Development and evaluation of wafer loaded with sertaconazole solid dispersion for the treatment of oral candidiasis

Abstract Candidiasis is one of the most common fungal infections of oral cavity in humans, causing great oral discomfort, pain and aversion to food. To develop more effective antifungal systems for the treatment of oral candidiasis, an oral mucoadhesive wafer containing sertaconazole solid dispersion (STZ-SD) was developed in this study. Dispersion of STZ in Soluplus® as a solubility enhancement excipient was done by melting, solvent evaporation and freeze drying method at various STZ to Soluplus® ratios. The optimized STZ-SD was then incorporated in the sodium carboxymethyl cellulose (SCMC) gel, xanthan gum gel, or their combination to prepare the lyophilized wafers. The swelling capacity, porosity, and mechanical, release and mucoadhesive properties of the wafers, together with their antifungal activity, were then evaluated. The melting method sample with the ratio of 8:1 showed the best results in terms of saturation solubility and dissolution rate. The STZ-SD-composite wafer exhibited higher hardness and mucoadhesion, as compared to those made of the SCMC polymer. The STZ-SD-wafer also exhibited a greater antifungal effect when compared to the STZ-wafer. The present study, thus, suggested that the STZ-SD-wafer could serve as a novel effective delivery system for oral candidiasis treatment.

Avaliação in vitro do potencial erosivo e cariogênico de antifúngicos tópicos / In vitro evaluation of erosive and cariogenic potential of topical antifungal agents

Introdução: a candidíase é uma infecção fúngica oportunista, causada pela proliferação e disseminação de espécies de Candida, que pode acometer a cavidade oral. Dentre os antifúngicos mais utilizados e de uso tópico, a nistatina é considerada o medicamento de primeira escolha. Objetivo: avaliar as propriedades físico-químicas de diferentes marcas de nistatina disponíveis no mercado, incluindo o pH, a acidez total titulável (ATT) e a determinação de sólidos solúveis totais (SST). Metodologia: trata-se de um estudo experimental in vitro, constituído por uma amostra de oito diferentes marcas de nistatina em suspensão oral de uso tópico. Foi analisado o potencial erosivo e cariogênico dessas soluções mediante a determinação de pH, ATT e SST (°Brix). Resultados: no tocante ao pH, verificou-se que a média obtida foi de 6,05 (± 0,66). Dois dos medicamentos analisados (marcas A e H) apresentaram pH abaixo do crítico para a dissolução do esmalte dental. Quanto à ATT das soluções, os valores variaram de 1,9 a 14,53 mL para atingir o pH neutro, indicando que as marcas B, C e E podem levar mais tempo para ser neutralizadas em razão da quantidade de solução necessária. A análise do °Brix revelou que a marca H apresentou o maior teor de açúcares em sua composição (44,9%). Conclusão: a formulação de nistatina da marca H apresentou pH endógeno mais crítico e percentual de sólidos solúveis totais elevado, sendo, portanto, a medicação com maior fator de risco para o desenvolvimento de cárie e erosão dentária, devendo ser consideradas as doses e frequências de uso, bem como os hábitos de higiene oral do paciente

Introduction: candidiasis is an opportunistic fungal infection caused by the proliferation and spread of Candida species that can affect the oral cavity. Among the most commonly used topical antifungal agents, nystatin is considered the first choice drug. Methodology: to evaluate the physical and chemical properties of different brands of nystatin available in the market, including pH, titratable acidity and determination of total soluble solids. Results: Regarding pH, it was verified that the mean obtained was 6.05 (± 0.66). Two of the analyzed drugs (A and H) presented pH below that considered critical for the dissolution of dental enamel. As for the titratable total acidity of the solutions, values ranged from 1.9 to 14.53 mL to reach neutral pH, indicating that the B, C and E marks may take longer to neutralize because of the amount of solution required. The analysis of ° Brix revealed that the H mark had the highest sugar content in its composition (44.9%). Conclusion: Nystatin brand H presented the worst indices in terms of endogenous pH and total sugar percentage, being therefore the medication with the highest risk factor for the development of caries and dental erosion.

Factores relacionados a candidiasis oral en niños y adolescentes con VIH, caracterización de especies y susceptibilidad antifúngica / Factors related to oral candidiasis in HIV children and adolescents, species characterization and antifungal susceptibility

Resumen Introducción: Se desconocen los factores asociados a la candidiasis oral en población pediátrica con infección por VIH de los países en desarrollo. Objetivo: Identificar los factores asociados a la colonización por Candida, candidiasis oral y la susceptibilidad in vitro a antifúngicos, en niños y adolescentes con infección por VIH institucionalizados en la ciudad de Tijuana, México. Materiales y Métodos: Se examinó la cavidad oral de 30 niños y adolescentes con infección por VIH, se obtuvo una muestra de la mucosa oral para identificar las especies de Candida mediante cultivo y auxonograma. La susceptibilidad a los antifúngicos se determinó de acuerdo al CLSI. Los indicadores del estado inmunológico y falla virológica se clasificaron conforme a la OMS. Resultados: Se identificaron seis especies de Candida, 53% colonizantes y 47% causantes de candidiasis. Los factores asociados a candidiasis fueron alta carga viral (p = 0,001), menor recuento de LTCD4+ (p = 0,002) y esquema TARAA (p ≤ 0,014). La especie prevalente fue C. glabrata (33%); sin embargo, C. albicans (27%) fue más resistente a fluconazol (p = 0,001). Las especies resistentes a itraconazol se identificaron en esquemas que incluyen un INNTR (p = 0,041). Conclusiones: Los niños y adolescentes con infección por VIH institucionalizados mostraron una prevalencia elevada de Candida spp. colonizante y resistencia a los antifúngicos relacionada con los INNTR .

Background: Factors associated with candidiasis and colonization in HIV-positive children and adolescents in developing countries are not well understood. Aim: To identify the factors associated with oral Candida colonization and candidiasis in institutionalized HIV-positive children and adolescents in Tijuana, México, as well as the response of the isolates to antifungals. Materials and Methods: Sample of the oral mucosa of 30 HIV positive children and adolescents were obtained to isolate and identify Candida species by culture and metabolic profile. Antifungal drugs susceptibility was determined according to CLSI. Indicators of immunological and virologic failure were classified in accordance to WHO criteria. Results: Six Candida species were identified from oral mucosa, 53% colonizers and 47% in candidiasis. Factors associated with candidiasis and oral colonization were viral load (p = 0,001), CD4+ counts (p = 0,002) and HAART regimen (p ≤ 0,014). The most prevalent species was C. glabrata (33%), but C. albicans (27%) was more resistant to fluconazole (p = 0,001). Itraconazol resistant species were identified in regimens that include an NNRTI (p = 0,041). Conclusion: HIV-positive children and adolescents living in an orphanage showed high prevalence of colonizing Candida spp. and resistance to antifungals, related to NNRTI.

Oral colonization by Candida species in HIV-positive patients: association and antifungal susceptibility study / Colonização oral por espécies de Candida em pacientes HIV positivo: estudo de associação e suscetibilidade antifúngica

ABSTRACT Objective To investigate antifungal susceptibility and factors associated with oral colonization by Candida species in HIV-positive patients. Methods A prospective study based on convenience sampling of subjects recruited from a pool of confirmed HIV-positive individuals seen at a specialty outpatient service in Rondonópolis, Mato Grosso, Brazil). Oral swabs were collected from 197 patients. Candida species were identified by standard microbiological techniques (phenotypic and molecular methods). Antifungal susceptibility was investigated using the broth microdilution method. Results A total of 101 (51.3%) patients were Candida spp carriers. Candida albicans was the most prevalent species (80%). Patients aged 45 to 59 years (Prevalence ratios: 1.90; 95%CI: 1.57-6.31) and 60 years or older (Prevalence ratios: 4.43; 95%CI: 1.57-34.18) were at higher risk of oral colonization by Candida species. Resistance to fluconazole and ketoconazole, or to itraconazole, corresponded to 1% and 4%, respectively. Conclusion Age (45 years or older) was the only factor associated with oral colonization by Candida . Low rates of antifungal resistance to azoles were detected in yeast isolates obtained from HIV-positive patients. Findings of this study may contribute to proper therapeutic selection for oral candidiasis in HIV-positive patients.

RESUMO Objetivo Investigar a suscetibilidade a antifúngicos e os fatores associados à colonização oral por espécies de Candida isoladas de pacientes HIV positivo. Métodos Estudo prospectivo realizado com amostragem por conveniência de indivíduos HIV positivo, acompanhados por um serviço de atendimento especializado da cidade de Rondonópolis, Mato Grosso, Brasil. Foram coletados swabs orais de 197 pacientes. As espécies de Candida foram identificadas por técnicas microbiológicas fenotípicas padrão e por método molecular. A suscetibilidade antifúngica foi determinada pelo método de microdiluição em caldo. Resultados Cento e um (51,3%) pacientes foram colonizados por Candida spp. Candida albicans foi a espécie mais prevalente (80%). Identificou-se um maior risco de colonização oral por espécies de Candida em pacientes com idade entre 45 e 59 anos (razão de prevalência: 1,90; IC95%: 1,57-6,31) e 60 anos ou mais (razão de prevalência: 4,43; IC95%: 1,57-34,18). A resistência ao fluconazol e ao cetoconazol foi de 1% cada e de 4% ao itraconazol. Conclusão O único fator associado à colonização oral por espécies de Candida foi ter 45 anos ou mais. Identificamos baixa taxa de resistência antifúngica aos azóis entre as leveduras isoladas de pacientes HIV positivo. Estes achados podem contribuir para selecionar o tratamento da candidíase oral em pacientes HIV positivos.

Clinical trial for evaluation of Ricinus communis and sodium hypochlorite as denture cleanser

Abstract The development of opportunistic infections due to poor denture hygiene conditions justified the search for effective hygiene protocols for controlling denture biofilm. Objective This study evaluated Ricinus communis and sodium hypochlorite solutions in terms of biofilm removal ability, remission of candidiasis, antimicrobial activity, and participant satisfaction. Material and Methods It was conducted a controlled clinical trial, randomized, double-blind, and crossover. Sixty-four denture wearers with (n=24) and without candidiasis (n=40) were instructed to brush (3 times/day) and immerse their dentures (20 min/day) in different storage solutions (S1 / S2: 0.25% / 0.5% sodium hypochlorite; S3: 10% R. communis; S4: Saline).The trial period for each solution was seven days and a washout period of seven days was used before starting the use of another solution. The variables were analyzed at baseline and after each trial period. The biofilm of inner surfaces of maxillary dentures was disclosed, photographed, and total and dyed areas were measured (Image Tool software). The percentage of biofilm was calculated. Remission of candidiasis was assessed by visual scale and score were attributed. Antimicrobial activity was assessed by the DNA-Checkerboard hybridization method. Patient satisfaction was measured using a questionnaire. Results S1 (4.41±7.98%) and S2 (2.93±5.23%) were more effective then S3 (6.95±10.93%) in biofilm remotion(P<0.0001). All solutions were different from the control (11.07±11.99%). S3 was the most effective solution in remission of candidiasis (50%), followed by S1 (46%). Concerning antimicrobial action, S1/S2 were similar and resulted in the lowest microorganism mean count (P=0.04), followed by S3. No significant differences were found with patient's satisfaction. Conclusions 10% R. communis and 0.25% sodium hypochlorite were effective in biofilm removal, causing remission of candidiasis and reducing the formation of microbial colonies in denture surfaces. All solutions were approved by patients.

Extracellular phospholipase production of oral Candida albicans isolates from smokers, diabetics, asthmatics, denture wearers and healthy individuals following brief exposure to polyene, echinocandin and azole antimycotics

Abstract Objective Candida albicans is the primary causative agent of oral candidosis, and one of its key virulent attributes is considered to be its ability to produce extracellular phospholipases that facilitate cellular invasion. Oral candidosis can be treated with polyenes, and azoles, and the more recently introduced echinocandins. However, once administered, the intraoral concentration of these drugs tend to be sub-therapeutic and rather transient due to factors such as the diluent effect of saliva and cleansing effect of the oral musculature. Hence, intra-orally, the pathogenic yeasts may undergo a brief exposure to antifungal drugs. We, therefore, evaluated the phospholipase production of oral C. albicans isolates following brief exposure to sub-therapeutic concentrations of the foregoing antifungals. Materials and methods Fifty C. albicans oral isolates obtained from smokers, diabetics, asthmatics using steroid inhalers, partial denture wearers and healthy individuals were exposed to sub-therapeutic concentrations of nystatin, amphotericin B, caspofungin, ketoconazole and fluconazole for one hour. Thereafter the drugs were removed and the phospholipase production was determined by a plate assay using an egg yolk-agar medium. Results The phospholipase production of these isolates was significantly suppressed with a percentage reduction of 10.65, 12.14, 11.45 and 6.40% following exposure to nystatin, amphotericin B, caspofungin and ketoconazole, respectively. This suppression was not significant following exposure to fluconazole. Conclusions Despite the sub-therapeutic, intra oral, bioavailability of polyenes, echinocandins and ketoconazole, they are likely to produce a persistent antifungal effect by suppressing phospholipase production, which is a key virulent attribute of this common pathogenic yeast.

Obtenção de gel mucoadesivo de nistatina para o tratamento da candidíase oral. Desenvolvimento e caracterização de dispersões sólidas de nistatina / Mucoadhesive gel obtaining nystatin for the treatment of oral candidiasis. Development and characterization of solid dispersions of nystatin

A nistatina (NYS) é o fármaco de primeira escolha no tratamento da candidíase oral, que frequentemente acomete mais os indivíduos imunocomprometidos e pacientes com outras desordens (diabetes não tratada, neoplasias, imunodeficiências). No mercado brasileiro, a NYS é encontrada na forma de suspensão oral aquosa, onde o procedimento para sua administração consiste em bochechar o medicamento. Apesar de haver a indicação de que se mantenha o contato direto entre fármaco e a mucosa oral, na qual se encontra a Candida spp., o que aumentaria expressivamente o sucesso terapêutico, a suspensão não apresenta tal propriedade. Assim, a NYS que é fármaco com ação efetiva contra a candidíase oral, é considerada pertencente à Classe IV do Sistema de Classificação Biofarmacêutica, ou seja, apresenta baixa solubilidade e baixa permeabilidade. A baixa solubilidade pode comprometer sua disponibilidade na cavidade oral, e consequentemente, sua ação farmacológica. Diante desse quadro, o objetivo do presente trabalho foi o desenvolvimento de dispersões sólidas de NYS para o tratamento da candidíase oral, e sua posterior incorporação em gel mucoadesivo oral, favorecendo a formulação no local de ação. As dispersões sólidas são sistemas farmacêuticos, onde um fármaco pouco solúvel em água encontra-se dispersado em um carreador, no estado sólido. Os carreadores normalmente são hidrofílicos, o que permite que esses sistemas sejam empregados para aumentar a solubilidade aquosa do fármaco. Assim, foram desenvolvidas as dispersões sólidas de NYS, pelo método de eliminação do solvente, empregando como carreadores, lactose, HPMC, poloxamer 407 e poloxamer 188. Essas foram submetidas à caracterização por análise térmica, usando os ensaios de calorimetria exploratória diferencial (DSC) e termogravimetria/termogravimetria derivada (TG/DTG). Dentre essas dispersões sólidas, aquelas que se mostraram com comportamento térmico sugerindo a formação de um novo "sistema", foram analisadas por meio de ensaio de solubilidade. Dessa forma, a formulação NYS DS G2 (49) se destacou, pois apresentou maior solubilidade em água (4,484 mg/mL); em pH 5,5 (4,249 mg/mL) e em pH 7,0 (4,293 mg/mL), ou seja, houve um aumento de 1,426 vezes em água; 4,227 vezes em pH 5,5; e 2,743 vezes em pH 7,0. Essa formulação foi, por fim avaliada por difração de raio-X e espectroscopia de infravermelho com transformada de Fourier, técnicas que corroboraram com a análise térmica quanto à indicação de formação da dispersão sólida. Por sua vez, essa dispersão sólida foi incorporada em 4 bases de géis mucoadesivos de carbopol ® 934 PNF, alterando apenas a concentração do polímero (0,5; 1,0; 1,5; 2,0 %p/p). Foi observado que a liberação de NYS DS G2 (49) foi superior, quando comparada à liberação de NYS MP a partir do gel, e através do ensaio de mucoadesão, percebeu-se que os géis desenvolvidos apresentaram propriedades mucoadesivas compatíveis com relatos na literatura, independentemente da quantidade de carbopol ® empregada. As características reológicas foram distintas, e foi observado que as formulações Gel A e Gel B, que possuem menor quantidade de polímero, tiverem um indicativo de comportamento de fluido newtoniano, diferente dos demais, o que pode não ser desejado para esse tipo de forma farmacêutica tópica e semi-sólida. Ao final desse trabalho, pode-se concluir que foi possível desenvolver um sistema farmacêutico na forma de dispersão sólida com maior solubilidade que a NYS pura, e sua incorporação em uma forma farmacêutica mucoadesiva, e que a liberação da NYS na forma DS foi muito superior que o fármaco na forma "convencional", o que permite que a NYS esteja mais disponível na cavidade oral, e também junto à mucosa bucal, o que levaria a efeito farmacológico mais efetivo do antifúngico

Nystatin (NYS) is the drug of first choice in the treatment of oral candidiasis that most often affect immunocompromised individuals, and patients with other disorders. In the Brazilian market, NYS is found in the form of aqueous oral suspension, a medication used in the form of mouthwash. Although there is an indication to maintain direct contact between the drug and the oral mucosa, where Candida spp. is found, as well as where therapeutic success would significantly be increased, the suspension has no such property. Thus, the NYS is an effective drug against oral candidiasis, and belongs to Class IV of the Biopharmaceutical Classification System, it has low solubility and low permeability. The low solubility can compromise its availability in the oral cavity, and consequently, its pharmacological action. Given this situation, the objective of this work was the development of solid dispersions of NYS for the treatment of oral candidiasis, and its subsequent incorporation into oral mucoadhesive gel, in order to facilitate its action. Solid dispersions are pharmaceutical systems, in which a solid drug poorly soluble in water is dispersed in a carrier. These carriers are usually hydrophilic, and this allows the systems to be employed in order to increase the aqueous solubility of the drug. Thus, the solid NYS dispersions were developed by the solvent evaporation method, employing lactose, HPMC, poloxamer 407 and poloxamer 188 as carrier. These samples were subjected to characterization by thermal analysis, using differential scanning calorimetry (DSC) and thermogravimetry / derivative thermogravimetry (TG / DTG). Among these solid dispersions, those samples which showed a specific thermal behavior suggesting the formation of new "system" were analyzed by solubility test. Thus, the NYS DS G2 formulation (49) stood out, once it showed greater solubility in water (4.484 mg/mL); at pH 5.5 (4.249 mg/mL) and pH 7.0 (4.293 mg/mL), in other words, an increase of 1,426 times in water; 4,227 times at pH 5.5; and 2,743 times at pH 7.0. This formulation was finally evaluated by X-ray diffraction, infrared spectroscopy with Fourier transform, techniques that corroborate the thermal analysis, indicating the formation of the solid dispersion. On the other hand, this solid dispersion was incorporated into 4 Carbopol ® 934 PNF mucoadhesive gels, with a variation of the polymer concentration. It was observed that NYS is improved of delivery from the gels, employing mucoadhesion test, and was also observed that the gels have mucoadhesive properties consistent with reports in the literature. However, the rheological characteristics are different, and it was observed that the Gel A and Gel B formulations, which has a lower amount of polymer behaved as a Newtonian fluid, which may not be desired for this type of topical gel. As conclusion, it was possible to develop a pharmaceutical system in the form of solid dispersion with greater solubility than the pure NYS, and their incorporation in a mucoadhesive dosage form and the release of NYS as DS was far superior wherein the drug in the "conventional" manner, which allows the NYS is longer available in the oral cavity, and also adjacent to the buccal mucosa, leading to more effective pharmacological effect of the antifungal agent

Obtenção de gel mucoadesivo de nistatina para o tratamento da candidíase oral. Desenvolvimento e caracterização de dispersões sólidas de nistatina / Mucoadhesive gel obtaining nystatin for the treatment of oral candidiasis. Development and characterization of solid dispersions of nystatin

A nistatina (NYS) é o fármaco de primeira escolha no tratamento da candidíase oral, que frequentemente acomete mais os indivíduos imunocomprometidos e pacientes com outras desordens (diabetes não tratada, neoplasias, imunodeficiências). No mercado brasileiro, a NYS é encontrada na forma de suspensão oral aquosa, onde o procedimento para sua administração consiste em bochechar o medicamento. Apesar de haver a indicação de que se mantenha o contato direto entre fármaco e a mucosa oral, na qual se encontra a Candida spp., o que aumentaria expressivamente o sucesso terapêutico, a suspensão não apresenta tal propriedade. Assim, a NYS que é fármaco com ação efetiva contra a candidíase oral, é considerada pertencente à Classe IV do Sistema de Classificação Biofarmacêutica, ou seja, apresenta baixa solubilidade e baixa permeabilidade. A baixa solubilidade pode comprometer sua disponibilidade na cavidade oral, e consequentemente, sua ação farmacológica. Diante desse quadro, o objetivo do presente trabalho foi o desenvolvimento de dispersões sólidas de NYS para o tratamento da candidíase oral, e sua posterior incorporação em gel mucoadesivo oral, favorecendo a formulação no local de ação. As dispersões sólidas são sistemas farmacêuticos, onde um fármaco pouco solúvel em água encontra-se dispersado em um carreador, no estado sólido. Os carreadores normalmente são hidrofílicos, o que permite que esses sistemas sejam empregados para aumentar a solubilidade aquosa do fármaco. Assim, foram desenvolvidas as dispersões sólidas de NYS, pelo método de eliminação do solvente, empregando como carreadores, lactose, HPMC, poloxamer 407 e poloxamer 188. Essas foram submetidas à caracterização por análise térmica, usando os ensaios de calorimetria exploratória diferencial (DSC) e termogravimetria/termogravimetria derivada (TG/DTG). Dentre essas dispersões sólidas, aquelas que se mostraram com comportamento térmico sugerindo a formação de um novo "sistema", foram analisadas por meio de ensaio de solubilidade. Dessa forma, a formulação NYS DS G2 (49) se destacou, pois apresentou maior solubilidade em água (4,484 mg/mL); em pH 5,5 (4,249 mg/mL) e em pH 7,0 (4,293 mg/mL), ou seja, houve um aumento de 1,426 vezes em água; 4,227 vezes em pH 5,5; e 2,743 vezes em pH 7,0. Essa formulação foi, por fim avaliada por difração de raio-X e espectroscopia de infravermelho com transformada de Fourier, técnicas que corroboraram com a análise térmica quanto à indicação de formação da dispersão sólida. Por sua vez, essa dispersão sólida foi incorporada em 4 bases de géis mucoadesivos de carbopol ® 934 PNF, alterando apenas a concentração do polímero (0,5; 1,0; 1,5; 2,0 %p/p). Foi observado que a liberação de NYS DS G2 (49) foi superior, quando comparada à liberação de NYS MP a partir do gel, e através do ensaio de mucoadesão, percebeu-se que os géis desenvolvidos apresentaram propriedades mucoadesivas compatíveis com relatos na literatura, independentemente da quantidade de carbopol ® empregada. As características reológicas foram distintas, e foi observado que as formulações Gel A e Gel B, que possuem menor quantidade de polímero, tiverem um indicativo de comportamento de fluido newtoniano, diferente dos demais, o que pode não ser desejado para esse tipo de forma farmacêutica tópica e semi-sólida. Ao final desse trabalho, pode-se concluir que foi possível desenvolver um sistema farmacêutico na forma de dispersão sólida com maior solubilidade que a NYS pura, e sua incorporação em uma forma farmacêutica mucoadesiva, e que a liberação da NYS na forma DS foi muito superior que o fármaco na forma "convencional", o que permite que a NYS esteja mais disponível na cavidade oral, e também junto à mucosa bucal, o que levaria a efeito farmacológico mais efetivo do antifúngico

Nystatin (NYS) is the drug of first choice in the treatment of oral candidiasis that most often affect immunocompromised individuals, and patients with other disorders. In the Brazilian market, NYS is found in the form of aqueous oral suspension, a medication used in the form of mouthwash. Although there is an indication to maintain direct contact between the drug and the oral mucosa, where Candida spp. is found, as well as where therapeutic success would significantly be increased, the suspension has no such property. Thus, the NYS is an effective drug against oral candidiasis, and belongs to Class IV of the Biopharmaceutical Classification System, it has low solubility and low permeability. The low solubility can compromise its availability in the oral cavity, and consequently, its pharmacological action. Given this situation, the objective of this work was the development of solid dispersions of NYS for the treatment of oral candidiasis, and its subsequent incorporation into oral mucoadhesive gel, in order to facilitate its action. Solid dispersions are pharmaceutical systems, in which a solid drug poorly soluble in water is dispersed in a carrier. These carriers are usually hydrophilic, and this allows the systems to be employed in order to increase the aqueous solubility of the drug. Thus, the solid NYS dispersions were developed by the solvent evaporation method, employing lactose, HPMC, poloxamer 407 and poloxamer 188 as carrier. These samples were subjected to characterization by thermal analysis, using differential scanning calorimetry (DSC) and thermogravimetry / derivative thermogravimetry (TG / DTG). Among these solid dispersions, those samples which showed a specific thermal behavior suggesting the formation of new "system" were analyzed by solubility test. Thus, the NYS DS G2 formulation (49) stood out, once it showed greater solubility in water (4.484 mg/mL); at pH 5.5 (4.249 mg/mL) and pH 7.0 (4.293 mg/mL), in other words, an increase of 1,426 times in water; 4,227 times at pH 5.5; and 2,743 times at pH 7.0. This formulation was finally evaluated by X-ray diffraction, infrared spectroscopy with Fourier transform, techniques that corroborate the thermal analysis, indicating the formation of the solid dispersion. On the other hand, this solid dispersion was incorporated into 4 Carbopol ® 934 PNF mucoadhesive gels, with a variation of the polymer concentration. It was observed that NYS is improved of delivery from the gels, employing mucoadhesion test, and was also observed that the gels have mucoadhesive properties consistent with reports in the literature. However, the rheological characteristics are different, and it was observed that the Gel A and Gel B formulations, which has a lower amount of polymer behaved as a Newtonian fluid, which may not be desired for this type of topical gel. As conclusion, it was possible to develop a pharmaceutical system in the form of solid dispersion with greater solubility than the pure NYS, and their incorporation in a mucoadhesive dosage form and the release of NYS as DS was far superior wherein the drug in the "conventional" manner, which allows the NYS is longer available in the oral cavity, and also adjacent to the buccal mucosa, leading to more effective pharmacological effect of the antifungal agent

Evaluation of effect of topical ozone therapy on salivary Candidal carriage in oral candidiasis.

Background and Aim: Ozone is highly valued for various therapeutic applications such as antimicrobial, antihypoxic, analgesic, and immunostimulating for more than a century in the medical profession. Ozone therapy is now gaining a strong foothold in dentistry. Ozone has bactericidal, fungicidal, and virucidal properties. Oral candidiasis is one of the most common opportunistic fungal infections of the oral cavity. Hence, a study was conducted to evaluate and compare the ability of ozonated water and topical clotrimazole in reducing the Candidal species colony‑forming unit (CFU) count in oral candidiasis. Materials and Methods: The study included 40 candidiasis patients of either sex aged between 18 and 60 years attending the Department of Oral Medicine and Radiology. The patients were randomly assigned to either topical ozone therapy or topical clotrimazole groups. Salivary Candidal CFU counts were assessed during and after the treatments. Results and Conclusion: There was gradual but significant reduction in Candidal CFU count in both groups. At the end of the treatment, Candidal CFU count reduction in ozone group (60.5% reduction) was more than the clotrimazole group (32.3% reduction). 14 patients (70%) with candidiasis in ozone group were reduced to 6 (30%) whereas only 8 patients (40%) out of 13 (65%) in clotrimazole group, although intergroup comparison was not statistically significant. Ozone therapy was much more effective in reducing the patients with candidiasis to a state of carriers. These findings suggest that ozonated water might be useful to treat oral candidiasis.

Chronic mucocutaneous candidiasis: a case with exuberant cutaneous horns in nipples

Chronic mucocutaneous candidiasis is a rare disorder characterized by persistent and recurrent infections by Candida due to changes in cellular immunity and may be associated with autoimmune endocrine disorders. It is refractory to the usual antifungal treatments, which merely control it with imidazole derivatives. This reports the case of a 50-year-old female patient who referred vaginal discharge associated with vulvar ulcerated lesions and whitish plaques on oral and genital mucous membranes of onset in adolescence besides cutaneous horns in nipples. The clinical picture, family history, culture and anatomopathological studies were consistent with chronic infection by candida. Treatment with systemic antifungals obtained partial response of lesions characterizing a clinical picture of Chronic Mucocutaneous Candidiasis.

Effect of Thymus vulgaris, Myrtus communis and nystatin on Candida albicans

Candida albicans is the most frequent etiological agent of oral candidiasis. This study was done to compare the anticandidal effect of Thymus vulgaris and Myrtus communis to nystatin on Candida albicans. In this laboratory study thirty-two strains of Candida albicans isolated from patients with oral candidiasis. Yeast suspension of Candida yeast cells was provided, subsquntly a serial dilution from Thymus vulgaris and Myrtus communis and Nystatin in Sabouraud Dextrose Agar [SDA] medium were prepared. Then a loop of Candida suspension was cultured on all of the solid media and was incubated at 25°C. The findings of fungus growing were recorded during 7 days. MIC of Thymus vulgaris, Myrtus communis L, mix of these essences and Nystatin was 0.390 microl/ml, 12.5 microl/ml, 0.78 microl/ml and 160 IU/ml, respectively. Thymus vulgaris contained antifungal activity against Candida albicans, but Myrtus communis demonstrated a very low activity against Candida albicans

Factors associated with time free of oral candidiasis in children living with HIV/AIDS, São Paulo, Brazil / Fatores associados ao tempo livre de candidíase oral em crianças vivendo com HIV/AIDS, São Paulo, Brasil / Factores asociados al tiempo libre y la candidiasis oral en niños que viven con VIH/SIDA, São Paulo, Brasil

In clinical practice, recurrence of thrush is common in children living with HIV/AIDS. The aim of this study was to determine the factors associated with time spent free of oral candidiasis using survival analysis for recurrent events. A retrospective cohort study was carried out with 287 children treated between 1985 and 2009 at a reference center in the city of São Paulo, Brazil. The Prentice, Williams and Peterson model for recurrent events was used for the investigation of factors associated with the time free of oral candidiasis. The following factors were associated with the time patients were free of oral candidiasis: moderate immunodepression (HR = 2.5; p = 0.005), severe immunodepression (HR = 3.5; p < 0.001), anemia (HR = 3.3; p < 0.001), malnutrition (HR = 2.6; p = 0.004), hospitalization (HR = 2.2; p < 0.001), monotherapy (HR = 0.5; p = 0.006), dual therapy (HR = 0.3; p < 0.001) and triple therapy/highly active antiretroviral therapy (HR = 0.1; p < 0.001). The method analyzed in the present study proved useful for the investigation of recurrent events in patients living with HIV/AIDS.

A recorrência da candidíase oral em crianças vivendo com HIV/AIDS é um acontecimento muito comum na prática clínica. O objetivo foi verificar os fatores associados ao tempo livre de candidíase oral, utilizando técnica de análise de sobrevida para eventos recorrentes. Estudo de coorte retrospectivo com 287 crianças, atendidas entre 1985 e 2009, em um serviço de saúde de São Paulo, Brasil. Foi utilizado o modelo marginal para eventos recorrentes de Prentice, Williams e Peterson para investigação dos fatores associados ao tempo livre de candidíase oral. Imunodepressão moderada (HR = 2,5; p = 0,005) ou grave (HR = 3,5; p < 0,001), anemia (HR = 3,3; p < 0,001), desnutrição (HR = 2,6; p = 0,004) e internação (HR = 2,2; p < 0,001), monoterapia (HR = 0,5; p = 0,006), terapia dupla (HR = 0,3; p < 0,001) e terapia tripla/HAART (HR = 0,1; p < 0,001) foram associados ao tempo livre de candidíase oral. A metodologia apresentada neste artigo pode ser bastante útil em pesquisas na área de HIV/AIDS, quando pretende-se estudar eventos com comportamento de recorrência.

La repetición de candidiasis oral en los niños que viven con VIH/SIDA es muy común en la práctica clínica. El objetivo fue verificar los factores asociados al tiempo libre y la candidiasis oral, usando la técnica de análisis de supervivencia para eventos recurrentes. Se realizó un estudio de cohorte retrospectiva con 287 niños que visitaron entre 1985 y 2009 un servicio de salud de São Paulo, Brasil. Se usó el modelo marginal para eventos recurrentes de Prentice, Williams y Peterson, con el fin de investigar los factores asociados. Moderada inmunodepresión (HR = 2,5; p = 0,005) o grave (HR = 3,5; p < 0,001), anemia (HR = 3,3; p < 0,001), desnutrición (HR = 2,6; p = 0,004) y hospitalización (HR = 2,2; p < 0,001), monoterapia (HR = 0,5; p = 0, 006), terapia dual (HR = 0,3; p < 0,001) y triple terapia/TARGA (HR = 0,1; p < 0,001) se asociaron al tiempo libre y la candidiasis oral. La metodología presentada en este artículo puede ser útil para la investigación en el área de VIH/SIDA, cuando se pretenda estudiar el comportamiento de la repetición del evento.

Effectiveness of mechanical brushing with different denture cleansing agents in reducing in vitro Candida albicans biofilm viability

The adhesion of Candida albicans to surfaces is the prerequisite for occurrence of denture stomatitis, a common disease diagnosed among denture wearers. A routine of denture cleansing is essential to prevent biofilm formation and the onset of this infection. The aim of this study was to investigate the effectiveness of combining brushing and cleansing agents in killing C. albicans biofilm. Disks of acrylic resin were made, sterilized, and inoculated with C. albicans (10(7) cfu/mL). After incubation (37°C/48 h), specimens were randomly assigned to 10 experimental groups (n=9): 5 subjected to brushing with distilled water or cleansing agents - dentifrice slurry, 2% chlorhexidine gluconate (CHX), 1% sodium hypochlorite (NaOCl), and Polident fresh cleanse® (combined method) - and 4 exposed to the cleansing agents without brushing (immersion). Non-cleansed specimens were used as positive controls. The viability of cells was evaluated by XTT reduction method. Results were analyzed by Mann-Whitney and Kruskal-Wallis tests (α=0.05). The combined method was significantly more effective (p<0.0001) in reducing biofilm viability than the immersion. Brushing with CHX and NaOCl resulted in 100% removal of the biofilm. Immersion in the agents reduced significantly (p<0.0001) the biofilm viability, with CHX being the most effective (p<0.0001). The use of the combined method of brushing with cleansing agents is an effective method to reduce C. albicans biofilm, being CHX and NaOCl the most effective solutions.

A adesão de Candida albicans às superfícies é o primeiro passo para o desenvolvimento da estomatite protética, uma infecção frequente diagnosticada entre os usuários de próteses. Uma adequada higienização é essencial para prevenir a formação de biofilme microbiano e o início desta infecção. O objetivo deste estudo foi avaliar a efetividade da escovação com diferentes soluções na eliminação de biofilme de C. albicans. Para isso, discos de resina acrílica foram confeccionados, esterilizados e inoculados com uma suspensão de 10(7) células/mL de C. albicans. Após incubação (37°C/48 h), os espécimes foram aleatoriamente divididos em 10 grupos experimentais (n=9): 5 submetidos à escovação com água ou agentes de limpeza (água destilada, dentifrício, digluconato de clorexidina (CHX) a 2%, hipoclorito de sódio (NaOCl) a 1% e Polident fresh cleanse®) e 4 apenas imersos nos agentes de limpeza. Espécimes não submetidos à higienização foram utilizados como controle positivo. A viabilidade celular foi verificada pelo teste de redução do XTT. Os resultados obtidos foram analisados pelos testes de Mann-Whitney e Kruskal-Wallis (α=0,05). A escovação com todos os agentes de limpeza apresentou redução significativamente superior (p<0,0001) na viabilidade do biofilme quando comparada à exposição dos espécimes às soluções. Escovação com CHX a 2% e NaOCl a 1% resultaram em 100% de inativação do biofilme. A exposição aos agentes de limpeza resultou em redução significativa (p<0,0001) na viabilidade celular, com CHX a 2% sendo o mais efetivo (p<0,0001). A utilização de agentes de limpeza em associação ao método de escovação provou ser efetivo para reduzir biofilme C. albicans, sendo as soluções de CHX e NaOCl as mais efetivas.

Poly (Methyl Methacrylate) absorption and releasing of nystatin and fluconazole / Absorção e liberação de nistatina e fluconazol por polimetilmetacrilato

Objectives: The aim of this study was to verify if there are poly (methyl methacrylate) (PMMA) absorptionand releasing of nystatin (NYS) and fluconazole (FLZ) after simulated treatment of oral candidosis. Materialsand methods: Specimens (30 × 25 × 5 mm) prepared with PMMA polymerized by hot water bath or microwaveenergy were immersed into NYS (3.12 μg/mL), FLZ (2.56 μg/mL) or deionized water (control) during14 days at 35 ± 2 °C. After treatment simulation, specimens were immersed into distilled water during 3, 7, 10and 14 days. The immersion liquid was changed after each analysis. Higher performance liquid chromatographywas used in order to detect antifungal compounds. In order to determine if there was surface depositionof drugs on PMMA resin, specimens were analyzed with electronic microscopy (SEM). Results: None of theantifungal agents was released from the PMMA resins. Conclusion: Within the limitations of this study, itcould be concluded that PMMA resins had no drug absorption with posterior release.

Objetivos: O objetivo deste estudo foi verificar se o poli (metil metacrilato) (PMMA) é capaz de absorver e liberar nistatina (NYS) e fluconazol (FLZ) após simular um tratamento para candidose oral. Materiais e métodos:Espécimes (30 × 25 × 5 mm) foram preparados em resina de PMMA por banho de água quente ou energia demicro-ondas e, em seguida, imersos em solução contendo NYS (3.12 μg/mL), FLZ (2.56 μg/mL) ou água deionizada(controle) durante 14 dias a 35 ± 2 °C. Após a simulação de tratamento, os espécimes foram imersos em água destilada durante 3, 7, 10 e 14 dias. O líquido de imersão foi trocado após cada análise. Cromatografia líquida de alta performance foi utilizada para detectar a presença dos agentes antifúngicos. Para determinar se houve deposição dos agentes antifúngicos na superfície de PMMA, os espécimes foram analisados por microscopia eletrônica de varredura(MEV). Resultados: Não houve liberação de agentes antifúngicos dos espécimes. Conclusão: Considerando as limitações deste estudo, pode-se concluir que a resina de PMMA não absorve ou libera agentes antifúngicos.

In vivo efficacy of alkaline peroxide tablets and mouthwashes on Candida albicans in patients with denture stomatitis

OBJECTIVE: Effective cleaning of dentures is important for the maintenance of good oral hygiene for denture stomatitis patients. The in vivo efficacy of three different brands of alkaline peroxide tablets (Polident, Efferdent, and Fittydent) and two mouthwashes (CloSYS II and Corsodyl) to eliminate Candida albicans on dentures was evaluated in this in vivo study. MATERIAL AND METHODS: Ninety denture wearers with clinical evidence of denture stomatitis were randomly divided into 5 test groups and 1 control group. Each group was further divided into three subgroups in which the dentures were subjected to 15-, 30-, and 60-min disinfection procedures. The dentures of each test group were treated with one of the cleaners, while those of the control group were treated with distilled water. Swab samples from the palatal surfaces (2 cm x 2 cm template delimited area) of the upper dentures were obtained before and after 15, 30, and 60 min periods of cleaner use and examined mycologically. RESULTS: The reduction in the number of colony-forming units (CFU) of C. albicans before, and after 15, 30, and 60 min of use of CloSYS II and Corsodyl was significantly greater than that of the control group (p<0.05). Moreover, there was no statistically significant difference (p>0.05) among Polident, Efferdent and the control group in any of the treatment periods. Dentures treated with Fittydent appeared to have a significantly greater reduction in the number of Candida spp. only after 60 min of treatment. CONCLUSIONS: The results of this study showed that the use of mouthwashes significantly reduced the number of microorganisms on dentures.

Atividade antifúngica do extrato de folhas de Psidium guajava sobre leveduras do gênero Candida / Antifungic activity of leaf extracts of Psidium guajava in Candida species

Candida é potógeno oportunista integrante da microbiota bucal do homem. Alterações imunológicas, químicas e mecânicas podem ocasionar ruptura do equilíbrio entre o fungo e o hospedeiro o que leva ao aparecimento da candidíase. As propriedades antifúngicas de substâncias extraídas de plantas vêm sendo relatadas em pesquisas realizadas em vários países, entre eles, o Brasil detentor de enorme biodiversidade. Este estudo teve como objetivo testar a atividade antifúngica das folhas de Psidium guajava, frente à Candida albicans, Candida krusei e Candida tropicalis. Os testes foram realizados através de inóculos obtidos a partir de culturas recentes dos microrganismos. Através do macerado hidroalcoólico das folhas obteve-se o extrato bruto para ser testado nas culturas. Como controles foram utilizados antimicrobianos (antisséptico bucal a base de Malva sylvestris, Fluconazol, e Gluconato de clorhexidina à 0,12%). O extrato da planta inibiu o crescimento das leveduras, assim como os agentes antimicrobianos testados, mas o Fluconazol em presença de C. tropicalis não inibiu o seu crescimento. Assim como os antissépticos bucais, o extrato de folhas de goiabeira foi capaz de inibir o crescimento do fungo, indicando uma perspectiva de utilização terapêutica em casos de candidíase bucal.

Candida is an opportunistic pathogen of the oral microbiota of man. Immunological, chemical and mechanical changes can cause disruption of the balance between the fungus and the host which leads to the appearance of candidiasis. The antifungal properties of substances extracted from plants have been reported in studies conducted in several countries, including Brazil, holder of great biodiversity. This study aimed to test the antifungal activity of Psidium guajava, in Candida albicans, Candida krusei and Candida tropicalis. The tests were performed from recent cultures of microorganisms. Through the hydroalcoholic macerate of leaf, the crude extract was obtained the to be tested on cultures. As controls were used antimicrobials (Fluconazole, mouthwash of Malva sylvestris and chlorhexidine gluconate 0.12%). The plant extract inhibited the growth of yeasts, as well as the antimicrobial agents tested, but the presence of fluconazole in C. tropicalis did not inhibit their growth. Like mouthwashes, the extract was able to inhibit the growth of the fungus, indicating a view to therapeutic use in cases of oral candidiasis.

Candidal colonization, strain diversity, and antifungal susceptibility among adult diabetic patients

Candidal colonization in diabetics is a matter of debate. The aim of this study is to investigate oral candidal colonization, strain diversity, antifungal susceptibility, and the influence of local and systemic host factors on candidal colonization in adult diabetics. We conducted a case-control study that compared 150 diabetics [49 type 1, 101 type 2] with 50 healthy controls. Two salivary samples were collected, using the oral rinse sampling method: one for salivary flow rate and pH determination, and the other for candidal colonization assessment. The candidal isolates were identified and tested in vitro for antifungal susceptibility using the commercial kit, Candifast. The relationship between specific host factors and candidal colonization was also investigated. Diabetics had a higher candidal carriage rate compared to controls, but not density. Candida albicans was the most frequently isolated species, but diabetics had a variety of other candidal species present. None of the control samples were resistant to any tested antifungal, while the diabetic samples had differing resistances to azole antifungals. Although there was a significant positive correlation between glycemic control and candidal colonization in type 2 diabetics, there was a negative correlation between salivary pH and candidal carriage in the controls versus density in type 2 diabetics. Diabetic patients not only had a higher candidal carriage rate, but also a variety of candidal species that were resistant to azole antifungals. Oral candidal colonization was significantly associated with glycemic control, type of diabetes, and salivary pH

Oral candidiasis in HIV+ patients under treatment with protease inhibitors

The purpose of this work was to evaluate the influence of Protease Inhibitors (PI) on the occurrence of oral candidiasis in 111 HIV+ patients under PI therapy (Group A). The controls consisted of 56 patients that were not using PI drugs (Group B) and 26 patients that were not using any drugs for HIV therapy (Group C). The patient's cd4 cell counts were taken in account for the correlations. One hundred and ninety three patients were evaluated. The PI did not affect the prevalence of oral candidiasis (p = 0.158) or the frequency of C. albicans isolates (p = 0.133). Patients with lower cd4 cell counts showed a higher frequency of C. albicans isolates (p = 0.046) and a greater occurrence of oral candidiasis (p = 0.036).