Poloxamer-enhanced solubility of griseofulvin and its related antifungal activity against Trichophyton spp

Abstract Poorly water-soluble drugs, such as the antifungal drug griseofulvin (GF), exhibit limited bioavailability, despite their high membrane permeability. Several technological approaches have been proposed to enhance the water solubility and bioavailability of GF, including micellar solubilization. Poloxamers are amphiphilic block copolymers that increase drug solubility by forming micelles and supra-micellar structures via molecular self-association. In this regard, the aim of this study was to evaluate the water solubility increment of GF by poloxamer 407 (P407) and its effect on the antifungal activity against three Trichophyton mentagrophytes and two T. rubrum isolates. The GF water solubility profile with P407 revealed a non-linear behavior, well-fitted by the sigmoid model of Morgan-Mercer-Flodin. The polymer promoted an 8-fold increase in GF water solubility. Fourier-transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), and 2D nuclear magnetic resonance (NMR Roesy) spectroscopy suggested a GF-P407 interaction, which occurs in the GF cyclohexene ring. These results were supported by an increase in the water solubility of the GF impurities with the same molecular structure. The MIC values recorded for GF ranged from 0.0028 to 0.0172 mM, except for T. Mentagrophytes TME34. Notably, the micellar solubilization of GF did not increase its antifungal activity, which could be related to the high binding constant between GF and P407.

A comparative clinical study on efficacy of terbinafine and griseofulvin in patients with tinea corporis

Background: The objective of the present study was to compare the efficacy of terbinafine and griseofulvin in patients with tinea corporis in a tertiary care hospital, Madurai.Methods: About 60 patients are selected from the outpatient department of Dermatology according to inclusion and exclusion criteria. They were divided into 2 groups of 30 patients each. Group 1 received tab. terbinafine 250 mg OD and group 2 received 250 mg BD for 4 weeks. All patients were investigated at baseline, end of 2nd week and at end of 4 weeks. Effectiveness of both the drugs were determined by achieving clinical as well as mycological cure. The results were recorded, tabulated and analysed using student抯 t test.Results: Patients in group 1 showed higher clinical and mycological cure rate when compared with group 2.Conclusions: Oral terbinafine is the effective antifungal agent in the treatment of extensive tinea corporis infection.

Effectiveness of modified Whitfield’s ointment with oral griseofulvin in the treatment of dermatophytosis poorly responsive to standard antifungal therapy: a randomized, double blind, within patient placebo control

Background:Dermatophytosis is a superficial fungal infection found in hot and humid areas particularly in tropical regions and affects thekeratinized regions of the body. It is usually treated with a combination of topical and systemic antifungal therapy as well as improved hygienic measures. Over the last few decades there has been an increase in the prevalence of dermatophyte infections which are poorly responding to standard antifungal therapy.Methods:Modified Whitfield’s ointment is a combination of 5%-5% Salicylic acid and Benzoic acid with an emulsifying ointment as a vehicle which has both a fungistatic and a keratolytic action. Oral Griseofulvin is a systemic antifungal agent which is a fungistatic agent. The combination of the above agents is synergistic. A randomized double blind, within-patient-placebo-controlled trial was designed for the treatment of dermatophytosis poorly responsive to standard antifungal therapy.Conclusions: This may shed light on the treatment of dermatophytosis poorly responsive to standard antifungal therapy.Trial Registration:This trial is registered with WHO trial registry number (Universal trial number): U111-1235-8791

In Vitro additive effect on griseofulvin and terbinafine combinations against multidrug-resistant dermatophytes

ABSTRACT Griseofulvin (GF) and terbinafine (TF) are commonly used drugs to treat dermatophytosis, a fungal infection of the skin. Today there is an increase in drug resistance to these antifungals which highlight the need for alternative synergistic therapies. Minimum Inhibitory Concentration (MIC) of GF and TF were determined against fungi clinical isolates from local hospitals with values ranging 0.03-2.0 µg mL-1 and 0.24-4.0 µg mL-1, respectively. A checkboard test was used to determine the combination of GF:TF which could induce an additive effect against the fungi isolates Multidrug-resistant isolates showed susceptibility after treatment with 16:2 µg mL-1 GF:TF. An MTT assay further verified that GF and TF combinations have greater additive effect against pathological and multidrug-resistant isolates than antifungals alone. Herein we disclose GF:TF combinations that could constitute as a possible new anti-dermatophyte therapy.

In-vitro antidermatophytic activity of essential oil of Psidium guajava (Linn.).

Dermatophyte with the ability to digest keratine invade and therve on keratinized of human and animals. In the present study, the activity of essential oil of Psidium guajava (Linn.) was evaluated against four selected dermatophytes, namely Microsporiumcanis, Trichophytomruburum, T. verrucossum, T. tonsurans. Dermatophyteswere isolated with the infected skin, scalp, nail and genital organs of patients from districts hospital, Bareilly. Griseofulvin was used as a standard antifungal drug against the test dermatophytes. Oil was extracted through clevenger’s apparatus. Maximum inhibition zone was reported 69 mm against T. verrucossum followed by 60 mm Trichophytomruburum, 48 mm Trichophytomruburum and 45mm Microsporiumcanis. All five concentrations of oil showed excellent inhibitory effect against all test dermatophytes as compared to standard antifungal used.

Inhibitory effect of griseofulvin on human prostate cancer PC-3 cells and Balb/c nude mice tumor xenograft / 中华泌尿外科杂志

Objective To study the anti-tumor effects of griseofulvin on human prostate cancer PC-3 cells both in vitro and in vivo. Methods PC-3 cells were treated with griseofulvin at various concentrations for48 h,cell survival rate was then measured by MTT assay.The changes of morphology were observed by fluorescence microscope; Annexin V-FITC apoptosis detection kit was used to detect apoptosis of the cells ; The enzyme activity changes of caspase-3,8,9 were detected by spectrophotometry.For in vivo study,we first established the PC-3 tumor model by grafting PC-3 cells in athymic nude mice,and then injected griseofulvin into the tumors.12 days after injection,the mice were sacrificed,the tumors were removed,weighed and the ratios of tumor-suppression were then calculated.We had detected the expressions of Bcl-2,Bax,p53 and Survivin with immumohistochemistry as well. Results MTT results showed that griseofulvin could significantly inhibit the proliferation of PC-3 cells in vitro in a dose-dependent manner,and the IC50 of griseofulvin was 18.17 ±2.10 μg/ml.Typical morphological changes of PC-3 cells were observed by microscope.The rates of apoptosis of griseofulvin treated PC-3 cells greatly increased compared with that of the control cells (31.37 ± 2.93％ vs 2.89 ± 0.67％,P ＜ 0.01 ).The caspase-3,caspase-8 and caspase-9 activities in griseofulvin treated PC-3 cells were significantly higher than those in control cells (0.562 ±0.050 vs0.113±0.014,0.337±0.053 vs 0.120±0.017,0.293±0.038 vs0.109±0.018,P＜0.01).On the 23th day after tumor vaccination,the tumor volume was 961.17 ± 78.12 mm3 in griseofulvin treated group and was 433.6 ± 12.8 mm3 in control group (P ＜ 0.01 ).The tumor weight was 742.50 ± 78.63 mg in griseofulvin treated group and was 1387.33 ± 71.47 mg3 in control group ( P ＜ 0.01 ).Bcl-2,Bax,p53 and Survivin protein expressions were 16.10 ± 3.45％,39.50 ± 6.88％,48.20 ± 8.04％,16.50 ± 2.22％ in griseofulvin treated group,respectively; 41.30 ± 3.95％,13.70 ± 2.98％,17.60 ± 3.21％,52.11 ± 6.28％ in control group,respectively.And there were significant differences in both groups (P ＜ 0.01 ).The in vivo data showed that griseofulvin suppressed the tumor growth conspicuously through down-regulating the expression of Bcl-2,Survivin,and up-regulating the expression of Bax,p53. Conclusions Griseofulvin can inhibit the growth of PC-3 and induce apoptosis of PC-3 cells.Griseofulvin inhibits the in vivo tumorigenicity of PC-3 cells.

Effects of Griseofulvin in the Treatment of Lichen Planus -A Study in BSMMU.

Lichen Planus (LP) is an inflammatory disorder of skin, mucous membranes, nails and hair. There are various modalities of treatment but none is curative. This prospective therapeutic trial was done among patients with lichen planus at the outpatient department of Dermatology & Venereology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka between November 2001 and April 2002. Total 20 patients were taken of them 12 were male and 8 were female with male to female ratio 3:2. Age of the patients was between 10 to 50 years. Patients were diagnosed clinically & confirmed histologically. They were treated with griseofulvin 500 mg daily for 6 months. Out of 20 patients, 8 had only oral lesions, of them 2 (25%) showed complete response, 3(37.5%) showed moderate improvement and 4 (37.5%) showed no response. Other 12 patients had lichen planus involving skin without oral mucosa, of them 4 (33.3%) showed moderate improvement, 4 (33.3%) showed no response and 4 (33.3%) patients worsens with treatment. So, success in patients with cutaneous lichen planus is less likely; however, griseofulvin may afford relief in selected patients with oral lesion. This study indicates that further prospective placebo controlled studies are needed to clarify the efficacy of griseofulvin in lichen planus.

Prescription auditing of griseofulvin in a tertiary care teaching hospital.

Background: Griseofulvin has been the mainstay of treatment for dermatophytosis since many years. Since it is a penicillium antibiotic and used commonly in the outpatient department, the prescription should be audited for its safety and quality. Clinical pharmacists being an important member of the healthcare system have an immense responsibility in delivering pharmaceutical care by auditing prescriptions in order to achieve rational and cost-effective medical care thereby improving patient's Quality of Life (QOL). Aims: To study the utilization of griseofulvin by auditing prescriptions, to assess the impact of griseofulvin on the QOL of patients and to emphasize role and responsibilities of a clinical pharmacist in the treatment outcome of dermatophytosis. Methods: 120 patients prescribed with griseofulvin in the dermatology outpatient department were included in the study. On the basis of therapeutic response, improvement was graded at the end of the treatment regimen. Adverse drug reactions (ADRs) during the treatment period were recorded. Laboratory investigations were performed at baseline and at the end of treatment. Quality of Life was measured at baseline and at the end of therapy. Results: 56.7% were females and 43.3% were males. The most common diagnosis was tinea corporis (44.17%) followed by tinea cruris (14.17%) and onychomycosis (9.17%). The most common ADR due to griseofulvin was headache (5.83%). 64.20% patients had complete cure following treatment with griseofulvin. The overall QOL score improved significantly following treatment with griseofulvin (P < 0.0001). Conclusion: Griseofulvin can be used extensively for the treatment of dermatophytosis as it has no serious adverse effects and has higher cure rates. Treatment with griseofulvin significantly improves the QOL in patients with dermatophytosis.

Erythema Nodosum Developed in a Child with Kerion Celsi / 대한피부과학회지

A 7 year-old boy visited our hospital with a 2 week history of inflammatory, pustular, tender patches and plaques on the right scalp and face area. He had been treated with topical steroid and antibiotics in a private clinic. In a KOH smear mount, multiple hyphaes and spores appeared on stratum corneum of the outer root sheath layer of his hair. The diagnosis of kerion celsi induced by dermatophytes was made. The patient was treated with oral griseofulvin, and on the 2nd day after starting treatment, multiple erythematous and tendered subcutaneous nodules occurred on his shin. A photosensitive dermatitis like lesion also occurred on his periorbital area. Griseofulvin changed to terbinafine. On the 6th day after treatment, the skin lesions on his face and scalp had improved, as had his shin lesions. The interest of this case lies in the unusual association of kerion and erythema nodosum, of which only eleven cases have been reported in dermatologic literature, and all cases were kerion induced Trichophyton species.

A Case of Plasma Cell Cheilitis / 대한피부과학회지

Plasma cell cheilitis is an idiopathic, benign, inflammatory mucosal condition characterized histologically by a dense band-like infiltrate of plasma cells in the upper dermis of the mucosa. In addition to the lips, the disease can affect the penis, vulva, buccal mucosa, palate, gingiva, tongue, epiglottis, and larynx. Plasma cell cheilitis of the lip appears as a circumscribed, flat to slightly elevated, eroded area, usually on the lower lip of an elderly person. We report a 70-year-old man who had a well-demarcated, erythematous, erosive lesion on his lower lip for 1 year. A biopsy specimen showed an upper dermal infiltrate that consisted mainly of plasma cells. Oral griseofulvin, 500mg/day, was begun, and 8 weeks later the lesion showed marked improvement.

Combination Therapy with Griseofulvin and Immunotherap (DNCB, DPCP)on Plane Warts / 대한피부과학회지

BACKGROUND: Although several kinds of treatment methods(destructive therapy, immunotherapy, etc) for plane warts have been attempted but there have been no entirely satisfactory treatments, because the plane wants are seen to recur frequently. OBJECTIVE: This study was aimed to evaluate the combination therapy of griseofulvin and immunotherapy(dinitrochlorobenzene=DNCB, diphenylcycloprope none=DPCP) on plane warts. METHOD: Sixteen patients(age range, 9 to 41; mean age, 21.8 years) with VPJ were treated with the combination therapy with griseofulvin(500mg/day) and single contact immunotherapy(DNCB or DPCP).

A Case of Generalized Lichen Planus Cured by Griseofulvin / 대한피부과학회지

Although a number of remedies like corticosteroids, retinoids, griseofulvin, PUVA, cyclosporine, antibiotics, dapsone, cyclophosphamide, surgery, methotrexate, radiation therapy, antimalarial drugs, psychotharapy and psychiatric medications have been used to treat lichen planus, there were no specific methods until now. We report herein an interesting case of lichen planus in which complete healing was achieved by griseofulvin administration. The patient was a 54-year-old male who for 3 months had variouly sized and shaped, flat-topped, scaly, violaceous papules and plaques on the whole of his body. We confirmed the patients disease as lichen planus by a histopathologic examination of a skin biopsy specimen and gave him 500mg ultramicronized griseofulvin daily in divided dosages. After 12 weeks of the medication nearly all of the skin lesions were regressed, and by 14 weeks all skin lesions had disappeared leaving hyperpigmentation. Up to now, l9 months after discontinuation of the medication, no recurrence of the disease has been noted.

Three Cases of Kerion Celsi Caused by Trichophyton tonsurans / 대한의진균학회지

We report three cases of kerion celsi caused by Trichophyton tonsurans in 16-year-old students of one high school wrestling team. The first case presented a 10x5cm and several 3~4cm sized, markedly inflammatory, boggy lesions on the scalp for 5 months. Other cases showed several 2~4cm sized, erythematous, follicular pustules and nodules with partial alopecia on the scalp for 2 months. Histopathology and results of mycologic study were consistent with kerion celsi due to Trichophyton tonsurans. All lesions were successfully treated with griseofulvin 500mg daily for 7~15weeks and short term therapy of low dose of prednisolone and cephadroxil.

A case of grideofulvin-induced phototoxic reaction / 대한피부과학회지

We report a case of a phototoxic reaction in a 48-year-old female induced by griseofulvin ingestion. The patient hac! erythematous papules, vesicles and patches on the sun-exposed areas. Phototest revealed a decreased minimal erythemal dose to UVA (10J/cm). Photopatch tests with 1%, 5%, 10% Griseofulvin ointment and vaseline as a control and photoingestion tests with Griseofulvin (50mg b.i.d.) were all negative. After the cessation of Griseofulvin, her skin lesions were markedly improved with complete loss of photosensitivity.

Effect of griseofulvin on lipid composition and membrane integrity in Microsporum 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 [14C] 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 [32P] 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.

Effect of ursodeoxycholic acid on experimental hepatic porphyria induced by griseofulvin

Griseofulvin(GF) has become the drug of choice as an antifungal agent for patients who suffer from many kinds of fungal infection. In order to clarify hepatic injury by griseofulvin(GF) overload and the effect of UDCA on GF-induced hepatic injury, the authors carried out biochemical, histologic, and ultrastructural studies of liver following treatment with griseofulvin and ursodeoxycholic acid(UDCA) in mice. Urine porphobilinogen excretion in the group treated with GF alone was significantly increased and reached the highest level in the 4th week and declined thereafter. Biochemical studies of the liver function showed no remarkable changes of serum bilirubin levels throughout the experimental period in all groups, except for SGPT and alkaline phosphatase activities which were significantly elevated and reached the highest level in the second week. Then they slightly decreased in GF treated groups(GF alone and GF plus UDCA) in comparison with the control group. Pathologic findings in the group treated with GF alone include focal liver cell necrosis(esp, zone 3), Mallory bodies in hepatocytes(esp, zone 1), Kupffer cell activation, and brown protoporphyrin pigments in the hepatocytes, bile canaliculi and interlobular bile ducts with a marked inflammatory cell infiltration in the portal tracts. Under the polarizing light microscope, bile ductular and canalicular thrombi showed a "Maltese cross" birefringence in mice treated with GF alone. There is no definite finding of fatty change in hepatocyte. Under the microscope, the liver appeared normal with an intact lobular architecture in the GF plus UDCA treated group. Electron microscopically, GF-induced changes include swelling of mitochondria, globular protoporphyrin crystals in the hepatocyte cytoplasm, markedly dilated bile cannaliculi and bile ducts and the formation of a Mallory hyaline bodies in the hepatocytes. There were no noticeable structural changes in the GF plus UDCA-treated group. Therefore the results suggest that GF causes hepatic injury, namely porphyria and cholestasis, and the treatment of UDCA may have cytoprotective and choleretic effects on GF-induced hepatic injuries.

Two Cases of Lichen Planus / 대한피부과학회지

We have experienced 2 cases of lichen planus. Case 1 was a. 76-year-old male who has suffered from discrete, scaly, round to polygonal papules on the trunk and the e:xtremiities for 3 months. The VDRL test for syphilis was reactive at a titer of 1:2 and the TPHA test was positive. The skin lesions were responded to 3 weekly injections of benzathine penicillin 2.4 million units, Case 2 was a 17-year-old male who has suffered from discrete, erythematous to violaceous colored, flat papules on the right shin for several months. He has treated with oral medication of griseofulvin. After 2 weeks of the medication, the skin ]esions showed improvement with gradual reduction of pruritus and flattening of the papules. About one month of the medication, all skin lesions cliappeared with dark brownish hue and hypopigmentation. And recurreci lesions after stopping medication are disappeared after 2 months of retreatment with griseofulvin.