Effect of Cimetidine and other antihistaminics on the elimination of aminopyrine,phenacetin and caffein

Cimetidine is widely prescribed for the treatment of peptic ulcer disease and has recently been shown to inhibit the metabolism of warfarin, antipyrine and diazepam. To further examine this phenomenon we investigated the effect of various doses of cimetidine and other related drugs on ¹⁴C-aminopyrine, ¹⁴C-phenacetin and ¹⁴C-caffeine breath tests. Cimetidine caused a dose-related inhibition of the metabolism of aminopyrine and caffeine but had no effect on the phenacetin breath test. Metiamide, H₁-antihistamines, phenothiazines and local anesthetics also inhibited the aminopyrine breath test. Cyproheptadine had no effect on either phenacetin or caffeine elimination. This study demonstrates a complex drug-drug interaction which may have widespread clinical implications.     

Immunity to Epstein-Barr virus in Hodgkin's disease preceded by infectious mononucleosis

A patient who developed Hodgkin''s disease four years after infectious mononucleosis had elevated serum antibody titres to Epstein-Barr virus and delayed hypersensitivity reactions to membrane antigens prepared from fresh autologous spleen, from spleen cells of another Hodgkin''s patient, and from cell lines known to carry the Epstein-Barr virus genome. Additional studies in more lymphoma patients will be needed to determine the significance of the reactivity against tumour and virus-associated antigens which has been documented in this patient.     

Sex steroids and 5-en-3 beta-hydroxysteroids in specific regions of the human brain and cranial nerves

Sex steroids and 5-en-3 beta-hydroxysteroids were determined by radioimmunoassay in specific regions of the human brain, in the anterior and posterior pituitary, in one sensory organ, the retina and in the cranial nerves. Progesterone, androstenedione, testosterone and estrone were found in all areas of the brain and in all the cranial nerves but not in all cases. There was no sex difference except in the case of androstenedione where values were higher in women in some brain areas. Estrone values were always higher than those of estradiol in both men and women. No 5 alpha-dihydrotestosterone was detected in any of the samples studied. The values for pregnenolone, dehydroepiandrosterone and their sulfates were much higher than those of the sex steroids in all areas of the brain and in all the cranial nerves. Values for pregnenolone were greater than those of its sulfate while those of dehydroepiandrosterone were in general equal to or higher than those of its sulfate. The values for pregnenolone were greater than those of dehydroepiandrosterone. There were no obvious regional differences in the concentrations of the 5-en-3 beta-hydroxysteroids either in specific areas of the brain or in the cranial nerves. But there was a definite trend for the free dehydroepiandrosterone values to be higher in women. The possible significance of these observations is discussed.     

Luteal phase variations in endogenous concentrations of prosta-glandins PGE and PGF and in the capacity for their in vitro formation in the human corpus luteum

One evidence for a luteolytic role for prostaglandin F₂α in the human is the increase in luteal PGF at times corresponding to luteolysis as reported earlier by us and other groups. There have been other contradictory reports on this point. In the present experiments we have measured the concentrations of PGE and PGF in 16 more human corpora lutea and have determined the capacity of those tissues to form PGE and PGF in vitro. PGF concentrations were highest in the mid luteal phase but were accompanied by high PGE concentrations. On the other hand, in the late luteal phase PGF concentrations, lower than in mid luteal but generally higher than in early luteal phase, were significantly higher than PGE concentrations. This pattern in PGE and PGF concentrations was also evident in the capacity of these tissues to form these compounds in vitro. In view of the known capacity of PGE₂ to counteract the luteolytic effect of PGF₂α, these variations in the relative concentrations of PGE and PGF during the luteal phase may be of significance in the process of luteolysis in the human.     

The role of the conjugated carbonyl of cytochalasin A in contractility inhibitions

A study of the mechanism of action of cytochalasin A (CA) in relation to its structural features and to its selective inhibition of certain contractile processes has been initiated. Quantitative structure-function analyses with several CA-related cytochalasins — including synthetic 21, 22-dihydro-CA (DHCA), the 22-β-mercaptoethanol CA-adduct, (CA-2ME), and the 22-dithiothreitol CA-adduct (CA-DTT) — have been carried out in a temperature sensitive gel-sol extract from Ehrlich ascites tumor cells. Each drug congener was purified to homogeneity by HPLC prior to biological testing. The undiminished inhibitory indices of DHCA and CA-2ME $\text{(}\text{ID}{}_{\mathrm{5\; 0}}\text{? 3.7 × 10}{}^{\mathrm{?7}}\text{M}\text{)}$ overrules the prior circumstantial evidence accumulated for the obligatory electrophilic interaction of this drug, at its α-β-unsaturated ketone region, with presumptive receptor nucleophiles.     

Lipofuscin like compound in mango

Thin layer chromatographic separation of chloroform-methanol extracts of mango on silica gel revealed a fluorescent substance in mango peel and pulp. The compound had fluorescence spectrum similar to that of lipofuscin, the age pigment of animal tissues and was found to be water insoluble and stable to ultraviolet irradiation. The fluorescent material appeared to be a lipoprotein.     

Dissociation of intracellular lysosomal rupture from the cell death caused by silica

The relationship between intracellular lysosomal rupture and cell death caused by silica was studied in P388d(1) macrophages. After 3 h of exposure to 150 μg silica in medium containing 1.8 mM Ca(2+), 60 percent of the cells were unable to exclude trypan blue. In the absence of extracellular Ca(2+), however, all of the cells remained viable. Phagocytosis of silica particles occurred to the same extent in the presence or absence of Ca(2+). The percentage of P388D(1) cells killed by silica depended on the dose and the concentration of Ca(2+) in the medium. Intracellular lyosomal rupture after exposure to silica was measured by acridine orange fluorescence or histochemical assay of horseradish peroxidase. With either assay, 60 percent of the cells exposed to 150 μg silica for 3 h in the presence of Ca(2+) showed intracellular lysosomal rupture, was not associated with measureable degradation of total DNA, RNA, protein, or phospholipids or accelerated turnover of exogenous horseradish peroxidase. Pretreatment with promethazine (20 μg/ml) protected 80 percent of P388D(1) macrophages against silica toxicity although lysosomal rupture occurred in 60-70 percent of the cells. Intracellular lysosomal rupture was prevented in 80 percent of the cells by pretreatment with indomethacin (5 x 10(-5)M), yet 40-50 percent of the cells died after 3 h of exposure to 150 μg silica in 1.8 mM extracellular Ca(2+). The calcium ionophore A23187 also caused intracellular lysosomal rupture in 90-98 percent of the cells treated for 1 h in either the presence or absence of extracellular Ca(2+). With the addition of 1.8 mM Ca(2+), 80 percent of the cells was killed after 3 h, whereas all of the cells remained viable in the absence of Ca(2+). These experiments suggest that intracellular lysosomal rupture is not causally related to the cell death cause by silica or {"type":"entrez-nucleotide","attrs":{"text":"A23187","term_id":"833253","term_text":"A23187"}}A23187. Cell death is dependent on extracellular Ca(2+) and may be mediated by an influx of these ions across the plasma membrane permeability barrier damaged directly by exposure to these toxins.