Effect Of Griseofulvin Research Articles

Enhancing the Antifungal Activity of Griseofulvin by Incorporation a Green Biopolymer-Based Nanocomposite.

Fungal biofilms have caused several medical problems, resulting in significant morbidity and mortality as well as poor response to antifungal drugs. The current study was designed to evaluate the enhancement of antifungal and anti-biofilm activity of Griseofulvin-loaded green nanocomposite-based biopolymers (Ge-Nco) of glycogen and gelatin against different strains of pathogenic Candida species. The prepared Ge-Nco was characterized using Fourier-transform infrared (FT-IR), X-ray diffraction pattern (XRD), scanning electron microscopy-energy dispersive X-ray (SEM-EDX) and transmission electron microscope (TEM). In addition, the morphology of the mature biofilm and the inhibition of biofilm was monitored and visualized using confocal laser scanning microscopy (CLSM). The minimal inhibitory concentrations (MIC) and (IC50) of Griseofulvin alone and the prepared Ge-Nco against three different strains of Candida sp. were determined according to Clinical and Laboratory Standards Institute (CLSI) method. The effects of Griseofulvin alone and Ge-Nco on the tested Candida sp. biofilm formation were determined by the crystal-violet staining protocol. The biofilm inhibition potential of Ge-Nco against the tested Candida sp. was detected and depicted under CLSM (2.5 D view). The findings depicted that Ge-Nco was prepared in nanometer size (10–23 nm). The observed minimum inhibitory concentration (MIC) of Griseofulvin alone and Ge-Nco against three different Candida sp. were found to be in range 49.9–99.8 μg/mL and 6.24–12.48 μg/mL, respectively. These results provide evidence for implementing efficient antivirulence approaches against three different Candida sp. that would be less likely to foster the emergence of resistance.

Comparative study of oral terbinafine vs. oral griseofulvin in the management of tinea capitis

<p class="abstract"><strong>Background:</strong> Tinea capitis (TC) is a common dermatophyte infection affecting primarily prepubertal children. The present study has been designed to assess the clinico-etiological profile of the T capitis and to compare the efficacy and tolerability of terbinafine with griseofulvin.</p><p class="abstract"><strong>Methods:</strong> One hundred fifty eight patients of T. capitis were divided into two groups of 79 patients each to receive either oral griseofulvin or terbinafine (according to weight). Patients in both the groups were followed up at 2, 4, 12 and 36 weeks. At every visit, clinical improvement was evaluated using clinical assessment severity score and the compliance, tolerability and side effects of the drugs were assessed along with KOH microscopy, fungal culture from the lesion and relevant blood investigations.<strong></strong></p><p class="abstract"><strong>Results:</strong> The clinical assessment score were statistically similar in group G and group T at the start of therapy. The decline in scores in both treatment groups was statistically significant at each follow up visit. In griseofulvin group, the mean score was declined from 5.9 at baseline to 4.24 at week 2 and 2.79 at week 4, 0.82 at week 12 and 1.24 at 36 week. In the terbinafine group, the score had a mean of 6.23 at 0 week and 4.03 at week 2, 2.32 at week 4, 0.69 at week 12 and 0.83 at week 36.</p><p><strong>Conclusions:</strong> At follow up study long lasting tissue effect of terbinafine was found but effect of griseofulvin was waned at 36 week. So terbinafine may be better option with similar side effect profile but it is better in residual clinical and mycological effect at higher cost.</p>

Systemic antifungal therapy for tinea capitis in children.

Systemic antifungal therapy for tinea capitis in children.

Microsporum audouiniitinea capitis in a Swiss school: assessment and management of patients and asymptomatic carriers

We report three cases involving 7- to 8-year-old children from a Swiss school who had refractory tinea capitis due to an unusual strain of Microsporum audouinii which perforates hair in vitro. The patients showed no response to modern oral antifungal drugs like terbinafine and fluconazole. After switching to oral griseofulvin, two of the patients had a complete recovery, while the third was cured after the introduction of oral itraconazole. Given the high potential for contagion of this anthropophilic dermatophyte, all family members and three entire school classes were screened using the 'toothbrush technique'. Three family members and five class-mates were found to be asymptomatic carriers of M. audouinii and were consequently treated to avoid further transmission or reinfection of the treated patients. This is the first report of an outbreak of M. audouinii in Switzerland and underlines the importance of screening all contacts of patients with M. audouinii tinea capitis. Further, the effectiveness of griseofulvin in Microsporum tinea capitis has been corroborated, while newer antimycotic drugs like fluconazole or terbinafine failed.

The effect of griseofulvin on the gene regulation of β-tubulin in the dermatophyte pathogen Trichophyton rubrum

Griseofulvin - a mold metabolite produced by Penicillium griseofulvum - is an antifungal drug whose interaction with tubulin is poorly understood. In this study we cloned the beta-tubulin gene in Trichophyton rubrum, which encodes a polypeptide with 447 amino acids (accession number AAV33733). Nucleotide sequence comparison in data banks for both the partial DNA and its deduced amino acid sequence revealed significant homology with members of the eukaryotic beta-tubulin gene family. Investigation based on real-time polymerase chain reaction (PCR) indicated that griseofulvin treatment of T. rubrum fungal cells decreased the expression of the beta-tubulin gene in a dose-dependent manner. However, fluconazole had no effect on the beta-tubulin transcript level under the same circumstances. The identification of this vital gene, which is potentially involved in many cellular functions in pathogenic dermatophyte fungi, is the first step towards understanding the functional characteristics of beta-tubulin in such fungi and may help in the development of new antifungal drugs against dermatophytes.

Effects of griseofulvin in medium-term liver carcinogenesis assay and peripheral blood micronucleus test in rat.

Published data have suggested a possible link between the tumor promoting activity and the aneugenic properties of griseofulvin. The present study was conducted to explore this relationship. Griseofulvin was evaluated both for its potential promoting activity in liver carcinogenesis in partially hepatectomized F344 male rats initiated by diethylnitrosamine and for its genotoxic potential in the peripheral blood micronucleus assay. Rats were treated daily with 2,000 mg/kg body weight by oral gavage for 12 weeks in the medium-term carcinogenesis bioassay. GST-P-positive foci (mean number and surface area) and altered cell foci were compared in the liver of rats treated with griseofulvin alone, diethylnitrosamine alone,and griseofulvin in addition to diethylnitrosamine by using immunohistochemical and histopathological evaluation, respectively. This evaluation allowed the conclusion that griseofulvin did not initiate the carcinogenic process but rather had a potential in the liver for tumor promoting activity. Griseofulvin was found to be negative in the rat peripheral blood micronucleus test when given at a daily oral dose of 2,000 mg/kg body weight for at least 3 weeks.

Acute effects of griseofulvin on the pharmacokinetics and pharmacodynamics of warfarin in rats.

It has been reported that prothrombin time (PT), which is prolonged by warfarin, is reduced when patients on warfarin also take griseofulvin repeatedly. We investigated the cause of the drug interaction and the initial effects of griseofulvin on warfarin pharmacokinetics. Total cytochrome P-450, and the activities of aminopyrine N-demethylase, aniline p-hydroxylase and 7-ethoxycoumarin O-deethylase, after repeated administration of griseofulvin (100 mg/kg orally daily for 5 days) were examined. Acute effects of single doses of griseofulvin (100 mg/kg) on coagulation activity (prothrombin time) and warfarin pharmacokinetics after administration of warfarin were also studied. Repeated administration of griseofulvin induced warfarin-metabolizing enzymes. In contrast, a single administration of griseofulvin increased prothrombin time and serum warfarin concentrations. The activity of a warfarin-metabolizing enzyme (7-ethoxycoumarin O-deethylase) was reduced when griseofulvin was added to rat liver microsomes. The results suggest that reduced warfarin action after repeated administration of griseofulvin may be due to induction of warfarin-metabolizing enzymes, but that there is also an initial increase in warfarin action.

Toxic Effects of Griseofulvin: Disease Models, Mechanisms, and Risk Assessment

Griseofulvin (GF) has been in use for more than 30 years as a pharmaceutical drug in humans for the treatment of dermatomycoses. Animal studies give clear evidence that it causes a variety of acute and chronic toxic effects, including liver and thyroid cancer in rodents, abnormal germ cell maturation, teratogenicity, and embroyotoxicity in various species. No sufficient data from human studies are available at present to exclude a risk in humans; therefore, attempts were made to elucidate the mechanisms responsible for the toxic effects of GF and to address the question whether such effects might occur in humans undergoing GF therapy. It is well documented that GF acts as a spindle poison and its reproductive toxicity as well as the induction of numerical chromosome aberrations and of micronuclei in somatic cells possibly may result from disturbance of microtubuli formation. Likewise, a causal relationship between aneuploidy and cancer has been repeatedly postulated. However, a critical survey of the data available on aneuploidogenic chemicals revealed insufficient evidence for such an association. Conceivably, other mechanisms may be responsible for the carcinogenic effects of the drug. The induction of thyroid tumors in rats by GF is apparently a consequence of the decrease of thyroxin levels and it is unlikely that such effects occur in GF-exposed humans. The appearance of hepatocellular carcinomas (HCC) in mice on GF-supplemented diet is preceded by various biochemical and morphological changes in the liver. Among these, hepatic porphyria is prominent, it may result from inhibition of ferrochelatase and (compensatory) induction of ALA synthetase. GF-induced accumulation of porphyrins in mouse liver is followed by cell damage and necrotic and inflammatory processes. Similar changes are known from certain human porphyrias which are also associated with an increased risk for HCC. However, the porphyrogenic effect of GF therapy in humans is moderate compared with that in the mouse model, although more detailed studies should be performed in order to clarify this relationship on a quantitative basis. A further important effect of GF-feeding in mice is the formation of Mallory bodies (MBs) in hepatocytes. These cytoskeletal abnormalities occur also in humans, although under different conditions; their appearance is associated with the induction of liver disease and HCC. Chronic liver damage associated with porphyria and MB formation, enhanced cell proliferation, liver enlargement, and enzyme induction all may contribute to the hepatocarcinogenic effect of GF in mice. In conclusion, further investigation is required for adequate assessment of health risks to humans under GF therapy.

Variation of mouse oocyte sensitivity to griseofulvin-induced aneuploidy during the second meiotic division.

The effects of griseofulvin (GF) treatment during the second meiotic division of oogenesis were investigated by cytogenetic analysis of mouse one-cell (1-Cl) zygotes. After determining the duration of fertilization and the second meiotic division, 1500 mg/kg GF were administered to superovulated mice at 10, 12 or 14 h after human chorionic gonadotrophin (HCG) injection. The results showed that GF reduced the frequencies of fertilized oocytes (P < 0.01) and of 1-Cl zygotes that reached the first mitotic metaphase stage (P < 0.001). Aneuploidy was induced regardless of the moment of treatment, but the various treatment times were associated with statistically different (P < 0.05) levels of hyperdiploidy. The maximum frequency of hyperdiploidy (39.6%) occurred when GF was given 10 h after HCG. Polyploid 1-Cl zygotes were significantly induced only at the 10 and 12 h treatment times and their level never exceeded 1.8% of fertilized oocytes. GF also induced abnormalities of chromosome condensation along with centromeric chromosome associations. These results support the conclusion that GF treatment during the second meiotic division induced aneuploidy, polyploidy, and reduced rates of fertilization and zygotic development. Also, the time of chemical treatment influenced the frequencies of these effects.

Griseofulvin-induced aneuploidy and meiotic delay in female mouse germ cells. II. Cytogenetic analysis of one-cell zygotes

The effects of griseofulvin (GF) upon the first meiotic division of female mouse germ cells were evaluated by cytogenetic analysis of first-cleavage (1-Cl) zygotes. The present study is an extension of an investigation that began with the cytogenetic analysis of metaphase II (M II) oocytes. Different doses (200, 666, 1332, 2000 mg/kg) were tested by oral administration of GF to superovulated animals either at the time of human chorionic gonadotrophin (HCG) injection or 2 h post HCG. When GF was given at the time of HCG, significant dose-dependent increases of different types of cytogenetically abnormal cells were found. These included zygotes containing ostensibly female-derived M I or M II arrested chromosomes and polyploid zygotes. The total yields of these aberrations were 2.9, 4.3, 26.2, 60.6, and 64.1% for control, 200, 666, 1332, and 2000 mg/kg, respectively. The origin of these zygotes was attributed to the fertilization of oocytes that had been previously arrested at M I. No significant induction of hyperploidy was detected. Developmentally abnormal zygotes were still observed when GF was administered 2 h post HCG, although their frequencies were significantly lower than in the first series of experiments. The yields of developmentally abnormal zygotes were 49, 10.2, and 23.6% at 200, 666, and 2000 mg/kg. Additionally, a dose-dependent increase in the frequency of hyperploid zygotes was detected up to a maximum of 36.5% at 2000 mg/kg. These results confirm the cytogenetic observations from M II oocytes after GF treatment under the same experimental conditions; namely, a dramatic change in the oocyte target susceptibility to GF occurred within a short time period. Also, the present study demonstrated that most of GF-induced aneuploid oocytes were fertilized and reached first-cleavage metaphase.

Labelling in vivo and chirality of griseofulvin-derived N-alkylated protoporphyrins

1. We have compared the response to griseofulvin of rats and mice and, in mice, the effect of griseofulvin itself with that of two of its analogues. The severity of protoporphyria shows a correlation with the accumulation of both types of N-alkylated porphyrins previously described after treatment with this drug, namely N-methylproptoporphyrin and the N-griseofulvin protoporphyrin adduct. 2. Both N-alkylporphyrins are chiral, are labelled from 5-amino[4-14C]laevulinate, and their liver accumulation can be inhibited by pretreatment with a suicide substrate of cytochrome P-450, which also prevents porphyria. 3. These findings suggest that cytochrome P-450 is involved in the mechanism of griseofulvin-induced protoporphyria by generating N-methylprotoporphyrin. The N-griseofulvin protoporphyrin adduct may also originate from cytochrome P-450, but more work is necessary to elucidate whether it acts as the precursor for N-methylprotoporphyrin.

Effect of griseofulvin on lipid composition and membrane integrity inMicrosporum gypseum

The effect of griseofulvin on lipid constituents and membrane permeability of Microsporum gypseum has been investigated. Mycelia grown in medium containing griseofulvin (IC50 concentration) possessed a lower content of total lipids, phospholipids and sterols. This inhibitory effect was further supported by decreased incorporation of ( 14 C) acetate in total lipids, total phospholipids and sterols. Decrease in total phospholipids was also reflected to a varying extent in all individual phospholipids. An increase in the unsaturated to saturated fatty acid ratio was observed in mycelia grown in medium containing griseofulvin. Membrane permeability was affected by griseofulvin as shown by increased K + -efflux and greater leakage of intracellular ( 32 P) labelled components from prelabelled cells. Our results suggest that the antifungal activity of griseofulvin is partially due to its secondary effect on lipid constituents of Microsporum gypseum.

The effect of griseofulvin on the heme pathway—II. An exhaustive analysis during short and long-term challenge

1. A clear biphasic response of the enzyme activities as a function of intoxication time due to the topical cutaneous griseofulvin treatment was observed. 2. The initial acute induction of ALA-S activity would be due to depletion of free heme in the regulatory pool caused by cytochrome P 450 destruction. 3. The second induction peak, would be due to less heme formation, secondary to the ferrochelatase inhibition, as expected for the erythropoietic protoporphyria model. 4. The biphasic response of hepatic ALA-D and PBGase activities would be related to ALA-S activity changes and the subsequent augmented available substrates. 5. Endogenous liver porphyrin distribution in cytosolic, mitochondrial and nuclear fractions was investigated. 6. The in vitro biosynthesis of porphyrins confirmed both the biphasic model and the hepatic porphyrins subcellular distribution. 7. Two mechanisms to explain the action of griseofulvin at shorter and longer times of intoxication are proposed.

Effects of griseofulvin and nocodazole on the accumulation of autophagic vacuoles in ehrlich ascites tumor cells

Accumulation of autophagic vacuoles (AVs) is a phenomenon observed in various cells treated with the microtubule inhibitor vinblastine. In order to test whether the accumulation of AVs is a result of retarded fusion of autophagosomes and lysosomes an investigation was carried out to ascertain whether other antimicrotubular drugs, e.g., nocodazole and griseofulvin, also induce accumulation of AVs. Ehrlich ascites tumor cells were incubated with nocodazole (20 μg/ml) or griseofulvin (50 μg/ml). Morphometric analyses were performed after incubation periods of 3, 30, 60, and 120 min. The volume densities of autophagic vacuoles did not differ significantly from the control values after the various incubation periods tested. It was concluded that intact microtubules are not needed in the fusion of autophagosomes and lysosomes and that vinblastine accelerates the rate of AV formation.

The effect of griseofulvin on the heme pathway. Studies on tissue explant cultures

The effect of griseofulvin on porphyrin biosynthesis was studied in vitro and in vivo using liver and skin explants from mice. Neither porphyrin nor precursors accumulation was detected after in vitro treatment of explants with griseofulvin. Culture medium porphyrins formed from added σ-amino-laevulinic acid (ALA) were increased after oral chronic intoxication. Similar results were obtained by cutaneous and oral intoxication. Consequently griseofulvin topical application is proposed as an alternative method to produce experimental erythropoietic protoporphyria. Probable intoxication mechanism are proposed to explain the porphyrinogenic action of griseofulvin.

Therapeutic concentrations of griseofulvin do not affect yeast cell phagocytosis by monocytes.

The effect of griseofulvin on monocyte phagocytosis was assessed by studying the uptake of fluorescent yeast cells by glass-adherent monocytes (a fluorescence-quenching technique). In contrast to other microtubule antagonists, griseofulvin did not inhibit monocyte phagocytosis. It is suggested that the lack of griseofulvin interference with essential leukocyte functions is a possible explanation for the fact that the microtubule antagonist griseofulvin serves as a comparatively safe and harmless drug.

Effects of griseofulvin on enzymes associated with phase I and II of drug metabolism

Effects of griseofulvin on enzymes associated with phase I and II of drug metabolism

Griseofulvin-induced alterations in site of dividing nuclei and structure of septa in a dikaryon ofSchizophyllum commune

Ultrastructural study of a dikaryon of the basidiomyceteSchizophyllum commune showed that treatment with griseofulvin affected the site of the dividing nuclei and the location and structure of the septa. The microtubules were considered to be the primary target of griseofulvin, since they participate in nuclear division and movement in the hyphae, and their assembly is known to be in other organisms than fungi inhibited by griseofulvin. It is pointed out that dikaryotic hyphae with two nuclei and a clamp connection per cell are more sensitive indicators of the effect of griseofulvin than homokaryotic hyphae, whose structure is less complex.

Genetic effects of griseofulvin on plant cell cultures

Griseofulvin induces metaphase arrest and polyploidization in plant cells in culture; after which a process of chromosome segregation follows. During this process spontaneous or induced recessive mutations become expressed through the formation of homozygotes or monosomics. This finding can be of use whenever the isolation of recessive mutations is needed and haploid culture is difficult.

Effects of griseofulvin on cytology, growth, mitosis and branching of Polyporus arcularius

Griseofulvin had the following effects on the growth of hyphae of Polyporus arcularius : slowing of elongation rate, curling, increased branching. The distribution of nuclei and the sites of mitosis were altered by the drug, but the total number of nuclei in the entire apical system was unchanged. Little difference was seen in ultrastructure between treated and untreated hyphae.