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PubMed1998

In vitro efficacy and fungicidal activity of voriconazole against Aspergillus and Fusarium species.

Twenty-nine Aspergillus isolates and 25 Fusarium isolates underwent in vitro antifungal susceptibility testing by a broth macrodilution procedure adapted from the National Committee for Clinical Laboratory Standards guidelines. The MIC50s of both voriconazole and amphotericin B were 0.5 microg/ml and 1 microg/ml against species of Aspergillus and Fusarium, respectively, while the MIC90s of both agents were 1 and 2 microg/ml. Voriconazole was more active in vitro than amphotericin B: the geometric mean MICs of voriconazole and amphotericin B against Aspergillus spp. were 0.36 microg/ml and 0.64 microg/ml, respectively. Voriconazole also demonstrated fungicidal activity against Aspergillus spp., with 86% (24/29) of isolates exhibiting minimum lethal concentrations of < or = 4 microg/ml.

Antifungal Agents↗
PubMed1988

Antagonism of the direct fungicidal action of miconazole by miconazole fungistasis.

A weakly fungistatic concentration of miconazole in lag phase yeast cultures of Candida albicans antagonized development of phenotypic susceptibility to the direct fungicidal action of high-level (i.e. greater than 10(-5) M) miconazole. After development in the absence of drug, maintenance of susceptibility upon continued incubation was also antagonized by low levels of miconazole. This auto-antagonistic effect has important clinical implications.

Candida albicans↗
PubMed1986

Serum fungistatic and fungicidal activity in volunteers receiving antifungal agents.

The serum levels of two imidazoles, ketoconazole and Bayer n7133, when administered alone or in combination with rifampin, were measured in volunteers and the serum antifungal activity was determined against various fungal strains. Serum levels were measured by high pressure liquid chromatography and correlated with serum fungistatic activity as determined in microtiter plates. Ketoconazole showed a wide range of serum levels, suggesting individual variations. The addition of two doses of rifampin significantly decreased serum levels of both imidazoles and no synergism was observed. Serum fungicidal activity could only occasionally be demonstrated against one strain of Candida albicans and Candida stellatoidea. Serum fungistatic activity significantly correlated with the serum levels of both imidazoles. This approach should be investigated in patients to establish its potential clinical relevance for managing invasive fungal infections.

Aspergillus fumigatus↗
PubMed2005

Fungicidal effect of resveratrol on human infectious fungi.

Resveratrol, a phenolic antioxidant found in grapes, has been known to mediate various biological activities on the human body. In the present study, we tested the antifungal activity of resveratrol against human pathogenic fungi before carrying out further studies to elucidate the antifungal mechanism(s) of resveratrol. Resveratrol displayed potent antifungal activity against human pathogenic fungi at concentration levels of 10-20 microg/mL. Furthermore, time-kill curve exhibited fungicidal effect of resveratrol on C. albicans, but the compound had no hemolytic activity against human erythrocytes. The destruction of C. albicans cells by resveratrol was confirmed by scanning electron microscopy. These results suggest that resveratrol could be employed as a therapeutic agent to treat fungal infections of humans.

Antifungal Agents↗
PubMed1986

Stereo-selective interaction of enantiomers of diniconazole, a fungicide, with purified P-450/14DM from yeast.

R(-) isomer of diniconazole [S-3308L, (E)-1-(2,4-dichlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-l-yl)-1-+ ++penten-3-ol], a newly developed fungicide strongly inhibited lanosterol 14 alpha-demethylation catalyzed by a yeast cytochrome P-450 (P-450/14DM). On the other hand, S(+) isomer of diniconazole was a weaker inhibitor for P-450/14DM. The R(-) isomer combined with both ferric and ferrous P-450/14DM and interfered binding of CO to the cytochrome. The S(+) isomer also interacted with both forms of P-450/14DM but the absorption spectra of the S(+)-diniconazole complexes were different from those of the R(-)-diniconazole complexes. Furthermore, S(+) isomer did not significantly interfere the binding of CO to P-450/14DM. These observations suggest that P-450/14DM discriminates enantiomers of diniconazole and the R(-) isomer is more favorably fit for the active site of the cytochrome.

Antifungal Agents↗
PubMed1987

Teratogenic effects of the fungicide maneb on chick embryos.

The teratogenicity of a commercial formulation of the fungicide maneb (Maneb 80, containing 80% manganese ethylenebisdithiocarbamate and 20% inert ingredients) in chick embryos was evaluated. Unincubated eggs (157-207 per treatment group) were immersed in 0.5, 1.5, 4.5, or 13.5 g/liter maneb aqueous solutions for 30 sec. Two control groups were used: one group of 200 eggs was immersed in tap water and a second group of 205 eggs was immersed in a solution of the inert ingredients (sodium lignin sulfonate and n-butylnaphthalene sulfonate) at the concentration present in the 13.5 g/liter maneb solution. Eggs were then incubated for 19 days. A single treatment with maneb was teratogenic at all concentrations tested, producing mainly unilateral lower limb deformities. No adverse effects on development were noticed after exposure to the inert ingredients.

Animals↗
PubMed1989

Study of possible teratogenic effects of the fungicide maneb on chick embryos.

The teratogenicity of the fungicide maneb (80% active ingredient and 20% inert ingredients) in chick embryos was evaluated. Eggs, before incubation, were dipped in 0.2% or 1.2% aqueous dispersions of maneb for 30 seconds. An untreated group, a water group and a formulation ingredient group, at the concentration present in the 1.2% maneb group, ensured control in the study. Eggs were incubated for 18 days then transferred to hatching racks and allowed to hatch normally. Viable chicks and chicks "dead in shell" were assessed for external deformities. There was no evidence that maneb or its formulation ingredients were teratogenic or embryotoxic to developing chick embryos.

Animals↗
PubMed1988

Sister-chromatid exchanges and chromosomal aberrations in chick embryos after treatment with the fungicide maneb.

The genotoxic potential of a commercial formulation of the fungicide maneb (Maneb 80, containing 80% manganese ethylenebisdithiocarbamate as active ingredient) in chick embryos was evaluated, using as genetic end-points the frequency of sister-chromatid exchanges (SCE) and of chromosomal aberrations. Unincubated eggs were dipped in 0, 0.5, 1.5, 4.5, 13.5 or 27 g/l maneb aqueous solutions for 30 sec. Eggs were then incubated for 4 days. Maneb significantly increased SCE values at 13.5 g/l and at 27 g/l (means 1.33 and 1.74) over the control value (mean 0.87). The concentration of 27 g/l, which corresponds to 10.8 times the recommended maximum application level for use in the field, also resulted in a high mortality rate. No clastogenic effects following exposure to maneb were observed.

Animals↗
PubMed1988

Cytogenetic effects of Cuman L, a dithiocarbamate fungicide.

Cuman L, a dithiocarbamate fungicide, was assessed for its effects in the germ cells and the bone marrow erythrocytes of Swiss Albino male mice. The 3 sublethal doses of 350, 700 and 1050 mg/kg b.w. of Cuman L induced a significant (P less than 0.01) increase in the number of chromosomal aberrations in the germ cells. A significant increase (P less than 0.01) in the percentage of micronuclei in the erythrocytes was also induced by the three doses.

Animals↗
PubMed1987

Histopathological and biochemical changes in the liver of a teleost fish, Channa punctatus (Bloch) induced by a mercurial fungicide.

The chronic toxic effects of a prolonged exposure of 6 months, from January to June, to a 'safe dose' (0.20 mg litre(-1)) of a commercial organomercurial fungicide, Emisan (methoxy ethyl mercuric chloride: MeEHgCl), on the histophysiology of liver in adults and young (yearlings) of Channa punctatus, are described in this investigation. In both of the experimental groups, liver histology exhibited various abnormalities, including hyperplasia, nuclear pyknosis, fatty necrosis, and degeneration of hepatocytes leading to tumour and syncytium formation, which are indicative of carcinogenesis. Apart from this, blood vessel congestion and oedema were also observed in young treated fish. In the livers of both exposed groups, corresponding with this cellular damage, a marked reduction in hepatosomatic index, levels of total protein and lipid, and an elevation in cholesterol and acid and alkaline phosphatase contents were recorded. However, these alterations were more pronounced in young than in adult fish. These Emisan-induced, histopathological and biochemical changes are suggestive of severe hepatic dysfunction, which may result in the impairment of the physio-metabolic process, in this species.

Journal Article↗
PubMed1991

The fungicide benomyl (methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate) causes testicular dysfunction by inducing the sloughing of germ cells and occlusion of efferent ductules.

Adult male Sprague-Dawley rats (100 days of age) were given single oral doses of the fungicide benomyl (methyl 1-(butylcarbamoyl)-2- benzimidazolecarbamate) in dosages ranging from 25 to 800 mg/kg body weight. The testis and excurrent ducts were examined at 2 and 70 days posttreatment to determine the chemical effects on spermatogenesis and the epididymis. Primary effects seen at 2 days postexposure were testicular swelling and occlusions of the efferent ductules. Mean testis weight peaked with 400 mg/kg. Premature release of germ cells (sloughing), detected even with the lowest dosage (25 mg/kg), was the most sensitive short-term response to benomyl. Sloughing was found primarily in Stage VII of the spermatogenic cycle at the lower dosages, but at higher dosages sloughing extended into all stages except for Stages VIII-XI. Occlusions of the efferent ductules of the testis were dose-dependent and correlated with testis weight. Sperm and sloughed germ cells were compacted in the ductal lumen of occluded ductules, which were surrounded by two to four layers of polymorphonuclear leukocytes and other inflammatory cells. Although the caput epididymidis contained sloughed germ cells and appeared swollen, evidence of permanent occlusion was not found. The long-term (70 days) effects of benomyl were decreased testis weight (at 400 mg/kg), dose-dependent increases in seminiferous tubular atrophy, and increases in the number of reproductive tracts containing occluded efferent ductules. Fibrosis, granulomas, and abnormal growth were long-term consequences of occluded ductules, which were present 100% of the time in testes containing 26-100% seminiferous tubular atrophy. Only a few testes were found to be completely regressed. Occlusion of efferent ductules and disruption of the seminiferous epithelium by sloughing of germ cells are overlapping dose-dependent mechanisms responsible for short- and long-term effects of benomyl on the rat testis.

Animals↗
PubMed1980

An investigation of some genetic toxicological effects of the fungicide benomyl.

The widely used fungicide benomyl (methyl-1-(butylcarbamoyl)-2-benzimidazole carbamate) and its breakdown product methyl-2-benzimidazole carbamate (MBC) have been reported to have mutagenic activity in some organisms. In experiments with Drosophila melanogaster we found (i) there was no significant increase in recessive lethal frequency after feeding adult flies with Benlate did not increase chromosome breakage or loss significantly; (ii) there was a relatively high incidence of sterility when males of one strain (Oregon R) were fed Benlate or MBC. In experiments in which cultures of human lymphocytes were exposed in vitro to 0.5 mg/ml MBC we observed extreme contraction of the chromosomes but found no evidence of an increase in the number of cells with chromosome aberrations. We conclude that benomyl and MBC are unlikely to be strong mutagens, but more research is needed to exclude the possibility that they are capable of inducing genetic damage in the germ cells of higher organisms.

Animals↗
PubMed1980

Testing of the fungicide maneb for carcinogenicity in two populations of the European crested newt.

The carcinogenic effects of the fungicide manganese ethylenebisdithiocarbamate (maneb) have been investigated in 2 populations of adult crested newt, which have different prevalences of spontaneous melanoma. Animals were exposed percutaneously to a 5 ppm solution of maneb 4 days a week for 37 weeks. No differences in tumor incidence were found between control and maneb-treated animals of either population. Most of the control and treated animals from Settala (Milan) died within 7 months because of the development of widely disseminated melanomas. Tumor incidence was 94% in controls and 98% in maneb-treated newts. In the population from Bagnaia (Perugia) the incidences of melanoma were 7% and 2%, respectively.

Animals↗
PubMed1992

Fungicidal effect of human lactoferrin against Candida albicans.

Human lactoferrin (LF) in its iron-free state (apo LF), killed Candida albicans in a time- and dose-dependent way. The lethal effect was stronger at pH 7.0 than at pH 5.5 and maximum inhibition at neutral pH was achieved in 25 min when the fungal cells were exposed to LF in 0.05 mM KCl at 37 degrees C. Fe(3+)-saturated LF had no fungicidal activity. Apo LF-mediated killing was also temperature-dependent with enhanced inhibition at higher temperatures (37 degrees, 42 degrees C). The presence of 1 mM D-glucose did not affect the candidacidal activity of apo LF but both phosphate and bicarbonate ions at physiological salivary concentrations completely blocked the anti-fungal effect. Therefore it seems unlikely that LF belongs to the major host defence factors against oral candidosis.

Antifungal Agents↗
PubMed1990

Induction of gastric mucosal cell proliferation by the fungicide captan: role of tyrosine kinases.

Captan (1,2,3,6-tetrahydro-N-trichloromethylthiophthalmide), a widely used fungicide, has been shown to induce carcinoma in the gastrointestinal tract of rodents. However, little is known about the captan induction of early biochemical changes in the gastrointestinal tract. The present investigation examines the changes in gastric mucosal proliferative activity in 2-month-old Fischer 344 rats following a daily injection (s.c.) of captan (100 mg/kg body wt.) in DMSO while being infused (osmotic minipump) with the same compound (7.14 mg captan/kg body wt./h) for 2 weeks. The control rats received the vehicle the same way. The change in proliferative activity was related to tyrosine kinase (Tyr-k) activity and tyrosine-specific phosphorylation of protein(s) in gastric mucosal membranes since these intracellular events are thought to play an important role in proliferation, differentiation and transformation of cells. After 2 weeks of captan administration gastric mucosal DNA synthesis and thymidine kinase activity (indicators of proliferative activity) were increased by 330% (P less than 0.025) and 98% (P less than 0.025), respectively, when compared with the corresponding controls. Gastric mucosal DNA content was also increased by 90% (P less than 0.025) after administration of captan. These increases were associated with about 3-fold rise in Tyr-k activity and 2-fold increase in tyrosine phosphorylation of 6 mucosal membrane proteins with Mr of 105, 90, 60, 55, 48 and 37 kDa. We conclude that captan stimulates gastric mucosal cell proliferation, and activation of Tyr-k and tyrosine phosphorylation of certain membrane proteins may be important in the regulation of this process.

Animals↗
PubMedDate not supplied

Neurobehavioral effect of triadimefon, a triazole fungicide, in male and female rats.

Triadimefon is a widely used systemic fungicide, yet there is little published information on its effects in mammals. This study describes the effects of triadimefon in male and female rats using a functional observational battery (FOB), motor activity (measured in a figure-eight maze), and operant performance (responding under a fixed-interval 3-min schedule). For the FOB, Long-Evans hooded rats were tested immediately before dosing and 0.5, 4, 24, and 48 hr after IP dosing with either vehicle, 30, 100, or 300 mg/kg triadimefon. Prominent effects of triadimefon (100 and 300 mg/kg) included increased arousal, stereotypies involving repetitive sniffing, head bobbing, and pacing, and self-mutilation. Dose-related handling-induced convulsions, changes in reflexes and sensory reactivity, hypothermia, and body weight loss were also significant findings. Doses of 30, 75 and 150 mg/kg triadimefon increased figure-eight maze activity whereas 300 mg/kg decreased activity. Habituation of activity during the session as well as the spatial distribution within the maze were also affected by triadimefon. Overall rates of responding maintained by fixed-interval milk reinforcement were increased at 30 and 56 mg/kg, and decreased at 100 and 200 mg/kg. Responding within the 3-min fixed-interval was also affected, with low rates normally occurring early in the interval markedly increased. These effects on operant performance were similar to those seen following d-amphetamine, and were attenuated by pretreatment with chlorpromazine (0.5 mg/kg). On many measures, female rats appeared to be somewhat more sensitive than males. Recovery was evident in some measures the day after dosing, but the effects of high doses (greater than or equal to 100 mg/kg) were typically prolonged (several days). Thus triadimefon produced a unique neurotoxic syndrome which is similar in many aspects to that produced by CNS stimulants.

Animals↗
PubMed2005

Chromosomal aberrations and frequency of micronuclei in sheep subchronically exposed to the fungicide Euparen Multi (tolylfluanid).

We analyzed chromosome aberrations, micronucleus frequency, mitotic index (MI), and nuclear division index (NDI) in peripheral lymphocytes of sheep subchronically exposed to the fungicide Euparen Multi (containing 50% tolylfluanid). Euparen Multi was administered by rumen sonde to group of Merino sheep (seven sheep/group) at 93 mg/kg body weight (1/20 LD50) daily for 28 days to assess its genotoxic effects. The frequencies of aberrant cells (ABC) in the experimental and control groups were 5.50+/-1.38% and 2.40+/-1.14%, respectively, and the increase in ABC in the treated group was significant (P = 0.003). Significantly increased numbers of chromatid breaks (5.67+/-1.21% against 2.40+/-1.14%; P = 0.001), chromatid gaps (10.33+/-2.73% against 4.00+/-1.23%; P = 0.001), and chromosome gaps (1.83+/-0.75% against 0.80+/-0.45%; P = 0.025) and exchanges (3.17+/-1.94% against 0.20+/-0.45%; P = 0.009) were observed in exposed animals in comparison to control animals. The frequency of micronuclei (MN) was 29.40+/-5.86 per 1000 binucleated cells in peripheral lymphocytes of sheep in the control group and 49.57+/-19.12 per 1000 binucleated cells in the treated group. A significant increase in the frequency of MN in peripheral lymphocytes also was observed between the two groups (P = 0.0477). No statistical differences in MI and NDI values were found in the groups (P = 0.181 and 0.761, respectively). Thus, our results suggest that exposure to Euparen Multi may cause genome damage in somatic cells.

Aniline Compounds↗