In vivo and in vitro studies on multidirectional mechanism of anti-allergic activity of budesonide.

Most studies on the effects of glucocorticosteroid therapy in rhinitis relate to their inhibitory effect on activation and the number of inflowing cells that are involved in the development and maintenance of inflammation. It is also very important to determine the range of effect of budesonide on residing cells (epithelial cells). The purpose of this study was to evaluate the effect of local budesonide therapy on the cytological image of the nasal mucosa, with attention paid to columnar cells in patients with rhinitis. The in vivo results obtained were analyzed in correlation with changes in normal CHO-K1 cells exposed to budesonide at concentrations falling within the pharmacological dose range. Fifty patients diagnosed with rhinitis with suspected allergic background without nasal polyps were included in clinical trials. The control group were 10 healthy people without clinical signs of rhinitis. Only in patients with homogeneous cytological picture, exfoliative cytology was performed before treatment and after 4 weeks of therapy with budesonide used in aerosol form. Papanicolaou and Pappenheim - stained smears were evaluated qualitatively and quantitatively for changes in nasal mucosal cells. The nasal mucosal image of the patients before treatment clearly indicated the pathological state confirmed by the presence of numerous neutrophils, eosinophils, abundant bacterial flora and goblet or epithelial cells prevalence. In contrast, in smears of patients post-treatment budesonide observed a clear improvement in their nasal mucosa by reducing inflammation. There was a significant increase in the number of columnar cells and the appearance of very numerous epithelial cells with increased cytoplasmic vacuolization and visible leucophagocytosis. In vitro studies were performed on normal CHO-K1 cells that were treated with budesonide at concentrations of 0.5 µM - 45 µM. After 48 hours of incubation with the test agent, the samples were prepared for optical microscopy using the H&E method and transmission electron microscopy. Comparison of cells exposed to budesonide with control cells (without addition of test agent) revealed vacuolization changes with autophagy. Apoptotic changes have also been demonstrated, which occured to a lesser extent than vacuolization. The changes observed after budesonide treatment in the cytological picture of patients with allergic rhinitis indicate the therapeutic effect of this drug. On the other hand, the changes observed in the cytoplasm of epithelial cells, such as autophagy (clearly promoted in CHO-K1 cells) and leucophagocytosis, may indicate an additional mechanism of action for budesonide.

Cytological assessment of the epithelial cells of the nasal mucous membrane after local fluticasone therapy.

The majority of cytological studies concern the influence of glucocorticosteroids on cells involved in creating and sustaining inflammation, such as eosinophils or neutrophils. Much less attention is devoted to epithelial cells. It should also be noticed that glucocorticosteroid drugs administered nasally for local action can significantly change the cytological image of the nasal mucous membrane. Therefore, the purpose of this research was to cytologically assess the influence of topical fluticasone therapy on the nasal mucous membrane cells, with special attention for the changes in the morphology of epithelial cells. The research samples were taken from patients with symptoms of chronic rhinitis and suspected allergies. The research was a two-step process. In the first step, a smear was taken from the surface of the nasal mucous membrane of the above-mentioned patients before the start of therapy and the obtained cytological image was compared with a control image of the nasal mucous of healthy people. Step two involved the cytology of the same patients after 4 weeks of fluticasone therapy, applied as a nasal aerosol in two doses of 50 µg to each nostril once per day, in the combined daily dose of 200 µg (for adults and children aged 12 or more). Children aged between 4 and 12 were given a single dose of 50 µg to each nostril once per day, in a daily dose of 100 µg. Based on smears stained according to the Papanicolaou and Pappenheim method, a qualitative and quantitative analysis of changes in the mucous membrane of nasal cells was performed. The cytological assessment of nasal mucous membrane stains of patients with chronic rhinitis before fluticasone treatment enabled a diagnosis of chronic infectious rhinitis, compared through the presence of numerous neutrophils and bacteria. The studied samples did not show significant changes in the morphology of epithelial cells, only a few cells with mild vacuolation changes of the cytoplasm were found. The use of fluticasone, however, caused a significant decrease in the neutrophilia and the appearance of numerous epithelial cells with intensified cytoplasm vacuolation in the sample. The results obtained allow us to conclude that standard fluticasone therapy as administered nasally in aerosol form to patients with diagnosed nonallergic nasal mucous membrane inflammation caused a significant reduction in the inflammation without showing cytological characteristics of damage to the epithelium of the nasal mucous membrane. The intensified vacuolation observed in the cytoplasm of epithelial cells, most prominently in the columnar cells, might suggest the stimulation of autophagic processes.

Myasthenia gravis, pernicious anemia, and Hashimoto's thyroiditis.

A 68-year-old woman with clinical, electromyographic, and pharmacologic evidence of myasthenia gravis experienced increasing proximal and bulbar muscular weakness. The diagnosis of pernicious anemia was established by typical abnormalities in the peripheral blood and bone marrow aspirate, the serum B12 level, by results of the Schilling test, and by the presence of serum parietal cell antibody. The diagnosis of Hashimoto's thyroiditis was established by the presence of diffuse thyroid enlargement, microsomal thyroid antibodies, an increased thyroid stimulating hormone level, and depressed T2 and T4 levels.

Comparison of verapamil, diltiazem, and labetalol on the bioavailability and metabolism of imipramine.

Twelve healthy male subjects completed this randomized, placebo controlled, four-period crossover trial to determine the effect of verapamil, diltiazem, and labetalol on the bioavailability and metabolism of imipramine. Subjects received a 7-day course of one of four treatments; verapamil (120 mg every 8 hr), diltiazem (90 mg every 8 hr), labetalol (200 mg every 12 hr), or placebo (every 12 hr) during each study period. Imipramine (100 mg) was administered orally on the morning of day 4 of each study period. Plasma and urine samples were collected periodically over the ensuing 96 hours. Samples were assayed by HPLC for imipramine, desipramine, 2-hydroxyimipramine, and 2-hydroxydesipramine. Verapamil, diltiazem, and labetalol increased imipramine area under the plasma concentration time curve (relative bioavailability) as compared with placebo by 15%, 30%, and 53%, respectively. Verapamil and diltiazem did not demonstrate consistent changes in the formation of the measured metabolites. Labetalol caused a significant decrease in the amount of imipramine metabolized to 2-hydroxyimipramine (mean decrease: 22%) and from desipramine to 2-hydroxydesipramine (mean decrease: 8%). The molar ratios of plasma AUC of 2-hydroxyimipramine and 2-hydroxydesipramine to the parent compounds were significantly decreased. Since these metabolic processes are dependent on the cytochrome P450IID6 isozyme, these data suggest that labetalol decreases the oral clearance of imipramine by inhibiting this system. All three of these commonly used agents decreased the oral clearance of imipramine. These drug interactions could lead to elevated imipramine concentrations and have the potential for clinically important adverse events.

Hairy cell leukemia and a fatal periarteritis nodosa-like syndrome.

We studied a patient with hairy cell leukemia (HCL) in whom periarteritislike lesions of multiple medium-sized arteries developed. There were many aneurysms distributed through the visceral organs. One ruptured into the abdomen, causing death. A previous study suggested that HCL may predispose to periarteritis nodosa, but recently a reversed temporal sequence of vasculitis and HCL was postulated. Our patient's course lends further support to the concept that HCL predisposes to vasculitis and periarteritislike lesions.

The insulin, glucose and cholesterol level and activity of lysosomal enzymes in the course of the model alloxan diabetes.

OBJECTIVES: The study was carried out on fifty male rabbits of the New Zealand White breed. Diabetes was caused by a single, intravenous alloxan injection. Rabbits which had glycaemia 7th day after the alloxan administration higher than 11 millimol/litre were selected for the studies. They were divided into 5 groups: I - control (without diabetes); II - 3-week diabetes; III - 6-week diabetes; IV - 3-month diabetes; V - 6-month diabetes. METHODS: In control and experimental rabbits the activity of beta-glucuronidase, N-acetyl-beta-glucosaminidase, lysosomal acid phosphatase, leucine aminopeptidase, cathepsin D, and lysosomal arylesterase was determined in lysosomal fractions of the liver and kidney. RESULTS: Alloxan caused lowering of the activity of all the investigated enzymes in the kidney and liver except lysosomal arylesterase. CONCLUSION: Alloxan injection caused a significant increase in the activity of all the investigated enzymes. The advisable lysosomal enzymes may be useful for the monitoring of the course and effectiveness of diabetes therapy.

[Analysis of chrono-inotropy of the myocardium in poikilothermic animals]. / K analizu khrono-inotropii miokarda poikilotermykh zhivotnykh.

Chrono-ionotropic interrelationships were studied in isolated strips of the myocardium of poikilothermous animals (frogs and fishes) in conditions of either stationary or transitional regimens of stimulation. In the stationary regimen, the rhythm-strength relation is simple and corresponds to a parabolic curve. While changing the lesser frequency of stimulation for greater one, both the positive and negative transitional abbreviating stirs were observed, in contrast to literature references. The phenomena of positive and negative transitional stairs were concluded to be unrelated to species while being a general biological form of the myocardium response to change of the stimulation rhythm.

[Effect of the rest interval on the contractile activity of the myocardium]. / Vliianie intervala pokoia na sokratitel'nuiu aktivnost' miokarda.

Isolated strips of the heart auricles and ventricles of frogs at high stimulation frequencies revealed rest potentiation which depended both on the stimulation rhythm and on the duration of rest interval. Amphibians as well as warm-blooded animals and fish seem to display a possibility of Ca++ entering a cell during the period of rest via non-electrogenic calcium canals, but in amphibians this mechanism of the myocardium activation is compansatory, rather.

[The "staircase" phenomenon in the myocardial activity of fishes and amphibians]. / O fenomene "lestnitsy" v deiatel'nosti miokarda ryb i amfibii.

Studies have been made on chrono- and inotropic effects in the heart of the frog Rana temporaria and fishes Silurus glanis and Cyprinus carpio during stationary and transitional stimulation. In contrast to data in the literature, no interspecific differences were found in changes of the amplitude of cardiac contractions induced by changes in rhythmic stimulation.

Activity of lysosomal system in mouse liver after taxol administration.

1. The effect of taxol on selected lysosomal enzymes (cathepsin D, lysosomal lipase, beta-glucuronidase, beta-glucosidase, alanine aminopeptidase) in mouse hepatocytes after 24-hr treatment by increasing doses (0.75 mg/kg bw, 1.25 mg/kg bw and 2.5 mg/kg bw) was studied. 2. The segments were also taken from the mice for ultrastructural studies with the use of electron microscopy. The greatest changes in activity of enzymes at the taxol dose of 2.5 mg/kg bw were as follows: the activity of cathepsin D increased by 71%, that of alanine aminopeptidase increased by 103%, that of beta-glucuronidase decreased by 45% and that of beta-glucosidase decreased by 63%. 3. The significant changes observed in the hepatocyte ultrastructure were closely correlated with biochemical changes that were dependent on the taxol dosage.

Remission in a patient with Menetrier's disease: spontaneous or induced by treatment?

Remission in a patient with Menetrier's disease occurred 2 months after presentation with anasarca and marked hypoproteinemia. As such spontaneous remission of Menetrier's disease is unusual, we have analyzed our patient and the only five previously reported cases we could find. In our patient, conservative therapy, depriving the gastrointestinal tract of food, institution of parenteral alimentation, and suppression of gastric secretion appeared to be associated with remission. Such an approach should be tried in other patients with Menetrier's disease.

Bronchogenic carcinoma and diabetes insipidus: case report and review.

Tumor metastasis to the posterior pituitary-hypothalamic area rarely is expressed by either clinical or radiographic evidence. A case is reported of widespread metastic ACTH secreting bronchogenic carcinoma presenting to the clinician as diabetes insipidus. This type of tumor associated with diabetes insipidus is apparently rare, as is antemortem radiographic documentation of metastasis to the pituitary--hypothalamic region. A review of the ten-year experience of Loyola University Medical Center and Hines VA Hospital with the association of bronchogenic carcinoma and diabetes insipidus is presented with a brief review of metastic disease to the pituitary.

Brachial plexus neuritis and fatal hemorrhage following Aspergillus infection of a Hickman catheter.

A patient with relapse of acute granulocytic leukemia developed an Aspergillus infection along the subcutaneous tract of a silicone rubber indwelling central venous catheter. The infection invaded the brachial plexus resulting in paralysis of the right upper extremity and subsequently invaded a major artery of the arm resulting in the demise of the patient. Both an infectious brachial plexus neuritis and fatal hemorrhage secondary to a Hickman catheter are apparently rare.

Activity of some lysosomal enzymes in plasma and leucocytes of rabbits exposed to effect of retinol and hydrocortisone.

Observing activity of some lysosomal enzymes in blood serum and leucocytes of rabbits subjected to injection of 200,000 units of retinol and 25 mg of hydrocortisone/kg of body weight it was found that: 1. In the effect of retinol administration there was an increase in the activity AP, BGAL, BGLU, AspAT and lipase in blood serum after 72 hours and NAGL after 168 hours while in leucocytes BGAL and NAGL after 72 hours and AGAL after 168 hours. 2. As a result of hydrocortisone injection the activity of all the enzymes examined (except Ala-Na) in blood serum increased markedly already after 24-48 hours. 3. In leucocytes hydrocortisone caused a significant increase in the activity of AP, BGRD, NAGL, BGAL, AGAL and cathepsin D. 4. The glucose level in blood plasma decreased after 48 hours and 120 hours after hydrocortisone injection and 168 hours after retinol injection.