Ultrasmall magnolol/ebselen nanomicelles for preventing renal ischemia/reperfusion injury.

Renal ischemia/reperfusion injury (RIRI) is an inevitable complication following kidney transplantation surgery, accompanied by the generation of a large amount of free radicals. A cascade of events including oxidative stress, extreme inflammation, cellular apoptosis, and thrombosis disrupts the microenvironment of renal cells and the hematological system, ultimately leading to the development of acute kidney injury (AKI). The current research primarily focuses on reducing inflammation and mitigating damage to renal cells through antioxidative approaches. However, studies on simultaneously modulating the renal hematologic system remain unreported. Herein, potent and novel drug-loaded nanomicelles can be efficiently self-assembled with magnolol (MG) and ebselen (EBS) by π-π conjugation, hydrophobic action and the surfactant properties of Tween-80. The ultrasmall MG/EBS nanomicelles (average particle size: 10-25 nm) not only fully preserve the activity of both drugs, but also greatly enhance drug utilization (encapsulation rates: MG: 90.1%; EBS: 49.3%) and reduce drug toxicity. Furthermore, EBS, as a glutathione peroxidase mimic and NO catalyst, combines with the multifunctional MG to scavenge free radicals and hydroperoxides, significantly inhibiting inflammation and thrombosis while effectively preventing apoptosis of vascular endothelial cells and renal tubular epithelial cells. This study provides a new strategy and theoretical foundation for the simultaneous regulation of kidney cells and blood microenvironment stability.

Safety and efficacy of new generation azole antifungals in the management of recalcitrant superficial fungal infections and onychomycosis.

INTRODUCTION: Terbinafine is considered the gold standard for treating skin fungal infections and onychomycosis. However, recent reports suggest that dermatophytes are developing resistance to terbinafine and the other traditional antifungal agents, itraconazole and fluconazole. When there is resistance to terbinafine, itraconazole or fluconazole, or when these agents cannot used, for example, due to potential drug interactions with the patient's current medications, clinicians may need to consider off-label use of new generation azoles, such as voriconazole, posaconazole, fosravuconazole, or oteseconazole. It is essential to emphasize that we do not advocate the use of newer generation azoles unless traditional agents such as terbinafine, itraconazole, or fluconazole have been thoroughly evaluated as first-line therapies. AREAS COVERED: This article reviews the clinical evidence, safety, dosage regimens, pharmacokinetics, and management algorithm of new-generation azole antifungals. EXPERT OPINION: Antifungal stewardship should be the top priority when prescribing new-generation azoles. First-line antifungal therapy is terbinafine and itraconazole. Fluconazole is a consideration but is generally less effective and its use may be off-label in many countries. For difficult-to-treat skin fungal infections and onychomycosis, that have failed terbinafine, itraconazole and fluconazole, we propose consideration of off-label voriconazole or posaconazole.

Treatment of vaginitis caused by non-albicans Candida species.

INTRODUCTION: In the face of increased frequency of non-albicans Candida vulvovaginitis (VVC) reported worldwide, there is a paucity of effective oral and topical antifungal drugs available. Drug selection is further handicapped by an absence of data of clinical efficacy of available antifungal drugs for these infections. AREAS COVERED: In this review, attention is directed at the cause of drug shortage as well as increased frequency of non-albicans Candida (NAC) vulvovaginitis. There is widespread recognition of reduced in vitro azole drug susceptibility in NAC species. Moreover, antifungal susceptibility tests have not been standardized or validated for NAC isolates, hence clinicians rely on an element of empiricism especially given the absence of randomized controlled comparative studies targeting NAC species. Clinical spectrum of NAC species isolates is highly variable with ongoing difficulty in determining a causal role in symptomatic patients. EXPERT OPINION: We have entered the era of demand for Candida species-specific therapy and although consensus treatment guidelines are emerging, new antifungal agents that target these multiple-azole resistant or relatively resistant vaginal NAC species are urgently needed.

Exophiala dermatitidis as a cause of central line associated bloodstream infection in an infant: Case report and literature review / Exophiala dermatitidis como causante de infección del torrente sanguíneo asociada a catéter central en un lactante: reporte de un caso y revisión de la literatura

BACKGROUND: Exophiala dermatitidis is a dematiaceous fungus known to cause superficial, subcutaneous, cutaneous and deep seated infections, and rarely central line associated bloodstream infection (CLABSI). A case of CLABSI due to E. dermatitidis in an infant is described. CASE REPORT: Clinical and laboratory data were extracted from patient's chart and laboratory records. The isolate was identified as E. dermatitidis by phenotypic characterization and sequencing of the ITS and LSU regions of the ribosomal DNA. Medline search was done to review all cases of CLABSI due to E. dermatitidis. Among the azoles tested, posaconazole (0.06mg/l), voriconazole (0.03mg/l) and itraconazole (0.03mg/l) showed very low MICs when compared to fluconazole (4mg/l). CONCLUSIONS: As we did not found in the literature any case of CLABSI due to E. dermatitidis in an infant, we report the first one. Sequencing is a mandatory method for accurately identifying this species. Prompt removal of the central line, followed by a treatment with amphotericin B or an azole, seems to be the most effective treatment

ANTECEDENTES: Exophiala dermatitidis es un hongo dematiáceo conocido por causar infecciones superficiales, subcutáneas, cutáneas y profundas, y rara vez infección del torrente sanguíneo asociada a catéter central (central line associated bloodstream infection [CLABSI]). Se describe un caso de CLABSI debido a E. dermatitidis en un bebé. CASO CLÍNICO: Los datos del paciente se extrajeron de la historia clínica y de los registros de laboratorio. El aislamiento se identificó como E. dermatitidis mediante caracterización fenotípica y la secuenciación de las regiones ITS y LSU del ADN ribosómico. Se realizó una búsqueda en Medline para revisar todos los casos de CLABSI debidos a E. dermatitidis. Entre los azoles evaluados, el posaconazol (0,06mg/l), el voriconazol (0,03mg/l) y el itraconazol (0,03mg/l) mostraron valores de MIC muy bajos en comparación con el fluconazol (4mg/l). CONCLUSIONES: Tras la revisión de todo lo publicado en la literatura, presentamos el primer caso de CLABSI debido a E. dermatitidis en un lactante. La secuenciación es necesaria para identificar con precisión esta especie. La retirada inmediata del catéter venoso central seguida de un tratamiento con anfotericina B o un azol es el tratamiento más efectivo

Antifungal therapy with azoles and the syndrome of acquired mineralocorticoid excess.

The syndromes of mineralocorticoid excess describe a heterogeneous group of clinical manifestations leading to endocrine hypertension, typically either through direct activation of mineralocorticoid receptors or indirectly by impaired pre-receptor enzymatic regulation or through disturbed renal sodium homeostasis. The phenotypes of these disorders can be caused by inherited gene variants and somatic mutations or may be acquired upon exposures to exogenous substances. Regarding the latter, the symptoms of an acquired mineralocorticoid excess have been reported during treatment with azole antifungal drugs. The current review describes the occurrence of mineralocorticoid excess particularly during the therapy with posaconazole and itraconazole, addresses the underlying mechanisms as well as inter- and intra-individual differences, and proposes a therapeutic drug monitoring strategy for these two azole antifungals. Moreover, other therapeutically used azole antifungals and ongoing efforts to avoid adverse mineralocorticoid effects of azole compounds are shortly discussed.

"Azole" as privileged heterocycle for targeting the inducible cyclooxygenase enzyme.

An over-expression of COX-2 isoenzyme belonging to the Cyclooxygenase Enzyme Family triggers the overproduction of pro-inflammatory prostaglandins that instigate the development of chronic inflammation and related disorders. Hence, the rationally designed drugs for mitigating over-activity of COX-2 isoenzyme play a regulatory role toward the alleviation of the progression of these disorders. However, a selective COX-2 inhibition chemotherapy prompts several side effects that necessitate the identification of novel molecular scaffolds for deliberating state-of-the-art drug designing strategies. The heterocyclic "azole" scaffold, being polar and hydrophilic, possesses remarkable physicochemical advantages for designing physiologically active molecules capable of interacting with a wide range of biological components, including enzymes, peptides, and metabolites. The substituted derivatives of azole nuclei enable a comprehensive SAR analysis for the appraisal of bioactive profile of the deliberated molecules for obtaining the rationally designed compounds with prominent activities. The comprehensive SAR analysis readily prompted the identification of Y-shaped molecules and the eminence of bulkier group for COX-2 selective inhibition. This review presents an epigrammatic collation of the pharmacophore-profile of the chemotherapeutics based on azole motif for a selective targeting of the COX-2 isoenzyme.

Therapeutic approaches against coronaviruses acute respiratory syndrome.

Coronaviruses represent global health threat. In this century, they have already caused two epidemics and one serious pandemic. Although, at present, there are no approved drugs and therapies for the treatment and prevention of human coronaviruses, several agents, FDA-approved, and preclinical, have shown in vitro and/or in vivo antiviral activity. An in-depth analysis of the current situation leads to the identification of several potential drugs that could have an impact on the fight against coronaviruses infections. In this review, we discuss the virology of human coronaviruses highlighting the main biological targets and summarize the current state-of-the-art of possible therapeutic options to inhibit coronaviruses infections. We mostly focus on FDA-approved and preclinical drugs targeting viral conserved elements.

Aerosol Inhalation Delivery of Triazavirin in Mice: Outlooks for Advanced Therapy Against Novel Viral Infections.

Under pandemic-caused emergency, evaluation of the potential of existing antiviral drugs for the treatment of COVID-19 is relevant. Triazavirin, an antiviral drug developed in Russia for per-oral administration, is involved in clinical trials against SARS-CoV-2 coronavirus. This virus has affinity to epithelial cells in respiratory tract, so drug delivery directly in lungs may enhance therapeutic effect and reduce side effects for stomach, liver, kidneys. We elaborated ultrasonic method of triazavirin aerosol generation and investigated the inhalation delivery of this drug in mice. Mean particle size and number concentration of aerosol used in inhalation experiments are 560 nm and 4 × 105 cm-3, respectively. Aerosol mass concentration is 1.6 × 10-4 mg/cm3. Inhalation for 20 min in a nose-only chamber resulted in 2 mg/kg body delivered dose and 2.6 µg/mL triazavirin concentration in blood plasma. Elimination rate constant determined in aerosol administration experiments was ke = 0.077 min-1, which agrees with the value measured after intravenous delivery, but per-oral administration resulted in considerably lower apparent elimination rate constant of pseudo-first order, probably due to non-linear dependence of absorption rate on triazavirin concentration in gastrointestinal tract. The bioavailability of triazavirin aerosol is found to be 85%, which is about four times higher than for per-oral administration.

Safety of current therapies for onychomycosis.

INTRODUCTION: Onychomycosis is the most common nail disease seen in clinical practice. Treatment options include systemic and topical therapies, as well as devices. Following clinical and mycologic diagnosis, treatment must be individualized, accounting for disease severity, infecting organism(s), comorbidities, patient characteristics and drug/device efficacy. Safety is the most important consideration in choosing the most appropriate therapeutic modality. AREAS COVERED: This review covers currently available treatments for onychomycosis, with an emphasis on safety and tolerability. Medications and devices were analyzed for side effects, drug-drug interactions, and safety during pregnancy and breastfeeding. EXPERT OPINION: Systemic antifungals offer greater efficacy for onychomycosis treatment but are limited by risks of systemic toxicity and drug-drug interactions. The risk of terbinafine-induced hepatotoxicity is negligible in healthy patients. Systemic therapies, especially azole antifungals, are associated with numerous drug-drug interactions, some of which are life-threatening and fatal. Thus, a detailed medication history is critical before prescribing these medications. Topical antifungals are well tolerated and generally safe, with only potential local side effects. Systemic and topical onychomycosis treatments should not be prescribed during pregnancy and breastfeeding. Laser therapy is likely less effective than systemic and topical therapies, but may be safely used during pregnancy and breastfeeding.

A phase 2a randomised, double-blind, placebo-controlled, parallel-group, add-on clinical trial of ebselen (SPI-1005) as a novel treatment for mania or hypomania.

RATIONALE: Lithium is an effective prophylactic and anti-manic treatment in bipolar disorder; however, its use is declining through perceived poor tolerance and toxicity. Lithium inhibits inositol monophosphatase (IMPase), a probable key therapeutic mechanism. The anti-inflammatory drug, ebselen, also inhibits IMPase and appears well-tolerated and safe. OBJECTIVES: To assess the efficacy of adjunctive ebselen in mania using the Young Mania Rating Scale (YMRS) (primary outcome) and the Altman Self-Rating Mania (ASRM) Scale and Clinical Global Impression-Severity Scale (CGI-S) among the secondary outcomes. METHODS: Randomised, double-blind, placebo-controlled, parallel-group trial conducted between October 2017 and June 2019, at Oxford Health NHS Foundation Trust. Pharmacy-controlled randomisation was computer-generated, with full allocation concealment. In/outpatients (n = 68) aged 18-70, experiencing mania or hypomania, were assigned to 3 weeks ebselen (600 mg bd) (n = 33) or placebo (n = 35). Participants received usual clinical care and psychotropic medication. RESULTS: Ebselen was numerically, but not statistically, superior to placebo in lowering scores on the YMRS (adjusted mean difference and 95% confidence interval, - 1.71 (- 5.34 to 1.91), p = 0.35) and ASRM (- 1.36 (- 3.75 to 1.17), p = 0.29). However, scores on the CGI-S were significantly lower at week 3 in ebselen-treated participants (adjusted mean difference, - 0.58 (- 1.14 to - 0.03), p = 0.04). A post hoc analysis excluding patients taking concomitant valproate treatment magnified the difference between ebselen and placebo on the YMRS. Adverse events were comparable between groups, and mild. CONCLUSIONS: Ebselen merits further investigation where concomitant psychotropic medication is better controlled and participants taking valproate are excluded. If effective, ebselen's superior tolerance and safety could make it a useful alternative to lithium. TRIAL REGISTRATION: Trial Registry: www.clinicaltrials.gov , Identifier: NCT03013400.

Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of uncomplicated vulvovaginal candidiasis (thrush).

BACKGROUND: Anti-fungals are available for oral and intra-vaginal treatment of uncomplicated vulvovaginal candidiasis. OBJECTIVES: The primary objective of this review is to assess the relative effectiveness (clinical cure) of oral versus intra-vaginal anti-fungals for the treatment of uncomplicated vulvovaginal candidiasis. Secondary objectives include the assessment of the relative effectiveness in terms of mycological cure, in addition to safety, side effects, treatment preference, time to first relief of symptoms, and costs. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trials registers on 29 August 2019 together with reference checking and citation searching. SELECTION CRITERIA: We included randomised controlled trials published in any language comparing at least one oral anti-fungal with one intra-vaginal anti-fungal in women (aged 16 years or over) with a mycological diagnosis (positive culture, microscopy for yeast, or both) of uncomplicated vulvovaginal candidiasis. We excluded trials if they solely involved participants who were HIV positive, immunocompromised, pregnant, breast feeding or diabetic. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. MAIN RESULTS: This review includes 26 trials (5007 participants). Eight anti-fungals are represented. All but three trials included participants with acute vulvovaginal candidiasis. Trials were conducted in Europe: UK (3), Croatia (2). Finland (2), the Netherlands (2), Germany (1), Italy (1), Sweden (1) and one trial across multiple European countries, USA (7) Thailand (2), Iran (2), Japan (1) and Africa (Nigeria) (1). The duration of follow-up varied between trials. The overall risk of bias of the included trials was high. There was probably little or no difference shown between oral and intra-vaginal anti-fungal treatment for clinical cure at short-term follow-up (OR 1.14, 95% CI 0.91 to 1.43; 13 trials; 1859 participants; moderate-certainty evidence) and long-term follow-up (OR 1.07, 95% CI 0.77 to 1.50; 9 trials; 1042 participants; moderate-certainty evidence). The evidence suggests that if the rate of clinical cure at short-term follow-up with intra-vaginal treatment is 77%, the rate with oral treatment would be between 75% and 83%; if the rate of clinical cure at long term follow-up with intra-vaginal treatment is 84%, the rate with oral treatment would be between 80% and 89%. Oral treatment probably improves mycological cure over intra-vaginal treatment at short term (OR 1.24, 95% CI 1.03 to 1.50: 19 trials; 3057 participants; moderate-certainty evidence) and long-term follow-up (OR 1.29, 95% CI 1.05 to 1.60; 13 trials; 1661 participants; moderate-certainty evidence). The evidence suggests that if the rate of mycological cure at short-term follow-up with intra-vaginal treatment is 80%, the rate with oral treatment would be between 80% and 85%; if the rate of mycological cure at long-term follow-up with intra-vaginal treatment is 66%, the rate with oral treatment would be between 67% and 76%. In terms of patient safety, there is a low risk of participants withdrawing from the studies due to adverse drug effects for either treatment (23 trials; 4637 participants; high-certainty evidence). Due to the low certainty of evidence, it is undetermined whether oral treatments reduced the number of side effects compared with intra-vaginal treatments (OR 1.04, 95% CI 0.84 to 1.29; 16 trials; 3155 participants; low-certainty evidence). The evidence suggests that if the rate of side effects with intra-vaginal treatment is 12%, the rate with oral treatment would be between 10% and 15%. We noted that the type of side effects differed, with intra-vaginal treatments being more often associated with local reactions, and oral treatments being more often associated with systemic effects including gastro-intestinal symptoms and headaches. Oral treatment appeared to be the favoured treatment preference over intra-vaginal treatment or no preference (12 trials; 2206 participants), however the data were poorly reported and the certainty of the evidence was low. There was little or no difference in time to first relief of symptoms between oral and intra-vaginal treatments: four trials favoured the oral treatment, four favoured intra-vaginal, one study reported no difference and one was unclear. The measurements varied between the 10 trials (1910 participants) and the certainty of the evidence was low. Costs were not reported in any of the trials. AUTHORS' CONCLUSIONS: Oral anti-fungal treatment probably improves short- and long-term mycological cure over intra-vaginal treatment for uncomplicated vaginal candidiasis. Oral treatment was the favoured treatment preference by participants, though the certainty of this evidence is low. The decision to prescribe or recommend an anti-fungal for oral or intra-vaginal administration should take into consideration safety in terms of withdrawals and side effects, as well as cost and treatment preference. Unless there is a previous history of adverse reaction to one route of administration or contraindications, women who are purchasing their own treatment should be given full information about the characteristics and costs of treatment to make their own decision. If health services are paying the treatment cost, decision-makers should consider whether the higher cost of some oral anti-fungals is worth the gain in convenience, if this is the patient's preference.

Dapsone for Pneumocystis jirovecii pneumonia prophylaxis - applying theory to clinical practice with a focus on drug interactions.

Pneumocystis jirovecii pneumonia (PJP) is a potentially life-threatening infection that occurs in immunocompromised individuals. The incidence can be as high as 80% in some groups but can be reduced to less than 1% with appropriate prophylaxis. HIV-infected patients with a low CD4 count are at the highest risk of PJP. Others at substantial risk include haematopoietic stem cell and solid organ transplant recipients, those with cancer (particularly haematologic malignancies), and those receiving glucocorticoids, chemotherapeutic agents, and other immunosuppressive medications. Trimethoprim-sulfamethoxazole is an established first-line line agent for prevention and treatment of PJP. However, in some situations, this medication cannot be used and dapsone is considered a suitable cost-effective second line agent. However, information on potential interactions with drugs commonly used in immunosuppressed patients is lacking or contradictory. In this this article we review the metabolic pathway of dapsone with a focus on interactions and clinical significance particularly in patients with haematological malignancies. An understanding of this process should optimise the use of this agent.

Refractory mucocutaneous leishmaniasis resolved with combination treatment based on intravenous pentamidine, oral azole, aerosolized liposomal amphotericin B, and intralesional meglumine antimoniate.

INTRODUCTION: Mucocutaneous leishmaniasis (MCL) is a complication of tegumentary leishmaniasis, causing potentially life-threatening lesions in the ear, nose, and throat (ENT) region, and most commonly due to Leishmania (Viannia) braziliensis. We report a case of relapsing MCL in an Italian traveler returning from Argentina. CASE DESCRIPTION: A 65-year-old Italian male patient with chronic kidney disease, arterial hypertension, prostatic hypertrophy, and type-2 diabetes mellitus was referred for severe relapsing MCL acquired in Argentina. ENT examination showed severe diffuse pharyngolaryngeal edema and erythema, partially obstructing the airways. A nasopharyngeal biopsy revealed a lymphoplasmacytic inflammation and presence of Leishmania amastigotes, subsequently identified as L. (V.) braziliensis by hsp70 PCR-RFLP analysis and sequencing. Despite receiving four courses of liposomal amphotericine B (L-AmB) and two courses of miltefosine over a 2-year period, the patient presented recurrence of symptoms a few months after the end of each course. After the patient was referred to us, a combined treatment was started with intravenous pentamidine 4 mg/kg on alternate days for 10 doses, followed by one dose per week for an additional seven doses, intralesional meglumine antimoniate on the nasal lesion once per week for six doses, oral azoles for three months, and aerosolized L-AmB on alternate days for three months. The treatment led to regression of mucosal lesions and respiratory symptoms. Renal function temporarily worsened, and the addition of insulin was required to maintain glycemic compensation after pentamidine discontinuation. CONCLUSIONS: This case highlights the difficulties in managing a life-threatening refractory case of MCL in an Italian traveler with multiple comorbidities. Even though parenteral antimonial derivatives are traditionally considered the treatment of choice for MCL, they are relatively contraindicated in cases of chronic kidney disease.The required dose adjustment in cases of impaired renal function is unknown, therefore the use of alternative drugs is recommended. This case was resolved with combination treatment, including aerosolized L-AmB, which had never been used before for MCL.

Potential benefit of combination antifungal therapy in Aspergillus endocarditis.

Aspergillus endocarditis (AE) is a rare condition with a mortality rate greater than 60%. While it is generally accepted that both antifungal therapy and surgery are necessary for survival, the optimal antifungal regimen is unclear. A 62-year-old man was diagnosed with AE of a prosthetic aortic valve, complicated by cerebral emboli. He underwent debridement of the aortic valve abscess and valve replacement, and was managed with a combination of liposomal amphotericin B and voriconazole for 7 weeks followed by long-term suppressive azole therapy. He remained well at follow-up 18 months later. Data from a review of case reports published between 1950 and 2010 revealed greater survival rates in patients managed with two or more antifungals as opposed to single agent therapy. We provide an updated literature review with similar findings, suggesting that dual agent antifungal therapy should be considered in patients with AE.

Proposal of a Safe and Effective Study Design for CYP3A-Mediated Drug-Drug Interactions.

Numerous drug-drug interaction (DDI) trials have to be conducted in healthy volunteers based on current regulatory guidelines. Because the worst-case scenario of strong cytochrome P450 (CYP) inhibitors has to be tested, the results and their validity have to be balanced with the risk to volunteer safety. The use of ketoconazole in clinical DDI studies has been discouraged by regulatory agencies due to an alleged risk of liver injury. In order to reduce the risk to healthy volunteers, we carried out a study with single-day exposure to each of 6 perpetrator azole fungistatic drugs. They were evaluated regarding their CYP3A inhibition using microdosed midazolam and a limited sampling strategy. Ratios of areas under the concentration-time curves ranged from 1.93 with isavuconazole to 8.42 with ketoconazole. The highest number of adverse events occurred with voriconazole, followed by ketoconazole; 2 dropouts occurred due to adverse events following itraconazole administration. Literature data on adverse events of azole fungistatic drugs in DDI trials are rare and inconclusive. Only in recent years with the newer drugs are they more precise and reliable. It can be concluded that the duration of preexposure of perpetrator drugs can be reduced to 1 hour before administration of the victim drug. This still can be sufficient to achieve the scientific objectives of the trial with the lowest possible risk.

Non-surgical treatment options for pulmonary aspergilloma.

Aspergilloma, also known as mycetoma or fungus ball, is the most common manifestation of pulmonary involvement by Aspergillus species. The fungal ball typically forms within preexisting cavities of the lungs. Diagnosis requires both radiographic evidence along with serologic or microbiologic evidence of Aspergillus species involvement. While clinical features such as hemoptysis, chest pain, shortness of breath, cough, and fever are helpful in diagnosis, they are non-specific symptoms. Surgery is currently the mainstay of treatment for aspergilloma but is associated with considerable mortality and morbidity. Alternative options exist for patients who are poor surgical candidates and for those who prefer a less invasive treatment modality. Systemic treatment with amphotericin B is ineffective and is not recommended as a monotherapy, but systemic azoles is effective in approximately 50-80% of patients. Potential alternatives to surgery include intracavitary instillation or endobronchial administration of antifungal medication, as well as direct transbronchial aspergilloma removal. Bronchial artery embolization and radiotherapy are options to manage hemoptysis until definite eradication of the aspergilloma. More rigorous studies are needed to better establish non-surgical treatment paradigm for inoperable patients.

Diphenyl diselenide is as effective as Ebselen in a juvenile rat model of cisplatin-induced nephrotoxicity.

BACKGROUND: Cisplatin (CIS) is widely used in the chemotreatment of pediatric tumors. However, the CIS use is limited because of its high incidence of toxicity, mainly nephrotoxicity. Although there are many studies about CIS-related nephrotoxicity in animal models, only a few studies focus on juvenile animals. Because redox disturbances have been associated with kidney damage induced by CIS, this study aimed to compare the effectiveness of Ebselen and diphenyl diselenide (PhSe)2 against nephrotoxicity induced by CIS in juvenile rats. METHODS: Juvenile Wistar rats were randomly divided into six groups: rats from groups I to III received an intraperitoneal (i.p.) injection with saline solution. The other groups received CIS (i.p., 6 mg/kg) on the first day. One hour before CIS injection and on the next four days, animals of groups III and V were intragastrically treated with Ebselen (11 mg/kg) whereas those from groups IV and VI received (PhSe)2 (12 mg/kg). After 24 h of the last treatment, blood and kidney were collected, and the parameters of renal function and oxidative stress were determined. RESULTS: Kidney damage induced by CIS was confirmed by the increase of creatinine, urea and uric acid levels in the blood of juvenile rats. The renal oxidative disturbance was characterized by an increase in the levels of thiobarbituric acid reactive substances (TBARS), protein carbonyl, and nitrogen oxides (Nox), as well as the decrease in non-protein thiol content (NPSH), glutathione-S-transferase (GST), catalase (CAT) and superoxide dismutase (SOD) activities. CIS inhibited the activities of δ-aminolevulinic acid dehydratase (δ-ALA-D) and Na+, K+-ATPase and down-regulated the Nrf2/Keap-1/HO-1 pathway in the kidney of juvenile rats. CONCLUSION: Both Ebselen and (PhSe)2 modulated back to the normal levels all parameters altered by the CIS administration in the kidney of juvenile rats. Thus, this study shows that (PhSe)2 was as effective as Ebselen in protecting the kidney against oxidative damage caused by CIS in rats.

Synergistic Effects of Efflux Pump Modulators on the Azole Antifungal Susceptibility of Microsporum canis.

The microbiologic and clinical resistance of dermatophytes is seldom reported, and the mechanisms associated with resistance are not well known. This study investigated the effect of efflux pump modulators (EPMs) (i.e., haloperidol HAL and promethazine PTZ) and their inhibiting activity on the minimum inhibitory concentrations of itraconazole (ITZ) and fluconazole (FLZ) against selected M. canis strains. M. canis strains with low (≤ 1 µg/ml itraconazole and < 64 µg/ml fluconazole) and high (> 1 µg/ml itraconazole and ≥ 64 µg/ml fluconazole) azole MIC values were tested using Checkerboard microdilution assay. The disk diffusion assay, the minimum fungicidal concentration and the time-kill assay were also performed in order to confirm the results of checkerboard microdilution assay. The MIC values of ITZ and FLZ of M. canis decreased in the presence of subinhibitory concentrations of HAL and PTZ, the latter being more effective with a greater increased susceptibility. Synergism was observed in all strains with high azole MICs (FICI < 0.5) and no synergism in the strains with low azole MICs. A fungicidal activity was observed after 48 h of incubation when ITZ and FLZ were tested in combination with HAL or PTZ. These results suggest that the drug efflux pumps are involved in the defense mechanisms to azole drugs in M. canis strains. The synergism might be related to an increased expression of efflux pump genes, eventually resulting in azole resistance phenomena. Complementary studies on M. canis resistance are advocated in order to investigate the molecular mechanisms of this phenomenon.