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The Isakower phenomenon is a situation in which an individual typically experiences perceptions of enlargement or thickening, altered states of consciousness, sensations of floating, and impressions of the emergence and disappearance of an oral mass. This paper defines the phenomenon, reviews the literature, and describes a case in which a patient experienced it. The patient manifested the phenomenon symptomatically in the aftermath of a toxic state, and the elements were analysed for several years. There was support for Isakower's original thesis that the regressive states serve to defend against threatening incestuous fantasies. However, the Isakower phenomenon in this patient was the result of a multiplicity of determinants, largely defensive, involving many developmental levels.

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The influence of the alpha-receptor agonist oxymetazoline, the antihistaminics mepyramine and cimetidine and of cromoglicic acid disodium salt (disodium cromoglycate, DSCG) on the hypotension produced by the trypanocidal diamidines pentamidine, diamidinophenylindole (DAPI) and diimidazolinophenylindole (DIPI) was investigated. 75-100 nmol/kg oxymetazoline were effective only in DAPI-treated animals and diminished the drop of the systolic blood pressure by 25-49%. Pretreatment with DSCG was ineffective in all groups under the conditions used. Preapplication of a combination of 5 mumol/kg mepyramine and 10 mumol/kg cimetidine was effective only in pentamidine-treated animals and reduced the drop of the systolic pressure by 57%.

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A method is reported for the determination of the fluorescent, antileukemic diimidazolinyl compounds 261/96(1). 253/152(2) and 272/131(3) in plasma. HPLC is performed on a RP-2 10 microns column with a mobile phase of methanol/water (1:1, v/v), to which 0.005 mol/l octanesulfonic acid sodium and 0.003 mol/l dimethyloctylamine are added. Samples are prepared by precipitation of plasma proteins with a mixture of methanol-70% perchloric acid. The assay is linear up to 750 ng/ml for all compounds with limits of determination of 4 ng/ml, 2 ng/ml and 0.5 ng/ml for compounds 1, 2 and 3, respectively. Coefficients of variation are below 10 percent at all concentrations studied.

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The histamine levels in rat plasma treated with various new trypanocidal diamidines and diimidazolines were evaluated by HPLC and fluorometric detection. Equimolar doses (10 mumol/kg) of the new compounds raised the plasma histamine level to a much smaller degree than pentamidine or diminazene.

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A series of trypanocidal diamidines and diimidazolines known to cause severe hypotension were tested for their alpha-adrenoceptor blocking properties in vitro. At the postsynaptic alpha 1-receptor of the guinea-pig aorta in vitro all compounds at doses of 0.5 to 50 mumol/l showed weak antagonistic effects against noradrenaline. Similar results were obtained at the presynaptic alpha 2-receptor of the rat vas deferens.

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The fluorescent diamidines (E)-2,2'-vinylenedi-1-benzo [b] furane-5-carboxamidine dihydrochloride (I) and 2-[2-(6-amidinoindole-2-yl)-(E)-vinyl]-1-benzofurane-5-ca rbo xamidine dihydrochloride (II) were determined in the plasma of experimental animals by high-performance liquid chromatography with a mobile phase of methanol-water (60:40, v/v) containing 0.005 M octanesulphonic acid and 0.003 M dimethyloctylamine. Samples were prepared by precipitation of plasma proteins with methanol-perchloric acid. Quantitation was performed by measuring the peak heights after monitoring the native fluorescence. The assay was linear over the range 5-750 ng/ml for I and 5-500 ng/ml for II, with limits of determination of 2.5 ng/ml for I and 1.5 ng/ml for II. Coefficients of variation were below 10% at all concentrations studied.

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The fluorescent trypanocidal diamidines 2-(4-amidinophenyl)indole-6-carboxamidine dihydrochloride (I, DAPI), 2-(4-amidinophenyl)benzo[b]thiophene-6-carboxamidine dihydrochloride (II) and 2-(4-amidinophenyl)-1-benzofurane-5-carboxamidine dihydrochloride (III) were determined in plasma, urine, faeces and tissues of experimental animals using quantitative thin-layer chromatography. Samples were extracted with n-octanol after addition of sodium hydroxide and subsequently re-extracted into 0.1 M hydrochloric acid. Chromatography was performed on silica gel plates under nitrogen with n-butanol saturated with 2 M hydrochloric acid. Quantitation was performed by measuring native fluorescence using a fluorodensitometer. The respective diamidines were used as internal standards for each other to ensure precision (coefficient of variation less than 7%) and accuracy of the assay. Calibration curves were linear up to 150 ng/ml of sample solution with detection limits of 10 ng/ml of sample solution for I and III and 50 ng/ml for II. The described method has been successfully used for pharmacokinetic studies in experimental animals.

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Earlier studies showed that Nuclear Yellow (NY), True Blue (TB) and Fast Blue (FB) are transported retrogradely through axons to their parent cell bodies. NY produces a yellow fluorescent labeling of the neuronal nucleus at 360 nm excitation wavelength, while TB and FB produce a blue fluorescence of the cytoplasm at this same wavelength. Therefore, NY may be combined with TB or FB in double-labeling experiments demonstrating the existence of axon collaterals. However, retrograde neuronal labeling with TB or FB requires a relatively long survival time, while NY requires a short survival time since NY migrates rapidly out of the retrogradely labeled neurons. This complicates double-labeling experiments since TB and FB must be injected first and NY later, a short time before the animal is sacrificed. We report a new yellow fluorescent tracer which labels mainly the nucleus and migrates much more slowly out of the retrogradely labeled neurons than NY. This new tracer can be used instead of NY in combination with TB or FB in double-labeling experiments and unlike NY can be injected at the same time as TB or FB. The new tracer is a diamidino compound (no. 28826) which is commercially available. It will be referred to as Diamidino Yellow Dihydrochloride (DY . 2HCl). According to the present study DY . 2HCl is transported over long distances in rat and cat, and produces a yellow fluorescence of the neuronal nucleus at 360 nm excitation wavelength, resembling that obtained with NY. When combined with TB or FB, DY . 2HCl is as effective as NY in double labeling of neurons by way of divergent axon collaterals.

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Thirteen serine proteinase inhibitors of the guanidine, monoamidine and diamidine type were tested for their ability to inhibit the proteinase acrosin present in the acrosome of ejaculated and capacitated boar spermatozoa. All compounds studied proved to be potent in-vitro inhibitors of acrosin. Inhibition constants (Ki) in the range of 1.2 x 10(-7) to 6 x 10(-8) M were found for the reversible inhibitors. The intra-acrosomal inhibition of acrosin was assessed by the gelatin substrate film method: 2 guanidinobenzoates, one monoamidine and one diamidine derivative proved to inhibit acrosin completely in intact spermatozoa. Intravenous injection of 6-amidino-2-(4-amidinophenyl)-indole had no effect on fertilization, but application of 4-nitrophenyl-4-guanidinobenzoate in a vaginal suppository gave a 50% reduction of fertilization.

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A series of 96 diarylamidine (and diarylimidazoline) derivatives were evaluated for their inhibitory effects on the growth and DNA synthesis of murine leukemia L1210 cells. The amidino- and imidazolino-substituted aryl moieties of the compounds consisted of phenyl, indole, indene, benzofuran, benzo[b]thiophene or benzimidazole. Several of these compounds were found to inhibit L1210 cell proliferation with an ID50 (50% inhibitory dose) of 1 microgram/ml or lower. Structure-function analysis revealed that the antitumor cell activity of the diarylamidines depended on the planarity of the molecule, the presence of amidino- (or, preferably, imidazolino-) groups on both aryl moieties, the nature of the bridge connecting the two aryl moieties (preferably no bridge at all, phenoxy or ethene) and, finally, the nature of the aryl moieties (preferably, benzofuran or benzo[b]thiophene). Hence, compound 20 (6-(2-imidazolin-2-yl)-2-[4-(2-imidazolin-2-yl)phenyl] benzo[b]thiophene) emerged as the most potent inhibitor of L1210 cell growth (ID50: 0.21 micrograms/ml). Its inhibitory potency was similar to that of the well-known trypanocidal drug ethidium bromide (compound 98). For all diarylamidine derivatives taken together, some correlation (r = 0.612) was noted between the log ID50 for L1210 cell proliferation and the log ID50 for L1210 cell DNA synthesis (as monitored by [methyl-3H]dThd incorporation). These findings suggest that the inhibitory effects of the diarylamidines on L1210 cell proliferation may at least partially reside in an inhibition of DNA synthesis. Compound 41 (2,2'-vinylenedi-1-benzofuran-5-carboxamidine), that exhibited a potent antitumor activity in vitro (ID50: 1.5 micrograms/ml), was further evaluated for its antitumor efficacy in vivo and found to increase the median survival time of L1210 cell-inoculated BDF1 mice up to 204%, if administered at a dose of 200 mg/kg.

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Antimalarial 6-aminoquinolines (1a-c) were acylated (3a-c, 5a) and alkylated (4a-c, 6a) at the secondary aromatic 6-amino group with the aim of studying the influence of a tertiary aromatic 6-amino group on antimalarial activity and toxicity. 4 derivatives (9e-g) of 4-amino-7-chloroquinoline with a tertiary aromatic 4-amino group were synthesized to study the influence of such a variation on the biological activity of the 4-aminoquinolines. The N-alkylated derivatives 4a-c, 6a, 9f-g were active against malaria (P. vinckei/mice).

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3 derivatives 2g--i of 6-(4-diethylamino-1-methylbutylamino)-4-methoxy-2-methylquinoline and 6 derivatives 2k--p of 6-(4-diethylamino-1-methylbutylamino)-2,4-dimethylquinoline were synthesized with variations of substituents in positions 5 and 8 (--H, --OH, --OCH3, --CH3, --Cl) with the aim of studying the influence of these substituents, which facilitate, complicate or prevent oxidation to o- and (or) p-quinones, on antimalarial activity and toxicity. One methoxy group is necessary for activity against Plasmodium vinckei in position 5 or 8, no substituent that prevents oxidation is allowed in para position to this methoxy group.

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13 analogues 3c-p of 6-(4-diethylamino-1-methylbutylamino)-5,8-dimethoxy-2-methylquinoline (2a) and 6-(4-diethylamino-1-methylbutylamino)-5,8-dimethoxy-2,4-dimethylquinoline (2b) were synthesized with variations of alkoxysubstituents (-O-n-C4H9, -O-n-C8H17, -O CH(CH3)2, -O(CH2)2OCH3, -O(CH2-CH2O)2CH3, -O(CH2)2N(C2H5)2) in positions 5 and(or) 8 with the aim of studying the influence on antimalarial activity and toxicity. All derivatives were active against P, vinckei (mouse).

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The utility of a newly synthesized chemical variation of DAPI (4'-6-diamidino-2-phenyl-indole), D 287/170, for differential staining of constitutive heterochromatin in man is demonstrated. Direct staining of human chromosomes with D 287/170 results in brilliant fluorescence of the paracentromeric C-band of chromosome 9, of a proximal short-arm segment of chromosome 15, and of certain heterochromatic regions in the Y. Bright, but less conspicuous fluorescence is occasionally seen at the centromeres of other chromosomes. The staining differentiation obtained by D 287/170 is very distinct, and the intensity of the fluorescent light is unusually high. The new fluorochrome should prove particularly useful for detecting and analyzing human chromosome 9 heterochromatin at various stages of the cell cycle in normal and structurally altered chromosomes.

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The antifungal and antibacterial properties of a series of 70 diarylamidine derivatives were evaluated. Several of these compounds exhibited considerable antimicrobial potency. A survey of the structure-activity relationship demonstrated that minor structural variations resulted in significant changes of antimicrobial activity. In general, the structural features required for antifungal activity coincided with those required for antibacterial activity. Both the antifungal and the antibacterial properties of the diarylamidines depended on the presence and the positions, of both amidino groups, on the nature of the central bridge connecting the two aryl moieties, and on the nature of these aryl residues (preferably indole). The most active compound was evaluated for its activity against Candida albicans infection in mice.

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Two new fluorescent retrograde neuronal tracers are reported: Nuclear Yellow (Hoechst S 769121), which mainly labels the neuronal nucleus; and Fast Blue (diamidino compound 253/50), which mainly labels the neuronal cytoplasm. Both tracers appear to be transported effectively over long distances in rat and cat.

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Pairs of fluorescent A-T specific dyes and nonfluorescent agents with similar or complementary base pair binding specificity were used to analyse the extent to which banding patterns in human chromosomes obtained by fluorescent staining can be modified by counterstaining. By testing a variety of different combinations of drugs, essentially three types of alterations were observed. Enhanced contrast of specific heterochromatic regions was obtained with pentamidine, or netropsin, in conjunction with the fluorescent stains Hoechst 33258, DAPI or DIPI, the resulting banding patterns being similar to that reported for distamycin A plus DAPI (DA-DAPI banding [21]. Uniform quenching of Hoechst 33258, DAPI or DIPI fluorescence was induced by counterstaining with stilbamidine or berenil. The combination of echinomycin with DAPI resulted in an improved contrast of DAPI banding on chromosome arms and pale fluorescence on major autosomal C band regions. In addition, a subdivision of the heterochromatic part of the Y chromosome may be discerned by this latter technique.

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