.), and 11 to the hydroxyzine hydrochloride group (25 mg t.i.d.). Demographic data were statistically similar for all variables assessed in the three treatment groups. Seven (58%) of the diphenhydramine patients withdrew before the end of the study, six because of lack of efficacy and one because of drowsiness. Two (18%) of the hydroxyzine hydrochloride patients withdrew, one because of lack of efficacy and one because of drowsiness. Two patients (15%) in the astemizole group withdrew, one because of adverse reaction, and the other because of lack of efficacy. Mean total symptom scores and mean individual symptom scores were lower in the astemizole group than in the other two groups. Wheal area measurements (0.1 mg/mL histamine challenge) decreased more in the astemizole and hydroxyzine hydrochloride groups than in the diphenhydramie group (P = .02). With regard to symptoms, 12/13 patients in the astemizole group improved clinically during their treatment period, versus 8/11 in the hydroxyzine hydrochloride group and 5/12 in the diphenhydramine group. The mean time to first observed therapeutic effect (maintained for three consecutive days) was 5.5 days in the astemizole group, 10.9 days in the hydroxyzine hydrochloride group, and 7.2 days in the diphenhydramine group. In this study, astemizole was as effective as hydroxyzine in patients treated for chronic idiopathic urticaria.     

The effect of chronic administration of hydroxyzine on hydroxyzine pharmacokinetics in dogs

Subsensitivity to H1-receptor antagonists has been attributed to autoinduction of enzyme systems and increased clearance rates during chronic drug administration. We studied the changes in serum half-life values and clearance rates in dogs who were administered hydroxyzine, 0.7 mg/kg, intramuscularly, daily, for 150 days. Pharmacokinetic studies were performed on the first day of drug administration, and on days 30, 60, 90, 120, and 150. The mean serum half-life value on day 30, 60, and 120 was significantly longer (p less than 0.05) than that of 2.4 +/- 0.3 hours obtained on day 1. The mean clearance values obtained on days 30, 60, 90, 120, and 150 were significantly slower (p less than 0.05) than the value of 25.12 +/- 4.13 ml/min/kg obtained on day 1 but were not significantly different from each other. Mean serum hydroxyzine concentrations were often significantly higher on the later study days than on day 1. The mean apparent volume of distribution values obtained on days 30, 60, 90, 120, and 150 did not differ significantly from the value of 5.0 +/- 1.5 L/kg obtained on day 1. This study adds to the mounting evidence that subsensitivity to the effects of an H1-receptor antagonist is not due to autoinduction of enzyme systems, more rapid clearance of the drug, and lower concentrations of the drug in serum and tissue.     

Mediator release in local heat urticaria: protection with combined H1 and H2 antagonists

Two patients with local heat urticaria were examined for evidence of histamine release and for changes in mast cell morphology after local heat challenge. Both patients demonstrated significant release of histamine into the draining venous blood in the challenged arm. Biopsy specimens revealed mucosal edema after 30 min, followed by a mononuclear, perivascular infiltrate by 6 hr, and increasing in intensity by 24 hr. Degranulated mast cells were observed by electron microscopy. Heat challenge was repeated after treatment with hydroxyzine, cimetidine, or a combination of both drugs. Neither hydroxyzine nor cimetidine alone affected the clinical response to challenge, but both drugs together completely abolished the clinical response. In addition, the combination of both drugs taken regularly completely prevented symptoms. This observation suggests that histamine is one of the major mediators of this disorder and that both H1 and H2 receptors are operative.     

Mycophenolate mofetil in neuropsychiatric systemic lupus erythematosus

Neuropsychiatric abnormalities frequently occur in patients with systemic lupus erythematosus, affecting as many as 14-75% of people with this disease. High-dose steroid with or without anticoagulation is the mainstay of treatment in neuropsychiatric systemic lupus erythematosus (NPSLE). Use of mycophenolate as a steroid sparing drug may be a potential alternative agent in the therapy of NPLE, but lack of randomized trials and cost prohibit its widespread use. Its safety profile is higher than that of cyclophosphamide and azathioprine. We report a successfully treated case of neuropsychiatric systemic lupus erythematosus, presenting as psychosis, whose long-term remission was maintained on treatment with mycophenolate mofetil.     

Hydroxyzine inhibits experimental allergic encephalomyelitis (EAE) and associated brain mast cell activation

Experimental allergic encephalomyelitis (EAE) has been used as an animal model for the human demyelinating disease multiple sclerosis (MS). In acute MS or EAE, early disruption in the integrity of the blood-brain-barrier (BBB) precedes brain infiltration by inflammatory cells or any clinical evidence of disease. BBB permeability could be affected by vasoactive mediators and cytokines released from perivascular brain mast cells. We investigated the number and degree of activation of brain mast cells in EAE and the effect of the heterocyclic histamine-1 receptor antagonist hydroxyzine, a piperazine compound known to also block mast cells. Acute EAE was induced in Lewis rats by immunization with whole guinea pig spinal cord homogenate and complete Freund's adjuvant (CFA). A second group of animals were treated orally with hydroxyzine for one day before immunization and then continuously for 14 days. Control rats were treated with CFA or hydroxyzine alone. The clinical progression of EAE was assessed on days 10, 12 and 14 after immunization. The number of metachromatic mast cells and the degree of degranulation was assessed in the thalamus with light microscopy. At day 14, there was a three-fold increase in the number of brain mast cells with EAE, as compared to controls. These cells were positive for the immunoglobulin E binding protein (FcepsilonRI), while those from control rats were not. Over 40% of all thalamic mast cells studied in EAE showed partial staining or extruded secretory granule indicative of secretion. Hydroxyzine treatment inhibited (p<0.05) the progression and severity of EAE by 50% and the extent of mast cell degranulation by 70% (p<0.05). These findings indicate that brain mast cells are associated with EAE development and that inhibition of their activation correlates positively with the clinical outcome.     

Clinical Features of Fixed Drug Eruption at a Tertiary Hospital in Korea

Purpose

Fixed drug eruption (FDE) is characterized by a well-defined erythematous patch, plaque, or bullous eruption that recurs at the same site as the result of systemic exposure to a causative drug, and resolves with or without hyperpigmentation. This study was carried out to identify the common causative drugs and clinical features of FDE in Korea.

Methods

We reviewed electronic medical records of all patients diagnosed with FDE from January 2000 to December 2010 at a tertiary hospital in Korea.

Results

A total of 134 cases were diagnosed as FDE. The mean age was 35.9 years (range, 0-82 years) and 69 (51.5%) of the patients were male. The mean duration from the first event to attending hospital was 1.9 years (range, 1-20 years). The mean number of recurrences was 2.6 (1-10), and 72.6% of patients sought medical care after experiencing symptoms twice or more. Four patients (3.1%) needed hospitalization. The most common sites were the upper extremities (47.7%), followed by the lower extremities, face, abdomen, chest, buttocks and perineum. Clear documentation on the causative drugs was available for 38 patients (28.4%), and among these, non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen accounted for 71.1% of cases, and antibiotics accounted for 15.8%. Eighty patients (59.7%) underwent active treatment for FDE, and topical steroids were most frequently prescribed (43.3%), with systemic steroids used in 11.2% of patients.

Conclusions

NSAIDs and acetaminophen were the main causative agents of FDE, however, the causative agents were not assessed in 25% of patients.     

Suppression of histamine-induced pruritus by three antihistaminic drugs.

A double-blind crossover study of inhibition of histamine-induced pruritus by three commonly prescribed antihistamines was conducted on 28 normal subjects. Drugs used included diphenhydramine HCl (Benadryl), cyproheptadine (Periactin), hydroxyzine HCl (Atarax), and a lactose placebo in identical capsules. Intradermal histamine dose-response thresholds of pruritus were obtained before and after pretreatment with the three antihistamines and placebo in each subject. Analysis of data revealed a fivefold increase above baseline of the histamine dose required to produce pruritus following both cyproheptadine and placebo. This compared to a tenfold increase following diphenhydramine and a 750-fold increase following hydroxyzine HCl. The most common side effect was drowsiness, which occurred with all three drugs.     

Influence of steroid treatment's duration in patients with active Crohn's disease

Steroids are very useful drugs in the treatment of active Crohn's disease (CD), but clinical relapses after steroid withdrawal may be very high.We investigated the efficacy of two steroid regimens of different duration in inducing remission and in maintaining it after drug suspension.Patients with active CD were randomly assigned to scheme A, lasting 7 weeks (27 patients), or to scheme B, lasting 15 weeks (27 patients). Remission rates at the end of the treatment were 81% for scheme A and 85% for scheme B. Relapse rates at 6 months after stopping the treatment were 50% (11 patients) and 52% (12 patients), respectively.Remission rates seem not to be influenced by the duration of the treatment, but patients recently treated with steroids showed a higher relapse rate if they received the short-duration treatment.     

Influence of steroid treatment's duration in patients with active Crohn's disease

Steroids are very useful drugs in the treatment of active Crohn's disease (CD), but clinical relapses after steroid withdrawal may be very high.We investigated the efficacy of two steroid regimens of different duration in inducing remission and in maintaining it after drug suspension.Patients with active CD were randomly assigned to scheme A, lasting 7 weeks (27 patients), or to scheme B, lasting 15 weeks (27 patients). Remission rates at the end of the treatment were 81% for scheme A and 85% for scheme B. Relapse rates at 6 months after stopping the treatment were 50% (11 patients) and 52% (12 patients), respectively.Remission rates seem not to be influenced by the duration of the treatment, but patients recently treated with steroids showed a higher relapse rate if they received the short-duration treatment.     

Relationship Between Cell Proliferation and Eruption Rate in the Rat Incisor

The aim of this study was to further define the relationship between cell proliferation and the rate of tooth eruption in the rat incisor. Vinblastine is a drug that blocks cellular mitosis and was used to inhibit cell proliferation in the odontogenic region of rat incisors that were submitted to a shortening treatment or to higher masticatory forces. Male Wistar rats were divided into five groups: normofunctional (control group for incisor eruption), hypofunctional (incisor submitted to eruption acceleration), hyperfunctional (incisors under higher masticatory forces), hypofunctional with vinblastine and hyperfunctional with vinblastine. In incisors submitted to shortening procedures, a significant decrease in the eruption rate and cell proliferation was observed two days after vinblastine injection, suggesting that incisor eruption is dependent on cell proliferation. Anat Rec, 296:1096–1101, 2013. © 2013 Wiley Periodicals, Inc.     

Danazol in treatment of lupus thrombocytopenia.

Seven patients with systemic lupus erythematosus (SLE), persistent thrombocytopenia (TP), in whom it was considered undesirable to institute an increase in steroid or immunosuppressive agents, were treated with danazol. Five patients completed the minimum period of 8 weeks. Two patients showed early response to danazol but were switched over to cyclophosphamide or azathioprine after 4 weeks because of systemic disease. Of the remaining five patients, four had complete responses. In one patient who failed treatment the TP was considered to be related to another drug (ranitidine). Other manifestations of SLE also improved with treatment. Side effects included amenorrhea in one patient, and hypoglycemia and hyponatremia in another. Infections were absent. Danazol can be a useful alternative treatment of lupus TP.     

IVIg selectively and rapidly decreases circulating pathogenic autoantibodies in pemphigus vulgaris

BACKGROUND: Intraveneous immunoglobulin (IVIg) is increasingly used to treat pemphigus vulgaris (PV). The mechanism by which it does so is not known. The following study was conducted to confirm the effectiveness of IVIg for the acute control of active PV and to elucidate the mechanism by which it does. METHODS: Twelve patients with active and severe PV unresponsive to conventional therapy with high doses of systemic steroids together with or without a cytotoxic drug were treated with a single dose of IVIg (400 mg/kg/day for 5 days). All patients were concurrently given cyclophosphamide or azathioprine of not already on one of these two drugs. The primary end-points were healing of skin lesions, changes in serum levels of intercelular (IC) autoantibodies and in steroid doses one to 3 weeks after initiation of IVIg. RESULTS: Within 1 week of initiating IVIg the activity of PV was controlled in most cases. Within 3 weeks the average baseline dose of systemic steroid was reduced by 40%. Serum levels of IC antibodies rapidly declined by an average of 59% within 1 week of initiating IVIg and by 70% within 2 weeks. The decrease was selective, as the average serum levels of antibody to varicella-herpes zoster did not decrease in the 4 patients in whom they were measured. The decrease in IC antibodies was inversely related to serum levels of total inmmunoglobulin (IgG). The decrease in IC antibodies was not due to blocking factors in the IVIg preparation and was too rapid to be due to suppression of IgG synthesis, suggesting that it resulted from increased catabolism. CONCLUSIONS: IVIg can rapidly control active PV unresponsive to conventional therapy by causing a selective and very rapid decline in the autoantibodies that mediate the disease. We believe it does so by increasing the catabolism of all serum IgG antibodies, and that this results in a selective decrease in only abnormal autoantibodies as catabolized normal anti bodies are replaced by those present in the IVIg preparation. IVIg is the first treatment that achieves the ideal therapeutic goal in auto-antibody diseases, the selective removal of the pathogenic antibodies without affecting the level of normal antibodies.     

A controlled trial of therapy in chronic urticaria

Nineteen patients with chronic idiopathic urticaria (duration 2 to 192 mo) referred to our clinic as therapeutic failures were treated sequentially with five regimens. These were administered orally in a double-blind random sequence and included hydroxyzine pamoate (25 mg q.i.d.) plus one of the following: (1) placebo, (2) terbutaline (2.5 mg q.i.d.), (3) cyproheptadine (4 mg q.i.d.), (4) chlorpheniramine (4 mig q.i.d.), (5) cimetidine (300 mg q.i.d.). Therapeutic response was assessed by patient's subjective choice, symptom diary scores, and suppression of wheal response to intradermal injections of histamine and compound 48/80. At least 35% improvement was noted in all patients with an average optimal response of 70%. The hydroxyzine-cimetidine combination was favored by 11 of 19 (58%) patients, in addition to producing the lowest symptom scores and the greatest histamine-48/80 wheal suppression. These results support the efficacy of combination H1 and H2 antihistamines in the management of some patients with difficult chronic urticaria.     

A study of clinical significance of leucocyte migration test in drug eruption]

In 202 patients suspected of drug eruption, the identification of the allergenic drugs were performed by leucocyte migration test (LMT). Leucocyte migration activating factor (LMAF) was detected in 94 cases (46.5%) and Leucocyte migration inhibitory factor (LMIF) in 93 cases (46.0%) for tests either without patients' serum or with patient's serum. Either LMAF or LMIF was detected in 158 cases (78.2%). LMAF was detected in 46 cases (22.8%) for tests only without patient's serum, and in 68 cases (33.7%) for tests only with patient's serum. Accordingly, LMAF was found significantly more frequently with patient's serum than without patient's serum (p < 0.01, chi 2-test). The drugs showing either LMAF-positive or LMIF-positive were detected in 193 of all 647 suspected drugs, in which 53 drugs (27.5%) were beta-lactam antibiotics and 36 (28.0%) were non-steroidal antiinflammatory drugs. LMAF was detected significantly higher than LMIF in beta-lactam antibiotics-induced eruptions (p < 0.01, chi 2-test), which LMIF was detected significantly higher than LMAF in non-steroidal antiinflammatory drugs-induced eruptions (p < 0.01, chi 2-test). Our finding indicate that both LMAF and LMIF may be involved in the pathogenesis of drug eruptions, that the detection of either LMAF or LMIF may be valuable to identify the allergenic drugs in drug eruption by means of LMT and that the production of LMAF may be enhanced in the presence of patients' sera. Furthermore, the pathogenic mechanism of beta-lactam antibiotics-induced eruption may be different from that of non-steroidal antiinflammatory drugs-induced eruption.