Staphylococcus aureus (SA) is usually present not only in the skin lesions of atopic dermatitis (AD) but also in the atopic dry skin. SA discharges various toxins and enzymes that injure the skin, results in activation of epidermal keratinocytes, which produce and release IL-18. IL-18 that induces the super Th1 cells secreting IFN-gamma and IL-13 is supposed to be involved in development of AD and its pathogenesis. Indeed, the number of SA colonies on the skin surface and the serum IL-18 levels in patients with AD significantly correlated with the skin scores of AD lesions. Also, there is strong positive correlation between the skin scores and serum IL-18 levels in DS-Nh mice (P<0.0001, r=0.64), which develop considerable AD-like legions when they are housed under conventional conditions, but develop skin legions with less severity and less frequency under specific pathogens free (SPF) conditions. Therefore, they are well-known as model mice of AD, in which SA is presumed to be critical factor for the development of AD lesions. Also, theses DS-Nh mice pretreated with Cy developed more remarkable AD-like lesions in comparison with non-treated ones. The levels of INF-r and IL-13 in the supernatants of the lymph node cell cultures stimulated with staphylococcal enterotoxin B (SEB) or ConA were increased in the Cy-treated mice, although the serum levels of total IgE were not. In this experiment, we revealed that Cy-treated mice, to which CD25 +CD4 + reguratory T cells taken from non-treated ones had been transferred, developed the AD-like legions with less severity and less number of SA colonies on the skin surface. Therefore, it is presumed that CD25 +CD4 + reguratory T cells might be involved in the suppression of super Th1 cells which are induced by IL-18 and are involved in the development of AD-like lesions rather than IgE production. The efficient induction of CD25 +CD4 + reguratory T cells is expected for the new type of treatment of AD. We also found that farnesol (F) and xylitol (X) synergistically inhibited biofilm formation by SA, and indeed the ratio of SA in total bacteria at sites to which the FX cream containing F and X had been applied was significantly decreased 1 week later, accompanied with improvement of AD, when compared with that before application and at placebo sites. Therefore, the FX cream is a useful skin-care agent for atopic dry skin colonized by SA. The nerve growth factor (NGF) in the horny layer (the horn NGF) of skin lesions on the cubital fossa was collected by tape stripping and measured using ELISA in AD patients before and after 2 and 4 weeks treatments. Simultaneously, the itch and eruptions on the whole body and on the lesions, in which the horn NGF was measured, were recorded, and also the peripheral blood eosinophil count, serum LDH level and serum total IgE level were examined. The level of NGF was significantly higher in AD patients than in healthy controls, correlated with the severity of itch, erythema, scale/xerosis, the eosinophil count and LDH level, and also significantly decreased after treatments with olopatadine and/or steroid ointment for 2 and 4 weeks. Therefore, the measurement of the NGF by this harmless method seems to be useful to assess the severity of AD and the therapeutic effects on AD. In AD patients, C-fiber in the epidermis increase and sprout, inducing hypersensitivity, which is considered to aggravate the disease. Semaphorin 3A (Sema3A), an axon guidance molecule, is a potent inhibitor of neurite outgrowth of sensory neurons. We administered recombinant Sema3A intracutaneously into the skin lesions of NC/Nga mice, an animal model of AD, and investigated the effect of Sema3A on the skin lesions and their itch. Sema3A dose-dependently improved skin lesions and attenuated the scratching behavior in NC/Nga mice. Histological examinations revealed a decrease in the epidermal thickness, the density of invasive nerve fibers in the epidermis, inflammatory infiltrate including mast cells and CD4 +T cells, and the production of IL-4 in the Sema3A-treated lesions. Because the interruption of the itch-scratch cycle likely contributes to the improvement of the AD-like lesions, Sema3A is expected to become a promising treatment of patients with refractory AD.
Animals ; Axons ; Bacteria ; Biofilms ; Cell Culture Techniques ; Colon ; Dermatitis, Atopic ; Dibenzoxepins ; Enterotoxins ; Enzyme-Linked Immunosorbent Assay ; Eosinophils ; Epidermis ; Erythema ; Farnesol ; Horns ; Humans ; Hypersensitivity ; Immunoglobulin E ; Interleukin-13 ; Interleukin-18 ; Interleukin-4 ; Keratinocytes ; Lymph Nodes ; Mast Cells ; Mice ; Models, Animal ; Nerve Fibers ; Nerve Growth Factor ; Neurites ; Semaphorin-3A ; Semaphorins ; Sensory Receptor Cells ; Skin ; Staphylococcus aureus ; T-Lymphocytes ; Th1 Cells ; Xylitol ; Olopatadine Hydrochloride

Doxepin hydrochloride cream with potent H1 and H2 blocker activity is a tricyclic antidepressant, which is structurally similar to phenothiazines, and also known to be a contact sensitizer and photosensitizer. We report a case of allergic contact dermatitis due to doxepin hydrochloride cream in a 75-year-old-man, who developed facial edema and eczema at the application sites (face, neck and upper trunk) within several hours of application of doxepin hydrochloride cream. Clinicians should be aware of the possibility of allergic contact dermatitis to doxepin cream, if the condition worsens with use of this medication.
Dermatitis, Allergic Contact* ; Dermatitis, Contact ; Doxepin* ; Eczema ; Edema ; Neck ; Phenothiazines

Solar urticaria is an uncommon disorder characterized by pruritus, erythema and whealing occurring minutes after exposure to sunlight or artificial radiation, and generally resolves in a few hours. A 46-year-old woman presented with a 2-year history of pruritus and whealing, which occurred immediately after exposure to sunlight. Phototesting elicited urticarial reactions in the UVA and visible sepectra. The results of passive and reverse passive transfer studies were all negative. The patient was treated with cetirizine, doxepin and prednisolone. After 2 months of the treatment, the symptoms did not appear.
Cetirizine ; Doxepin ; Erythema ; Female ; Humans ; Middle Aged ; Prednisolone ; Pruritus ; Sunlight ; Urticaria*

BACKGROUND: Eczematous dermatitis is associated with severe pruritus, but there are only a few effective treatment modalities. Preliminary studies suggest that topical application of doxepin cream is effective in the treatment of eczematous dermatitis. OBJECTIVE: This study was undertaken to evaluate the efficacy and safety of topical 5% doxepin cream in reducing ruritus associated with eczematous dermatitis in Korea. METHODS: A total of 62 patients with eczematous dermatitis, who daily experienced severe pruritus for at least 1 week, were enrolled in the study. Five percent doxepin cream was applied twice a day on the baseline visit, and four times daily for up to 7 days. We evaluated pruritus scores using visual analog scales, which consisted of a 100-mm horizontal line labeled "no itch" and "worst itch imaginable" at opposite ends. RESULTS: Pruritus scores evaluated by patients revealed significantly-better improvement on each visit day. Furthermore, there was a significant decrease in the pruritus scores and erythema evaluated by physicians on each visit day. Furthermore, the most common adverse effects were a stinging sensation and aggravation of erythema at the site of application. CONCLUSION: Five percent doxepin cream is safe and effective in reducing pruritus in patients with eczematous dermatitis.
Bites and Stings ; Doxepin* ; Eczema* ; Erythema ; Humans ; Korea ; Pruritus ; Sensation ; Visual Analog Scale

BACKGROUND: Optimal use of tricyclic antidepressants (TCAs) requires serum monitoring to determine if the appropriate therapeutic range has been attained and to assess possible side effects. This study was to evaluate the resolution capacity of the following four mobile phases which were previously reported; mobile phase I (methanol, acetonitrile and 5 mmol/L Na2HPO4: 41/15/44 by volume), II (methanol, acetonitrile and 5 mmol/L Na2HPO4,: 15/60/25 by volume), III (acetonitrile and 2-propanol: 95/5 by volume) and IV (methanol and n-butylamine: 99.5/0.5 by volume). METHODS: Amitriptyline (AT), nortriptyline (NT), imipramine (IMI) and doxepin (DOX) were used for the selection of appropriate mobile phase in high performance liquid chromatographic (HPLC) determination. TCAs were extracted from serum with hexane, isoamyl alcohol (99:1). The drug was re-extracted into 0.1 N HCl and an aliquot was injected into the HPLC. The analytical column was C-18 reversed phase column (3.9 mm x 30 cm; Waters, USA) with the flow rate of 1.5 mL/min. The UV detector signal was monitored at 254 nm. RESULTS: Mobile phase I disclosed 9.8-15.8 retention time (min), 5.1-8.8 capacity ratio and 1.0-2.2 resolution factors for the above four TCAs. Precision studies using this mobile phase demonstrated a coefficient variation of 2.4-4.7% in the concentration range of 500-125 ng/mL. Analytical recovery of AT and IMI was 85-90% at a concentration of 125 ng/mL and 250 ng/mL. CONCLUSIONS: Mobile phase I provided a reliable and excellent resolution of TCAs in the use of HPLC with the C-18 reversed phase column and UV absorbance detector.
2-Propanol ; Amitriptyline ; Antidepressive Agents, Tricyclic* ; Chromatography, High Pressure Liquid ; Doxepin ; Imipramine ; Nortriptyline

BACKGROUND: Atopic dermatitis is associated with severe pruritus for which effective topical treatment is lacking. As a potent H1 and H2 antagonist, the antipruritic effect of topical doxepin has been demonstrated in eczematous dermatitis. OBJECTIVE: We evaluated the efficacy and safety of topical 5% doxepin cream in relieving pruritus associated with atopic dermatitis. METHODS: A total of 44 patients with atopic dermatitis, who had moderate to severe daily pruritus for at least 1 week, were enrolled in the double-blind, vehicle-controlled study. Randomly assigned 5% doxepin cream or vehicle cream was applied four times daily for 7 days trial. RESULTS: Relief of pruritus was achieved in 85% of doxepin-treated patients and 57% of vehicle-treated patients by day 7. At each study visit, the physician's global evaluation for relief of pruritus showed significant improvement in the doxepin treatment group (p < 0.01). Visual analogue scales for pruritus severity and pruritus relief showed similar improvements in the doxepin-treated group. The most common adverse effects reported included localized erythema, xerosis (doxepin group, n=5; vehicle group, n=3) and drowsiness (doxepin group, n=2; vehicle group, n=0). CONCLUSION: Topical doxepin is effective in reducing pruritus in patients with atopic dermatitis. It has apparently a short-term low risk of major side effects or sensitization.
Dermatitis, Atopic* ; Doxepin* ; Eczema ; Erythema ; Humans ; Pruritus ; Sleep Stages ; Weights and Measures

PURPOSE: To compare the inhibitory effects of various tricyclic antidepressants (TCAs) on contractile response of the rat vas deferens to electrical stimulation of hypogastric nerve. MATERIALS AND METHODS: A total of forty Spraque Dawley rats (weight 300-350gm) were divided into 8 groups (n=5 in each): doxepine, amitriptyline, trimipramine, desipramine, imipramine, clomipramine, protriptyline, and prazosin treated groups. Before (baseline pressure) and 20 minutes after intravenous injection of each agent (0.1-, 1-, 10-, and 20-fold of therapeutic doses for human in each agent), the hypogastric nerves, iden tified under operative microscope, were electrically stimulated with rectangular pulses of 0.5 mseconds duration, 10 Hz, and 10 V for 10 seconds. Dose of drug administered was gradually increased in order of 0.1- to 20-fold dose. RESULTS: All drugs tested in this study caused dose-dependent inhibition of the rat intravasal pressure induced by the electrical stimulation of hypogastric nerve. Inhibitory potency of each drug was doxepine (88.5% and 96.5% at 10- and 20-fold dose)> OR = amitriptyline (76.8% and 91.8%)>clomipramine (66.7% and 74.4%)> OR =imipramine (48.2% and 67.0%)=prazosin (45.6% and 63.5%)=trimipramine (52.7% and 65.4%)> OR =desi pramine (45.3% and 49.0%)> protriptyline (18.9% and 19.9%). CONCLUSIONS: Inhibitory effects of TCAs on contractile response of the rat vas deferens to electrical stimulation of hypogastric nerve would increase in proportion to their potency of alpha1-adrenoceptor blocking actions.
Amitriptyline ; Animals ; Antidepressive Agents, Tricyclic* ; Clomipramine ; Desipramine ; Doxepin ; Electric Stimulation* ; Humans ; Imipramine ; Injections, Intravenous ; Prazosin ; Protriptyline ; Rats* ; Trimipramine ; Vas Deferens*

OBJECTIVES: We aimed to investigate the discontinuation rate and reasons of doxepin base prescription pattern in insomnia outpatients of psychiatry department of a university hospital. METHODS: 534 patients prescribed doxepin were screened. 201 patients were included and reviewed for their medical records retrospectively. The discontinuation rate and reasons of doxepin after 2 months of prescription were investigated. Patients were divided into three groups according to the prescription patterns. The initial group, prescribed doxepin as the first hypnotic, the add-on group, prescribed doxepin while maintaining existing hypnotics, and the switching group, prescribed doxepin after discontinuation of existing hypnotics. RESULTS: The discontinuation rate after 2 months of prescription of doxepin was 56.2%. There were significant differences in the discontinuation rate among three groups. The initial group had the highest while the add-on group had the lowest (p=0.018). In reasons for discontinuation of doxepin among three groups, lack of efficacy (p < 0.001) and adverse events (p < 0.001) were significantly higher in the add-on group. In the initial group, patient's refusal (p=0.022) and unknown or loss to follow up (p < 0.001) were significantly higher. CONCLUSIONS: The results of this study suggested that add-on is superior than switching method and gradual reduction of existing hypnotics is necessary to maintain doxepin treatment and prevent adverse events. Additional large scale prospective studies are needed to evaluate various factors and risks of discontinuation of doxepin.
Doxepin ; Follow-Up Studies ; Humans ; Hypnotics and Sedatives ; Medical Records ; Methods ; Outpatients ; Prescriptions ; Prospective Studies ; Retrospective Studies ; Sleep Initiation and Maintenance Disorders

PURPOSE: To evaluate the effect of olopatadine and ketotifen to stabilize mast cells using human umbilical cord blood-derived mast cells (hCBMCs). METHODS: Using cultured hCBMCs, we divided the cells into the Ketotifen fumarate treatment group, the Olopatadine hydrochloride treatment group, the positive control group, and the negative control group. The histamine release inhibition rate was then observed. RESULTS: Ketotifen and olopatadine both showed the highest inhibition rate of histamine release at a concentration of 10(-3.5)M (Ketotifen, 48% and Olopatadine, 62%). The histamine release inhibition rate of olopatadine was 28% at a concentration of 10(-5.5)M, but ketotifen demonstrated a low histamine release inhibition rate at the same concentration. Ketotifen and olopatadine showed no histamine release inhibition at concentrations of 10(-2)~10(-2.5)M, and 10(-6)M. CONCLUSIONS: Ketotifen and olopatadine demonstrated histamine inhibition in the concentration range of 10(-3) to 10(-5)M. Olopatadine showed a slightly stronger response than ketotifen in the inhibition of histamine release.
Histamine ; Histamine Release ; Humans* ; Ketotifen* ; Mast Cells* ; Umbilical Cord* ; Olopatadine Hydrochloride

Second-generation antihistamines are widely prescribed for the control of symptoms of allergic inflammation such as itchy hives, coryza, and itchy eyes. In rare circumstances, these drugs might provoke allergic inflammation. Hypersensitivity to bepotastine besilate, a second-generation antihistamine has never been reported. A 17-year-old schoolgirl, whose paroxysmal itchy hives had been controlled with bepotastine, experienced aggravation of the hives. An oral provocation test confirmed her hypersensitivity to bepotastine and cross-reactivity to levocetirizine. She showed no reaction to chlorpheniramine, ketotifen, or olopatadine among the 13 antihistamines tested. While searching for an antihistamine to control her itchy hives, we found that she also exhibited cross-reactivity to various antihistamines with different chemical structures from that of bepotastine, which is not predicted according to the chemical classification of antihistamines. We report a case of hypersensitivity to bepotastine besilate in a patient with chronic spontaneous urticaria.
Adolescent ; Chlorpheniramine ; Classification ; Drug Hypersensitivity ; Histamine Antagonists ; Humans ; Hypersensitivity ; Inflammation ; Ketotifen ; Olopatadine Hydrochloride ; Urticaria