Formulation and in vitro evaluation of carbopol 934-based modified clotrimazole gel for topical application.

The aim of present study was to enhance topical permeation of clotrimazole gel preparation by using various permeability enhancers such as coconut oil, pistachio oil and sodium lauryl sulphate (SLS). Clotrimazole gel preparations were prepared and optimized by using three factor, five level central composite design. A second-order polynomial equation was generated in order to estimate the effect of independent variables i.e. coconut oil (X1), pistachio oil (X2) and sodium lauryl sulphate (X3) at various dependent variables i.e. flux (Y1), lag time (Y2), diffusion coefficient (Y3), permeability coefficient (Y4), and input rate (Y5) of clotrimazole gel formulations. Ex vivo skin permeation study was performed through rat skin by using modified Franz diffusion cell system. Optimized formulation F8 exhibited highest flux 2.17 µg/cm2/min, permeability coefficient 0.0019 cm/min and input rate 1.543 µg/cm2/min, along with moderate lag time 77.27 min and diffusion coefficient 0.063 cm2/min, which is further supported by anti-fungal activity that exhibited more prominent zone of inhibition against Candida albicans, Aspergillus niger and Mucor. Thus, it can be concluded that permeation of clotrimazole gel was enhanced by various combination of coconut oil, pistachio oil and sodium lauryl sulphate but optimized formulation F8 containing 0.4 ml pistachio oil, 0.8 ml coconut oil and 0.04 g of SLS exhibited more pronounced and promising effect through rat skin.

Comparison of the efficacy of a novel sustained release clotrimazole varnish and clotrimazole troches for the treatment of oral candidiasis.

OBJECTIVES: Candida albicans is a common fungal infection and is commensal in 40-65 % of healthy adults. The development and pharmacokinetics of a novel sustained release clotrimazole varnish (Clot-SRV) for topical oral use have been reported. The aim of this study was to compare the efficacy of this varnish with clotrimazole troche treatment of oral candidiasis. MATERIALS AND METHODS: Of the 12 patients with denture stomatitis treated for 14 days, six used Clot-SRV (study group) and six clotrimazole troches (control). The patients were instructed to use Clot-SRV (50 mg of clotrimazole) once a day, and the control group was instructed to use five troches of 10 mg clotrimazole/day. Microbiological samples were obtained from saliva, buccal mucosa, palate, and denture. The degree of erythema was recorded at three time points, and subjective opinions noted using a questionnaire. RESULTS: At the end of the study, the control group had relatively more cases of erythema on all examined surfaces; patients who applied the Clot-SRV had significantly lower levels of candida on the denture surfaces and in saliva, and had better compliance to the medication. CONCLUSIONS: The novel clotrimazole sustained release varnish may be an important part of a new protocol for oral candidiasis, with improved clinical outcomes.

Evaluation of the supply of antifungal medication for the treatment of vaginal thrush in the community pharmacy setting: a randomized controlled trial / Evaluación del suministro de medicación antifúngica para el tratamiento de la candidiasis vaginal en la farmacia comunitaria: ensayo controlado aleatorizado

Background: The Pharmaceutical Society of Australia have developed “guidance” for the supply of several medicines available without prescription to the general public. Limited research has been published assessing the effect of these guidelines on the provision of medication within the practice of pharmacy. Objectives: To assess appropriate supply of nonprescription antifungal medications for the treatment of vaginal thrush in community pharmacies, with and without a guideline. A secondary aim was to describe the assessment and counseling provided to patients when requesting this medication. Methods: A randomized controlled trial was undertaken whereby two simulated patients conducted visits to 100 randomly selected community pharmacies in a metropolitan region. A product-based request for fluconazole (an oral antifungal that has a guideline was compared to a product-based request for clotrimazole (a topical antifungal without a guideline). The same patient details were used for both requests. Outcome measures of the visits were the appropriateness of supply and referral to a medical practitioner. Results: Overall 16% (n=16) of visits resulted in an appropriate outcome; 10% (n=5) of fluconozaole requests compared with 22% (n=11) of clotrimazole requests (chi-square=2.68, p=0.10). There was a difference in the type of assessment performed by pharmacy staff between visits for fluconazole and clotrimazole. A request for clotrimazole resulted in a significant increase in frequency in regards to assessment of the reason for the request (chisquare= 8.57, p=0.003), symptom location (chisquare= 8.27, p=0.004), and prior history (chisquare= 5.09, p=0.02). Conclusions: Overall practice was poor, with the majority of pharmacies inappropriately supplying antifungal medication. New strategies are required to improve current practice of community pharmacies for provision of non-prescription antifungals in the treatment of vaginal thrush (AU)

Antecedentes: La Sociedad Farmacéutica de Australia ha desarrollado una “guía” para el suministro de varios medicamentos sin prescripción al público general. Se ha publicado poca investigación evaluando el efecto de estas guías sobre la provisión de medicación en la práctica de la farmacia. Objetivos: Evaluar el suministro apropiado de antifúngicos sin receta para el tratamiento de candidiasis vaginal en farmacias comunitarias, con y sin guía. Un objetivo secundario fue describir la evaluación y el consejo proporcionado a los pacientes cuando solicitaban esta medicación. Métodos: Se realizó un ensayo controlado aleatorizado donde dos pacientes simulados condujeron visitas a 100 farmacias comunitarias aleatoriamente seleccionadas en una región metropolitana. Se comparó una solicitud de un producto con fluconazol (antifúngico oral que tiene guía) con una solicitud de un producto con clotrimazol (un antifúngico tópico sin guía). Los mismos datos de los pacientes fueron usados en ambas solicitudes. Las medidas de resultados en las visitas fueron la adecuación del suministro y la remisión al médico. Resultados: Un total de un 16% (n=16) de las visitas produjeron resultados apropiados; 10% (n=5) de fluconazol comparadas con el 22% (n=11) de clotrimazol (chi-square= 2,68, p=0,10). Hubo una diferencia significativa en el tipo de evaluación realizada por el personal de la farmacia entre las visitas del fluconazol y del clotrimazol. La solicitud de clotrimazol produjo un aumento significativo en la frecuencia de la evaluación de la causa de la solicitud (chi-square = 8,57, p=0,003), localización de los síntomas (chi-square= 8,27, p=0,004), e historia previa (chi-square = 5,09, p=0,02). Conclusiones: En general la práctica fue pobre, con la mayoría de las farmacias suministrando inadecuadamente la medicación antifúngica. Se requieren nuevas estrategias para mejorar la práctica actual de las farmacias comunitarias en el suministro de antifúngicos sin receta para la candidiasis vaginal (AU)

A novel sustained-release clotrimazole varnish for local treatment of oral candidiasis.

The use of dental varnish for therapeutic purposes has been reported for fluoride or antibacterial drugs. Our objectives were to develop a sustained-release varnish containing an antifungal drug (clotrimazole) for topical application and to evaluate the release rate of the drug in human saliva in comparison with an available commercial troche and their acceptance by healthy volunteers. Following in vitro optimization of the release rate from the varnish, we have embarked on a crossover comparative study assessing the oral sensations and pharmacokinetics of a 10-mg clotrimazole oral troche versus a 10-mg sustained-release clotrimazole varnish in 14 human volunteers over a period of 5 h. Saliva samples were assessed for clotrimazole concentration by high performance liquid chromatography analysis. The volunteers' evaluation of the varnish and troche (taste, other sensory changes, convenience, and oral suitability) were recorded. At all time points, salivary clotrimazole concentrations were higher, and the terminal half-life was significantly prolonged in the varnish group in comparison to the control group. This can be attributed to continuous release of clotrimazole from the varnish formulation. The duration of the drug over the minimal inhibitory concentration, following application of the varnish, was more than threefold longer than following administration of the troche. The developed sustained-release varnish can be applied in patients at a lower frequency than troches, thus, achieving higher patient compliance and efficacy. This novel varnish application can serve as the basis for a new treatment approach to oral candidiasis, a very common chronic opportunistic infection with improved clinical outcome.

Novel inhibitors of the Gardos channel for the treatment of sickle cell disease.

Sickle cell disease (SCD) is a hereditary condition characterized by deformation of red blood cells (RBCs). This phenomenon is due to the presence of abnormal hemoglobin that polymerizes upon deoxygenation. This effect is exacerbated when dehydrated RBCs experience a loss of both water and potassium salts. One critical pathway for the regulation of potassium efflux from RBCs is the Gardos channel, a calcium-activated potassium channel. This paper describes the synthesis and biological evaluation of a series of potent inhibitors of the Gardos channel. The goal was to identify compounds that were potent and selective inhibitors of the channel but had improved pharmacokinetic properties compared to 1, Clotrimazole. Several triarylamides such as 10 and 21 were potent inhibitors of the Gardos channel (IC50 of <10 nM) and active in a mouse model of SCD. Compound 21 (ICA-17043) was advanced into phase 3 clinical trials for SCD.

Preparation and evaluation of proliposomes containing clotrimazole.

Clotrimazole (CT)-containing proliposomes were prepared by penetrating an ethanol solution of CT and Egg phosphatidylcholine (PC) into microporous sorbitol particles, followed by vacuum evaporation of the solvent. As a result, CT proliposomes with free-flowing flowability were obtained. On contact with water, the proliposomes were rapidly converted into a liposomal dispersion, in which a certain amount of CT was entrapped by the liposomes. The result in scanning electronic micrograph confirmed the formation of liposomes structures from proliposomes, and the particles revealed round or ellipse. The ratio of drug to total lipid, ratio of PC to cholesterol and ratio of lipid to sorbitol affected the entrapment efficiency (EE%). The EE% of optimized formulation (CT 10 mg, 0.1 g total lipid, PC/CH ratio is 60 : 40 and 1 g sorbitol) in this investigation was 96.2+/-1.5%. The proliposomes system can provide sustaining release in simulated vaginal fluid at 37+/-1 degrees C for 24 h. In-vivo performance of blank proliposomes, a physical mixture of sorbitol and drug, clotrimazole proliposomes and commercial ointment formulation were evaluated using antifungal activity test. At 7 d post-dose, the c.f.u. of C. albicans decreased in proliposomes-treated groups than ointment and the physical mixture (t-Student, p<0.05). The results indicated that CT-containing vaginal proliposomes prolonged drug release and may increase amount of drug retention into the mucosa to result in more antifungal efficacy. In addition, CT-proliposomes did not affect the morphology of vaginal tissues. Therefore, the dosage form might be further developed for safe, convenient, and effective treatment of vaginal candidasis with reduced dosing interval.

An evaluation of a low-density DNA microarray using cytochrome P450 inducers.

The aim of this study was to validate a low-density DNA microarray "Rat HepatoChip", which contains 59 genes from a range of potential toxic markers and drug metabolism-related genes. Liver mRNA was isolated from rats dosed with six different chemicals, dexamethasone, troleandomycin, miconazole, clotrimazole, and methylclofanapate, which are all known to induce different cytochrome P450 genes, and isoniazid, which does not cause histopathological changes. Replicate microarrays were used to measure the variability in the chips and in the process. The average variability in signal between different chips observed in triplicate experiments was 33% ranging from 21 to 39% depending on genes. We also demonstrated a strong correlation between the liver histopathology and the gene expression profiles indicating that the gene expression profile reflects histopathological changes. These results suggest that the Rat HepatoChip microarray may provide a fast and effective tool for assessing the toxicity profile of developmental drug candidates during the drug discovery process.

Comparación de la eficacia y tolerancia del clotrimazol

En un estudio randomizado abierto, se comparó la eficacia y la tolerancia del Clotrimazol en una sola dosis de 500 mg con el Miconazol en una dosis de 1200 mg para el tratamiento de la micosis vaginal por Cándida albicans. Se tomaron dos grupos, el primero de 25 pacientes para recibir el tratamiento en estudio y el segundo de 28 pacientes para el control. Se analizaron los resultados clínicos a la 1§ y 4§ semanas de iniciado el tratamiento, tomando cultivos de control, en cada una de las visitas. Se comprobó la hipótesis que, para muestras con distribución similar, el Clotrimazol en una sola dosis de 500 mg es tan eficaz como el Miconazol en una dosis de 1200 mg. La tolerancia de ambos fue excelente