Neurochemical and behavioral characterization of potential antidepressant properties of indeloxazine hydrochloride

The potential antidepressant properties of indeloxazine hydrochloride were examined in vitro and in vivo. Indeloxazine showed preferential affinity for both [3H] citalopram (Ki: 22.1 nM) and [3H]nisoxetine binding sites (Ki: 18.9 nM) in membranes of the rat cerebral cortex. In microdialysis studies, intraperitoneal injection of indeloxazine (3 and 10 mg/kg) dose-dependently increased the extracellular level of both serotonin and norepinephrine in rat frontal cortex of freely moving rats. Amitriptyline was almost equivalent to indeloxazine in these two assays with the exception of a much weaker effect on extracellular serotonin levels. Spontaneous [3H]serotonin release from rat cortical synaptosomes was significantly enhanced by indeloxazine (10-1000 nM). In behavioral studies, indeloxazine increased the number of wheel rotations in forced swimming tests in both ICR mice (50 mg/kg, p.o.) and SAMP8//YAN, a substrain of senescence-accelerated mouse (20 and 30 mg/kg, p.o.). Indeloxazine (3-10 mg/kg p.o.) also inhibited the incidence of muricide in raphe-lesioned rats. These results suggest that indeloxazine is an inhibitor of serotonin and norepinephrine uptake and has potential antidepressant properties. In addition, the drug-induced enhancement of serotonin release may contribute to its potent effects on the serotonergic system in vivo.     

Stevens-Johnson syndrome caused by a health drink (Eberu) containing ophiopogonis tuber

Stevens-Johnson syndrome is considered to be a severe type of erythema exsudativum multiforme. It is characterized by erythema with bullous and eroded lesions of skin and mucous membranes. We report a case of Steven-Johnson syndrome following consumption of a health drink containing ophiopogonis tuber. A 66-year-old female took an O.T.C. health drink for fever. The next morning, she noted erythema and swelling of her face, neck, and chest. She started to develop bullous and eroded lesions on the skin of her entire body and the mucous membranes of her oral cavity, conjunctiva, and cornea, and she became feverish. She had high degrees of corneal erosion and liver dysfunction. Skin biopsy showed diffuse necrosis of the epidermis. After admission to the hospital, steroid pulse therapy (1000 mg/day of methylprednisolone sodium succinate) was continued for 5 days. The health drink induced a positive drug lymphocyte stimulation test (DLST) and patch test. A challenge test was done with a one hundredth dose, and it was positive. We did patch tests with all components of the drink and found that Mai-Meu-Dong-Tang (ophiopogonis) alone was positive at 72 hours. There is no previous report of Stevens-Johnson syndrome caused by a health drink or Mai-Meu-Dong-Tang. Even though it is a health drink, we should be aware of the possibility of a severe reaction.     

Comparison between eosinophilic markers in induced sputum and blood in asthmatic patients

BACKGROUND: The usefulness and safety of the analysis of blood inflammatory markers in asthma are widely recognized. Recently, the analysis of induced sputum has been proposed as a safe, non-invasive tool in the study of airway inflammation in asthma. OBJECTIVE: Our aim was to test whether sputum analysis is more useful than blood analysis in the evaluation of airway inflammation in untreated and treated asthmatic patients. METHODS: Twelve untreated patients with mild to moderate asthma underwent a methacholine challenge test, sputum induction and blood sampling. A group of 14 normal subjects was also evaluated for baseline comparison. The same evaluation was repeated after 3 months of budesonide treatment. Before and after treatment, we tested the relationship of eosinophilic markers in induced sputum and blood with clinical and functional data. We also compared eosinophilic markers in induced sputum with the same markers in blood. RESULTS: Untreated patients showed a significant relationship between sputum eosinophils and symptom score, and between sputum eosinophilic cationic protein and symptom score, FEV1 and PD20FEV1. No relationship between blood eosinophilic markers and clinical or functional data was observed. In budesonide-treated patients, both sputum and blood eosinophils were significantly lower than in untreated patients, but eosinophil decrease was greater in sputum than in blood. Sputum eosinophilic proteins were also significantly lower in treated patients, whereas serum eosinophilic proteins were low at baseline and remained unchanged after treatment. Sputum eosinophilic markers were lower in normal subjects than in both untreated and treated patients, while blood eosinophils, but not serum eosinophilic cationic protein, were lower in normals than in untreated patients. CONCLUSIONS: The analysis of induced sputum is more useful than the analysis of blood in the evaluation of asthma severity and of the effect of glucocorticoid treatment in patients with mild to moderate asthma.     

Facilitation of acetylcholine release in rat frontal cortex by indeloxazine hydrochloride: involvement of endogenous serotonin and 5-HT4 receptors

Effects of indeloxazine hydrochloride, an inhibitor of serotonin (5-HT) and norepinephrine (NE) reuptake with a facilitatory effect on 5-HT release, on acetylcholine (ACh) output in frontal cortex of conscious rats were characterized using an in vivo microdialysis technique. Systemic administration of indeloxazine (3 and 10 mg/kg, i.p.) increased ACh and 5-HT output in a dose-dependent manner. Depletion of endogenous monoamines by reserpine and of 5-HT by p-chlorophenylalanine, but not that of catecholamines by alpha-methyl-p-tyrosine, significantly attenuated the facilitatory effect of indeloxazine on ACh release. When applied locally by reverse dialysis, indeloxazine (10 and 30 microM) and the selective 5-HT reuptake inhibitor citalopram (10 microM), but not the NE reuptake inhibitor maprotiline (30 microM), increased cortical ACh output. Indeloxazine (10 mg/kg)-induced increase in ACh release was significantly inhibited by local application of the 5-HT4 receptor antagonists RS23597 (50 microM) and GR113803 (1 microM), while the 5-HT1A antagonist WAY-100135 (100 microM), 5-HT1A/1B/beta-adrenoceptor antagonist (-)propranolol (150 microM), 5-HT2A/2C antagonist ritanserin (10 microM) and 5-HT3 antagonist ondansetron (10 microM) failed to significantly modify this effect. Neither depletion of monoamines nor treatment with serotonergic antagonists significantly changed the basal ACh level, indicating that endogenous monoamines do not tonically activate ACh release. These results suggest that indeloxazine-induced facilitation of ACh release in rat frontal cortex is mediated by endogenous 5-HT and involves at least in part cortical 5-HT4 receptors.     

Healing of Bone Affections and Gangrene with Low-Intensity Laser Irradiation in Diabetic Patients Suffering from Foot Infections

In this study, we investigated the effect of pentoxifylline, an inhibitor of TNF-alpha, on the contact sensitivity response induced by nickel. For induction, open epicutaneous sensitization by NiSO4. 6 H2O (25% aq.) solution was applied on the backs of 38 albino guinea pigs 5 days a week for 4 weeks. NaCl (0.9%) solution was applied epicutaneously to 10 albino guinea pigs as a control group. 19 were sensitized by nickel and developed positive patch test reactions. Patch tests were repeated after 10 of the sensitized pigs were given pentoxifylline 20 mg/kg/day orally. At the end of this study, only 2 positive patch test reactions were observed in the pentoxifylline-treated group, while 7/9 of the untreated guinea pigs developed positive reactions. These results suggest that pentoxifylline inhibits the contact sensitivity response induced by nickel only during drug administration.     

Intravenous desensitization to mechlorethamine in patients with psoriasis

Eight patients with psoriasis who had developed contact allergy to mechlorethamine hydrochloride (nitrogen mustard) were subjected to a regimen of intravenous infusion of small amounts of the drug in an attempt to produce desensitization. Although three of eight developed negative patch tests and were presumed to be desensitized, only one patient was able to use the drug therapeutically, and then only for a period of eight months, after which allergy recurred. The other two patients whose allergic contact dermatitis was abolished by the infusions were unable to use mechlorethamine therapeutically because of pruritus. Seven patients experienced some adverse reaction to the infusion. Intravenous desensitization of psoriatic patients who are allergic to mechlorethamine was not successful enough as a useful clinical procedure to allow them to once again use the drug therapeutically.     

Allergy testing in serious cutaneous drug reactions--harmful or beneficial?

We report on 3 cases of adverse cutaneous drug reactions of erythema multiforme type. Despite the serious previous clinical conditions, patch tests with the possible causative drugs have been performed in all our patients, because of multiple candidate drugs and the need of the patients for further treatment with at least some of the agents. We demonstrate that patch tests are a good and safe approach to initial evaluation of the nature of a cutaneous drug reaction. In the case of a positive patch test reaction to one of the substances, re-exposure to the non-reactants in a clinical setting is recommended. If a one-side-blinded placebo-controlled challenge test is well tolerated, then the clinician should be able to reintroduce drugs previously suspected as causing the allergy.     

Eosinophilic pustular folliculitis (Ofuji's disease) in myelodysplastic syndrome

We describe a case of eosinophilic pustular folliculitis (EPF, Ofuji's disease) in a 12-year-old male who suffered from myelodysplastic syndrome. Bone marrow study revealed an increase in the eosinophil cell line without peripheral blood eosinophilia in our case. We suggest that the immunologic abberations ascribed to myelodysplastic syndrome and the increase in the eosinophil cell line in the bone marrow might play roles in the development of EPF in our case.     

Inhaled vancomycin-induced allergic reaction in decontamination of respiratory tracts for allogeneic bone marrow transplantation

A 34-year-old male suffered from an allergic reaction after inhalation of decontaminating drugs for BMT. Clinical challenge tests were undertaken to determine the causal drug. It was found that vancomycin hydrochloride (VCM) repeatedly induced dyspnea, fever, hypoxia, eosinophilia, and elevation of CRP. Therefore, clindamycin (CLDM) was used instead of VCM for decontamination of patient respiratory tract. Although complete decontamination of the respiratory tract was not achieved during the leukocytopenic period, BMT was successful, and there were no life-threatening infectious complications. Although inhaled VCM-induced allergic reaction may be a very rare complication in the BMT setting, careful clinical attention should be paid to such patients.     

Dopamine agonists prevent or counteract the suppression of brain stimulation reward by fenfluramine

Eighteen male subjects participated in a clinical study to examine a skin patch method of monitoring drug use. On the first day of each of two periods, 14 Band-aid type collection devices (sweat patches) were applied to a subject's torso, biceps, and back. On the following day, the subject took 50 or 126 mg cocaine hydrochloride intranasally. A 1-week interval separated treatment periods, and the order of dose levels was counterbalanced. On the days subjects received cocaine, one patch was removed before treatment, and five were removed after treatment. Subjects then returned over the next 7 days for removal of the remaining patches. They provided urine samples immediately after each patch removal. A group of 18 nondrug users also wore patches for up to 12 days. Analysis of the patch content yielded cocaine levels from the cocaine subjects that accurately reflected usage. Mean levels for 16 subjects were significantly different for the two treatment doses. However, given the between-dose and between-subject variability, the data cannot be used to determine either dose or time of use. The data do indicate, however, that the patch technology can be used to diagnose a single episode of cocaine use as far back as 7 days.     

Photoleukomelanodermatitis (Kobori) induced by afloqualone

We reported a case of photoleukomelanodermatitis (Kobori) type drug eruption due to afloqualone (Arofuto). The patient was given afloqualone and imipramine hydrochloride (Chrytemin) for cervical spondylosis from November of 1990. Edematous erythema with slight itching appeared on the sun-exposed areas in December of 1990. As drug eruption was suspected, drugs were ceased, and the cutaneous lesions almost disappeared but pigmentations and depigmentations developed in spots in sun-exposed areas in March of 1991. Photopatch and oral challenge tests were positive.     

Bronchial reactions to exposure to welding fumes

OBJECTIVES: To study the airway response and its mechanism to welding fumes in six welders with respiratory symptoms. METHODS: Methacholine and welding challenge tests were carried out. The concentration of welding fumes during the exposure test was measured. On two subjects who developed bronchoconstricition to welding challenge, additional tests were carried out including prick, patch, and inhalation challenges with metal salt solutions. RESULTS: Three subjects developed immediate bronchial reaction to exposure to welding fume; one to mild steel and stainless steel welding, another to mild steel and galvanised welding, and one only to galvanised welding. They all had a moderate to pronounced degree of non-specific bronchial hyperresponsiveness. The concentration of fumes during welding tests, particularly to galvanised welding, was high. An inhalation challenge test with zinc chloride salt solution in two subjects who reacted to galvanised welding was negative. Prick and patch tests with zinc chloride were also negative. CONCLUSION: The airway response to welding in these subjects is non-specific and is due to irritation rather than to sensitisation.     

Spectrofluorimetric determination of prenalterol hydrochloride in pharmaceutical preparations and biological fluids

A simple and highly sensitive fluorimetric method was developed for the routine determination of prenalterol hydrochloride in bulk, in dosage forms and in biological fluids. The method is based on the fluorescence induced by reaction of the nitroso-derivative of prenalterol hydrochloride with 2-cyanoacetamide in the presence of ammonia. The different experimental parameters were carefully studied and incorporated into the procedure. The fluorescence is measured at 440 nm after excitation at 368 nm. Fluorescence intensity is a linear function of prenalterol hydrochloride concentration over the range of 0.1-2.8 microg x ml(-1) in the solution finally measured. A proposal for the reaction pathway was suggested.     

Fixed drug eruption due to allylisopropylacetylurea

We report a case of fixed drug eruption due to allylisopropylacetylurea. A 21-year-old female developed purplish-red round eruptions on her neck and left thigh after taking an analgesic containing isopropylantipyrine, allylisopropylacetylurea, phenacetin and anhydrous caffeine. Patch testing with the analgesic and its ingredients on the eruptive area showed positive reactions to the analgesic and allylisopropylacetylurea, while patch testing on the non-eruptive area showed negative reactions. We diagnosed her condition as a fixed drug eruption due to allylisopropylacetylurea in an analgesic.     

Transdermal nitroglycerin: clinical and pharmacokinetic consequences of renewing the patch and the application site

OBJECTIVE: We examined whether nitroglycerin (glyceryl trinitrate, GTN) patch treatment for 24 h could induce local cutaneous changes that impaired drug delivery and clinical efficacy. METHODS: Twenty angina patients were exercise-tested after 2 and 24 h of treatment and then 2 h after patch renewal. The patch was either renewed on a new skin location or on the previous application site in a randomised, double-blind, cross-over protocol. GTN plasma concentrations and finger plethysmography were obtained before and after each exercise test. RESULTS AND CONCLUSIONS: The clinical efficacy, the effect seen on plethysmography and the GTN plasma concentrations tended to increase after patch renewal, regardless of the application site of the renewed patch. Hence, cutaneous changes of clinical importance could not be demonstrated.     

A case of food-dependent exercise-induced anaphylaxis induced by shrimp

The clinical study and in vitro study used with leukocytes were made of a case of food-dependent exercise-induced anaphylaxis induced by shrimp. A 26-year-old man experienced anaphylactic reaction of nasal obstruction, face edema and dyspnea while running 90 minutes after eating shrimp. He experienced similar episodes two years ago in his past history. IgE-RAST was positive for shrimp. Anaphylactic reaction and elevation of plasma histamine levels were verified by exercise challenge test after eating 100 g shrimp. At the same time, we verified the dedine of plasma cAMP levels after eating shrimp. In leukocyte stimulating test used with shrimp antigen, histamine level elevations, which were lower compared with calcium ionophore A23187 (Ca I 10(-6) M) stimulation, were recognized in dose dependent manner in this patient. But in normal subject, histamine level elevations were not recognized. We diagnosed him food-dependent exercise-induced anaphylaxis. It was suggested that there was relation between histamine release and decline of cAMP levels of plasma after eating shrimp in this case.     

Combined analysis of two studies using the conjunctival allergen challenge model to evaluate olopatadine hydrochloride, a new ophthalmic antiallergic agent with dual activity

PURPOSE: To evaluate the effectiveness and safety of olopatadine hydrochloride and to determine its optimal concentration and the onset and duration of action for treating allergic conjunctivitis. Olopatadine is a new topical ophthalmic antiallergic agent that demonstrates activity as both an antihistamine and a mast cell stabilizer. Two double-masked, randomized, placebo-controlled, contralateral eye comparison studies were conducted using the conjunctival allergen challenge model. METHODS: A total of 169 subjects received 0.05% or 0.1% olopatadine. Study subjects were healthy adult men and women with a history of active allergic conjunctivitis within the previous two seasons but not receiving current treatment. With an allergen dose that produced signs and symptoms of allergic conjunctivitis at visits 1 and 2, the conjunctival allergen challenge was performed 27 minutes after study drug administration at the third visit (onset-of-action challenge) and at 8 hours after study drug administration at the fourth visit (duration-of-action challenge). Olopatadine was administered in one eye and placebo in the opposite eye. Itching and redness were scored for both eyes at 3, 10, and 20 minutes after the conjunctival allergen challenge. RESULTS: Both 0.05% and 0.1% concentrations of olopatadine were significantly (P < .05) more effective than placebo in inhibiting itching and redness at all evaluations when administered 27 minutes or 8 hours before the conjunctival allergen challenge. There were no serious or drug-related ocular or nonocular adverse events in either study. CONCLUSION: These findings demonstrate the rapid and prolonged (at least 8 hours) ocular antiallergic action of olopatadine.     

A complex photodermatosis: solar urticaria progressing to polymorphic light eruption

Causative agents of drug eruptions are frequently unknown, and skin tests with candidate drugs would be useful before systemic challenge. It remains to be clarified how phostosentive lichenoid drug eruptions are induced, but allergy, including delayed type allergy, has been suggested. Two patients who had taken anti-tuberculous drugs developed a lichenoid drug eruption, primarily on sun-exposed skin. Patch and photopatch tests were performed with each of the ingested drugs (10% in petrolatum). Photopatch tests to isoniazid (INH) were positive. These were confirmed by oral challenge followed by irradiation with UVA. In conclusion, photopatch tests facilitated identification of the causative drug in two patients with photosensitive lichenoid eruptions to INH.     

Studies on transdermal delivery system of dihydroetorphine hydrochloride

A transdermal delivery system of dihydroetorphine hydrochloride (DHE-TDS) was developed. The DHE-TDS mainly composed of polyvinyl alcohol, polyvinyl pyrrolidone and lactose. Tests on rabbits showed only slight skin irritation according to federal hazardous substances act. By giving DHE-TDS to rabbits, DHE release was shown to be governed by first-order mechanism. When DHE-TDS was given to Wistar rats, a relatively stable blood drug concentration was observed from 4-32 h after drug administration. Writhing tests showed that one dose of DHE-TDS would maintain the narcotic action on rats for at least 48 h.