Susceptibility of Trichophyton rubrum to griseofulvin

Two hundred and seventy isolates of Trichophyton rubrum from 182 patients were subjected to susceptibility testing with griseofulvin according to Granade & Artis. A slight modification of the method concerning homogenization procedures gave better growth of controls in our investigation. In 245 cases an MIC could be determined. Among these isolates, seven strains from six patients presented MICs between 2 and 3 micrograms griseofulvin per ml, a value which, according to Artis et al., is to be considered as relatively resistant. The other isolates proved to be more susceptible to griseofulvin. Three of the patients showed no indication of therapeutic failure of griseofulvin treatment. The other three patients had onychomycoses of long standing and had been treated with griseofulvin previously with little or limited success. It is our conclusion that griseofulvin susceptibility testing is not a reliable instrument in explaining failure of griseofulvin therapy in Trichophyton rubrum mycoses.     

Efficacy of topical griseofulvin in treatment of tinea corporis

Tinea infections are among the most common dermatological conditions throughout the world. Griseofulvin is a classical oral fungistatic antibiotic, active against Epidermophyton floccosum, Trichophyton and Microsporum species, the causative fungi of tinea corporis. To evaluate the efficacy of topical griseofulvin in the treatment of tinea circinata using three different vehicles for drug delivery. Sixteen patients with tinea circinata were instructed to apply either griseofulvin gel form in group A or a similar placebo gel for control group; a niosomal gel formulation of griseofulvin for group B or; a liposomal gel formulation of griseofulvin for group C. Patients were evaluated both clinically and mycologically after 3 weeks. Marked improvement was seen for groups A, B and C both clinically and mycologically while no improvement was observed in the placebo group. Mild and transient irritation was reported in four patients. Our results show that topical griseofulvin preparations may be effective and safe in treating tinea circinata and that further large-scale studies may establish the high efficacy of the niosomal gel formulation.     

In vivo efficacy of griseofulvin against multiple myeloma

We recently confirmed that ciclopirox olamine inhibits Wnt/beta catenin signalling in myeloma. Griseofulvin (GF) has similar chemical features as compared to ciclopirox olamine. In this study the anti-tumor effect of GF was investigated. GF demonstrated a major apoptotic activity in various human and murine myeloma and lymphoma cell lines as well as in human primary cells. In vivo, tumor growth as well as overall survival were significantly reduced in mice treated with GF as compared to untreated mice. In conclusion, our results reveal a significant selective induction of apoptosis by GF and suggest a significant in vivo effect against myeloma.     

Thyroid tumours in rats and hepatomas in mice after griseofulvin treatment.

Griseofulvin, an antibiotic used to treat dermatophystosis, was tested for carcinogenicity in mice, rats and hamsters. Three groups of mice and rats were given the drug in powdered diet in alternating 5-week periods for life, at dose levels of 3.0%, 1.5% and 0.3% (mice) and 2.0%, 1.0% and 0.2% (rats). A group of mice and 3 groups of hamsters received continuous daily treatment for life with griseofulvin at 3.0%, 1.5%, 0.3% and 0.1% dose levels respectively. A significant incidence of hepatic tumours was observed at the 2 higher treatment levels in mice. Also, statistically significant rates (P less than or equal to 0.001 and/or P less than or equal to 0.020) of thyroid tumours, indicating a dose-response, were recorded in male rats at the 2.0%, 1.0%, and 0.2% dose levels, and in females at the 2.0% and 1.0% dose levels. Hamsters did not develop neoplasms in response to treatment at any level.     

Modulation of hepatic heme-binding Z protein in mice by the porphyrogenic carcinogens griseofulvin and hexachlorobenzene

Some reports link human hepatic porphyria with a risk of hepatocellular carcinoma. Hepatic protoporphyria and uroporphyria were induced in mice by feeding griseofulvin and hexachlorobenzene (HCB), respectively. These chemicals also cause liver cancer. Hepatic immunoreactive cytosolic levels of heme-binding Z protein (HBP) were reduced by 81% (griseofulvin) and 55% (HCB). In contrast, both treatments caused a greater than 4-fold increase in the immunoreactive levels of glutathione S-transferase isozymes (GST) which like HBP also bind heme. Unlike in vitro studies in the presence of porphyrins, no cross-linking of HBP was observed in vivo.     

Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype-based screen

A major drawback of cancer chemotherapy is the lack of tumor-specific targets which would allow for the selective eradication of malignant cells without affecting healthy tissues. In contrast with normal cells, most tumor cells contain multiple centrosomes, associated with the formation of multipolar mitotic spindles and chromosome segregation defects. Many tumor cells regain mitotic stability after clonal selection by the coalescence of multiple centrosomes into two functional spindle poles. To overcome the limitations of current cancer treatments, we have developed a cell-based screening strategy to identify small molecules that inhibit centrosomal clustering and thus force tumor cells with supernumerary centrosomes to undergo multipolar mitoses, and subsequently, apoptosis. Using a chemotaxonomic selection of fungi from a large culture collection, a relatively small but diverse natural product extract library was generated. Screening of this compound library led to the identification of griseofulvin, which induced multipolar spindles by inhibition of centrosome coalescence, mitotic arrest, and subsequent cell death in tumor cell lines but not in diploid fibroblasts and keratinocytes with a normal centrosome content. The inhibition of centrosome clustering by griseofulvin was not restricted to mitotic cells but did occur during interphase as well. Whereas the formation of multipolar spindles was dynein-independent, depolymerization of interphase microtubules seemed to be mechanistically involved in centrosomal declustering. In summary, by taking advantage of the tumor-specific phenotype of centrosomal clustering, we have developed a screening strategy that might lead to the identification of drugs which selectively target tumor cells and spare healthy tissues.     

Induction of neoplasms in Egyptian toads Bufo regularis by oil of chenopodium.

Feeding the Egyptian toad Bufo regularis with oil of the chenopodium plant induced hepatocellular carcinomas in 23% of the animals, and metastases of the primary liver tumors appeared in the kidneys of 6 toads. The earliest evidence of tumors appeared after 3 months of treatment. The average latent period of tumor induction was 3.6 +/- 0.4 months. It is speculated that oil of chenopodium may be one of the constituents of Chenopodium ambrosoides which is responsible for tumor induction in the toads B. regularis.     

In vitro evaluation of griseofulvin against clinical isolates of dermatophytes from Isfahan

Fifty dermatophyte isolates, recently obtained from clinical materials, belonging to Trichophyton mentagrophytes, T. verrucosum, Microsporum canis and Epidermophyton floccosum were examined for their susceptibility to griseofulvin. The minimum inhibitory concentration (MIC) values were obtained using the modified microdilution method. All 100% tested isolates had MIC geometric mean at a concentration between 0.43 and 0.95 microg ml(-1) The MIC(90)s and MIC(50)s were 8 microg ml(-1) and <0.25-1 microg ml(-1) respectively. From all isolates, 12% including three T. verrucosum, one M. canis and two T. mentagrophytes isolates had MIC values out of the standardized range, therefore, they were considered as relatively griseofulvin-resistant. At least some of the isolates tested might be difficult to eradicate in clinical terms with griseofulvin treatment in Isfahan.     

Induction of breast neoplasia and lung granulomas in mice by an antifungal drug (griseofulvin)

Infiltrating duct carcinomas were induced in the mammary glands of 7 out of 60 experimental female mice force-fed with the antifungal drug griseofulvin, at a daily dose lever of 0.3 mg/30g body weight, for 12 months. The first mammary gland tumor appeared 8 months after the initiation of feeding. Other pathological changes such as bronchocentric granulomas appeared in some male and female treated animals (16.5%).     

In vitro susceptibility of dermatophytes from Munich to griseofulvin, miconazole and ketoconazole

Various recent clinical isolates of Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis and Epidermophyton floccosum from Munich were subjected to antimicrobial susceptibility testing using the microdilution method. Both azoles miconazole and ketoconazole were found to be more active than griseofulvin. Comparatively high inhibitory concentrations of griseofulvin were especially found with Tr. mentagrophytes. On the whole miconazole turned out to be even somewhat more effective than ketoconazole. Considering the minimum inhibitory concentrations found at least some of the strains tested might not be open to eradication in clinical terms with conventional treatment protocols.     

In vitro susceptibility of Trichophyton mentagrophytes arthroconidia to clotrimazole and griseofulvin in human corneocyte suspensions.

The use of corneocytes in suspension as a medium for the study of the effect of antifungal drugs on Trichophyton mentagrophytes arthroconidia was investigated. In the presence of clotrimazole or griseofulvin, arthroconidia germination in a suspension of corneocytes and in Sabouraud glucose liquid medium was significantly reduced compared with germination in drug-free media. Where antifungals were added to arthroconidia after an activation period during which germination occurred, any further germination was inhibited. The data showed that the growth of T. mentagrophytes in the presence of corneocytes offered a simple, rapid, inexpensive and relevant model for the assessment of antifungal activity of compounds for the treatment of dermatophytosis.     

Carcinogenic effect of force-feeding an extract of black pepper (Piper nigrum) in Egyptian toads (Bufo regularis)

50 male and 50 female Bufo regularis were treated, by force-feeding, with an extract of black pepper, at a dose level of 2 mg, 3 times a week for 5 months. The first tumors appeared after 2 months. Liver tumors (hepatocellular carcinomas, lymphosarcomas and fibrosarcomas) were found in 12 males and 18 females. Metastatic deposits of hepatocellular carcinomas were registered in the spleen, kidney, fat body and ovary.     

Management of the axilla in conservatively treated breast cancer: 592 patients treated at Institut Gustave-Roussy

Between June 1970 and April 1982, 592 patients with unilateral T1 and small T2 breast cancers were managed conservatively at the Institut Gustave-Roussy. The treatment policy for the axilla was to perform a lower axillary dissection and to proceed to axillary clearance ( +/- radiotherapy) in patients with axillary invasion by tumor (N+). Some N+ patients had only lower axillary dissection and radiotherapy. Five hundred fifty-eight patients underwent axillary surgery which was a lower axillary dissection in 374 patients (67%) and axillary clearance in 184 patients (33%). There was axillary invasion in 198 cases (36%). Only five patients relapsed in the axilla and the probability of axillary relapse at 5 years was 1.2%. There were no axillary relapses in N+ patients who had had an axillary clearance whether irradiated or not. The incidence of upper limb complications was significantly greater in patients undergoing axillary surgery and radiotherapy compared with axillary surgery alone (p less than 0.0001). It is concluded that a lower axillary dissection accurately identifies N-patients and an axillary clearance in N+ patients ensures good local control and avoids the morbidity associated with axillary irradiation.     

The use of toads (Bufo regularis) in a new biological assay for screening chemicals or drugs which induce leukaemia in man

Injection of Egyptian toads Bufo regularis, with adriamycin subcutaneously in the dorsal lymph sac at a dose level of 0.1 mg/toad, once every 3 weeks for 3 months induced pronounced alterations in the blood cells. These alterations were more or less similar to the criteria reported in human leukaemia. These changes were all comparable to those observed after the treatment of the experimental animals with the chemical carcinogen 7,12-dimethylbenz(a)anthracene. It is speculated that toads (Bufo regularis) can be used as biological test animals for screening chemicals or drugs which induce leukaemia in man.