Selective inhibition of the a form of monoamine oxidase by 4-dimethylamino-α-methylphenylalkylamine derivatives in the rat

The inhibitory effects on monoamine oxidase (MAO) of some dimethylamino-α-phenylalkylamine derivatives were examined in a rat brain mitochondrial preparation in vitro and in rat brain slices following oral administration. In the in vitro assay the compounds were shown to be selective inhibitors of the A form of MAO, being 100–600 limes more potent in inhibiting the deamination of [¹⁴C]5-hydroxytryptamine than that of [¹⁴C]phenetylamine. Using an ex vivo brain slice technique it was found that the new compounds were reversible and very selective inhibitors of type A MAO in the rat brain and the most potent compounds (FLA 405, 314, 336 and 558) were equipotent with clorgyline. The compounds increased the monoamine concentrations in whole rat brain, particularly that of 5-hydroxytryptamine, in the same dose range which produced MAO inhibition. Some of the new compounds, e.g. FLA 336 and FLA 717, caused only weak potentiation of the vaso-pressor effect of orally administered tyramine.     

Attachment styles,traumatic events,and PTSD: a cross-sectional investigation of adult attachment and trauma

The aim of the present study was to examine the association between post-traumatic stress disorder (PTSD) and adult attachment in a young adult population. A sample of 328 Danish students (mean age 29.2 years) from four different schools of intermediate education level were studied by the Harvard Trauma Questionnaire (HTQ), the Revised Adult Attachment Scale (RAAS), the Trauma Symptom Checklist (TSC), the Crisis Support Scale (CSS), the Coping Style Questionnaire (CSQ), and the World Assumption Scale (WAS). Attachment styles were associated with number of PTSD symptoms, negative affectivity, somatization, emotional coping, attributions, and social support. The distribution of attachment styles in relation to PTSD symptoms could be conceived as uni-dimensional.     

Synergistic antileukemic effect of two polyamine synthesis inhibitors. Host survival and cell-cycle kinetic analysis

alpha-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, was used alone and in combination with multiple doses of methylglyoxal-bis(guanylhydrazone) (MGBG) to treat mice with systemic L1210 leukemia. Used as a single agent (administered p.o. as a 3% solution in tap water), DFMO exerted a weak therapeutic effect against this tumor. The therapeutic effect of MGBG (administered i.p. at 50 mg/kg/day) was only slightly better. However, 1-3 days of pretreatment with DFMO strongly potentiated the effect of MGBG treatment. Thus, mice treated with the combination exhibited an increase in life span of up to 138%. The prolonged survival of leukemic mice treated with a combination of DFMO and MGBG was associated with inhibition of polyamine synthesis and a marked decrease in the spermidine and spermine content of the tumor cells as compared to untreated controls. As a consequence, there was a continuous decrease in the S- and G2-phase fractions with a concomitant increase in G1. Used singly, DFMO and MGBG had no significant effect on the cell-cycle distribution. The effects of the combination of DFMO and MGBG on the cell-cycle distribution are consistent with the contention that polyamine deficiency primarily interferes with initiation of DNA synthesis. However, the possibility that selective S-phase kill partly contributes to this change in cell-cycle distribution cannot be excluded.     

Three-dimensional computed tomography imaging in an animal model of emphysema.

Emphysema is a major health problem and novel drugs are needed. Animal disease models are pivotal in their development, but the validity and sensitivity of current tools for the evaluation of drug efficacy is limited. The usefulness of micro computed tomography (CT) as an innovative tool to assess emphysema in a mouse model was investigated. Serial CT scans were performed in bi-weekly intervals in Smad3 knockout (KO) mice, which spontaneously develop airspace enlargement. Lung density was quantified in two- and three-dimensional images and correlated to mean linear intercept and lung compliance. CT scans of Smad3 KO lungs revealed a significant decrease in lung density at age 8 weeks and a further progression at age 14 weeks with respect to age-matched wild-type (WT) animals. Emphysema could be reliably assessed with both the two- and three-dimensional approach, but the three-dimensional approach was superior, due to normalisation to lung volumes and less variability. Lung compliance by week 14 was 0.053+/-0.005 and 0.034+/-0.002% of maximum volume.cmH(2)O(-1) for KO and WT mice, respectively, reflecting significant physiologically relevant emphysema. Small animal computed tomography imaging and density quantification in a reconstructed three-dimensional image is a useful tool for quantifying emphysematous changes in an animal disease model. It adds significant information to conventional assessment.     

Effects of acute and repeated administration of amiflamine on monoamine oxidase inhibition in the rat

The inhibitory effect on monoamine oxidase (MAO) of the reversible MAO-A inhibitor (+)-4-dimethylamino-2,alpha-dimethylphenethylamine [amiflamine, FLA 336(+)] was evaluated in the rat after acute and repeated (twice daily for two weeks) oral treatment. MAO activity was measured ex vivo in slices from the hypothalamus and the duodenum for both MAO-A and MAO-B. Amiflamine selectively inhibited the A form of MAO after repeated as well as after acute treatment (ED50 approximately 7 mumoles/kg both acute and repeated). In the brain slices this inhibition corresponded to a decrease in the concentration of 5-hydroxyindoleacetic acid (5-HIAA) and to an increase in the concentration of 5-HT in the hypothalamus, the hippocampus and the striatum. The concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) was decreased in the striatum to the same extent as the decrease in the 5-HIAA concentrations. The effect on the homovanillic acid (HVA) concentration was somewhat weaker as was the increase in the concentration of dopamine. No essential difference was found after acute and chronic treatment on the amine and metabolite levels. The MAO activity returned to normal 24 hours after final dosing. A large difference between the neuronal and the extraneuronal protection against the phenelzine-induced irreversible MAO inhibition in the hypothalamus was found after both acute and repeated treatment. The ED50 of the protection within the serotonergic neurons was 1.3 mumoles/kg p.o. (acute) and 0.75 mumoles/kg p.o. (repeated). Amiflamine was 3 times less potent within noradrenergic neurons than within serotonergic neurons. A brain to plasma ratio of about 20:1 was found for amiflamine and its metabolites. The plasma and the brain concentrations of the N-demethylated metabolite [FLA 788(+)] exceeded that of amiflamine after a single dose, whereas the N,N-demethylated [FLA 668(+)] was found in low concentrations. The effect on MAO-A correlated significantly with the plasma and the brain concentration of FLA 788(+).