Potent antibacterial fluoroquinolones with marked activity against Leishmania donovani in vivo.
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4-Quinolones↗
Biomedical subjects
W Raether
Publications and source records attributed to W Raether.
Comparative morphology of human and animal malaria parasites. I. Host-parasite interface.
Human and animal malaria parasites (Plasmodium falciparum, P. malariae, P. vivax, P. berghei, P. gallinaceum) were studied using special fixation and standardized methods, with special attention to their effects on host cells. Morphological alterations induced by the parasites in infected erythrocytes included knobs, invaginations, and caveola-vesicle complexes on the surface of the host cell and clefts, microvesicles, and small vesicles in the cytoplasm of the infected erythrocytes. For P. malariae, the ultrastructural study revealed invaginations with associated microvesicles, but knobs did not occur on the surface of infected erythrocytes. The development of invaginations and microvesicles in P. malariae-infected erythrocytes corresponded to the morphological alterations induced by P. vivax. A new hypothesis concerning the origin of Schüffner's dots is discussed.
Animals↗
Effects of halofuginone lactate on lymphocytes and MDBK cells infected with Theileria annulata and/or vesicular stomatitis virus (VSV): an in vitro study.
Cultures of cattle lymphocytes (lymphoblasts) infected up to 90% with Theileria annulata schizonts and cultures of Madin Darby bovine kidney cells of cattle (MDBK) noninfected or infected with vesicular stomatitis virus (VSV) were exposed to different concentrations (50, 100, or 500 micrograms/ml) of halofuginone lactate in RPMI and MEM medium, respectively. It was found that a concentration of 50 micrograms/ml halofuginone was sufficient to destroy Theileria-infected as well as double-infected lymphocytes (VSV, T. annulata) within 2-6 h of incubation. The same concentration of halofuginone could also damage VSV-infected MDBK cells, leading to a rupture of the host cells, with a maximum of damaged cells within 21-29 h of incubation. In contrast, noninfected control cells (lymphocytes and MDBK cells) tolerated halofuginone at a concentration of 500 micrograms/ml even after prolonged (53-h) incubation periods.
Animals↗
Effects of dimethylsulfoxide and the deep-freezing process on the infectivity, motility, and ultrastructure of Trypanosoma cruzi.
The effects of dimethylsulfoxide (DMSO, final concentration 5%) and the deep-freezing process on the infectivity (ID50), motility, and ultrastructure of nontreated and DMSO-treated Trypanosoma cruzi suspensions (PSG-3 buffer with 10% horse serum) were investigated prior to and after cryopreservation in liquid nitrogen. DMSO equilibration caused distinct suppression of motility and characteristic, fine structural alterations in numerous organelles, such as myelin-like structures in the cytoplasm and/or inside the mitochondrial apparatus, enlargement of the perinuclear space, endoplasmic reticulum, and mitochondrial cristae, as well as condensation of the kinetoplast with loss of its lamellar structure. There was no evidence of loss of infectivity in DMSO-treated parasites. DMSO-treated and deep-frozen organisms showed, however, very similar fine structural alterations, although damage occurring during freezing and thawing was more pronounced. Apart from the frequently enlarged kinetoplast and the loosening of its mitochondrial matrix, numerous trypanosomes revealed total disintegration of the kinetoplast-mitochondrion complex with loss of its whole matrix. Deep-frozen trypanosomes were significantly less infective to mice than nontreated organisms, and their motility was strongly suppressed. These results suggest that cryopreservation and thawing of T. cruzi may lead to severe damage of the mitochondrial apparatus and thus to heavy disorders of metabolic function, exhaustion of the metabolic pool, and finally, to death of such damaged trypanosomes, despite the use of DMSO as a cryoprotective agent.
Animals↗
A more sophisticated method of determining the fungicidal effect of water-insoluble preparations with a cell harvester, using miconazole as an example.
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Analysis of Variance↗
Evaluation of fungicidal action in vitro and in a skin model considering the influence of penetration kinetics of various standard antimycotics.
Ciclopiroxolamine (Loprox) was the first representative of hydroxpyridones to be developed as a topical antifungal. In the microtitration test and in a skin model using excised skin prices of slaughtered pigs, the fungistatic and fungicidal activity as well as the penetration kinetics of ciclopiroxolamine and ciclopirox were compared with those of the azole compounds bifonazole, clotrimazole, econazole, miconazole, oxiconazole, and tioconazole, and with other antimycotics such as naftifine, sulbentine, tolciclate, and tolnaftate. Clotrimazole had an in vitro inhibitory activity superior to that of the hydroxypyridone ciclopiroxolamine; the latter compound, however, exhibited faster penetration and higher inhibitory or fungicidal activity than the azoles and other antimycotics in the pig skin model. Studies of cream formulations with antimycotics at the bottom layer of the stratum corneum (close to the stratum granulosum) showed that ciclopiroxolamine cream had the most prominent inhibitory effect (93%) and the highest fungicidal activity (98%). The other antimycotics tested exhibited growth inhibition rates of 50% or less and lower fungicidal rates. Inoculated pig skin was treated with lacquer formulations to show that ciclopirox completely inhibited the growth of Trichophyton mentagrophytes, whereas the clotrimazole-treated samples allowed only 0.47% growth. The fungicidal activity of lacquer formulations was 99% for ciclopirox and around 90% for most of the azoles on the pig skin model. The necessity of models tackling the complex penetration kinetics in human skin was discussed.
Animals↗
Ultrastructure of the amoebo-flagellate Protonaegleria westphali.
Investigation of the ultrastructure of Protonaegleria westphali has been carried out by means of scanning electron microscopy (SEM) and transmission electronmicroscopy (TEM). SEM investigation demonstrated much enlarged trophozoites, flagellates and cysts corresponding to those under light microscopical observation. In situ fixation of moving trophozoites revealed attachment to the substratum by many uroidal and lateral filopodia. The typical flagellate stage has four flagella inserted two by two at the anterior pole of the cell. The smooth wall of cysts had prominent pores sealed by a mucous plug. Apart from their greater size, trophozoites and cysts resemble those of the genus Naegleria. Mitochondria are not as elongated as in the case of Naegleria; rather, they are round. The cyst is surrounded by a thick, layered endocyst (0.2-0.5 micron) and a delicate ecotcyst loosely apposed to the endocyst. Both walls join at the region of the prominent pores, forming a characteristically thick collar. This, together with the pore structure (up to 1.0 micron in diameter) places the amoeba in group I of N. gruberi, according to Pussard and Pons (1979). The flagellate state usually has four flagella which are anchored firmly by a prominent flagellar apparatus or mastigont at the anterior pole of the cell, comparable to that of the genus Tetramitus. The flagella show a typical 9 + 2 arrangement of microtubules (MT) and are surrounded by a sheath which is continuous with the cell membrane. Main elements of the mastigont could be demonstrated as typical kinetosomes of 0.75 micron length. Each is closely associated with the cross-striated rhizoplast located perpendicular to it.(ABSTRACT TRUNCATED AT 250 WORDS)
Amoeba↗
Antimalarial and anticoccidial activity of 3-aryl-7-chloro-3,4-dihydroacridine-1,9-(2H,10H)-diones. 1-Imines, 1-amines, 1-oximes, 1-hydrazones and related compounds.
Out of more than 130 synthesized derivatives of floxacrine and of 10-deoxyfloxacrine, such as 3-(4-trifluoromethyl-phenyl) or 3-(4-chlorophenyl)-7-chloro-10-hydroxy- or -10-deoxy-3,4-dihydroacridine- 1,9(2H,10H)-dione 1-imines and 1-hydrazones, more than 45 showed an activity against asexual stages of Plasmodium berghei in the mouse which was comparable with or superior to that of floxacrine. More than 25 derivatives of the 3-(4-chlorophenyl)-floxacrine series and 3-(4-chlorophenyl)-10-deoxy-floxacrine series are more effective than floxacrine against Eimeria tenella infection in chickens. 1-Amino compounds of the various series proved of be generally inactive, as did fragments of the structure of and compounds related to floxacrine. Structure-activity relations are suggested on the basis of examples.
Acridines↗
[Light and electron microscopy studies of the developmental cycle and effect of pentamidine on the morphology of intra-erythrocyte stages of Babesia microti].
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Amidines↗
[Potential filaricides. Suramin analogs].
A series of suramin analogues has been synthesized in which the methyl groups of suramin have been replaced by hydrogen, alkyl, phenyl, and fluoro substituents, or which contain more than two methyl groups. The substances have been screened against Dipetalonema viteae in Meriones unguiculatus, Litomosoides carinii in Sigmodon hispidus and L. carinii in Mastomys natalensis, respectively. Small structural modifications have a marked influence on the antifilarial activity. There are marked differences between antifilarial and trypanocidal activities. A symmetrical molecule structure seems not to be essential for the antifilarial activity.
Animals↗
Chemotherapeutically active anthraquinones. II. Aminomethylanthraquinones.
Basically substituted 2,6- and 2,7-bis-amino-methylanthraquinones have a pronounced in vitro and in vivo effect against Entamoeba hystolytica (extraintestinal amoebiasis in golden hamsters) and marked interferon-inducing properties. In 2,6- and 2,7-bis-aminomethyl-anthraquinones only the introduction of hydroxyl groups in 1,5 or 1,8 position led to an additional high systemic activity against Trichomonas foetus in NMRI mice, but it also resulted in the loss of the interferon-inducing effect. Both substance classes included several compounds whose effects against E. histolytica or T. foetus were either comparable or superior to those of standard compounds ornidazole and tinidazole.
Amebiasis↗
Amidoximes of pentamidine: synthesis, trypanocidal and leishmanicidal activity.
For the study of the biotransformation of pentamidine and the evaluation of its trypanocidal and leishmanicidal properties the N-hydroxylated derivatives II and III were prepared. In II and III, one or both the terminal amidine moieties of pentamidine are replaced by an amidoxime. These amidoximes II and III were tested against various Trypanosoma species and Leishmania donovani in mice and golden hamsters, respectively. The studies demonstrate that the pentamidine derivatives II and III were active against various trypanosomes (T. brucei; T. vivax; T. congolense). However, besides having a pronounced activity against Trypanosoma rhodesiense compounds II and III exhibit a less action on other Trypanosomes than the standard drugs diminazene and in some cases the parent compound pentamidine. Derivatives II and III were also distinctly active against Leishmania donovani but their leishmanicidal effect was slightly less marked than that of pentamidine.
Animals↗
The action of salinomycin-Na and lasalocid-Na on chloroquine- and mepacrine-resistant line of Plasmodium berghei K 173-strain in Wistar rats.
Salinomycin-Na and lasalocid-Na, two ionophorous antibiotics known for their anticoccidial activity, exhibit in vivo blood schizontocidal action on the Plasmodium berghei Keyberg 173 RC/M line that has a high level of resistance to chloroquine and mepacrine. Salinomycin was found to have a greater effect than lasalocid on asexual stages of this line. Trophozoites and schizonts were no longer found after a single dose of 20 mg/kg or five doses of 1.25 mg/kg of salinomycin whereas a single dose of 40 mg/kg or five doses of 20 mg/kg of lasalocid showed no marked effect on parasitaemia within 96 h of starting treatment in rats. Some toxicological data show that lasalocid, however, is better tolerated in domestic animals than salinomycin. Early morphological changes in asexual blood stages were membrane-coiling in the cytoplasm followed by vacuolization and disruption of the cell membrane or pellicle after treatment with both compounds. In particular mature schizonts were totally destroyed showing enormously large vacuoles. Toxicological data and blood schizontocidal activity indicate the narrow safety margin in P. berghei infected rats, and place salinomycin in the 'markedly toxic' group of antimalarial compounds.
Animals↗
Ultrastructural changes of Trichomonas vaginalis prior and after cryopreservation.
Fine structural changes of Trichomonas vaginalis are described prior and after the freezing process in liquid nitrogen. Dimethyl sulfoxide (DMSO) used as the cryoprotectant caused distinct alterations of the cytoplasm when trichomonads were equilibrated with 5% DMSO under various experimental conditions. Changes were bubble-like protrusions, fissuration and/or vacuolation of the cytoplasm, doubling and removal or/and rupture of the cell membrane. Apart from these findings cryopreservation caused marked alterations on the hydrogenosomes, such as condensation and flocculence of the usually homogeneous contents; in addition numerous hydrogenosomes fused while loosing membrane at the site of fusion. However, several parasites revealed normal hydrogenosomes after the freezing process. It is assumed that these organisms survived freezing and thawing as demonstrated by successful cultivation of recovered trichomonads.
Animals↗
Antibacterial and antifungal activity of Avarone and Avarol.
The sesquiterpenoid hydroquinone and quinone, Avarol and Avarone, were previously found to be potent antitumor agents (Müller et al., 1984). In the present study it is reported that in aqueous solution (pH 7.2), in the presence of dimethylsulfoxide, Avarol is converted to Avarone. Avarone and to a smaller extent also Avarol were active against a variety of grampositive bacterial species. The highest activity was determined for Streptococcus pneumoniae and Erysipelothrix rhusiopathiae (MIC 0.781 mg/l). The antibacterial activity can be augmented 2 to 4-fold by lowering the pH in the culture medium from 7.0 to 6.0. The efficiency of Avarone and Avarol was abolished in the presence of serum. No antibacterial activity was determined in gramnegative bacterial species. In addition, Avarol and to a smaller extent also Avarone displayed an antifungal activity on Trichophyton species and Microsporum canis (MIC: 15.6-62.5 mg/l), while Avarone and not Avarol was active on Aspergillus niger, no activity was found against Candida species. These data indicate that the antitumor agents Avarol/Avarone display also antibacterial- and antifungal activities against a limited range of microorganisms.
Bacteria↗
Caerulomycin, an antifungal antibiotic with marked in vitro and in vivo activity against Entamoeba histolytica.
The anti-amoebic action of the bipyridyl antibiotic caerulomycin was assessed in vitro and in vivo using various strains of Entamoeba histolytica from polyxenic, axenic and monoxenic cultures. Minimum inhibition concentrations of caerulomycin (metronidazole) were 7.5 (5), 15.6(1.95) and 60 (2.5) micrograms/ml against polyxenic, axenic and monoxenic cultures of E. histolytica, respectively. The ED50 values ascertained in golden hamsters (extraintestinal amoebiasis) and rats (intestinal amoebiasis) after the oral route were 136 and 199 mg/kg (X4), respectively. Metronidazole proved to be approximately four times more active against tissue forms of E. histolytica than caerulomycin [ED50 of metronidazole: less than 40 mg/kg (X4)]. The antibiotic was slightly superior to metronidazole in its action on lumen forms of E. histolytica [ED50 of metronidazole: 233 mg/kg (X4)]. The antibiotic was in some cases toxic to hamsters and rats within the therapeutic range.
2,2'-Dipyridyl↗
Ketoconazole and other potent antimycotic azoles exhibit pronounced activity against Trypanosoma cruzi, Plasmodium berghei and Entamoeba histolytica in vivo.
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Amebiasis↗
Effect of salinomycin-Na on malaria parasites (Plasmodium falciparum and P. berghei).
In vitro exposure of Plasmodium falciparum and P. berghei to salinomycin-Na showed that 10 min incubation in RPMI 1640 medium containing 100 micrograms/ml of the polyether antibiotic led to complete destruction of most parasites; in media containing 10 or 1 microgram/ml salinomycin-Na some young developmental stages seemed to survive, apparently due to the protection of the mostly intact host cell. In vitro treatment of rats infected with P. berghei revealed that a single subcutaneous (oral) dose of 20 mg/kg (80 mg/kg salinomycin-Na caused complete destruction of parasites. Incipient degeneration of the parasites could be already observed 1 h after treatment. After 22 h parasites had disappeared from blood smears. Repeated subcutaneous doses of the polyether as low as 5 mg/kg (X3) completely destroyed the asexual stages of P. berghei. During the ultrastructural investigation of the action of salinomycin-Na it was found that initially the inner lacunes (such as endoplasmic reticulum and perinuclear space) and the mitochondrion were markedly swollen. This was followed by mitochondrial disruption with rupture of the parasites' pellicle. Since the infected host cells also ruptured, mainly extracellular parasites were seen in blood smears beginning 6 h after treatment. Salinomycin-Na seems to act similarly on the malarial parasites and on the free merozoites of chicken intestinal coccidia.
Animals↗