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Naphthalene, a cytotoxic moiety, is an extensively explored aromatic conjugated system with applications in various pathophysiological conditions viz. anticancer, antimicrobial, anti-inflammatory, antiviral, antitubercular, antihypertensive, antidiabetic, anti-neurodegenerative, antipsychotic, anticonvulsant, antidepressant. Naphthalene epoxides and naphthoquinones are most reactive metabolites of naphthalene and are responsible for the covalent interaction with cysteine amino acid of cellular proteins for cytotoxic nature. Many naphthalene derived bioactive phytoconstituents are present in nature including podophyllotoxins (Etoposide, teniposide), bis-ANS 82, Rifampicin, Justiprocumin A, B, Patentiflorin A. The naphthalene-based molecules, viz. Naphyrone, tolnaftate, naftifine, nafcillin, terbinafine, propranolol, nabumetone, nafimidone, naproxen, duloxetine, lasofoxifene, bedaquiline etc. have also been approved by FDA and are being marketed as therapeutics. Thus, the naphthalene scaffold emerges as an important building block in drug discovery owing to its broad spectrum of biological activities through varying structural modifications. This review incorporates the pharmacological aspects of different types of chemically modified naphthalene-based molecules along with their activity profile. This compiled information may serve as a benchmark for the alteration of existing ligands to design novel potent molecules with lesser side effects.

Large flat colorless needles of tolnaftate have been obtained from Tinactin, and have been shown to contain a 50:50 mixture of the (+ap,−sp,+ac,−ac) and (−ap,+sp,−ac,+ac) conformers. This finding fills a long-standing void in the structural chemistry of this classic anti­fungal compound, and suggests that prior theoretical models used to explain the spectroscopy, bioactivity, and mode of binding of tolnaftate to squalene epoxidase are probably inappropriate or suspect., Tolnaftate, a classic anti­fungal compound, has been found to crystallize from 1:1 (v/v) acetone–water as large flat colorless needles in the centrosymmetric monoclinic space group P21/c. These crystals contain a 50:50 mixture of the (+ap,−sp,+ac,−ac) and (−ap,+sp,−ac,+ac) conformers. The bond lengths in the central CNOS unit are 1.3444 (19), 1.3556 (18) and 1.6567 (15) Å for C—N, C—O and C—S, respectively, and the CNOS and C3N moieties are flat and nearly coplanar with each other, consistent with the C—N bond possessing partial double-bond character. Tolnaftate and the four most closely related N,N-di­substituted thio­carbamates in the Cambridge Structural Database (CSD) all exist as E-conformational isomers in the solid state. Among these five compounds, tolnaftate is the only one in which the N-tolyl moiety is positioned trans to the S atom, i.e. the N-aryl substituent in each of the other compounds is positioned cis to their respective S atom. Notably, and more importantly, our experimental X-ray structure is unlike all prior theoretical models available for tolnaftate. The implication, either directly or indirectly, is that some of those theoretical models used in earlier studies to explain the spectroscopic properties of tolnaftate and to suggest which protein–ligand inter­actions are responsible for the binding of tolnaftate to squalene epoxidase are either inappropriate or structurally unreasonable, i.e. the results and conclusions from those prior studies are in need of critical reassessment.

The present investigation deals with the formulation, optimization and evaluation of liquid crystalline cream of Tolnaftate. Brij-78 used as a surfactant, Cetostearyl alcohol was used as a co-surfactant and Silicon oil as a oil phase. Liquid crystalline cream system, has a potential for efficient delivery of Tolnaftate (1%), as topical dermal drug delivery system. The liquid crystalline system enhance the diffusion of water insoluble drug Tolnaftate through the skin for effective result. Liquid crystals (LC) are substances that flow like liquids but maintain some of the ordered structure characteristics of crystalline solids. Based on the ways that LCs are generated, they can be classified into two types 1) Thermotropic LCS and 2) Lyotropic LCs. Incorporation of the drug in liquid crystal increased its antimycotic activity against different antifungal microorganisms. Used surfactant enhance the penetration of drug and also improve the solubility of drug. The objective of this study was to increase the diffusion coefficient of drug through the formulation, and also to improve the availability of drug at the site of action. The prepared liquid crystalline cream exhibited the expected, viscosity, drug content, pH, spreadability, in vitro drug release and in vitro antimycotic inhibitory activity. Liquid crystalline cream for tolnaftate was found to be stable cream. It was found to have better in vitrorelease profile characteristics, and in vitro antimycotic activity, it can be concluded that the formulation F5 has better potential of antimicrobial activity and to enhance the diffusion of drug through the cream.

Antibody-Drug Conjugates (ADCs) consist of antibodies attached to cytotoxic small molecules or biological agents (i.e., payloads) through chemical linkers which may be cleavable or non-cleavable. The development of new ADCs is challenging, particularly the process of attaching the linker-payload construct to the antibody (i.e., the conjugation process). One of the major problems associated with conjugation is high hydrophobicity of the payload which can lead to low yields of the ADC through aggregation and/or lower than desired Drug-Antibody Ratios (DARs). We report here a UPLC-based assay that can be used to study the physicochemical properties of ADC payloads at an early stage of development, and to provide information on whether the hydrophilic-hydrophobic balance is suitable for conjugation or further physicochemical optimization is required. The assay is relatively simple to establish and should be of use to those working in the ADC area.

Objectives: Liposomes are colloidal particles formed as concentric bimolecular layers that are capable of encapsulating drugs. Liposomes have the potential for extending the duration of action for days or months. Tolnaftate is used as the topical antifungal agent. The purpose of this study was to provide the delivery of the topical drug at a sustained rate across intact skin to improve bioavailability. Methods: In present study, four different liposomes formulations of Tolnaftate were prepared by ethanol (solvent) injection method by varying the concentrations of phospholipids. The prepared liposomes were characterized for size, shape, entrapment efficiency, zeta potential, in-vitro drug release. Results: The % entrapment efficiency was found to be in the range of 90.24, 90.75, and 90.75%. The % entrapment efficiency of optimized batch LS4 was found to be 90.74 %. An in vitro drug release of about 82.114 % in 10 h was observed from optimum formulation of batch LS4. Conclusion: Based on different parameters like particle size, entrapment efficiency, drug release formulations of batch LS4 was selected as best formulation. Study concludes that Tolnaftate liposomes have potential for providing sustained delivery of drug. Peer Review History: Article received on- 15 November 2016, Revised on- 20 December, Accepted on- 3 January, Available online 15 January 2017 Academic Editor: Dr. Amany Mohamed Alboghdadly, Princess Nourah bint abdulrahman university, Riyadh, amalbgadley@pnu.edu.sa UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file: Reviewer's Comments: Average Peer review marks at initial stage: 4.0/10 Average Peer review marks at publication stage: 7.0/10 Reviewer(s) detail: Dr. Mahmut Yildiztekin, Mugla Sitki Kocman University, Turkey, mahmutyildiztekin@mu.edu.tr Dr. Mohamed Derbali, Faculty of Pharmacy, Monastir, Tunisia, mohamed.edderbali@gmail.com Similar Articles: FORMULATION AND EVALUATION OF ELASTIC LIPOSOMES OF DECITABINE PREPARED BY ROTARY EVAPORATION METHOD This article has been cited by: Wang S, Dong Y, Meng X. Expression and clinical significance of SERPINA3 and EFEMP2 in endometrial carcinoma. European Journal of Inflammation. January 2018. Pubmed

Tolnaftate is a thiocarbamate antifungal drug which is therapeutically active against dermatophytes that cause various forms of tinea. Due to the small amount of tolnaftate released from ordinary ointment bases and insufficient penetration through the infected skin layers the need to incorporate the drug in a more suitable pharmaceutical form has evolved. A provesicular system is one such form that can solve these problems. Once in contact with the skin, dilution with moisture occurs and the provesicular system rapidly transforms into a vesicular one. Provesicular systems were prepared according to full-factorial experimental design. Plain provesicular systems were compared with systems containing Phospholipon 80 H and Lipoid S45 as penetration enhancers. Design expert software was used to analyze the effect of formulation variables (type of Span used as well as the presence or the absence of the penetration enhancer and its type) on the dependent variables: percent encapsulation efficiency (EE%), vesicle size and percent in vitro drug released). Three formulations were chosen; a plain provesicular system (PV-2), one containing Phospholipon 80H (PV-6) and another containing Lipoid S45 (PV-10) with the goal to reveal the effect of penetration enhancer on morphology, rheological properties and ex vivo permeation using confocal laser scanning microscopy (CLSM). Analysis of CLSM results showed that the penetration enhancing effect for the tested formulations followed the order PV-10 PV-6 PV-2. Promising clinically active treatment for tinea patients could be expected as shown by the in vivo permeation results for the provesicular systems as suggested by the CLSM results.

Introduction: Prostate adenocarcinoma is the most frequently diagnosed malignancy, particularly for people >70 years old. The main challenge in the treatment of advanced neoplasm is bone metastasis and therapeutic resistance for known oncology drugs. Novel treatment methods to prolong the survival time and improve the life quality of these specific patients are required. The present study attempted to screen potential therapeutic compounds for the tumor through bioinformatics approaches, in order to provide conceptual treatment for this malignant disease. Methods: Differentially expressed genes were obtained from the Gene Expression Omnibus database and submitted into the Connectivity Map database for the detection of potentially associated compounds. Target genes were extracted from the search results. Functional annotation and pathway enrichment were performed for the confirmation. Survival analysis was used to measure potential therapeutic effects. Results: It was revealed that 3 compounds (vanoxerine, tolnaftate, and gabexate) may help to prolong the disease-free survival time from tumor metastasis of patients with the tumor. A total of 6 genes [also-keto reductase family 1 member C3 (AKR1C3), collagen type III α 1 chain (COL3A1), lipoprotein lipase (LPL), glucuronidase, β pseudogene 11 (GUSBP11), apolipoprotein E (APOE), and collagen type I α 1 chain (COL1A1)] were identified to be the potential therapeutic targets for the aforementioned compounds. Conclusion: In the present study, it was speculated that 3 compounds may function as the potential therapeutic drugs of bone metastatic prostate adenocarcinoma; however, further studies verifying vitro and in vivo are necessary.

Inspection of the electrochemical behavior tolnaftate (TNF), of a topical antifungal agent and its active hydrolysis products, was carried out by utilizing a disposable screen-printed carbon electrode (SPCE) for the first time. The voltammetric behavior of TNF was studied in various pH values using cyclic voltammetry and differential pulse voltammetry. A well-defined irreversible oxidation wave of TNF was observed at 1.20 V (vs. pseudo Ag/AgCl) and did not shift with different pH of solutions. The electro-analytical performance of the disposable SPCE was investigated in wide concentration ranges with limits of detection (LOD) of 0.24 μM and 3.76 μM in 0.1 M H2SO4 and B.R. buffer pH 7, respectively. Thus, the disposable SPCEs offer a sensitive and reproducible electrochemical platform for TNF in dosage forms. Further, the TNF was hydrolyzed in an alkaline medium to release its possible lethal products i.e. 2- Naphthol which can be analyzed voltammetrically without any interference so it is considered as a first selective stability-indicating assay for TNF.

Quadriderm cream was a combination of four components; Clioquinol (CLIO), Betamethasone (BETA), Tolnaftate (TOL), Gentamicin (GEN) in addition to the preservative Chlorocresol (CC). Four components CLIO, TOL, BETA, and CC were extracted in methanol and determined by mathematic filtration spectrophotometric techniques. The partially overlapped spectrum of CLIO was determined by constant value, constant multiplication, and concentration value methods then eliminated via spectrum subtraction (SS) to get the resolved ternary mixture of TOL, BETA, and CC with severely overlapping spectra. TOL was determined by derivative ratio at zero crossing point of BETA using CC as a divisor. While, BETA could be determined using TOL as a divisor at zero crossing of CC. BETA and CC were obtained using novel (DD1FS) followed by SS. By applying these novel procedures, the DD1 spectrum of each component alone was recovered where Pmax-min was directly proportional to its concentration. Liquid-liquid extraction technique was used for the semisolid dosage form where GEN was extracted with a mixture of chloroform: water (50:50, v/v); and the induced fluorescence obtained by derivatization with o-phthalaldehyde was measured at 419 nm after excitation at 359 nm. Accuracy and precision testing of the developed methods showed good results. Specificity of the methods was ensured and was successfully applied for the analysis of pharmaceutical formulation of the five components in combination. ICH guidelines were used for validation of the proposed methods. Statistical data were calculated, and the results were satisfactory revealing no significant difference regarding accuracy and precision.

Tolnaftate, a thionoester anti-fungal drug, was subjected to alkaline hydrolysis to produce methyl(m-tolyl)carbamic acid and β-naphthol (tolnaftate impurity A). N-Methyl-m-toluidine, tolnaftate impurity D, was synthesized and structurally elucidated along with tolnaftate alkaline degradation products using IR, H1 NMR and MS. Two stability-indicating HPTLC and RP-HPLC methods were developed and validated, for the first time, for determination of tolnaftate, its alkaline degradation products and toxic impurities in the presence of methyl paraben, as a preservative in Tinea Cure® cream. The proposed HPTLC method depended on separation of the studied components on TLC silica gel F254 plates using hexane-glacial acetic acid (8:2, v/v) as a developing system and scanning wavelength of 230 nm. The proposed RP-HPLC method was based on separation of the five components on an Eclipse plus C18 column. The mobile phase used was acetonitrile-water containing 1% ammonium formate (40:60, v/v), with a flow rate of 1 mL/min and detection wavelength of 230 nm. The proposed methods allowed the assay of tolnaftate toxic impurities, β-naphthol and N-methyl-m-toluidine, down to 2%, allowing tracing of β-naphthol that could be absorbed by the skin causing systemic toxic effects, unlike tolnaftate, indicating the high significance of such determination. International Conference on Harmonization guidelines were followed for validation.

© Ho and Zdilla 2018 Tolnaftate, a classic antifungal compound, has been found to crystallize from 1:1 (v/v) acetone–water as large flat colorless needles in the centrosymmetric monoclinic space group P21/c. These crystals contain a 50:50 mixture of the (+ap,−sp,+ac,−ac) and (−ap,+sp,−ac,+ac) conformers. The bond lengths in the central CNOS unit are 1.3444 (19), 1.3556 (18) and 1.6567 (15) Å for C—N, C—O and C—S, respectively, and the CNOS and C3N moieties are flat and nearly coplanar with each other, consistent with the C—N bond possessing partial double-bond character. Tolnaftate and the four most closely related N,N-disubstituted thiocarbamates in the Cambridge Structural Database (CSD) all exist as E-conformational isomers in the solid state. Among these five compounds, tolnaftate is the only one in which the N-tolyl moiety is positioned trans to the S atom, i.e. the N-aryl substituent in each of the other compounds is positioned cis to their respective S atom. Notably, and more importantly, our experimental X-ray structure is unlike all prior theoretical models available for tolnaftate. The implication, either directly or indirectly, is that some of those theoretical models used in earlier studies to explain the spectroscopic properties of tolnaftate and to suggest which protein–ligand interactions are responsible for the binding of tolnaftate to squalene epoxidase are either inappropriate or structurally unreasonable, i.e. the results and conclusions from those prior studies are in need of critical reassessment.

Introduction: Otomycosis, an infection of the ear canal by fungi, is prevalent in hot and humid weather. Nevertheless, there is not sufficient evidence for the effectiveness of different topical antifungal treatments. Tolnaftate, is a topical antifungal agent described to be effective in the treatment of otomycosis. Currently there are not sufficient studies that prove its efficacy. Objectives: To compare the efficacy of clotrimazole and tolnaftate administration in the treatment of otomycosis. Material and methods: A controlled, randomized and open clinical trial included patients diagnosed with fungal external otitis who were treated with topical antifungals, randomized into two treatment groups: (1) clotrimazole cream; (2) tolnaftate solution. They were microscopically evaluated at one and two weeks of treatment to determine resolution of disease. Recurrence and complications were recorded. Demographic and clinical variables were collected and analyzed. Follow-up and final outcomes (absence of infection) were compared between groups. Results: Forty eight patients were included, 28 in the clotrimazole group and 20 in the tolnaftate group. Spring was the weather most commonly associated with otomycosis, while otic manipulation was the risk factor more common in both groups. Predominant symptoms were itching and otic fullness. Aspergillus niger organism was isolated most frequently. Treatment with clotrimazole resulted in 75% resolution vs 45% resolution with treatment with tolnaftate at one week of treatment (p = 0.007). The Tolnaftate treatment group demonstrated higher recurrence rates and treatment failures, 20% and 15% respectively. Conclusions: Clotrimazole cream treatment is more effective than tolnaftate for uncomplicated otomycosis. More studies are needed to corroborate our results. Resumo Introdução: Otomicose, uma infecção fúngica do canal auditivo externo, é prevalente em climas quentes e úmidos. No entanto, a literatura não apresenta evidências suficientes sobre os diferentes tratamentos antifúngicos tópicos. O tolnaftato é um antifúngico tópico descrito como eficaz no tratamento da otomicose; entretanto, sua eficácia não está suficientemente comprovada. Objetivo: Comparar a eficácia do uso de clotrimazol e tolnaftato no tratamento da otomicose. Material e método: Ensaio clínico controlado e randomizado; incluiu pacientes diagnosticados com otite externa fúngica tratados com antifúngicos tópicos, randomizados em dois grupos de tratamento: 1) clotrimazole (creme); 2) solução de tolnaftato. Eles foram avaliados microscopicamente uma e duas semanas após o início do tratamento para avaliar a resolução da doença. Recorrência e intercorrências foram registradas; além disso, as variáveis demográficas e clínicas foram coletadas e analisadas. Os dados do acompanhamento e desfechos finais (ausência de infecção) foram comparados entre os grupos. Resultados: O estudo incluiu 48 pacientes, 28 dos quais foram alocados ao grupo clotrimazole e 20 ao grupo tolnaftato. A primavera foi a estação mais comum; a manipulação foi o fator de risco mais comum em ambos os grupos. Os sintomas mais comuns foram coceira e plenitude auricular. Aspergillus niger foi o micro-organismo mais comumente isolado. Após uma semana, o tratamento com clotrimazol apresentou uma taxa de resolução de 75% vs. 45% com o tratamento com tolnaftato (p = 0,007). O tratamento com tolnaftato apresentou maiores taxas de recidiva e falhas: 20% e 15%, respectivamente. Conclusões: Em casos de otomicose não complicada, o uso de clotrimazol (creme) é mais eficaz do que o de tolnaftato. Mais estudos são necessários para corroborar os presentes resultados.

Commentary on ‘A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts’ by Nobis M, Herrmann D et al., Cell Rep, 2017.

BET proteins such as Brd3 and Brd4 are chromatin-associated factors, which control gene expression programs that promote inflammation and cancer. The Nrf2 transcription factor is a master regulator of genes that protect the organism against xenobiotic attack and oxidative stress. Nrf2 has demonstrated anti-inflammatory activity and can support cancer cell malignancy. This review describes the discovery, mechanism and biomedical implications of the regulatory interplay between Nrf2 and BET proteins. Both Nrf2 and BET proteins are established drug targets. Small molecules that either activate or suppress these proteins are currently tested in clinical trials. The crosstalk between Nrf2 and BET proteins may have important, and until now overlooked, implications for the therapeutic effects of these drugs. Based on the information covered in this review, it should be possible to design combinatorial treatment strategies for cancer and inflammatory diseases, which may improve the efficacy of targeting a Nrf2 or BET proteins individually.

A comparative study using novel quadruple divisor and mean centering of ratio spectra spectrophotometric methods was developed for resolution of five- component mixture of Tolnaftate, β-naphthol (Tolnaftate alkaline degradation product and its toxic impurity), methyl(m-tolyl)carbamic acid (Tolnaftate alkaline degradation product), N-methyl-m-toluidine (Tolnaftate toxic impurity) and methyl paraben (as a preservative). For the novel quadruple divisor method, each component in the quinary mixture was determined by dividing the quinary mixture spectrum by a sum of standard spectrum of equal concentration of the other four components as a quadruple divisor. First derivative of each ratio spectra was then obtained which allowed selective determination of each component without interference from other components in the mixture. The second method was mean centering of ratio spectra that depended on utilizing the mean centered ratio spectra in four successive steps leading to enhancement of the signal to noise ratio. The absorption spectra of the five studied components were recorded in the wavelength range of 210–350 nm. The mean centered fourth ratio spectra amplitudes for each component were used for its determination. The developed methods were successfully applied for determination of laboratory prepared quinary mixtures to ensure method's specificity, then, were further applied on Tinea Cure® cream where no interference from excipients. For the first time, Tolnaftate was determined along with its toxic impurity; β-naphthol, that could be absorbed by the skin, causing systemic toxic effects, unlike Tolnaftate that poorly absorbed, indicating the significance of this work. The proposed methods were statistically compared with each other and with the reference method. Furthermore, ICH guidelines were followed for their validation.

Purpose: To validate a new and simple method for cleaning a manufacturing line for creams and ointments. Methods: The worst case product of the line chosen was a cream containing three practically insoluble ingredients: betamethasone, tolnaftate and cliquinol. The cleaning method utilized hot water and a commercial detergent, followed by rinsing. Validation methods included the visual inspection of the machine surface, swab sampling, microbial bioburden determination and testing the final rinse for conductivity, pH and total organic carbon (TOC) limits. Acceptance limit calculations depended on the figure tip unit (FTU). Results: No visual residue or chemical residue was detected above 674.37 ppm, which is the maximum allowable carry-over level of the drug. Similarly, microbial bioburden was < 25 CFU/swab - the acceptable limit. Conclusion: The method adopted to get rid of insoluble drug residue and microorganism from the cream and ointment production facility was successful. The method is simple and reproducible as indicated by the results of the three cleaning cycles. Keywords: Validation, Worst case product, Swab sampling, Finger-tip unit, Acceptance limits, Cream and ointment manufacturing line

A highly selective, sensitive, accurate, and reproducible luminescence procedure for determination of antifungal drug tolnaftate was developed. The introduced method was based on the formation of Europa Universalis III (Eu(III))-tolnaftate complex using sodium sulfite as a deoxygenated agent in the presence of acetate buffer (pH = 6) and micellar solution of anionic surfactant sodium dodecyl sulfate. The optimum conditions (effect of pH, buffer, surfactant, Eu(III), and sodium sulfite concentrations) for the luminescence signal were investigated and optimized. The luminescence signals were recorded at λex = 270 nm and λem = 460 nm. The method has a good linear response (0.2–130 μg/mL−1) between the luminescence intensity and the concentrations of the drug (r = 0.999), with a LOD 0.07 μg/mL−1 and LOQ 0.2 μg/mL−1. The luminescence signals of Eu (III)-tolnaftate-sodium dodecyl sulfate were found to be 200-fold more sensitive without the presence of micelle solution. The interferences of some additives, metals, amino acids, sugars, and other related pharmacological action drugs were examined and no interference was recorded. The proposed method was used for quick and simple determination of tolnaftate in its pharmaceuticals and biological fluids.

Several derivatives of substituted 1,2,4-triazole bearing the pyrazole (or oxadiazole) ring were synthesized via the reaction of 2,4-dihydro-4-benzyl-5-(isomeric pyridyl)-3H-1,2,4-triazole-3-thione 1a, 1b, 1c with ethyl chloroacetate, hydrazine hydrate, and acetyl acetone (or CS2/KOH) in absolute ethanol. The intermediate then undergoes an intramolecular cyclization in acidic medium. The newly synthesized compounds 4a, 4b, 4c to 7a, 7b, 7c were characterized using IR, NMR, and MS Spectroscopy. Some of the synthesized compounds 4,5,7a, 7b, 7c were evaluated for their antibacterial and antifungal activities. Most of these compounds indicated activity comparable to Gentamycine. Also some of them are more active than Tolnaftate, a known antifungal drug. J. Heterocyclic Chem., (2011)

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-β-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.

A highly, sensitive, indirect spectrophotometric method has been develop for the determination of tolnaftate in pharmaceutical preparations. The method is based on the oxidation of tolnaftate with Fe(III) in acidic medium. Fe (III) subsequently reduces to Fe(II),which is coupled with potassium ferricyanide after heating for 10 minutes at 70 0C to form prussian blue and the absorbance of the product was measured at 785 nm against a reagent blank. Beer's law was obeyed in the range of 0.02-0.16 ppm with molar absorptivity of 1.7 x106 L.mol-1.cm-1, relative standard deviation of the method was less than 2.5% and accuracy (average recovery %) was 100.3%. The effect of various factors such as temperature, heating time,concentration of reagents, and interferences were investigated to optimize the procedure. The proposed method has been applied for the determination of tolnaftate in pharmaceutical preparations (quadrim cream and topical solution). A statistical compartsion of these results with those of official method shows good agreement using "t" and "F" test at 95% confidence level. the results indicated that there is no systematic error and the present method has good validity.

Summary Haloprogin (2,4,5-trichlorophenyl-γ-iodopropargyl ether), a broad spectrum antimycotic, was investigated for its capacity to kill resting cells (micro- or macroconidia) of dermatophytes. The experimental conditions were such that a direct lethal action upon the spores could be detected. In contrast to tolnaftate, which did not exhibit such activity, haloprogin was sporicidal at 100 mg/ml for the following four species tested: Trichophyton mentagrophytes, Trichophyton ajelloi, Microsporum gypseumznd. Microsporum canis. The possible clinical implications of these findings are discussed. Zusammenfassung Die Untersuchungen sollten klaren, ob das synthetische Breitspektrum-Antimykotikum Haloprogin, chemisch ein (3-Jod-prop-2-in-yl)-(2,4,5-trichlor-phenyl)-ather, eine fungizide Wirkung auf Mikro-, bzw. Makrokonidien von Dermatophyten besitzt. Mit Hilfe der dabei angewandten Methode, eines Suspensionstestes, lies sich nachweisen, das Haloprogin ruhende Konidien der folgenden 4 Spezies Trichophyton mentagrophytes, Trichophyton ajelloi, Microsporum gypseum und Microsporum canis in vitro bei einer Konzentration von 100mg/ml abtotet. Die zurErzielung einer 99,9%igen Abtotungsrate erforderliche Kontaktzeit mit dem Antimykotikum betrug 24 bis 48 Stun-den. Tolnaftat, unter gleichen Bedingungen gepruft, wirkte nicht sporizid. In der Diskussion wird auf den moglichen klinischen Nutzen, der sich aus den experimentellen Befunden ergeben konnte, eingegangen.

Resume: 38 souches de Scopulariopsis brevicaulis isolees de prelevements au niveau de lesions de la peau et des phaneres sont testees comparativement a 3 souches de Scopulariopsis de reference, afin d'apprecier leur sensibilite aux antifongiques utilises dans le traitement des mycoses. Sont envisagees en utilisant les techniques de la C. M. I. (concentration minimum inhibitrice) sur trois milieux solides (Sabouraud, YMA, Casitone) les sensibilites vis-a-vis: - des antibiotiques: Nystatine, Amphotericine B, Pimaricine, Griseofulvine. - des derives imidazoles: Clotrimazole, Miconazole, Econazole, Isoconazole, Ketoconazole. - des antimetabolites: 5 FC - du Tolnaftate. Scopulariopsis brevicaulis possede generalement une grande resistance vis-a-vis des antifongiques. Parmi les antibiotiques testes la Griseofulvine et l'Amphotericine semblent inefficaces (C. M. I. sup. a 1000 γ/ml) la Nystatine possede une certaine activite (50 γ/ml) la Pimaricine etant la plus active (5 γ/ml). Parmi les produits chimiques la 5 FC et le Tolnaftate n'ont pas d'action (C. M. I. sup. a 1000 γ/ ml); par contre, les derives imidazoles possedent tous une efficacite certaine vis-a-vis de ce champignon dont le caractere pathogene est souvent discute. Summary: 38 strains of Scopulariopsis brevicaulis isolated from lesions of the skin and from cutaneous appandages were tested against antimycotics in comparison to 3 strains (2 S. brevicaulis, 1 S. brumptii) taken from culture collections. Minimal inhibitory concentrations were determined on different solid media using the following antifungals: nystatine, amphotericine B, pimaricine, griseofulvin, clotrimazole, miconazole, econazole, isoconazole, ketoconazole, 5-flucytosine, tolnaftate. In general, S. brevicaulis showed remarkable resistance against the antifugal substances. Among the antibiotics, griseofulvin and amphotericin B were without effect (MIC > 1000 μg/ml). Nystatine had some inhibitory activity (MIC = 50 μg/ml) while pimaricine was the most active substance (MIC = 5 μg/ml). Among the antimycotic chemicals, flucytosine and tolnaftate were ineffective while all the imidazoles had some inhibitory activity against this fungus whose role as pathogen is often discussed.

Zusammenfassung: In einer doppelblinden, kontrollierten und randomisierten Vergleidisstudie zwisdien zwei Patientengruppen zu je 10 Fallen mit Dermatomykosen wurden Wirkung und Vertraglidikeit von Piadar®-Tinktur mit Tonoftal®-Tinktur bei 2- bis 3maliger taglidier Anwendung wahrend einer 4wochigen Therapiedauer verglichen. Die auf die Diagnoseverteilung bezogene Ausgangslage war homogen. Bei der Mikroskopuntersudiung war in beiden Gruppen wirkungsmasig kein Unterschied nach-weisbar. Die Behandlungsdauer bis zur Negativierung (Mikroskopie und Kulturen) war bei beiden Praparaten gleich. Rotung, Schuppung und Juckreiz verschwanden praktisch vollstandig im zeitlidien Verlauf. Ein Untersdiied zwisdien den Praparaten (Wilcoxon-Test) besteht nicht, d. h. beide Substanzen waren bei guter Vertraglidikeit und dem Fehlen von Nebenwirkungen als gleich wirksam zu beurteilen. Klinisch hat sidi Piadar® bei Infektionen der Haut mit den besdiriebenen Erregern sowie mit Malassezia furfur bewahrt. Damit ist auch die Indikationsstellung fur die ortliche Anwendung von Piadar®, weldies systemisdi keine Wirkung zeigte, gegeben. Die Losung eignet sidi vorzuglidi fur die Behandlung intertriginoser Herde (submammar, Bauchfalten, Innenseite Obersdienkel). Die Dauer der Behandlung sollte sidi noch uber 8 Tage nadi erfolgter Abheilung erstrecken. Summary: The therapeutic effect and tolerance of Piadar® lotion in comparison to Tolnaftate solution were investigated in a double blind, controlled and randomized study. Two groups, each of 10 patients with dermatomycoses were subjected to 2 to 3 applications daily over a period of four weeks. Different diagnoses were equally distributed between the two groups. Microscopic controlls after treatment showed no differences between both groups. There was no difference in duration between both groups if the treatment was continued till microscopic and cultural tests were negative. During this time, erythema, scaling and itching disappeared completely, or almost so. According to the Wilcoxon test no difference between both drugs could be established, in other words: both drugs showed good tolerance, no side effects and equal efficacy. Clinically Piadar® proved to be useful in the treatment of fungal infections as mentioned, including those by Malassezia furfur. Thus, the range of topical applicability of Piadar® is characterized. The drug showed no systemic therapeutic effects. Piadar® lotion is especially useful for the treatment of intertriginous lesion (submammary, abdominal folds, genitocrural region). It is recommended to continue the treatment for another 8 days after clearing of the lesions clinically and mycologically.

Summary Mycological and histopathological studies were done on 200 pityriasis versicolor patients chosen at random. Pityrosporum spores and hyphae have been demonstrated in all cases through direct microscopical examination as well as in histopathological sections. Culturing succeeded in 71.2% of the cases on mycological agar with olive oil pipetted over the surface of the medium. Negative results were obtained in anaerobic atmosphere and when mineral oil was used. Subculture of the organism was successful in a fluid medium containing Czapek-Dox, yeast extract and Tween-20. Zusammenfassung Mykologische und histopathologische Untersuchungen wurden bei 200 nicht ausgesuchten Patienten mit Pityriasis versicolor durchgefuhrt. Sporen und Hyphen von Pityrosporum wurden in allen Fallen sowohl direkt mikroskopisch als auch in histopathologischen Schnitten nachgewiesen. Die Kultur gelang in 71,2% der Falle auf mykologischem Agar, auf dessen Oberflache Olivenol pipettiert worden war. Negative Ergebnisse wurden erzielt, wenn Mineralo1 verwendet wurde und in anaerober Atmosphare. Subkulturen gelangen in flussigem Medium aus Czapek-Dox-Losung, Hefeextrakt und Tween 80. Die Tatsache, das die gezuchteten Organismen in Kultur nur selten Hyphen bilden, kann durch den diphasischen Charakter erklart werden, d. h. der Organismus hat 2 Phasen: eine Hefeform und eine Mycelform; in der pathogenen Form im Gewebe werden sowohl Mycelien als auch Blastosporen gebildet, in Kultur jedoch im allgemeinen nur Blastosporen und selten Hyphen. Experimentelle Infektionen bei 20 Personen mit Hautgeschabsel oder Kulturmaterial von Pityrosporum orbiculare hatten keinen Erfolg. Dies stimmt mit den Befunden von Gordon uberein. Die direkten mikroskopischen Befunde und die kulturellen Untersuchungen waren negativ.

Summary: Short-term experiments on excised skin (human, pig) gave the following results: 1. In the tissue activity test with direct inoculation (D-TAT) commercial preparations of the non-azole antimycotics ciclopiroxolamine, tolnaftate and naftifine, produced higher inhibitory activity against Trichophyton mentagrophytes (standard strain) in various levels of the horny layer than were produced by the azole antimycotics econazole, miconazole, clotrimazole, oxiconazole and bifonazole. Fast drying solutions of antimycotics invariably gave higher inhibitory activities than creams. In the ultrafiltration tissue activity test (UFT- TAT) against Candida albicans (2 strains), antimycotic agents ranked in order of effectiveness as follows: ciclopiroxolamine – most of the azole antimycotics – bifonazole and naftifine. 2. In tests of fungicidal activity against T. mentagrophytes (2 strains) and Microsporum gypseum (1 strain) the first step was to inoculate the skin surface. After the horny layer had been penetrated by fungal mycelia, antimycotic agents of documented fungicidal potency, chiefly in the form of creams, were applied to the skin surface and left to act for up to 18 hours. The horny layer and epidermis were then scraped off and the concentration of viable fungi was determined. Ciclopiroxolamine cream and lotion produced by far the greatest diminution in viable fungi; creams containing oxiconazole and naftifine were moderately effective and those containing tioconazole and bifonazole produced a relatively small decrease in viable fungi. To avoid erroneous results it is important to homogenize and dilute the skin scrapings; if this is not done certain antimycotics will give misleadingly high fungal killing rates. At this early stage the scatter of results is still wide and minor differences in efficacy cannot as yet be detected with certainty. 3. From the results of various comparative tests it is evident that pig skin can be used as a substitute for human skin in the tests listed under 1. and 2. above. This discovery may make a valuable contribution towards limiting the need for experiments on living animals and trials on human beings. Zusammenfassung: In Kurzzeitversuchen an exzidierter Haut (Mensch, Schwein) wurde gefunden: 1. Im Gewebeaktivitatstest mit direkter Inokulation (D-GAT) wurde mit Handelspraparaten der Nichtazol-Antimykotika Ciclopiroxolamin, Tolnaftat und Naftifin in verschiedenen Hornschichtniveaus eine hohere Hemmaktivitat gegenuber Trichophyton mentagrophytes (Standard-Stamm) erzielt als mit solchen der Azol-Antimykotika Econazol, Miconazol, Clotrimazol, Oxiconazol und Bifonazol. Rasch trocknende Losungen von Antimykotika ergaben durchweg hohere Hemmaktivitaten als Cremes. Im Ultrafiltrations-Gewebeaktivitatstest (UFT-GAT) gegenuber Candida albicans (2 Stamme) ergab sich nach erzielter Wirksamkeit die Rangfolge Ciclopiroxolamine – Mehrzahl der Azolantimykotika – Bifonazol und Naftifin. 2. In Fungizidie-Testen gegenuber T. mentagrophytes (2 Stamme) und Microsporum gypseum (1 Stamm) wurde zunachst die Hautoberflache inokuliert. Nach Durchdringung der Hornschicht mit Pilzmyzelien wirkten auf die Hautoberflache bis zu 18 Stunden lang uberwiegend Cremes von als fungizid publizierten Antimykotika ein. Wahrend sich in abgeschabter Hornschicht und Epidermis der so bearbeiteten Hautoberflachen mit Ciclopiroxolamin-Creme und -Lotion die weitaus hochste Verminderung lebensfahiger Keime ergab, bewirkten Cremes mit Oxiconazol und Naftifin eine mittlere und solche mit Tioconazol und Bifonazol eine relativ niedrige Keimeliminierung. Zur Vermeidung von fehlerhaften Ergebuissen musten Homogenisierung und Verdunnung der Hautschabsel erfolgen, anderenfalls bei mehreren Antimykotika eine zu hohe Keimabtotung vorgetauscht worden ware. Wegen der vorerst noch hohen Streuung der Ergebnisse konnen kleinere Wirksamkeitsunterschiede noch nicht sicher erfast werden. 3. Nach dem Ergebnis verschiedener Vergleichstests kann in den Testen zu 1. und 2. Schweinehaut als Ersatz fur Haut vom Menschen dienen und durfte damit wesentlich zur Einschrankung von Versuchen am lebenden Tier und von Prufungen am Menschen beitragen.

A simple, rapid, reproducible, and economical HPTLC method has been established for analysis of tolnaftate in a topical solution. Silica gel 60 GF 254 HPTLC plates were used with toluene-chloroform 4:1 ( v/v ) as mobile phase; the retention factor was 0.59. UV detection was performed at 248 nm. Linear regression analysis showed response was a linear function of amount of tolnaftate in the range 100–400 ng per band. The amount of drug in the commercial formulation was 99.77 ± 0.86 and 99.54 ± 0.50% by peak height and peak area, respectively. Recovery of the drug, determined by the standard addition method, was 100.2 ± 1.0 and 99.59 ± 0.18%, again by peak height and peak area, respectively. The method was validated for accuracy, precision, and specificity.

An accurate and sensitive visible spectrophotometric method was developed and validated for the analysis of five antifungal drugs namely; clotrimazole, fluconazole, ketoconazole, miconazole nitrate and tolnaftate in pure as well as in their pharmaceutical dosage forms. This method was based on condensation of any of the cited drug with saturated solution of citric acid in anhydrous acetic anhydride in boiling water bath for about 20–30 min. The produced color was measured spectrophotometrically at 535 nm, after dilution with absolute ethanol. All variables affecting reaction conditions were optimized and the regression analysis of Beer’s plots showed good correlation coefficients (0.9996 - 0.9999) for the previously mentioned drugs in a general concentration range of 0.8–7 μg ml-1 with overall limits of detection and quantitation in the following ranges: 0.039–0.26 μg ml-1 and 0.13–0.87 μg ml-1, respectively. The proposed method has been applied successfully for the analysis of bulk drugs and their dosage forms such as topical powder and solution, oral and vaginal tablets, and topical creams. Overall percentage recoveries in the average range: 94.14–99.02% was obtained with considerable accuracy upon analysis of these dosage forms by the proposed method. No interference could be detected from betamethasone or dexamethosane, encountered excipients and additives. The obtained results have been compared with those obtained from reported and / or official method(s) and proper F- and t- values were observed; indicate no significance difference between the results of the proposed and reported methods. The good percentage recoveries and proper statistical data proved the efficiency of the proposed method for the analysis of the cited drugs in their commercial dosage forms with quite satisfactory precision.

Topical antifungal agents are not absorbed when given orally. They act by direct contact on the fungus, this type of action requires the simultaneous presence of antifungal and fungus for a minimum of time. There are a large number of compounds belonging to different families of antifungals: polyens, azoles, allylamine and morpholine and antiseptic substances. The treatment of oropharyngeal candidiasis is based on topical antifungal agents: amphotericin B or nystatin, imidazoles such as clotrimazole or miconazole. Systemic antifungal agents are indicated in case or poor compliance to topical agents, in prophylaxis of highly relapsing disease, in oesophageal candidiasis and in Candida onychomycosis. A topical antifungal agent is the first choice to treat Candida intertrigo. In any case predisposing factors should be eradicated or amended. Infection to Malassezia spp. are treated topically with azoles or selenium sulphur. Oral ketoconazole is an alternative in severe cases. Dermatophytosis requires a systemic antifungal treatment such as terbinafine in chronic, dry, moccassin type palmoplantar infection and for onychomycosis. Intertrigo and tinea corporis are treated with topical agents such as azoles, terbinafine or tolnaftate. Tinea capitis responds to oral griseofulvine, however a topical antifungal must be added to eradicate contagious conidia. Whatever the localisation is, an other superficial site of infection must be looked for and a source of infection should be investigated and eradicated.

We investigated the biochemical basis for resistance in six sequential clinical isolates of Trichophyton rubrum, from the same patient, which exhibited high-level primary resistance to terbinafine. Cellular ergosterol biosynthesis was measured by incorporation of [14C]acetate, and microsomal squalene epoxidase was assayed by conversion of [3H]squalene to squalene epoxide and lanosterol. Direct comparison was made with a terbinafine-susceptible reference strain of T. rubrum in which squalene epoxidase was previously studied. Resistant isolates displayed normal cellular ergosterol biosynthesis, although slight accumulation of radiolabeled squalene suggested reduced squalene epoxidase activity. Ergosterol biosynthesis in the resistant isolates was only inhibited by terbinafine concentrations above 1 microg/ml (IC50 5 microg/ml). In the reference strain, ergosterol biosynthesis was eliminated by terbinafine at 0.03 microg/ml in accordance with historical data. There was no significant difference in sensitivity between the six resistant isolates. Squalene epoxidase from resistant strains was three orders of magnitude less sensitive than normal enzyme to terbinafine (IC50 of 30 micromol/l and 19 n mol/l respectively). The epoxidase in the resistant strains was also unresponsive to tolnaftate. Resistance to terbinafine in these T. rubrum isolates appears to be due to alterations in the squalene epoxidase gene or a factor essential for its activity.

It is reported that antimycotic agents are effective for the treatment of patients with atopic dermatitis (AD). We studied in vitro effects of antimycotics on T helper-1 and T helper-2 cytokine production in anti-CD3 plus anti-CD28-stimulated T cells from AD patients and normal donors. The amounts of interleukin-4 (IL-4) and IL-5 secreted by anti-CD3/CD28-stimulated T cells were higher in AD patients than in normal donors. Azole derivatives, ketoconazole, itraconazole, miconazole and non-azole terbinafine hydrochloride and tolnaftate reduced IL-4 and IL-5 secretion without altering that of IFN-gamma and IL-2 in anti-CD3/CD28-stimulated T cells from both AD patients and normal donors. The azole derivatives were more inhibitory than non-azole antimycotics. These antimycotics reduced the anti-CD3/CD28-induced mRNA expression and promoter activities for IL-4 and IL-5. The cAMP analogue dibutyryl cAMP reversed the inhibitory effects of the antimycotics on IL-4 and IL-5 secretion, mRNA expression, and promoter activities. Anti-CD3/CD28 transiently (< or = 5 min) increased intracellular cAMP in T cells, and the increase was greater in AD patients than in normal donors. The increase of cAMP by anti-CD3/CD28 correlated with IL-4 and IL-5 secretion by anti-CD3/CD28. The transient cAMP increase was suppressed by antimycotics, and azole derivatives were more suppressive than non-azoles. Azole derivatives inhibited the activity of cAMP-synthesizing adenylate cyclase while terbinafine hydrochloride and tolnaftate enhanced the activity of cAMP-hydrolyzing cyclic nucleotide phosphodiesterase in AD and normal T cells. These results suggest that the antimycotics may suppress IL-4 and IL-5 production by reducing cAMP signal, and strengthen the concept of their potential use for the suppression of T helper-2-mediated allergic reactions.