Superficial fungal infections are common and treatment imposes economic burden on the patients. Government of India had introduced price control over griseofulvin and tolnaftate in 1995; however, this measure can only benefit the needy if the policy is harmonized with the health-care service provider, that is, dermatologists. The aim of this study was to evaluate the existing Government mechanisms over price control of antifungal medications and its reach to the people-in-need.A questionnaire-based, cross-sectional study was carried out over a period of 6 months. Questionnaire was mailed to members of a state branch of Indian Association of Dermatologists, Venereologists, and Leprologists. Responses reaching investigators within 2 months from the date of mailing were finally analyzed.Among 93 (41.33%) respondents, only 6 (6.5%) were aware of existing price control over griseofulvin but none about tolnaftate. Thirty-nine (41.9%) respondents were in favor of introducing price control on terbinafine and 42 (45.2%) for itraconazole. The topically preferred antifungals were primarily azoles and terbinafine, while among systemic antifungals, dermatologists mostly preferred fluconazole and terbinafine. The choice of antifungals by the dermatologists matched with the evidence-based dermatology data.Currently, price-controlled antifungal drugs are less commonly used by practitioners. Although the dermatologists favor price control, the initiative undertaken by the Government has not reached them. This shows the need to bridge the gap between policy makers and health-care service providers to help the ailing population.

Primary: to compare one-off administration of boric acid powder with courses of 1% acetic acid and ciprofloxacin eardrops in treating active chronic otitis media. Secondary: to evaluate the effectiveness of Quadriderm® cream in resistant active chronic otitis media; and to document side effects of these treatments, especially hearing loss.Randomised controlled trial.Outpatient department of a tertiary ENT unit.Hundred and fifty-nine patients over 6 years old with active chronic mucosal (without cholesteatoma) otitis media randomised to receive one of the three primary agents.All techniques employed were suitable for primary healthcare givers as well as specialists. After confirming eligibility, patients were randomly allocated to treatment. All ears underwent toilet with irrigation using clean water, a syringe and ambient light, with or without dry mopping, until the perforation was visible. The randomised solution was flushed through the middle ear and eustachian tube using a 'tragal pump' technique: saline was used as the solution for flushing in the boric acid powder arm. Patients allocated topical ear medication were given a bottle of eardrops to administer (six drops twice daily, 'pumped in') until finished. Those allocated boric acid powder had the external ear canals filled as a one-off treatment. Patients were followed up monthly thereafter.Primary: Dry (inactive) middle ears as assessed by the doctor. Secondary: Patient assessment of success; microbiologic culture and sensitivity; audiologic changes because of treatment; complications of treatment; costs of therapies.Ciprofloxacin eardrops and boric acid powder were statistically superior to 1% acetic acid eardrops in rendering active chronic otitis media inactive (73% dry ears for ciprofloxacin; 67% for boric acid powder; and 24% for acetic acid). There was no difference between the success rates of ciprofloxacin eardrops and boric acid powder. Quadriderm cream was effective in 85% of patients failing first-line therapy. No agent caused significant complications and specifically no hearing loss.This study showed a single application of boric acid powder following external auditory canal irrigation until the perforation was visible to be as effective as the current best practice of topical quinolone eardrops in active chronic otitis media. Boric acid powder is inexpensive and does not require patient compliance. Boric acid powder is a viable, less costly alternative to topical antibiotic/steroid ear drops in the developing world for active chronic otitis media. Acetic acid eardrops 1% are ineffective. Quadriderm cream, given as a one-off therapy, also appears to be effective.

Five fatty acids (oleic, linoleic, myristic, lauric and capric) were incorporated in 10% (w/w) into ointment formulation and their influence on lipophilic model drug tolnaftate release in vitro and enhancing effect on tolnaftate penetration into epidermis and dermis of human skin ex vivo were investigated. The prepared ointments were tested for homogeneity, pH and theological properties. In vitro release studies and ex vivo skin penetration experiments were carried out using Hanson and Bronaugh-type flow-through diffusion cells, respectively. Tolnaftate cumulative amount liberated from semisolids was assayed using UV-Vis spectrophotometer. After in vitro skin penetration studies, appropriately extracted human skin layers were analyzed for tolnaftate content using a validated HPLC method. Statistical analysis revealed that release rate of tolnaftate from control ointment and ointments with fatty acids was not significantly different and only 7.34-8.98% of drug was liberated into an acceptor medium after 6 h. Tolnaftate amount penetrating into 1 cm2 of epidermis from ointments containing oleic, linoleic, myristic and lauric acids was significantly greater (p < 0.05) than from the control ointment. Penetration enhancing ratios for these fatty acids for tolnaftate penetration into epidermis ranged from 1.48 to 1.75. In conclusion, fatty acids did not increase the liberation of tolnaftate from ointment formulation, but demonstrated their enhancing effect on tolnaftate penetration into human epidermis in vitro. Results from in vitro release experiments do not suit for prediction of the situation in the skin in vitro, if chemical penetration enhancers are incorporated into the ointment formulation.

Vibrational analysis of the thionocarbamate fungicide tolnaftate which is antidermatophytic, antitrichophytic and antimycotic agent, primarily inhibits the ergosterol biosynthesis in the fungus, was carried out using NIR FT-Raman and FTIR spectroscopic techniques. The equilibrium geometry, various bonding features, harmonic vibrational wavenumbers and torsional potential energy surface (PES) scan studies have been computed using density functional theory method. The detailed interpretation of the vibrational spectra has been carried out with the aid of VEDA.4 program. Vibrational spectra, natural bonding orbital (NBO) analysis and optimized molecular structure show the clear evidence for electronic interaction of thionocarbamate group with aromatic ring. Predicted electronic absorption spectrum from TD-DFT calculation has been compared with the UV-vis spectrum. The Mulliken population analysis on atomic charges and the HOMO-LUMO energy were also calculated. Vibrational analysis reveals that the simultaneous IR and Raman activation of the C-C stretching mode in the phenyl and naphthalene ring provide evidence for the charge transfer interaction between the donor and acceptor groups and is responsible for its bioactivity as a fungicide.

Abstract: Tolnaftate, an antifungal of thiocarbamate class, is used topically in 1% formulations. Its penetration into skin layers is a prerequisite for tolnaftate action against dermatophytes. The aim of this work was to optimize and validate a simple, rapid, accurate and reproducible procedure for tolnaftate assay in human skin samples and to apply this procedure for in vitro tolnaftate penetration studies. High performance liquid chromatography (HPLC) method with UV detection was used to validate tolnaftate assay for linearity, specificity, accuracy, precision, limit of quantitation, limit of detection, drug extraction recovery and stability in skin extracts. In vitro tolnaftate penetration studies were carried out using flow-through diffusion cells, mounted with human skin. Epidermis and dermis, separated by heat-separation method, were extracted using ultrasonication in methanol. Linear range of the analytical procedure was within 0.6-100 pg/mL. The assay was specific, accurate (within-day and between-day recovery values were 98.2-104.2% and 98.7-101.4%, respectively) and precise (within-day and between-day imprecision was = 3.8%). Mean extraction recoveries of tolnaftate from epidermis and dermis were satisfactory and reaching 90%. In vitro skin penetration studies revealed that after application of 1% (w/w) tolnaftate solution in polyethylene glycol 400 for 24 hours, the mean amount of tolnaftate penetrating into the epidermis and dermis was 2.60 +/- 0.28 microg/cm2 and 0.92 +/- 0.12 microg/cm2, respectively. A validated reliable HPLC method could be recommended for biopharmaceutical evaluation of tolnaftate preparations and studies of pharmacokinetics in human skin after in vitro penetration studies.

In animal models, chemical disruption of the Hedgehog (Hh) signaling pathway during embryonic development causes severe birth defects including holoprosencephaly and cleft lip and palate. The exact etiological basis of correlate human birth defects remains uncertain but is likely multifactorial, involving the interaction of genetic and environmental or chemical influences. The Hh transduction mechanism relies upon endogenous small molecule regulation, conferring remarkable pathway sensitivity to inhibition by a structurally diverse set of exogenous small molecules. Here, we employed small molecule screening to identify human exposure-relevant Hh signaling inhibitors. From a library of 4240 compounds, including pharmaceuticals, natural products, and pesticides, three putative Hh pathway inhibitors were identified: tolnaftate, an antifungal agent; ipriflavone, a dietary supplement; and 17-beta-estradiol, a human hormone and pharmaceutical agent. Each compound inhibited Hh signaling in both mouse and human cells. Dose-response assays determined the three compounds to be 8- to 30-fold less potent than the index Hh pathway inhibitor cyclopamine. Despite current limitations in chemical library availability, which narrowed the scope of this study to only a small fraction of all human exposure-relevant small molecules, three structurally diverse environmental Hh signaling inhibitors were identified, highlighting an inherent pathway vulnerability to teratogenic influences.

There presently exists a wide selection of choices in the treatment of superficial mycoses. The main categories of broad-spectrum agents are the allylamines and imidazoles, which have been tried and proven over more than 2 decades of usage with good safety. Nystatin and griseofulvin have even longer experience of about 5 decades but have niche usage for yeasts and dermatophytes, respectively. Although no new therapeutic groups have appeared, extensive development of vehicles and delivery systems has enhanced therapeutic results and increased patient compliance.

Aspergillus and Candida spp are the most frequently isolated fungi in patients with otomycosis. The diagnosis of otitis externa relies on the patient's history, otoscopic examination under microscopic control, and imaging studies. Direct preparation of the specimens, particularly with optical brighteners, mycologic culture, and histologic examination, is very important and strongly recommended for the correct diagnosis. Patients with noninvasive fungal otitis externa should be treated with intense débridement and cleansing, and topical antifungals. Topical antifungals, such as clotrimazole, miconazole, bifonazole, ciclopiroxolamine, and tolnaftate, are potentially safe choices for the treatment of otomycosis, especially in patients with a perforated eardrum. The oral triazole drugs, itraconazole, voriconazole, and posaconazole are effective against Candida and Aspergillus, with good penetration of bone and the central nervous system. These drugs are essential in the treatment of patients with malignant fungal otitis externa complicated by mastoiditis and meningitis.

Drug-membrane interactions play a crucial role in the pharmacology and activity of drugs. The measurement of drug association to lipid membranes has conventionally been measured by fluorescence and other spectroscopic methods. However, a main disadvantage of fluorescence labeling of drugs is that the introduction of fluorophores may change the molecules physical properties, such as charge, hydrophobic or hydrophilic character, and structure. To circumvent these problems, Ultraviolet-Visible Sum Frequency Generation (UV-Vis SFG) has been developed as an ultrasensitive and label-free technique to detect small-molecule drug association to lipid membranes. Four different classes of drugs, a nonsteroidal anti-inflammatory drug (ibuprofen), antibiotic (azithromycin), antifungal (tolnaftate), and local anesthetic (tetracaine), were examined. Drug association was measured on planar supported lipid bilayers (PSLBs) of 1,2-dioleoyl-sn-glycero-3-phophocholine (DOPC). Equilibrium association constants of the drugs were obtained and correlate well to the partition coefficients of the drugs in a liposome membrane-water system. UV-Vis SFG is a powerful and novel technique to directly measure the association of drugs to a single biological membrane without chemical modification.

An indirect spectrofluorimetric method with high sensitivity and selectivity was developed for the determination of antifungal drug: tolnaftate (TNF), depending on the supramolecular multi-recognition interaction among the anionic surfactant sodium laurylsulfate (SLS), beta-cyclodextrin (beta-CD) and beta-naphthol (ROH). The mechanism of the inclusion was studied and discussed by means of fluorescence spectrum, infra-red spectrograms and (1)HNMR spectroscopy. Results showed that the naphthalene ring of ROH and the hydrophobic hydrocarbon chain of SLS were included into the beta-CD's cavity to form a ROH:SLS:beta-CD ternary inclusion complex with stoichiometry of 1:1:1 at room temperature, which provided effective protection for the excited state of ROH. At lambda(ex)/lambda(em)=273/360 nm, the fluorescence intensity was linear over a tolnaftate concentration range of 2.46 x 10(-9) to 2.10 x 10(-6)mol L(-1). The detection limit and relative standard deviation was 7.50 x 10(-10)mol L(-1) and 1.4%, respectively. The interference of 31 foreign substances was slight. The proposed method had been successfully applied to the determination of tolnaftate in artificial mixed samples with almost quantitative recovery.