Effect of nitrofurylpropenylidene benzhydrazides against trichomonads, bacteria, yeasts and fungi with particular consideration of the results in the Ames test and host-mediated assay

11 out of 13 N-[3-[5-nitrofuryl-(2)-propenylidene)]-benzhydrazides described by us showed an in vitro activity against T. vaginalis almost equivalent to or approaching that of the standard substances metronidazole and tinidazole. One compound was markedly more effective; two compounds exhibited much weaker activity than the two reference substances. In the model of the T. foetus infection of mice, only two compounds came close to the chemotherapeutic effect of tinidazole when administered orally. The other compounds were less effective. Metronidazole showed an activity 10 times weaker than that of tinidazole in this animal model. The in vitro efficacy of the most active substances a and d on T. foetus infection paralleled the bacteriostatic effect against different species of bacteria. In comparison, d was more effective than a against T. vaginalis, 2 Candida strains and M. tuberculosis. In the Ames test, 5 out of the 13 described N-[3-[5-nitrofuryl-(2)-propenylidene))]-benzhydrazides proved mutagenic in test strains TA 98 and TA 100; this was the case also in strain TA 1537 for the microbiologically most promising compound a. Because of liver damage observed in the test on toxicity, the substance was not taken up in clinical studies. It is interesting to note that these substances were not found to be mutagenic in the host-mediated assay. No signs of chromosome breaks were observed for substances a and n in the micronucleus test. The relevance of these findings was discussed. Statistical procedures were described for both the Ames test and the host-mediated assay.     

New derivatives of 1-methyl-phthalazine with antimicrobial and fungistatic action]

In this paper we present the antimicrobial and antifungical action of some new salts of 1-methyl-phtalaziniums and their corresponding ylids. We also present conclusions concerning the relation between structure and biological activity. The test was performed using the diffusimetric method with rustless steel cylinders based on the diffusion on the tested substances on gelose surface. The salts of 1-methyl-phtalaziniums are always more active comparatively than their corresponding ylids. All the compounds but not all derivatives are more active on the Candida albicans.     

Effects of nitrendipine on cocaine-induced toxicity evaluated in primary myocardial cell cultures

Currently, there is no uniform treatment for abnormal cardiac events precipitated by cocaine use. However, clinical strategies include use of calcium channel antagonists for cardiovascular emergencies. In experimental situations using rats, simultaneous administration of nitrendipine (NIT) with cocaine to the whole animal (1.46 x 10(-3) mg/kg/min of NIT; 2 mg/kg/min of cocaine) and isolated retrograde perfused hearts (Langendorff; 1 x 10(-7) M NIT; 1 x 10(-7) to 1 x 10(-4) M cocaine) normalized cocaine-induced abnormalities in heart rhythm and provided protection from acute cocaine-induced morphological lesions. Using similar concentrations of NIT and cocaine, the purpose of this study was to evaluate the direct cardiac cellular effects of NIT on cocaine-induced alterations in beating activity, morphology, and lactate dehydrogenase (LDH) release in a controlled in vitro system of primary myocardial cell cultures. Cultures were established from hearts of 3-5-day-old Sprague-Dawley rats. After the cells had been maintained in culture for 4 days, evaluation of drug effects were made with exposure to 1 x 10(-3) and 1 x 10(-5) M cocaine alone and combinations of these two concentrations of cocaine with simultaneous exposure to 1 x 10(-7) M NIT for 1 to 24 h. Those cells exposed to 1 x 10(-5) M cocaine alone maintained some beating activity after 1, 4, and 24 h. Beating activity was significantly depressed after treatment with 1 x 10(-3) M cocaine alone and with both combinations of cocaine and NIT. Morphological integrity was maintained in all treatment groups for 1 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antimicrobial Activity of 6-Paradol and Related Compounds

The seeds of Aframomum melegueta K. Schum. (Zingiberaceae) yielded 6-paradol (1) and 6-shogaol (2) as the major antimycobacterium agents, based on a bioactivity-guided fractionation. These isolates were found to be active against Mycobacterium chelonei, M. intracellulare, M. smegmatis and M. xenopi (MIC 10-15 µg/ml). Derivatives were prepared in an attempt to define some of the structural parameters needed for antimicrobial activity. The desmethyl derivative of 1 retained the antimycobacterial activity and was found to be more active against Candida albicans than 1 and 2. Gingerone (9), not previously reported in this source, was found to be inactive. The identity of the compounds were confirmed by spectral analyses (UV, IR, NMR, and EIMS) and by comparison with reported data.     

N-(6,6-二甲基-2-庚烯-4-炔基)-N-甲基-α-取代-1-(4-取代)萘甲胺类的合成及抗真菌活性

根据氮唑类和烯丙胺类抗真菌化合物的构效关系、作用机理。设计合成了30个N-(6,6-二甲基-2-庚烯-4-炔基)-N-甲基-α-取代-1-(4-取代)萘甲胺类化合物。初步体外抑菌试验结果表明,大多数目标化合物对八种试验菌株都有不同程度的抗真菌活性。化合物Ⅰ_1a的真菌活性大致与克霉唑相当,对白念珠菌的活性明显高于naftifine和terbinafine,但对其它七种菌株的活性均不及naftifine和terbinafine;化合物Ⅲ_1a对八种试验菌株的活性均与terbinafine相当。     

Synthesis and antimicrobial activities of some new tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives of ampicillin

Compounds having alpha-[dihydro-5-substituted 6-thioxo-2H- 1,3,5-thiadiazine-3(4H)-yl]benzylpenicillin structure were synthesized by the reaction of ampicillin trihydrate, formaldehyde and dithiocarbamic acid salts. The structures were evident from chemical and spectral analysis. The antimicrobial activities of the compounds were investigated against some gram-positive (Staphylococcus aureus and Streptococcus faecalis) and gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria and some yeast-like fungi (Candida albicans, C. parapsilosis, C. stellatoidea and C. pseudotropicalis) and molds such as Trichophyton rubrum, T. mentagrophytes, Microsporum canis, M. gypseum, Penicillium and Aspergillus by the tube dilution method. In addition to MIC (minimal inhibitory concentration), MBC (minimal bactericidal concentration) and MFC (minimal fungicidal concentration) values were determined using ampicillin trihydrate as standard. The compounds synthesized were usually found as effective as ampicillin trihydrate against S. aureus and S. faecalis and less effective than ampicillin trihydrate against E. coli. Both the compounds synthesized and ampicillin trihydrate are ineffective in the concentrations studied against P. aeruginosa. Compound 10 and 11 are more effective against all the yeast-like fungi than the other compounds and ampicillin trihydrate.     

光学活性益康唑和咪康唑的对映体选择性合成及其抗真菌活性

首次用对映体选择性合成法制备了光学活性的益康唑和咪康唑。初步体外抗真菌活性试验结果表明,(R)-(—)-益康唑和(R)-(—)-咪康唑的抗真菌活性高于相应的(S)-异构体和外消旋体。     

In vitro activity of N-chlorotaurine (NCT) in combination with NH4Cl against Trichomonas vaginalis

Trichomoniasis, caused by the protozoan Trichomonas vaginalis, is usually treated with metronidazole, however resistance is on the rise. In this study, N-chlorotaurine (NCT), a new endogenous mild active chlorine compound for topical use, killed T. vaginalis in vitro within 15 min of treatment at a concentration of 55 mM (1%), which is well tolerated by human tissue. The activity of NCT was further enhanced by addition of ammonium chloride (NH(4)Cl). A combination of 5.5 mM (0.1%) NCT plus 19 mM (0.1%) NH(4)Cl killed 100% of trichomonads within 5 min.     

Inhibition of protein denaturation by fatty acids, bile salts and other natural substances: a new hypothesis for the mechanism of action of fish oil in rheumatic diseases

Natural hydrophobic substances like bile salts (cholate, deoxycholate, chenodeoxycholate, lithocholate and their conjugates with glycine and taurine), fatty acids (caprylic, capric, lauric, myristic, palmitic, stearic, oleic, linoleic, arachidonic, eicosapentaenoic and docosahexaenoic acid) were much more active (EC50 approximately 10(-4)-10(-5) M) than selected amino acids (EC50 > 10(-2) M) and inorganic salts (EC50 approximately 10(-1) M) in inhibiting heat-induced denaturation of human serum albumin in vitro. Fish oil, rich in n-3-polyunsaturated acids such as eicosapentaenoic acid and docosahexaenoic acid, administered p.o. (1 ml/kg) in the rat, protected ex vivo (after 2 hr) serum against heat-induced denaturation more than bendazac, a known antidenaturant drug. Thus, we speculated that the antidenaturant activity of fish oil may be partly (in addition to the known effect on endogenous eicosanoid composition) responsible for its beneficial effects in rheumatoid arthritis and other rheumatic conditions. In this connection, it is of note that the in vitro antidenaturant activity of fish oil fatty acids was higher than that of known antidenaturant drugs such as bendazac and bindarit and nonsteroidal anti-inflammatory drugs like phenylbutazone and indomethacin which could exert beneficial effects in chronic inflammatory conditions by stabilizing endogenous proteins.     

Action of carbacyclic 13,14-didehydro-analogs of prostacyclin on the contractile activity of the rat stomach muscles

The pharmacological activity of bicyclooctane and bicycloheptane analogues of prostacyclin was studied on the rat stomach muscle strip. All the analogues are partial agonists. EC50 of the most active of them, 5E isomer of bicyclooctane analogue, is 2.8.10(-7) M-1.2.10(-7) M. 5E isomers of both bicyclooctane and bicycloheptane analogues with a normal length of alpha-chain are at least by an order of values more active than the corresponding 5Z isomers. At the increase of alpha-chain by one methylene group the activity of 5E and 5Z isomers of bicycloheptane analogue becomes similar.     

光学活性益康唑和咪康唑的对映体选择性合成及其抗真菌活性

首次用对映体选择性合成法制备了光学活性的益康唑和咪康唑。初步体外抗真菌活性试验结果表明,(R)-(—)-益康唑和(R)-(—)-咪康唑的抗真菌活性高于相应的(S)-异构体和外消旋体。     

The activity of protease inhibitors against Giardia duodenalis and metronidazole-resistant Trichomonas vaginalis

Antiretroviral protease inhibitors were assessed in vitro for their activity against Giardia duodenalis and Trichomonas vaginalis. Kaletra (a co-formulation of ritonavir and lopinavir) was the most effective overall, with 50% effective drug concentrations (EC(50)) of 1.1-2.7 microM (ritonavir concentration) against G. duodenalis and 6.8-8 microM against metronidazole-sensitive and clinically metronidazole-resistant T. vaginalis. Minimal inhibitory concentrations were 2-2.5 microM and 10-50 microM for G. duodenalis and T. vaginalis, respectively. Within the range of human plasma concentrations for ritonavir, only G. duodenalis was inhibited. Lopinavir alone was less inhibitory than ritonavir but was associated with a blockage in cytokinesis of G. duodenalis trophozoites. Saquinavir was not effective. These findings are significant considering the association between human immunodeficiency virus and T. vaginalis, and between G. duodenalis and homosexual behaviour.     

Cortisol at physiological concentrations and prostaglandin E2 are additive inhibitors of human natural killer cell activity

The effects of cortisol and prostaglandin E2 on preparations of human peripheral blood mononuclear cells that mediate natural killer cytotoxicity were evaluated. Natural killer cell activity was measured using 51Cr-labelled K562 target cells and effector to target cell (E:T) ratios of 50:1, 25:1, 12.5:1 and 6:1. In vitro preincubation of mononuclear cell preparations for 20 h with 1 X 10(-8) to 1 X 10(-5) M cortisol resulted in a significant decrease of natural killer cell activity. The magnitude of the suppression was directly related to the steroid concentration and inversely related to the E:T ratio. Exposure of cortisol-treated mononuclear cells to 1 X 10(-6) M prostaglandin E2 resulted in a significantly higher level of inhibition than after treatment with the two agents singularly. In contrast, the concomitant incubation with 1 X 10(-5) to 1 X 10(-4) M theophylline, or with 1 X 10(-6) to 1 X 10(-5) M isobutyl-methylxanthine, two widely used phosphodiesterase inhibitors, failed to demonstrate a significant enhancement of cortisol-induced suppression. Prostaglandin E2-dependent inhibition, on the other hand, was more intense after the inhibition of phosphodiesterase activity. Taken together, these results show that cortisol at physiological concentrations has the property of depressing human natural killer cell activity in vitro and suggest that endogenous glucocorticoids play a role in the in vivo regulation of this natural cytotoxicity. Additionally, cortisol and prostaglandin E2 are additive inhibitors of natural killer cell activity. Since the effect of cortisol in our experiments was not changed by theophylline or isobutyl-methylxanthine it is conceivable that the hormone acts at a level different from the adenylate cyclase/phosphodiesterase system.     

A microbiological assessment of silver fusidate, a novel topical antimicrobial agent

The silver salt of fusidic acid is a novel antimicrobial agent. Against staphylococci, in vitro tests showed silver fusidate was more active than silver sulphadiazine, and the activities of the sodium and the silver salts of fusidic acid were correlated. Against streptococci, enterococci, clostridia, Candida albicans and a range of Gram-negative bacilli, silver fusidate was of similar activity to silver sulphadiazine. Silver fusidate at 1 g/l was bactericidal against eight strains of staphylococci, irrespective of their susceptibility to sodium fusidate. Emergence of resistance to silver fusidate was rare.     

In vitro antifungal and antibacterial activities of pentacycloundecane tetra-amines

The antifungal and antimicrobial activities of three pentacycloundecane (PCU) tetra-amine derivatives are reported herein. The in vitro activity of these PCU derivatives against yeasts (Candida albicans and non-albicans species) and filamentous fungi was evaluated using the Clinical and Laboratory Standards Institute (CLSI) M27-A2 and M38-A2 guidelines and the 2H-tetrazolium salt, (MTS) colorimetric method. The minimum inhibitory concentration against most of the tested clinical fungal strains for GKM8 and GKM9 derivatives ranges from 15.6 to 62.5 μg/mL while GKM11 ranged from 3.9 to 7.8 μg/mL. The GKM11 derivative was also active against fluconazole-resistant strains of fungi. The GKM11 derivative also exhibited promising activity against filamentous fungi in that it was 2.5 times more active than amphotericin B against Sporothrix schenckii. Antibacterial activity was determined using the broth microdilution method (BMM) and the iodonitrotetrazolium chloride (INT) colorimetric method. The GKM11 derivative was mainly active against Gram-positive bacteria with MIC ranging from 3.9 to 7.8 μg/mL. Activity against Gram-negative bacteria tested was limited to Escherichia coli and Elizabethkingia meningoseptica (MIC of 31 μg/mL).     

1-{2-[(4-取代苯基)甲氧基]-2-(取代苯基)乙基}-1H-氮唑类化合物的合成及抗真菌活性

根据氮唑类抗真菌化合物的构效关系和作用机理,设计合成了29个1-{2-[(4-取代苯基)甲氧基]-2-(取代苯基)乙基}-1H-氮唑类化合物,其中九个为首次报道。初步体外抑菌试验结果表明,大多数目标化合物对八种试验菌株都有不同程度的抗真菌活性。化合物14对白念珠菌的活性与克霉唑及益康唑相当,对其它七种试验菌株的活性明显强于克霉唑及益康唑。化合物4,12对白念珠菌活性差,对其它七种试验菌株的活性也强于克霉唑和益康唑。化合物5,6和23除对白念珠菌外,对其它七种试验菌株,也有较强活性。     

Synthesis and antimicrobial activities of some new tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives of cephalexin

In this study, compounds with a 7-[2-(dihydro-5-substituted 6-thioxo-2H-1,3,5-thiadiazine-3[4H]-yl)-2-phenyl]acetamido-3 -methyl-3- cephem-4-carboxylic acid structure were synthesized by reacting cephalexin monohydrate with formaldehyde and dithiocarbamic acid salts prepared from some primary amines. The structure of the compounds was confirmed by spectral data and elementary analysis. The antimicrobial activities of the compounds were investigated against some bacteria (Staphylococcus aureus, Streptococcus faecalis, Escherichia coli and Pseudomonas aeruginosa) and some Candida sp. (C. albicans, C. parapsilosis, C. stellatoidea and C. pseudotropicalis) by using tube dilution method. In microbiological studies, cephalexin monohydrate was used as reference standard. Both compounds were synthesized and cephalexin monohydrate was found ineffective against S. faecalis and P. aeruginosa in the concentrations studied. While most of the compounds showed bacteriostatic activity against S. aureus, compounds 1, 3 and 7 showed the same activity against E. coli. On the other hand, compound 3, 5, 6, 7 and 10 showed anticandidal activity, whereas cephalexin monohydrate was not active against any Candida sp. Compound 11 was found effective against C. stellatoidea and C. pseudotropicalis.     

磺柳硝胺的制备

本研究以磺基水杨酸为原料，与乙醇胺硝酸酯成盐，制备了新的硝乙胺衍生物－磺柳硝胺。体外药理实验表明，磺柳硝胺具有明显的血管舒张作用。     

1-{2-[(4-取代苯基)甲氧基]-2-(取代苯基)乙基}-1H-氮唑类化合物的合成及抗真菌活性

根据氮唑类抗真菌化合物的构效关系和作用机理,设计合成了29个1-{2-[(4-取代苯基)甲氧基]-2-(取代苯基)乙基}-1H-氮唑类化合物,其中九个为首次报道。初步体外抑菌试验结果表明,大多数目标化合物对八种试验菌株都有不同程度的抗真菌活性。化合物14对白念珠菌的活性与克霉唑及益康唑相当,对其它七种试验菌株的活性明显强于克霉唑及益康唑。化合物4,12对白念珠菌活性差,对其它七种试验菌株的活性也强于克霉唑和益康唑。化合物5,6和23除对白念珠菌外,对其它七种试验菌株,也有较强活性。     

Aetiology of male urethritis in patients recruited from a population with a high HIV prevalence

The aetiology of urethritis, the significance of potential pathogens and the relation of urethritis to HIV infection were determined in 335 men (cases) with and 100 men (controls) without urethral symptoms. Urethral swab specimens were tested for different organisms by PCR or by culture for Neisseria gonorrhoeae. The prevalence of N. gonorrhoeae and Chlamydia trachomatis was 52 and 16%, respectively. The potential pathogens: Mycoplasma genitalium, Ureaplasma urealyticum, Trichomonas vaginalis and herpes simplex virus (HSV), were present in 5, 36, 6 and 6% of the cases respectively. M. genitalium was the only potential pathogen associated with microscopic urethritis. After excluding gonococcal infections, U. urealyticum was more frequent in symptomatic patients, while the prevalence of T. vaginalis was similar among cases and controls. These results strongly suggest an a etiological role for M. genitalium in male urethritis, a possible role for U. urealyticum, but not for T. vaginalis. The control group, with 97% genital ulcer disease patients, was not suitable for the investigation of the role of HSV. The sero-prevalence of HIV was 45%. Current infections were not associated with HIV. However, a history of previous urethral discharge was associated with HIV in a multivariate analysis and supported the hypothesis that non-ulcerative sexually transmitted diseases facilitate HIV transmission.