Dose-independent confusion induced by voriconazole in a patient with Asian ancestry after allogeneic hematopoietic stem cell transplant.

PubMed

Hui, John

2016-02-01

This is the case of a 71-year-old man with Asian ancestry who had myelodysplastic syndrome admitted for allogeneic hematopoietic stem cell transplant. This case suggests that voriconazole-induced confusion is probably dose-independent and reversible with no residual symptoms after discontinuation of voriconazole. Patient can experience confusion even voriconazole is ordered according to package insert and serum voriconazole level is within therapeutic range (1-6 µg/mL). The onset of confusion can be delayed and sudden after seven days of voriconazole therapy. Genotyping of CYP2C19 can be tested for Asian populations since 15-20% of them could be poor metabolizers of voriconazole. © The Author(s) 2014.

Voriconazole pharmacokinetic variability in cystic fibrosis lung transplant patients.

PubMed

Berge, M; Guillemain, R; Boussaud, V; Pham, M-H; Chevalier, P; Batisse, A; Amrein, C; Dannaoui, E; Loriot, M-A; Lillo-Le Louet, A; Billaud, E M

2009-06-01

Aspergillosis is a high-risk complication in cystic fibrosis (CF) lung transplant patients. Azole antifungal drugs inhibit CYP3A4, resulting in significant metabolic drug-drug interactions. Voriconazole (VRZ) was marketed without therapeutic drug monitoring (TDM) recommendations, consistent with favorable pharmacokinetics, but regular determinations of plasma VRZ concentration were introduced in our center to manage interactions with calcineurin inhibitors and to document the achievement of therapeutic levels. VRZ TDM data analysis for trough concentration (C0) and peak concentration (C2) was carried out, using validated liquid chromatography assay with ultraviolet detection, for 35 CF lung transplant patients (mean age 25 years, mean weight 47 kg, balanced sex ratio) since 2003. Therapeutic range (C0: 1.5 +/- 0.5 - C2 : 4.0 +/- 1.0 mg/L) was expressed relative to pivotal pharmacokinetic trial data. The duration of VRZ treatment ranged from 9 days to 22 months. The recommended standard dose of VRZ (200 mg twice a day, following the loading dose) resulted in significant plasma concentrations (>0.5 mg/L) in 20% of CF lung transplant patients. Therapeutic concentrations were obtained using higher doses (average 570 +/- 160 mg/day, +43%, P<0.01). Despite adaptation, C0 remained <0.5 mg/L (11%), even when the drug was administered intravenously, highlighting the variability of VRZ pharmacokinetics, possibly enhanced by CYP2C19 polymorphism. The risk of inefficacy during periods of underdosage was overcome by treatment with antifungal drug combinations (caspofungin, n=10). The therapeutic index was limited by neurologic effects (14%) and hepatic abnormalities (30%). VRZ concentrations correlated significantly (P<0.01) with aspartate aminotransferase levels but not with bilirubin levels. VRZ acted as a metabolic inhibitor of tacrolimus (C0 to dose ratio 5.8 +/- 2.6, n=31/VRZ versus 1.7 +/- 0.9 alone, P<0.001). Large changes in azole concentration affected the magnitude of the drug-drug interactions and adjustment requirements. TDM is required because VRZ levels are often undetectable in treated CF lung transplant patients, supporting the use of antifungal drug combinations until achievement of VRZ C0 at a steady state between 1 and 2 mg/L. Plasma VRZ concentrations should be determined for the quantitative, individualized management of drug-drug interactions in lung transplant patients, in particular immunosuppressant such as tacrolimus, considering VRZ to be both a target and an inhibitor of CYP3A4.

Clinically Significant Enhancement of Voriconazole Efficacy by Moxifloxacin and Gentamicin in Fungal Keratitis.

PubMed

Matoba, Alice Y; Divatia, Mukul K; Arguello, Robert A; Chevez-Barrios, Paty

2018-05-01

To report the effect of topical antibiotics moxifloxacin 0.3% and gentamicin 0.3% on the clinical efficacy of topical antifungal agent voriconazole 1% in cases of culture- or biopsy-proven fungal keratitis. Two cases of fungal keratitis in which the addition of topical moxifloxacin or moxifloxacin and gentamicin led to an improved clinical response to topical voriconazole were reviewed retrospectively. One patient with clinical resistance of his fungal keratitis to both topical voriconazole and natamycin had resolution of his keratitis with the addition of topical moxifloxacin and gentamicin to voriconazole. One patient who had a poor response to topical voriconazole had a dramatic response to the increase of the voriconazole regimen and addition of moxifloxacin. In a subset of patients with fungal keratitis, the addition of topical moxifloxacin 0.3% or moxifloxacin 0.3% and gentamicin 0.3% may enhance the therapeutic effect of topical voriconazole 1%.

Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co-administered in healthy female subjects

PubMed Central

Andrews, Emma; Damle, Bharat D; Fang, Annie; Foster, Grover; Crownover, Penelope; LaBadie, Robert; Glue, Paul

2008-01-01

AIM To assess the two-way pharmacokinetic interaction between voriconazole and Ortho-Novum® 1/35, an oral contraceptive containing norethindrone 1 mg and ethinyl oestradiol 35 μg. METHODS In this open-label, three-period, fixed-sequence study, 16 healthy females received voriconazole (400 mg q12 h, day 1; 200 mg q12 h, days 2–4) (period 1), oral contraceptive (q24 h, days 12–32) (period 2), and combination voriconazole (400 mg q12 h, day 57; 200 mg q12 h, days 58–60) and oral contraceptive (q24 h, days 40–60) (period 3). RESULTS Voriconazole geometric mean AUCτ and Cmax increased 46% (12 682–18 495 ng h ml−1; 90% confidence interval [CI] 32, 61) and 14% (2485–2840 ng ml−1; 90% CI 3, 27), respectively, when co-administered with oral contraceptive vs. voriconazole alone. Ethinyl oestradiol geometric mean AUCτ and Cmax increased 61% (1031–1657 ng h ml−1; 90% CI 50, 72) and 36% (119–161 ng ml−1; 90% CI 28, 45), respectively, and norethindrone geometric mean AUCτ and Cmax increased 53% (116–177 ng h ml−1; 90% CI 44, 64) and 15% (18–20 ng ml−1; 90% CI 3, 28), respectively, during voriconazole co-administration vs. oral contraceptive alone. Neither ethinyl oestradiol nor norethindrone levels were reduced in subjects following voriconazole co-administration. Adverse events (AEs) were generally mild, occurring less in subjects receiving voriconazole alone (36 events) vs. oral contraceptive alone (88 events) or combination treatment (68 events); four subjects experienced a severe AE. CONCLUSIONS Co-administration of voriconazole and oral contraceptive increased systemic exposures of all analytes relative to respective monotherapy. Although generally safe and well tolerated, it is recommended that patients receiving co-administered voriconazole and oral contraceptive be monitored for development of AEs commonly associated with these medications. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Voriconazole, a broad-spectrum antifungal drug, is a substrate and inhibitor of CYP2C19 and CYP3A4 isozymes.Ethinyl oestradiol and norethindrone, components of the combination oral contraceptive drug Ortho-Novum® 1/35, also are substrates of cytochrome P450 CYP2C19 and CYP3A4 isozymes.Because co-administration of voriconazole and Ortho-Novum® 1/35 could potentially result in pharmacokinetic interactions that increase systemic exposure of one or both drugs to unsafe levels, clinical studies are needed to define better the two-way pharmacokinetic interaction between these drugs. WHAT THIS STUDY ADDS Although co-administered voriconazole and oral contraceptive did result in increased systemic exposures of all three drugs relative to respective monotherapy, co-administered treatment was generally safe and well tolerated.It is recommended, however, that patients receiving co-administered voriconazole and oral contraceptives be monitored for the development of adverse events commonly associated with these medications. PMID:18294327

Therapeutic drug monitoring of anti-infective agents in critically ill patients.

PubMed

Jager, Nynke G L; van Hest, Reinier M; Lipman, Jeffrey; Taccone, Fabio S; Roberts, Jason A

2016-07-01

Initial adequate anti-infective therapy is associated with significantly improved clinical outcomes for patients with severe infections. However, in critically ill patients, several pathophysiological and/or iatrogenic factors may affect the pharmacokinetics of anti-infective agents leading to suboptimal drug exposure, in particular during the early phase of therapy. Therapeutic drug monitoring (TDM) may assist to overcome this problem. We discuss the available evidence on the use of TDM in critically ill patient populations for a number of anti-infective agents, including aminoglycosides, β-lactams, glycopeptides, antifungals and antivirals. Also, we present the available evidence on the practices of anti-infective TDM and describe the potential utility of TDM to improve treatment outcome in critically ill patients with severe infections. For aminoglycosides, glycopeptides and voriconazole, beneficial effects of TDM have been established on both drug effectiveness and potential side effects. However, for other drugs, therapeutic ranges need to be further defined to optimize treatment prescription in this setting.

In Vitro Evaluation of the Type of Interaction Obtained by the Combination of Terbinafine and Itraconazole, Voriconazole, or Amphotericin B against Dematiaceous Molds▿

PubMed Central

Biancalana, Fernanda Simas Corrêa; Lyra, Luzia; Schreiber, Angélica Zaninelli

2011-01-01

In vitro associations using the checkerboard microdilution method indicated lower MIC ranges and MIC median values for each drug (terbinafine, itraconazole, voriconazole, and amphotericin B) in association than those obtained for each single drug. Fractional inhibitory concentration index (FIC) results showed 100% synergism in the association of terbinafine with voriconazole, 96.5% in the association of terbinafine with amphotericin B, and 75.9% in the association of terbinafine with itraconazole. Drug combinations may be useful for treatment of dematiaceous mold infections as an alternative treatment to enhance the effectiveness of each drug. PMID:21690288

Bioavailability of voriconazole in hospitalised patients.

PubMed

Veringa, Anette; Geling, Sanne; Span, Lambert F R; Vermeulen, Karin M; Zijlstra, Jan G; van der Werf, Tjip S; Kosterink, Jos G W; Alffenaar, Jan-Willem C

2017-02-01

An important element in antimicrobial stewardship programmes is early switch from intravenous (i.v.) to oral antimicrobial treatment, especially for highly bioavailable drugs. The antifungal agent voriconazole is available both in i.v. and oral formulations and bioavailability is estimated to be >90% in healthy volunteers, making this drug a suitable candidate for such a transition. Recently, two studies have shown that the bioavailability of voriconazole is substantially lower in patients. However, for both studies various factors that could influence the voriconazole serum concentration, such as inflammation, concomitant intake of food with oral voriconazole, and gastrointestinal complications, were not included in the evaluation. Therefore, in this study a retrospective chart review was performed in adult patients treated with both oral and i.v. voriconazole at the same dose and within a limited (≤5 days) time interval in order to evaluate the effect of switching the route of administration on voriconazole serum concentrations. A total of 13 patients were included. The mean voriconazole trough concentration was 2.28 mg/L [95% confidence interval (CI) 1.29-3.26 mg/L] for i.v. voriconazole administration and 2.04 mg/L (95% CI 0.78-3.30 mg/L) for oral administration. No significant difference was found in the mean oral and i.v. trough concentrations of voriconazole (P = 0.390). The mean bioavailability was 83.0% (95% CI 59.0-107.0%). These findings suggest that factors other than bioavailability may cause the observed difference in voriconazole trough concentrations between oral and i.v. administration in the earlier studies and stress the need for an antimicrobial stewardship team to guide voriconazole dosing. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Voriconazole-Induced Periostitis & Enthesopathy in Solid Organ Transplant Patients: Case Reports

PubMed Central

Sircar, Monica; Kotton, Camille; Wojciechowski, David; Safa, Kassem; Gilligan, Hannah; Heher, Eliot; Williams, Winfred; Thadhani, Ravi; Tolkoff-Rubin, Nina

2016-01-01

Background Voriconazole is frequently used to treat fungal infections in solid organ transplant patients. Recently, there have been reports suggesting that prolonged voriconazole therapy may lead to periostitis. Aim Here we present two cases of voriconazole-induced periostitis in solid organ transplant patients. Case Presentation Voriconazole was given to two transplant patients-one with a liver transplant and the second with a heart transplant, to treat their fungal infections. Both developed voriconazole-induced toxicity. While undergoing voriconazole therapy, they had incapacitating bone pain. The liver transplant patient had to be taken off voriconazole, and the heart transplant patient succumbed to non-voriconazole related causes. Conclusions Voriconazole therapy in two solid organ transplant patients resulted in periostitis. We provide potential etiologies underlying voriconazole-induced periostitis, including fluoride toxicity, abnormalities in the pulmonary vascular bed leading to the production of downstream inflammatory mediators, and abnormal pharmacokinetics of hepatic drug metabolism. In addition to monitoring blood voriconazole trough levels, we suggest careful assessment for musculoskeletal pain in patients undergoing voriconazole treatment for two months or more, particularly if their daily dosages of voriconazole exceed 500 mg per day. Appropriate workup should include measurement of alkaline phosphatase, voriconazole trough and fluoride levels as well as a bone scan. Overall, early recognition of voriconazole-induced musculoskeletal toxicity is important for better morbidity outcomes. PMID:27990445

Clinical usefulness of therapeutic drug monitoring of voriconazole in a university hospital.

PubMed

Cabral-Galeano, Evelyn; Ruiz-Camps, Isabel; Len-Abad, Oscar; Pou-Clavé, Leonor; Sordé-Masip, Roger; Meije-Castillo, Yolanda; Blanco-Grau, Albert; Barba-Suñol, Pere; Monforte-Torres, Victor; Román-Broto, Antonio; Pahissa-Berga, Albert; Gavaldà-Santapau, Joan

2015-05-01

The aim of this study was to assess the clinical usefulness of therapeutic drug monitoring (TDM) of voriconazole (VOR) in a university hospital. A retrospective review was conducted on the clinical records of 52 patients treated with VOR and on whom TDM was performed. Steady-state trough plasma VOR concentration was measured at least 5 days after starting treatment. The therapeutic range of plasma VOR concentration was defined as 1-5.5μg/mL. The most frequent underlying conditions in the study population were lung transplant (48.1%) and hematological malignancies (26.9%). At the first TDM in each patient, VOR levels were outside the therapeutic range in 16 (30.7%) cases: <1μg/mL in 10 (19.2%) and >5.5μg/mL in 6 (11.5%). Eleven patients (21.2%) experienced severe muscle weakness and had considerable difficulty walking. All these patients were receiving concomitant treatment with corticosteroids. Age younger than 30 years (p=.005) and cystic fibrosis as the underlying disease (p=.04) were factors associated with low VOR levels. Almost all patients who had VOR concentrations >1μg/mL at the first TDM had a successful outcome (96%). Plasma VOR concentrations were outside the therapeutic range at the first TDM in 30% (16/52) of patients. Age younger than 30 years and cystic fibrosis were factors associated with low VOR levels. The potential interactions between corticosteroids and VOR should be highlighted, as they could be responsible for a high rate of muscle weakness observed in our patients. Prospective trials are needed to investigate VOR TDM and corticosteroid pharmacokinetics. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Stability and uniformity of extemporaneous preparations of voriconazole in two liquid suspension vehicles at two storage temperatures.

PubMed

Nguyen, Kyvan Q; Hawkins, Michelle G; Taylor, Ian T; Wiebe, Valerie J; Tell, Lisa A

2009-07-01

To determine the stability and distribution of voriconazole in 2 extemporaneously prepared (compounded) suspensions stored for 30 days at 2 temperatures. Voriconazole suspensions (40 mg/mL) compounded from commercially available 200-mg tablets suspended in 1 of 2 vehicles. One vehicle contained a commercially available suspending agent and a sweetening syrup in a 1:1 mixture (SASS). The other vehicle contained the suspending agent with deionized water in a 3:1 mixture (SADI). Voriconazole suspensions (40 mg/mL in 40-mL volumes) were compounded on day 0 and stored at room temperature (approx 21 degrees C) or refrigerated (approx 5 degrees C). To evaluate distribution, room-temperature aliquots of voriconazole were measured immediately after preparation. Refrigerated aliquots were measured after 3 hours of refrigeration. To evaluate stability, aliquots from each suspension were measured at approximately 7-day intervals for up to 30 days. Voriconazole concentration, color, odor, opacity, and pH were measured, and aerobic and anaerobic bacterial cultures were performed at various points. Drug distribution was uniform (coefficient of variation, < 5%) in both suspensions. On day 0, 87.8% to 93.0% of voriconazole was recovered; percentage recovery increased to between 95.1% and 100.8% by day 7. On subsequent days, up to day 30, percentage recovery was stable (> 90%) for all suspensions. The pH of each suspension did not differ significantly throughout the 30-day period. Storage temperature did not affect drug concentrations at any time, nor was bacterial growth obtained. Extemporaneously prepared voriconazole in SASS and SADI resulted in suspensions that remained stable for at least 30 days. Refrigerated versus room-temperature storage of the suspensions had no effect on drug stability.

Assessing micafungin/triazole combinations for the treatment of invasive scedosporiosis due to Scedosporium apiospermum and Scedosporium boydii.

PubMed

Lackner, Michaela; Fernández-Silva, Fabiola; Guarro, Josep; Lass-Flörl, Cornelia

2014-11-01

Scedosporium infections are associated with high therapeutic failure rates. Combination therapy may be an alternative approach to improve outcome. The in vitro and in vivo efficacy of micafungin plus posaconazole or plus voriconazole was investigated herein. Scedosporium boydii (n = 17) and Scedosporium apiospermum (n = 26) were tested using the chequerboard method according to CLSI M38-A2 guidelines and the fractional inhibitory concentration index (FICI) was evaluated. In vivo outcome of micafungin plus posaconazole or micafungin plus voriconazole against two isolates of each of the mentioned species was evaluated in a well-established, immunocompromised, haematogenous murine model of systemic scedosporiosis. Survival and tissue burden in kidneys and brain were investigated. The FICI category of 'no interaction' was most frequent, while 'synergism' or 'antagonism' was rarely observed. FICI failed to predict the in vivo outcome of both combinatorial treatment strategies. In vivo outcome was strain-dependent rather than species-dependent, even though effects on fungal tissue burden were more pronounced for S. boydii. Both combinations improved survival significantly when compared with untreated controls and micafungin monotherapy. Voriconazole and posaconazole did not differ in their efficacy and micafungin failed to be effective. Combinations were by trend better than voriconazole and posaconazole as single therapy, but statistically significant differences were lacking. No benefit of the azole/echinocandin combination was found when compared with voriconazole and posaconazole monotherapies. FICI failed to predict the outcome of in vivo drug combinations in the murine study. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

In vitro antifungal susceptibility of clinical species belonging to Aspergillus genus and Rhizopus oryzae.

PubMed

Kachuei, R; Khodavaisy, S; Rezaie, S; Sharifynia, S

2016-03-01

Among filamentous fungal pathogens, Aspergillus spp. and zygomycetes account for highest rates of morbidity and mortality among immunocompromised patients. Recently developed antifungal drugs offer the potential to improve management and therapeutic outcomes of fungal infections. The aim of this study was to analyse the in vitro activities of voriconazole, itraconazole, amphotericin B and caspofungin against clinical isolates of Aspergillus spp. and Rhizopus oryzae. The in vitro antifungal susceptibility of 54 isolates belonging to different clinical isolates of Aspergillus spp. and R. oryzae was tested for four antifungal agents using a microdilution reference method (CLSI, M38-A2). All isolates were identified by typical colony and microscopic characteristics, and also characterized by molecular methods. Caspofungin (MEC range: 0.008-0.25 and MEC50: 0.0023μg/mL) was the most active drug in vitro against Aspergillus spp., followed by voriconazole (MIC range: 0.031-8 and MIC50: 0.5μg/mL), itraconazole (MIC range: 0.031-16 and MIC50: 0.25μg/mL), and amphotericin B (MIC range: 0.125-4 and MIC50: 0.5μg/mL), in order of decreasing activity. The caspofungin, voriconazole, and itraconazole demonstrated poor in vitro activity against R. oryzae isolates evaluated, followed by amphotericin B. This study demonstrates that caspofungin had good antifungal activity and azole agents had better activity than amphotericin B against Aspergillus species. Although, azole drugs are considered ineffective against R. oryzae. This result is just from a small scale in vitro susceptibility study and we did not take other factors into consideration. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole.

PubMed

Prajna, N Venkatesh; Krishnan, Tiruvengada; Mascarenhas, Jeena; Rajaraman, Revathi; Prajna, Lalitha; Srinivasan, Muthiah; Raghavan, Anita; Oldenburg, Catherine E; Ray, Kathryn J; Zegans, Michael E; McLeod, Stephen D; Porco, Travis C; Acharya, Nisha R; Lietman, Thomas M

2013-04-01

To compare topical natamycin vs voriconazole in the treatment of filamentous fungal keratitis. This phase 3, double-masked, multicenter trial was designed to randomize 368 patients to voriconazole (1%) or natamycin (5%), applied topically every hour while awake until reepithelialization, then 4 times daily for at least 3 weeks. Eligibility included smear-positive filamentous fungal ulcer and visual acuity of 20/40 to 20/400. The primary outcome was best spectacle-corrected visual acuity at 3 months; secondary outcomes included corneal perforation and/or therapeutic penetrating keratoplasty. A total of 940 patients were screened and 323 were enrolled. Causative organisms included Fusarium (128 patients [40%]), Aspergillus (54 patients [17%]), and other filamentous fungi (141 patients [43%]). Natamycintreated cases had significantly better 3-month best spectacle-corrected visual acuity than voriconazole-treated cases (regression coefficient=0.18 logMAR; 95% CI, 0.30 to 0.05; P=.006). Natamycin-treated cases were less likely to have perforation or require therapeutic penetrating keratoplasty (odds ratio=0.42; 95% CI, 0.22 to 0.80; P=.009). Fusarium cases fared better with natamycin than with voriconazole (regression coefficient=0.41 logMAR; 95% CI,0.61 to 0.20; P<.001; odds ratio for perforation=0.06; 95% CI, 0.01 to 0.28; P<.001), while non-Fusarium cases fared similarly (regression coefficient=0.02 logMAR; 95% CI, 0.17 to 0.13; P=.81; odds ratio for perforation=1.08; 95% CI, 0.48 to 2.43; P=.86). Natamycin treatment was associated with significantly better clinical and microbiological outcomes than voriconazole treatment for smear-positive filamentous fungal keratitis, with much of the difference attributable to improved results in Fusarium cases. Voriconazole should not be used as monotherapy in filamentous keratitis. clinicaltrials.gov Identifier: NCT00996736

In vitro susceptibility of filamentous fungi to itraconazole, voriconazole and posaconazole by Clinical and Laboratory Standards Institute reference method and E-test.

PubMed

Kondori, N; Svensson, E; Mattsby-Baltzer, I

2011-09-01

The use of anti-fungal agents has increased dramatically in recent years and new drugs have been developed. Several methods are available for determinations of their specific biological activities, i.e. the standard method for minimum inhibitory concentration-determination is described in M-38 [Clinical and Laboratory Standards Institute document M-38 (CLSI M-38)]. However, alternative methods, such as the E-test, are currently available in Mycology laboratories. The susceptibilities of clinical isolates of Aspergillus spp. (n = 29), Fusarium spp. (n = 5), zygomycetes (n = 21) and Schizophyllum (n = 1) were determined for itraconazole, voriconazole and posaconazole, using the CLSI M-38-A broth dilution method and also by the E-test. A good overall agreement (83.7%) between the two methods for all drugs and organisms was observed. Analyses of voriconazole showed a better agreement (93%) between the methods than posaconazole and itraconazole (85% and 74% respectively). Aspergillus spp. were the most susceptible fungi to the anti-fungal agents tested in this study. Posaconazole was the most active drug against filamentous fungi in vitro, followed by itraconazole and voriconazole. The latter (voriconazole) demonstrated no significant in vitro activity against zygomycetes. © 2010 Blackwell Verlag GmbH.

Characterization of the inhibitory effect of voriconazole on the fungicidal activity of amphotericin B against Candida albicans in an in vitro kinetic model.

PubMed

Lignell, Anders; Löwdin, Elisabeth; Cars, Otto; Sjölin, Jan

2008-07-01

The aim of the present investigation was to study and characterize the effect of voriconazole on the fungicidal activity of amphotericin B. Four strains of Candida albicans susceptible to voriconazole were exposed to voriconazole and amphotericin B, either alone, simultaneously or sequentially in an in vitro kinetic model. Bolus doses resulting in voriconazole and amphotericin B concentrations of 0.005-5 and 2.5 mg/L, respectively, were administered. Antifungal-containing RPMI 1640 was eliminated and replaced by a fresh medium using a peristaltic pump, with a flow rate adjusted to obtain the desired half-lives. With two drugs tested, a computer-controlled dosing pump compensated for differences in the elimination rates. Using static time-kill methodology, one C. albicans strain was exposed to 5 mg/L voriconazole for varying durations followed by 2.5 mg/L amphotericin B after three repeated washes of voriconazole. Voriconazole and amphotericin B treatment alone resulted in fungistatic and fungicidal activities, respectively. Simultaneous administration of voriconazole and amphotericin B resulted in fungicidal activity, whereas only fungistatic activity was observed when repeated doses of amphotericin B were administered sequentially after voriconazole at 24-96 h. The inhibition of the fungicidal activity of amphotericin B was voriconazole dose-dependent, but seemed to be recovered once the voriconazole concentration fell below the MIC. The fungicidal activity was quickly regained after the removal of voriconazole, irrespective of the duration of voriconazole pre-exposure. Voriconazole inhibited the fungicidal effect of sequentially administered amphotericin B in a concentration- and time-dependent manner; the clinical significance of this needs further investigation.

Microemulsions as vehicles for topical administration of voriconazole: formulation and in vitro evaluation.

PubMed

El-Hadidy, Gladious Naguib; Ibrahim, Howida Kamal; Mohamed, Magdi Ibrahim; El-Milligi, Mohamed Farid

2012-01-01

This work was undertaken to investigate microemulsion (ME) as a topical delivery system for the poorly water-soluble voriconazole. Different ME components were selected for the preparation of plain ME systems with suitable rheological properties for topical use. Two permeation enhancers were incorporated, namely sodium deoxycholate or oleic acid. Drug-loaded MEs were evaluated for their physical appearance, pH, rheological properties and in vitro permeation studies using guinea pig skin. MEs based on polyoxyethylene(10)oleyl ether (Brij 97) as the surfactant showed pseudoplastic flow with thixotropic behavior and were loaded with voriconazole. Jojoba oil-based MEs successfully prolonged voriconazole release up to 4 h. No significant changes in physical or rheological properties were recorded on storage for 12 months at ambient conditions. The presence of permeation enhancers favored transdermal rather than dermal delivery. Sodium deoxycholate was more effective than oleic acid for enhancing the voriconazole permeation. Voriconazole-loaded MEs, with and without enhancers, showed significantly better antifungal activity against Candida albicans than voriconazole supersaturated solution. In conclusion, the studied ME formulae could be promising vehicles for topical delivery of voriconazole.

Study of Pathogens of Fungal Keratitis and the Sensitivity of Pathogenic Fungi to Therapeutic Agents with the Disk Diffusion Method.

PubMed

Wang, Lulu; Wang, Liya; Han, Lei; Yin, Weijing

2015-01-01

To identify the causative fungi of fungal keratitis, test their susceptibility to antifungal agents with the disk diffusion method and study the relationship between the organisms, the inhibition zones and the clinical outcomes. 535 patients with fungal keratitis in one eye were included in this study. Pathogenic fungi were isolated by corneal scraping, identified by fungal cultivation and subjected to drug sensitivity tests conducted with the disk diffusion method. The patients were treated initially with voriconazole, terbinafine and natamycin eye drops for one week. Further treatment continued using the most effective drug according to the drug sensitivity results. The patients were followed up every week until three months after cured. The inhibition zones of fungi cultured with voriconazole, terbinafine and natamycin were compared. The relationship between inhibition zones and organism, organism and treatment results measure, and each treatment results measure and inhibition zones were evaluated. Of 535 patients, 53.84%, 19.25% and 26.91% were infected with Aspergillus, Fusarium and other fungi, respectively. Keratitis patients infected with Aspergillus keratitis had the worst outcome. The size of the inhibition zones of Aspergillus spp., Fusarium spp. and other fungal genera differed significantly in response to voriconazole, terbinafine and natamycin. The inhibition zone associated with natamycin correlated significantly with the clinical outcome of fungal keratitis (OR = 0.925), but no other such correlations were found for the other drugs tested. Aspergillus and Fusarium were the predominant pathogenic genera causing fungal keratitis in our patients. Among the causative fungi, infections due to Aspergillus spp. were associated with the worst outcomes. The inhibition zones of fungal isolates in response to natamycin significantly correlated with the treatment outcomes of keratitis. Specifically, the smaller the natamycin inhibition zone, the lower the probability that the fungal keratitis had been eliminated.

Argon laser photocoagulation versus intrastromal voriconazole injection in treatment of mycotic keratitis

PubMed Central

Khater, Mohammad M.; El-Shorbagy, Mohammad S.; Selima, Adel A.

2016-01-01

AIM To compare argon laser photocoagulation and intrastromal injection of voriconazole as adjunctive treatment modalities in cases of resistant mycotic corneal ulcers. METHODS Two groups each of them included 20 cases of resistant mycotic corneal ulcers. Both groups treated with local and systemic specific antimicrobial drugs guided with culture and sensitivity results. In one group argon laser photocoagulation was used as an adjunctive therapy to the specific antifungal drugs and in the other group, intrastromal injection of voriconazole was done besides the specific antifungal drugs. The 40 cases included in the study were proven according to culture and sensitivity to be 28 cases with pure fungal results and 12 cases with mixed (fungal and bacterial). In argon laser group, argon laser irradiation of the corneal ulcer was performed using argon laser 532 nm wavelength (Carl Zeiss LSL 532s AG; Meditec, Inc.) after fluorescein staining. In the other group, voriconazole solution (500 µg/mL) was prepared and injected in the corneal stroma. All cases were followed up for 3mo after healing was achieved. RESULTS Complete healing of the epithelial defect and resolution of stromal infiltration with no adverse effects were achieved in argon laser group in duration ranged from 2-4wk in 90% of cases. In voriconazole group 4 cases needed amniotic membrane graft due to thinning and 16 cases healed in duration ranged from 2-6wk (80% of cases). CONCLUSION Argon laser photocoagulation is superior to intrastromal voriconazole injection in treatment of resistant fungal corneal ulcers. PMID:26949639

An open-label comparative pilot study of oral voriconazole and itraconazole for long-term treatment of paracoccidioidomycosis.

PubMed

Queiroz-Telles, Flavio; Goldani, Luciano Z; Schlamm, Haran T; Goodrich, James M; Espinel-Ingroff, Ana; Shikanai-Yasuda, Maria A

2007-12-01

In previous studies, itraconazole was revealed to be an effective therapy and was considered to be the gold standard treatment for mild-to-moderate acute and chronic clinical forms of paracoccidioidomycosis. A pilot study was conducted to investigate the efficacy, safety, and tolerability of voriconazole for the long-term treatment of acute or chronic paracoccidioidomycosis, with itraconazole as the control treatment. A randomized, open-label study was conducted at 3 Brazilian tertiary care hospitals. Patients were randomized (at a 2 : 1 ratio) to receive oral therapy with voriconazole or itraconazole for 6 months. Patients receiving >or=1 dose of study drug were evaluated for safety; patients with confirmed paracoccidioidomycosis who completed >or=6 months of therapy (treatment-evaluable patients) were evaluated for treatment efficacy. Satisfactory global response was assessed at the end of treatment. Fifty-three patients were evaluated for treatment safety (35 received voriconazole, and 18 received itraconazole). Both drugs were well tolerated. The most common treatment-related adverse events in the voriconazole group included abnormal vision, chromatopsia, rash, and headache; the most common treatment-related adverse events in the itraconazole group included bradycardia, diarrhea, and headache. Liver function test values were slightly higher in patients receiving voriconazole than in those receiving itraconazole; 2 patients in the voriconazole group were withdrawn from treatment because of increased liver function test values. In the intent-to-treat populations, the satisfactory response rate (i.e., complete or partial global response) was 88.6% among the voriconazole group and 94.4% among the itraconazole group. The response rate among treatment-evaluable patients was 100% for both treatment groups; no relapses were observed after 8 weeks of follow-up. This is, to our knowledge, the first study to demonstrate that voriconazole is as well tolerated and effective as itraconazole for the long-term treatment of paracoccidioidomycosis.

Voriconazole-induced musical hallucinations.

PubMed

Agrawal, A K; Sherman, L K

2004-10-01

1 Voriconazole (Vfend) is a second-generation azole antifungal that is increasing in popularity especially for the treatment of invasive aspergillosis as well as empirically for the febrile neutropenic patient. In addition, voriconazole tends to have a mild side effect profile with reversible visual disturbances being the most widely described effect. We describe a patient who had musical hallucinations secondary to voriconazole. The patient was a 78-year-old man admitted for induction of chemotherapy for acute myelogenous leukemia (AML) who began to have auditory hallucinations, specifically of Christmas music, the 2nd day of voriconazole therapy. His psychiatric evaluation was otherwise unremarkable. After discontinuing voriconazole the hallucinations decreased in intensity by the 2nd day and ceased altogether by the 3rd day. An extensive literature search, including Pfizer drug trial safety data, yielded no other reports of auditory hallucinations with voriconazole. Several other interesting cases of musical hallucinations secondary to a variety of causes have been reported in the literature, and are reviewed. Notably, musical hallucinations tend to occur secondary to temporal lobe insults and often are of a religious or patriotic theme.

Isavuconazole Concentration in Real-world Practice: Consistency with Results from Clinical Trials.

PubMed

Andes, David; Kovanda, Laura; Desai, A; Kitt, Theresa; Zhao, M; Walsh, Thomas J

2018-05-07

Clinical use of voriconazole, posaconazole, and itraconazole revealed the need for therapeutic drug monitoring (TDM) of plasma concentrations of these antifungal agents. This need for TDM was not evident from clinical trials of these drugs. In order to establish if this requirement also applies to isavuconazole, we examined the plasma concentrations of 283 samples receiving isavuconazole in clinical practice and compared the values to those from clinical trials. The concentration distributions from real-world use and clinical trials were nearly identical (>1 μg/mL in 90% of patients). These findings suggest that routine TDM may not be required for isavuconazole in most instances. Copyright © 2018 American Society for Microbiology.

Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment.

PubMed

Mehta, Nilesh M; Halwick, David R; Dodson, Brenda L; Thompson, John E; Arnold, John H

2007-06-01

Using an ex vivo simulation model we set out to estimate the amount of drug lost due to sequestration within the extracorporeal circuit over time. Simulated closed-loop extracorporeal membrane oxygenation (ECMO) circuits were prepared using a 1.5-m2 silicone membrane oxygenator. Group A consisted of heparin, dopamine, ampicillin, vancomycin, phenobarbital and fentanyl. Group B consisted of epinephrine, cefazolin, hydrocortisone, fosphenytoin and morphine. Drugs were tested in crystalloid and blood-primed circuits. After administration of a one-time dose of drugs in the priming fluid, baseline drug concentrations were obtained (P0). A simultaneous specimen was stored for stability testing at 24 h (P4). Serial post-membrane drug concentrations were then obtained at 30 min (P1), 3 h (P2) and 24 h (P3) from circuit fluid. One hundred and one samples were analyzed. At the end of 24 h in crystalloid-primed circuits, 71.8% of ampicillin, 96.7% of epinephrine, 17.6% of fosphenytoin, 33.3% of heparin, 17.5% of morphine and 87% of fentanyl was lost. At the end of 24 h in blood-primed extracorporeal circuits, 15.4% of ampicillin, 21% of cefazolin, 71% of voriconazole, 31.4% of fosphenytoin, 53.3% of heparin and 100% of fentanyl was lost. There was a significant decrease in overall drug concentrations from 30 min to 24 h for both crystalloid-primed circuits (p = 0.023) and blood-primed circuits (p = 0.04). Our ex vivo study demonstrates serial losses of several drugs commonly used during ECMO therapy. Therapeutic concentrations of fentanyl, voriconazole, antimicrobials and heparin cannot be guaranteed in patients on ECMO.

Flaws in design, analysis and interpretation of Pfizer's antifungal trials of voriconazole and uncritical subsequent quotations.

PubMed

Jørgensen, Karsten J; Johansen, Helle Krogh; Gøtzsche, Peter C

2006-01-19

We have previously described how a series of trials sponsored by Pfizer of its antifungal drug, fluconazole, in cancer patients with neutropenia handicapped the control drug, amphotericin B, by flaws in design and analysis. We describe similar problems in two pivotal trials of Pfizer's new antifungal agent, voriconazole, published in a prestigious journal. In a non-inferiority trial, voriconazole was significantly inferior to liposomal amphothericin B, but the authors concluded that voriconazole was a suitable alternative. The second trial used amphothericin B deoxycholate as comparator, but handicapped the drug by not requiring pre-medication to reduce infusion-related toxicity or substitution with electrolytes and fluid to reduce nephrotoxicity, although the planned duration of treatment was 84 days. Voriconazole was given for 77 days on average, but the comparator for only 10 days, which precludes a meaningful comparison. In a random sample of 50 references to these trials, we found that the unwarranted conclusions were mostly uncritically propagated. It was particularly surprising that relevant criticism raised by the FDA related to the first trial was only quoted once, and that none of the articles noted the obvious flaws in the design of the second trial. We suggest that editors ensure that the abstract reflects fairly on the remainder of the paper, and that journals do not impose any time limit for accepting letters that point out serious weaknesses in a study that have not been noted before.

Pharmacological considerations for azole antifungal drug management in cystic fibrosis lung transplant patients.

PubMed

Billaud, Eliane M; Guillemain, Romain; Berge, Maud; Amrein, Catherine; Lefeuvre, Sandrine; Louët, Agnès Lillo-Le; Boussaud, Véronique; Chevalier, Patrick

2010-11-01

This paper aims to present our experience in the pharmacological approach of the management of azole antifungal drugs in cystic fibrosis lung transplant patients. Cystic fibrosis (CF) lung transplantation is associated with multi-factorial care management, because of immunosuppressive requirements, risk of infections, frequency of gastro-oesophageal reflux disease, hepatic alterations and CF pharmacokinetics (PK) specificities that result in important PK variability. CF is associated with frequent colonization of the airways by filamentous fungi, especially by Aspergillus species. Today the antifungal therapeutic arsenal offers several possibilities for long-term oral therapy including azole drugs (itraconazole, voriconazole and posaconazole). Therefore, nephrotoxic amphotericin B should be avoided. The liver is important in the pharmacological profile of azole drugs, due to metabolic elimination, hepatotoxicity and PK drug-drug interaction (DDI) involving CYP3A4 metabolic inhibition. Targets for such DDI are numerous, but immunosuppressive drugs are of major concern, justifying combined therapeutic drug monitoring (TDM) of both azoles (inhibitors) and immunosuppressants (targets) on an individualized patient basis to adjust the coprescription quantitatively. The risk of long under-dosed periods, frequently addressed in this population, could justify, on a PK basis, the need for combination with an exclusive parenteral antifungal while waiting for azole relevant drug level. High PK variability, the risk of low exposure, therapeutic issues and DDI management in this complex underlying disease justify close monitoring with systematic combined TDM of azole and immunosuppressants, in case of coprescription.

Adjunctive Oral Voriconazole Treatment of Fusarium Keratitis

PubMed Central

Prajna, N. Venkatesh; Krishnan, Tiruvengada; Rajaraman, Revathi; Patel, Sushila; Shah, Ranjeet; Srinivasan, Muthiah; Devi, Lumbini; Das, Manoranjan; Ray, Kathryn J.; O'Brien, Kieran S.; Oldenburg, Catherine E.; McLeod, Stephen D.; Zegans, Michael E.; Acharya, Nisha R; Lietman, Thomas M.

2017-01-01

Importance Fusarium keratitis is common and often results in poor outcomes. No new treatments since natamycin have become available. Objective To explore the role of adjuvant oral voriconazole on clinical outcomes in Fusarium keratitis. Design, Setting, and Participants In this prespecified subgroup analysis of a multicenter, double-masked, placebo-controlled randomized clinical trial, 240 patients from the Aravind Eye Care System in India, the Lumbini Eye Hospital and Bharatpur Eye Hospital in Nepal, and the University of California, San Francisco, who had culture-positive fungal ulcer and baseline visual acuity of 20/400 or worse were randomized to receive oral voriconazole vs placebo. Enrollment started May 24, 2010, and the last patient study visit was November 23, 2015. All patients received topical voriconazole, 1%, and after the results of the Mycotic Ulcer Treatment Trial (MUTT) II became available, topical natamycin, 5%, was added for all patients. Data analysis was performed from September 2 to October 28, 2016. Main Outcomes and Measures The primary outcome of the trial was the rate of corneal perforation or the need for therapeutic penetrating keratoplasty. Secondary outcomes included rate of reepithelialization, best spectacle-corrected visual acuity, and infiltrate or scar size at 3 months. Results Of the 240 study participants, 72 (30.4%) were culture positive for Fusarium species (41 [56.9%] male and 31 [43.1%] female; median [interquartile range] age, 50 [45-57] years). Of these, 33 (45.8%) were randomized to oral voriconazole and 39 (54.2%) to placebo. Fusarium ulcers randomized to oral voriconazole had a 0.43-fold decreased hazard of perforation or therapeutic penetrating keratoplasty compared with placebo after controlling for baseline infiltrate depth (95% CI, 0.22-fold to 0.84-fold; P = .01). Multiple linear regression revealed a 1.89-mm decreased infiltrate and/or scar size at 3 weeks (95% CI, −2.69 to −1.09 mm; P < .001) and a 0.83-mm decreased infiltrate and/or scar size at 3 months after correcting for baseline values (95% CI, −1.33 to −0.32 mm; P = .001) in eyes randomized to oral voriconazole vs placebo. Eyes treated with oral voriconazole also had a mean 0.29 decreased logMAR (improved) (Snellen equivalent 20/40) visual acuity at 3 months after controlling for baseline visual acuity, although this finding was not statistically significant (95% CI, −0.57 to 0.002; P = .052). Conclusions and Relevance Although MUTT II could not find a benefit for all corneal ulcers, Fusarium keratitis may benefit from the addition of oral voriconazole to topical natamycin, and physicians should consider prescribing oral voriconazole in these cases. Trial Registration clinicaltrials.gov Identifier: NCT00996736 PMID:28426856

Adjunctive Oral Voriconazole Treatment of Fusarium Keratitis: A Secondary Analysis From the Mycotic Ulcer Treatment Trial II.

PubMed

Prajna, N Venkatesh; Krishnan, Tiruvengada; Rajaraman, Revathi; Patel, Sushila; Shah, Ranjeet; Srinivasan, Muthiah; Devi, Lumbini; Das, Manoranjan; Ray, Kathryn J; O'Brien, Kieran S; Oldenburg, Catherine E; McLeod, Stephen D; Zegans, Michael E; Acharya, Nisha R; Lietman, Thomas M; Rose-Nussbaumer, Jennifer

2017-06-01

Fusarium keratitis is common and often results in poor outcomes. No new treatments since natamycin have become available. To explore the role of adjuvant oral voriconazole on clinical outcomes in Fusarium keratitis. In this prespecified subgroup analysis of a multicenter, double-masked, placebo-controlled randomized clinical trial, 240 patients from the Aravind Eye Care System in India, the Lumbini Eye Hospital and Bharatpur Eye Hospital in Nepal, and the University of California, San Francisco, who had culture-positive fungal ulcer and baseline visual acuity of 20/400 or worse were randomized to receive oral voriconazole vs placebo. Enrollment started May 24, 2010, and the last patient study visit was November 23, 2015. All patients received topical voriconazole, 1%, and after the results of the Mycotic Ulcer Treatment Trial (MUTT) II became available, topical natamycin, 5%, was added for all patients. Data analysis was performed from September 2 to October 28, 2016. The primary outcome of the trial was the rate of corneal perforation or the need for therapeutic penetrating keratoplasty. Secondary outcomes included rate of reepithelialization, best spectacle-corrected visual acuity, and infiltrate or scar size at 3 months. Of the 240 study participants, 72 (30.4%) were culture positive for Fusarium species (41 [56.9%] male and 31 [43.1%] female; median [interquartile range] age, 50 [45-57] years). Of these, 33 (45.8%) were randomized to oral voriconazole and 39 (54.2%) to placebo. Fusarium ulcers randomized to oral voriconazole had a 0.43-fold decreased hazard of perforation or therapeutic penetrating keratoplasty compared with placebo after controlling for baseline infiltrate depth (95% CI, 0.22-fold to 0.84-fold; P = .01). Multiple linear regression revealed a 1.89-mm decreased infiltrate and/or scar size at 3 weeks (95% CI, -2.69 to -1.09 mm; P < .001) and a 0.83-mm decreased infiltrate and/or scar size at 3 months after correcting for baseline values (95% CI, -1.33 to -0.32 mm; P = .001) in eyes randomized to oral voriconazole vs placebo. Eyes treated with oral voriconazole also had a mean 0.29 decreased logMAR (improved) (Snellen equivalent 20/40) visual acuity at 3 months after controlling for baseline visual acuity, although this finding was not statistically significant (95% CI, -0.57 to 0.002; P = .052). Although MUTT II could not find a benefit for all corneal ulcers, Fusarium keratitis may benefit from the addition of oral voriconazole to topical natamycin, and physicians should consider prescribing oral voriconazole in these cases. clinicaltrials.gov Identifier: NCT00996736.

The Mycotic Ulcer Treatment Trial

PubMed Central

Prajna, N. Venkatesh; Krishnan, Tiruvengada; Mascarenhas, Jeena; Rajaraman, Revathi; Prajna, Lalitha; Srinivasan, Muthiah; Raghavan, Anita; Oldenburg, Catherine E.; Ray, Kathryn J.; Zegans, Michael E.; McLeod, Stephen D.; Porco, Travis C.; Acharya, Nisha R.; Lietman, Thomas M.

2013-01-01

Objective To compare topical natamycin vs voriconazole in the treatment of filamentous fungal keratitis. Methods This phase 3, double-masked, multicenter trial was designed to randomize 368 patients to voriconazole (1%) or natamycin (5%), applied topically every hour while awake until reepithelialization, then 4 times daily for at least 3 weeks. Eligibility included smear-positive filamentous fungal ulcer and visual acuity of 20/40 to 20/400. Main Outcome Measures The primary outcome was best spectacle-corrected visual acuity at 3 months; secondary outcomes included corneal perforation and/or therapeutic penetrating keratoplasty. Results A total of 940 patients were screened and 323 were enrolled. Causative organisms included Fusarium (128 patients [40%]), Aspergillus (54 patients [17%]), and other filamentous fungi (141 patients [43%]). Natamycin-treated cases had significantly better 3-month best spectacle-corrected visual acuity than voriconazole-treated cases (regression coefficient=−0.18 logMAR; 95% CI, −0.30 to −0.05; P=.006). Natamycin-treated cases were less likely to have perforation or require therapeutic penetrating keratoplasty (odds ratio=0.42; 95% CI, 0.22 to 0.80; P=.009). Fusarium cases fared better with natamycin than with voriconazole (regression coefficient=−0.41 logMAR; 95% CI, −0.61 to −0.20; P<.001; odds ratio for perforation=0.06; 95% CI, 0.01 to 0.28; P<.001), while non-Fusarium cases fared similarly (regression coefficient=−0.02 logMAR; 95% CI, −0.17 to 0.13; P=.81; odds ratio for perforation=1.08; 95% CI, 0.48 to 2.43; P=.86). Conclusions Natamycin treatment was associated with significantly better clinical and microbiological outcomes than voriconazole treatment for smear-positive filamentous fungal keratitis, with much of the difference attributable to improved results in Fusarium cases. Application to Clinical Practice Voriconazole should not be used as monotherapy in filamentous keratitis. Trial Registration clinicaltrials.gov Identifier: NCT00996736 PMID:23710492

In Vitro Antifungal Susceptibility of Oral Candida Isolates from Patients Suffering from Caries and Chronic Periodontitis.

PubMed

De-la-Torre, Janire; Ortiz-Samperio, María Esther; Marcos-Arias, Cristina; Marichalar-Mendia, Xabier; Eraso, Elena; Echebarria-Goicouria, María Ángeles; Aguirre-Urizar, José Manuel; Quindós, Guillermo

2017-06-01

Caries and chronic periodontitis are common oral diseases where a higher Candida colonization is reported. Antifungal agents could be adjuvant drugs for the therapy of both clinical conditions. The aim of the current study has been to evaluate the in vitro activities of conventional and new antifungal drugs against oral Candida isolates from patients suffering from caries and/or chronic periodontitis. In vitro activities of amphotericin B, fluconazole, itraconazole, miconazole, nystatin, posaconazole and voriconazole against 126 oral Candida isolates (75 Candida albicans, 18 Candida parapsilosis, 11 Candida dubliniensis, six Candida guilliermondii, five Candida lipolytica, five Candida glabrata, four Candida tropicalis and two Candida krusei) from 61 patients were tested by the CLSI M27-A3 method. Most antifungal drugs were highly active, and resistance was observed in less than 5% of tested isolates. Miconazole was the most active antifungal drug, being more than 98% of isolates susceptible. Fluconazole, itraconazole, and the new triazoles, posaconazole and voriconazole, were also very active. Miconazole, fluconazole and voriconazole have excellent in vitro activities against all Candida isolates and could represent suitable treatment for a hypothetically adjunctive therapy of caries and chronic periodontitis.

Plasma Concentrations of Itraconazole, Voriconazole, and Terbinafine When Delivered by an Impregnated, Subcutaneous Implant in Japanese Quail ( Coturnix japonica ).

PubMed

Souza, Marcy J; Redig, Patrick; Cox, Sherry K

2017-06-01

Aspergillosis is a common fungal infection in both wild and pet birds. Although effective antifungal medications are available, treatment of aspergillosis can require months of medication administration, which entails stressful handling one or more times per day. This study examined the delivery of the antifungal drugs itraconazole, voriconazole, and terbinafine to Japanese quail ( Coturnix japonica ) via an impregnated implant. Implants contained 0.5, 3, 8, or 24 mg of itraconazole, voriconazole, or terbinafine. The implants were administered subcutaneously over the dorsum and between the scapulae. Blood was collected from birds before and 2, 7, 21, 42, and 56 days after implant placement. Plasma was analyzed by high-performance liquid chromatography for concentrations of itraconazole, voriconazole, or terbinafine, as appropriate. During the course of the study, targeted terbinafine concentrations were achieved in some birds at various time points, but concentrations were inconsistent. Itraconazole and voriconazole concentrations were also inconsistent and did not reach targeted concentrations. Currently, the implant examined in this study cannot be recommended for treatment of aspergillosis in avian species.

Disseminated Scedosporium prolificans infection in an 'extensive metaboliser': navigating the minefield of drug interactions and pharmacogenomics.

PubMed

Trubiano, J A; Paratz, E; Wolf, M; Teh, B W; Todaro, M; Thursky, K A; Slavin, M A

2014-09-01

We report a case of non-fatal disseminated Scedosporium prolificans infection, including central nervous system disease and endophthalmitis, in a relapsed acute myeloid leukaemia patient with extensive CYP2C19 metabolism. Successful treatment required aggressive surgical debridement, three times daily voriconazole dosing and cimetidine CYP2C19 inhibition. In addition, the unique use of miltefosine was employed due to azole-chemotherapeutic drug interactions. Prolonged survival following disseminated S. prolificans, adjunctive miltefosine and augmentation of voriconazole exposure with cimetidine CYP2C19 inhibition has not been reported. © 2014 Blackwell Verlag GmbH.

[Invasive mould disease in haematological patients].

PubMed

Ruiz-Camps, Isabel; Jarque, Isidro

2014-01-01

Invasive mould infections (IMI) are a persistent problem with high morbidity and mortality rates among patients receiving chemotherapy for hematological malignancies and hematopoietic stem cell transplant recipients. Management of IMI in this setting has become increasingly complex with the advent of new antifungal agents and diagnostic tests, which have resulted in different therapeutic strategies (prophylactic, empirical, pre-emptive, and directed). A proper assessment of the individual risk for IMI appears to be critical in order to use the best prophylactic and therapeutic approach and increase the survival rates. Among the available antifungal drugs, the most frequently used in the hematologic patient are fluconazole, mould-active azoles (itraconazole, posaconazole and voriconazole), candins (anidulafungin, caspofungin and micafungin), and lipid formulations of amphotericin B. Specific recommendations for their use, and criteria for selecting the antifungal agents are discussed in this paper. Copyright © 2014. Published by Elsevier Espana.

Molecular and cellular responses of the pathogenic fungus Lomentospora prolificans to the antifungal drug voriconazole.

PubMed

Pellon, Aize; Ramirez-Garcia, Andoni; Buldain, Idoia; Antoran, Aitziber; Rementeria, Aitor; Hernando, Fernando L

2017-01-01

The filamentous fungus Lomentospora (Scedosporium) prolificans is an emerging opportunistic pathogen associated with fatal infections in patients with disturbed immune function. Unfortunately, conventional therapies are hardly of any use against this fungus due to its intrinsic resistance. Therefore, we performed an integrated study of the L. prolificans responses to the first option to treat these mycoses, namely voriconazole, with the aim of unveiling mechanisms involved in the resistance to this compound. To do that, we used a wide range of techniques, including fluorescence and electron microscopy to study morphological alterations, ion chromatography to measure changes in cell-wall carbohydrate composition, and proteomics-based techniques to identify the proteins differentially expressed under the presence of the drug. Significantly, we showed drastic changes occurring in cell shape after voriconazole exposure, L. prolificans hyphae being shorter and wider than under control conditions. Interestingly, we proved that the architecture and carbohydrate composition of the cell wall had been modified in the presence of the drug. Specifically, L. prolificans constructed a more complex organelle with a higher presence of glucans and mannans. In addition to this, we identified several differentially expressed proteins, including Srp1 and heat shock protein 70 (Hsp70), as the most overexpressed under voriconazole-induced stress conditions. The mechanisms described in this study, which may be directly related to L. prolificans antifungal resistance or tolerance, could be used as targets to improve existing therapies or to develop new ones in order to successfully eliminate these mycoses.

Cost-Effectiveness Analysis of Isavuconazole vs. Voriconazole as First-Line Treatment for Invasive Aspergillosis.

PubMed

Harrington, Rachel; Lee, Edward; Yang, Hongbo; Wei, Jin; Messali, Andrew; Azie, Nkechi; Wu, Eric Q; Spalding, James

2017-01-01

Invasive aspergillosis (IA) is associated with a significant clinical and economic burden. The phase III SECURE trial demonstrated non-inferiority in clinical efficacy between isavuconazole and voriconazole. No studies have evaluated the cost-effectiveness of isavuconazole compared to voriconazole. The objective of this study was to evaluate the costs and cost-effectiveness of isavuconazole vs. voriconazole for the first-line treatment of IA from the US hospital perspective. An economic model was developed to assess the costs and cost-effectiveness of isavuconazole vs. voriconazole in hospitalized patients with IA. The time horizon was the duration of hospitalization. Length of stay for the initial admission, incidence of readmission, clinical response, overall survival rates, and experience of adverse events (AEs) came from the SECURE trial. Unit costs were from the literature. Total costs per patient were estimated, composed of drug costs, costs of AEs, and costs of hospitalizations. Incremental costs per death avoided and per additional clinical responders were reported. Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted. Base case analysis showed that isavuconazole was associated with a $7418 lower total cost per patient than voriconazole. In both incremental costs per death avoided and incremental costs per additional clinical responder, isavuconazole dominated voriconazole. Results were robust in sensitivity analysis. Isavuconazole was cost saving and dominant vs. voriconazole in most DSA. In PSA, isavuconazole was cost saving in 80.2% of the simulations and cost-effective in 82.0% of the simulations at the $50,000 willingness to pay threshold per additional outcome. Isavuconazole is a cost-effective option for the treatment of IA among hospitalized patients. Astellas Pharma Global Development, Inc.

Isothermal microcalorimetry for antifungal susceptibility testing of Mucorales, Fusarium spp., and Scedosporium spp.

PubMed

Furustrand Tafin, Ulrika; Meis, Jacques F; Trampuz, Andrej

2012-08-01

We evaluated isothermal microcalorimetry for real-time susceptibility testing of non-Aspergillus molds. MIC and minimal effective concentration (MEC) values of Mucorales (n = 4), Fusarium spp. (n = 4), and Scedosporium spp. (n = 4) were determined by microbroth dilution according to the Clinical Laboratory Standard Institute M38-A2 guidelines. Heat production of molds was measured at 37 °C in Sabouraud dextrose broth inoculated with 2.5 × 10(4) spores/mL in the presence of amphotericin B, voriconazole, posaconazole, caspofungin, and anidulafungin. As determined by microcalorimetry, amphotericin B was the most active agent against Mucorales (MHIC 0.06-0.125 μg/mL) and Fusarium spp. (MHIC 1-4 μg/mL), whereas voriconazole was the most active agent against Scedosporium spp. (MHIC 0.25 to 8 μg/mL). The percentage of agreement (within one 2-fold dilution) between the MHIC and MIC (or MEC) was 67%, 92%, 75%, and 83% for amphotericin B, voriconazole, posaconazole, and caspofungin, respectively. Microcalorimetry provides additional information on timing of antifungal activity, enabling further investigation of drug-mold and drug-drug interaction, and optimization of antifungal treatment. Copyright © 2012 Elsevier Inc. All rights reserved.

Formulation and evaluation of voriconazole ophthalmic solid lipid nanoparticles in situ gel.

PubMed

Pandurangan, Dinesh Kumar; Bodagala, Prathima; Palanirajan, Vijayaraj Kumar; Govindaraj, Saravanan

2016-01-01

In the present investigation, solid lipid nanoparticles (SLNs)-loaded in situ gel with voriconazole drug was formulated. Further, the formulation was characterized for pH, gelling capacity, entrapment efficiency, in vitro drug release, drug content, and viscosity. Voriconazole is an antifungal drug used to treat various infections caused by yeast or other types of fungi. Film hydration technique was used to prepared SLNs from lecithin and cholesterol. Based on the entrapment efficiency 67.2-97.3% and drug release, the optimized formulation NF1 of SLNs was incorporated into in situ gels. The in situ gels were prepared using viscosity-enhancing polymers such as Carbopol and (hydroxypropyl)methyl cellulose (HPMC). Formulated SLN in situ gel formulations were characterized, which showed pH 4.9-7.1, drug content 65.69-96.3%, and viscosity (100 rpm) 120-620 cps. From the characterizations given above, F6 was optimized and evaluated for microbial assay and ocular irritation studies. Microbial assay was conducted by the cup-plate method using Candida albicans as the test organism. An ocular irritation study was conducted on albino rabbits. The results revealed that there was no ocular damage to the cornea, conjunctiva, or iris. Stability studies were carried out on the F6 formulation for 3 months, which showed that the formulation had good stability. These results indicate that the studied SLNs-loaded in situ gel is a promising vehicle for ocular delivery.

Two Voriconazole salts: Syntheses, crystal structures, solubility and bioactivities

NASA Astrophysics Data System (ADS)

Tang, Gui-Mei; Wang, Yong-Tao

2018-01-01

Two Voriconazole salts, namely, (H2FZ)2+·2(Cl-) (1) and (HFZ)+·NO3- (2) (FZ = (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidiny)-1-(1H-1,2,4-triazol-1-yl)-2-butanol) have been obtained through the reaction of Voriconazole, hydrochloric acid and nitrate acid, respectively. They were structurally characterized by FT-IR, elemental analyses (EA), single crystal X-ray diffraction, and thermogravimetric analysis (TGA). A variety of hydrogen bonds (Osbnd H⋯N, Nsbnd H⋯Cl/O, Csbnd H⋯N/OF/Cl) were observed in the compounds 1 and 2, through which a 3D supramolecular architecture is generated. Both two salts 1 and 2 show the promising bioactivities against Aspergillus species (Aspergillus niger, Aspergillus terreus, Aspergillus fumigatus and Aspergillus flavus) and Candida ones (Candida albicans, Candida krusei, Candida glabrata and Cryptococcus neoformans), which is obviously more excellent than that of FZ. Additionally, the solubility of two salts is considerably higher than that of the drug Voriconazole.

Species-specific antifungal susceptibility patterns of Scedosporium and Pseudallescheria species.

PubMed

Lackner, Michaela; de Hoog, G Sybren; Verweij, Paul E; Najafzadeh, Mohammad J; Curfs-Breuker, Ilse; Klaassen, Corné H; Meis, Jacques F

2012-05-01

Since the separation of Pseudallescheria boydii and P. apiosperma in 2010, limited data on species-specific susceptibility patterns of these and other species of Pseudallescheria and its anamorph Scedosporium have been reported. This study presents the antifungal susceptibility patterns of members affiliated with both entities. Clinical and environmental isolates (n = 332) from a wide range of sources and origins were identified down to species level and tested according to CLSI M38-A2 against eight antifungal compounds. Whereas P. apiosperma (geometric mean MIC/minimal effective concentration [MEC] values of 0.9, 2.4, 7.4, 16.2, 0.2, 0.8, 1.5, and 6.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) and P. boydii (geometric mean MIC/MEC values of 0.7, 1.3, 5.7, 13.8, 0.5, 1.4, 2.3, and 11.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) had similar susceptibility patterns, those for S. aurantiacum, S. prolificans, and S. dehoogii were different from each other. Voriconazole was the only drug with significant activity against S. aurantiacum isolates. The MIC distributions of all drugs except voriconazole did not show a normal distribution and often showed two subpopulations, making a species-based prediction of antifungal susceptibility difficult. Therefore, antifungal susceptibility testing of all clinical isolates remains essential for targeted antifungal therapy. Voriconazole was the only compound with low MIC values (MIC(90) of ≤ 2 μg/ml) for P. apiosperma and P. boydii. Micafungin and posaconazole showed moderate activity against the majority of Scedosporium strains.

Species-Specific Antifungal Susceptibility Patterns of Scedosporium and Pseudallescheria Species

PubMed Central

Lackner, Michaela; de Hoog, G. Sybren; Verweij, Paul E.; Najafzadeh, Mohammad J.; Curfs-Breuker, Ilse; Klaassen, Corné H.

2012-01-01

Since the separation of Pseudallescheria boydii and P. apiosperma in 2010, limited data on species-specific susceptibility patterns of these and other species of Pseudallescheria and its anamorph Scedosporium have been reported. This study presents the antifungal susceptibility patterns of members affiliated with both entities. Clinical and environmental isolates (n = 332) from a wide range of sources and origins were identified down to species level and tested according to CLSI M38-A2 against eight antifungal compounds. Whereas P. apiosperma (geometric mean MIC/minimal effective concentration [MEC] values of 0.9, 2.4, 7.4, 16.2, 0.2, 0.8, 1.5, and 6.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) and P. boydii (geometric mean MIC/MEC values of 0.7, 1.3, 5.7, 13.8, 0.5, 1.4, 2.3, and 11.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) had similar susceptibility patterns, those for S. aurantiacum, S. prolificans, and S. dehoogii were different from each other. Voriconazole was the only drug with significant activity against S. aurantiacum isolates. The MIC distributions of all drugs except voriconazole did not show a normal distribution and often showed two subpopulations, making a species-based prediction of antifungal susceptibility difficult. Therefore, antifungal susceptibility testing of all clinical isolates remains essential for targeted antifungal therapy. Voriconazole was the only compound with low MIC values (MIC90 of ≤2 μg/ml) for P. apiosperma and P. boydii. Micafungin and posaconazole showed moderate activity against the majority of Scedosporium strains. PMID:22290955

Statins and Voriconazole Induce Programmed Cell Death in Acanthamoeba castellanii

PubMed Central

López-Arencibia, Atteneri; Sifaoui, Ines; Reyes-Batlle, María; Valladares, Basilio; Martínez-Carretero, Enrique; Piñero, José E.; Maciver, Sutherland K.; Lorenzo-Morales, Jacob

2015-01-01

Members of the genus Acanthamoeba are facultative pathogens of humans, causing a sight-threatening keratitis and a life-threatening encephalitis. In order to treat those infections properly, it is necessary to target the treatment not only to the trophozoite but also to the cyst. Furthermore, it may be advantageous to avoid parasite killing by necrosis, which may induce local inflammation. We must also avoid toxicity of host tissue. Many drugs which target eukaryotes are known to induce programmed cell death (PCD), but this process is poorly characterized in Acanthamoeba. Here, we study the processes of programmed cell death in Acanthamoeba, induced by several drugs, such as statins and voriconazole. We tested atorvastatin, fluvastatin, simvastatin, and voriconazole at the 50% inhibitory concentrations (IC50s) and IC90s that we have previously established. In order to evaluate this phenomenon, we investigated the DNA fragmentation, one of the main characteristics of PCD, with quantitative and qualitative techniques. Also, the changes related to phosphatidylserine exposure on the external cell membrane and cell permeability were studied. Finally, because caspases are key to PCD pathways, caspase activity was evaluated in Acanthamoeba. All the drugs assayed in this study induced PCD in Acanthamoeba. To the best of our knowledge, this is the first study where PCD induced by drugs is described quantitatively and qualitatively in Acanthamoeba. PMID:25733513

Virulence and antifungal therapy of murine disseminated infection by Rhodotorula mucilaginosa.

PubMed

Thomson, Pamela; López-Fernández, Loida; Guarro, Josep; Capilla, Javier

2017-09-01

Rhodotorula infections have emerged in recent years causing mainly fungemia associated to high mortality. We have evaluated the in vitro activity of nine antifungal drugs against four clinical strains of Rhodotorula mucilaginosa, being amphotericin B, voriconazole and posaconazole the most active compounds. The experimental virulence of this fungus and the efficacy of the three mentioned drugs were evaluated in disseminated infections in neutropenic mice. Infection resulted in a high fungal load in all the organs studied without evident particular tropism. All treated animals showed reduced burden respect to the control in a strain dependent manner being voriconazole slightly superior to posaconazole and amphotericin B. Copyright © 2017 Elsevier Inc. All rights reserved.

Development and validation of a new method to simultaneously quantify triazoles in plasma spotted on dry sample spot devices and analysed by HPLC-MS.

PubMed

Baietto, Lorena; D'Avolio, Antonio; Marra, Cristina; Simiele, Marco; Cusato, Jessica; Pace, Simone; Ariaudo, Alessandra; De Rosa, Francesco Giuseppe; Di Perri, Giovanni

2012-11-01

Therapeutic drug monitoring (TDM) of triazoles is widely used in clinical practice to optimize therapy. TDM is limited by technical problems and cost considerations, such as sample storage and dry-ice shipping. We aimed to develop and validate a new method to analyse itraconazole, posaconazole and voriconazole in plasma spotted on dry sample spot devices (DSSDs) and to quantify them by an HPLC system. Extraction from DSSDs was done using n-hexane/ethyl acetate and ammonia solution. Samples were analysed using HPLC with mass spectrometry (HPLC-MS). Accuracy and precision were assayed by inter- and intra-day validation. The stability of triazoles in plasma spotted on DSSDs was investigated at room temperature for 1 month. The method was compared with a validated standard HPLC method for quantification of triazoles in human plasma. Mean inter- and intra-day accuracy and precision were <15% for all compounds. Triazoles were stable for 2 weeks at room temperature. The method was linear (r(2) > 0.999) in the range 0.031-8 mg/L for itraconazole and posaconazole, and 0.058-15 mg/L for voriconazole. High sensitivity was observed; limits of detection were 0.008, 0.004 and 0.007 mg/L for itraconazole, posaconazole and voriconazole, respectively. A high degree of correlation (r(2) > 0.94) was obtained between the DSSD method and the standard method of analysis. The method that we developed and validated to quantify triazoles in human plasma spotted on DSSDs is accurate and precise. It overcomes problems related to plasma sample storage and shipment, allowing TDM to be performed in a cheaper and safer manner.

[In vitro activity of voriconazole against yeast and algae isolates according to new resistance pattern cut-off points].

PubMed

Pemán, J; Cantón, E; Calabuig, E; Bosch, M; Valentí, A; Viudes, A; Gobernado, M

2006-03-01

Voriconazole is a second-generation triazole derived from fluconazole but with greater potency and spectrum of activity, showing good in vitro activity against Candida, Cryptococcus and Aspergillus species, and other filamentous and dimorphic fungi. It can be administered orally or intravenously. It was initially approved in 2002 by the U.S. Food and Drug Administration as a treatment option for invasive aspergillosis and Fusarium and S. apiospermum infections showing resistance or intolerance to other antifungals; later on, it also received approval in the United States and Europe as a treatment option for esophageal candidiasis; candida infection in non-neutropenic patients; disseminated candidiasis of skin, abdomen, kidney and bladder; and injuries. Recently, the Clinical Laboratory Standard Institute established some provisional break points for voriconazole, classifying isolates with an MICor=4 mg/l as resistant. In line with these new data, we performed a systematic review of literature on in vitro activity of voriconazole against yeast and algae isolates, and compared it to that of fluconazole and itraconazole. The review included a total of 27,340 yeast isolates, 24,177 of Candida species, 2,726 of Cryptococcus species, 453 of other species, and 104 Prototheca. The yeast isolates resistant to voriconazole is approximately 1%, and 71% of fluconazole-resistant isolates are susceptible to voriconazole.

Effect of Oral Voriconazole on Fungal Keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II): A Randomized Clinical Trial.

PubMed

Prajna, N Venkatesh; Krishnan, Tiruvengada; Rajaraman, Revathi; Patel, Sushila; Srinivasan, Muthiah; Das, Manoranjan; Ray, Kathryn J; O'Brien, Kieran S; Oldenburg, Catherine E; McLeod, Stephen D; Zegans, Michael E; Porco, Travis C; Acharya, Nisha R; Lietman, Thomas M; Rose-Nussbaumer, Jennifer

2016-12-01

To compare oral voriconazole with placebo in addition to topical antifungals in the treatment of filamentous fungal keratitis. The Mycotic Ulcer Treatment Trial II (MUTT II), a multicenter, double-masked, placebo-controlled, randomized clinical trial, was conducted in India and Nepal, with 2133 individuals screened for inclusion. Patients with smear-positive filamentous fungal ulcers and visual acuity of 20/400 (logMAR 1.3) or worse were randomized to receive oral voriconazole vs oral placebo; all participants received topical antifungal eyedrops. The study was conducted from May 24, 2010, to November 23, 2015. All trial end points were analyzed on an intent-to-treat basis. Study participants were randomized to receive oral voriconazole vs oral placebo; a voriconazole loading dose of 400 mg was administered twice daily for 24 hours, followed by a maintenance dose of 200 mg twice daily for 20 days, with dosing altered to weight based during the trial. All participants received topical voriconazole, 1%, and natamycin, 5%. The primary outcome of the trial was rate of corneal perforation or the need for therapeutic penetrating keratoplasty (TPK) within 3 months. Secondary outcomes included microbiologic cure at 6 days, rate of re-epithelialization, best-corrected visual acuity and infiltrate and/or scar size at 3 weeks and 3 months, and complication rates associated with voriconazole use. A total of 2133 patients in India and Nepal with smear-positive ulcers were screened; of the 787 who were eligible, 240 (30.5%) were enrolled. Of the 119 patients (49.6%) in the oral voriconazole treatment group, 65 were male (54.6%), and the median age was 54 years (interquartile range, 42-62 years). Overall, no difference in the rate of corneal perforation or the need for TPK was determined for oral voriconazole vs placebo (hazard ratio, 0.82; 95% CI, 0.57-1.18; P = .29). In prespecified subgroup analyses comparing treatment effects among organism subgroups, there was some suggestion that Fusarium species might have a decreased rate of perforation or TPK in the oral voriconazole-treated arm; however, this was not a statistically significant finding after Holms-Šidák correction for multiple comparisons (effect coefficient, 0.49; 95% CI, 0.26-0.92; P = .03). Patients receiving oral voriconazole experienced a total of 58 adverse events (48.7%) compared with 28 adverse events (23.1%) in the placebo group (P < .001 after Holms-Šidák correction for multiple comparisons). There appears to be no benefit to adding oral voriconazole to topical antifungal agents in the treatment of severe filamentous fungal ulcers. All patients in this study were enrolled in India and Nepal; therefore, it is possible that organisms in this region may exhibit characteristics different from those in other regions of the world. clinicaltrials.gov Identifier: NCT00996736.

Pharmacoeconomic evaluation of fluconazole, posaconazole and voriconazole for antifungal prophylaxis in patients with acute myeloid leukaemia undergoing first consolidation chemotherapy.

PubMed

Heng, Siow-Chin; Slavin, Monica A; Al-Badriyeh, Daoud; Kirsa, Sue; Seymour, John F; Grigg, Andrew; Thursky, Karin; Bajel, Ashish; Nation, Roger L; Kong, David C M

2013-07-01

Fluconazole, posaconazole and voriconazole are used prophylactically in patients with acute myeloid leukaemia (AML). This study evaluated the clinical and economic outcomes of these agents when used in AML patients undergoing consolidation chemotherapy. A retrospective chart review (2003-10) of AML patients receiving consolidation chemotherapy was performed. Patients were followed through their first cycle of consolidation chemotherapy. Antifungal prescribing patterns, clinical outcomes and resource consumptions were recorded. A decision analytical model was developed to depict the downstream consequences of using each antifungal agent, with success defined as completion of the designated course of initial antifungal prophylaxis without developing invasive fungal disease (IFD). Cost-effectiveness and sensitivity analyses were performed. A total of 106 consecutive patients were analysed. Baseline characteristics and predisposing factors for IFD were comparable between groups. Three IFDs (one proven, one probable and one suspected) occurred, all in the posaconazole group. Patients receiving posaconazole had the highest rate of intolerance requiring drug cessation (13% versus 7% in each of the fluconazole and voriconazole groups). Fluconazole conferred overall savings per patient of 26% over posaconazole and 13% over voriconazole. Monte Carlo simulation demonstrated a mean cost saving with fluconazole of AU$8430 per patient (95% CI AU$5803-AU$11 054) versus posaconazole and AU$3681 per patient (95% CI AU$990-AU$6319) versus voriconazole. One-way sensitivity analyses confirmed the robustness of the model. This is the first study to show that, in the setting of consolidation therapy for AML, fluconazole is the most cost-effective approach to antifungal prophylaxis compared with posaconazole or voriconazole.

Voriconazole-induced periostitis in two post-transplant patients

PubMed Central

Bucknor, Matthew D.; Gross, Andrew J.; Link, Thomas M.

2013-01-01

While drug-related periostitis has been known of for many years, the specific association of diffuse periostitis with voriconazole (most frequently in transplant patients) has only been recently explicitly addressed in the literature. Recognition of the radiologic and clinical manifestations of voriconazole-related periostitis is important for helping to narrow an otherwise broad differential diagnosis. We present two cases that illustrate different radiologic presentations of this painful cause of diffuse periostitis. Case 1 features a 60 year-old woman with a history of orthotopic heart transplant who was hospitalized for “full body pain” with progressively worsening bone tenderness involving the humeri, knees, femurs, hips, and hands. Case 2 describes a 48 year-old man with a history of acute lymphoblastic leukemia status post stem cell transplant who presented with diffuse arthralgias involving bilateral ankles, knees, wrists, and elbows. PMID:24421948

In vitro susceptibility of filamentous fungi from mycotic keratitis to azole drugs.

PubMed

Shobana, C S; Mythili, A; Homa, M; Galgóczy, L; Priya, R; Babu Singh, Y R; Panneerselvam, K; Vágvölgyi, C; Kredics, L; Narendran, V; Manikandan, P

2015-03-01

The in vitro antifungal activities of azole drugs viz., itraconazole, voriconazole, ketoconazole, econazole and clotrimazole were investigated in order to evaluate their efficacy against filamentous fungi isolated from mycotic keratitis. The specimen collection was carried out from fungal keratitis patients attending Aravind eye hospital and Post-graduate institute of ophthalmology, Coimbatore, India and was subsequently processed for the isolation of fungi. The dilutions of antifungal drugs were prepared in RPMI 1640 medium. Minimum inhibitory concentrations (MICs) were determined and MIC50 and MIC90 were calculated for each drug tested. A total of 60 fungal isolates were identified as Fusarium spp. (n=30), non-sporulating moulds (n=9), Aspergillus flavus (n=6), Bipolaris spp. (n=6), Exserohilum spp. (n=4), Curvularia spp. (n=3), Alternaria spp. (n=1) and Exophiala spp. (n=1). The MICs of ketoconazole, clotrimazole, voriconazole, econazole and itraconazole for all the fungal isolates ranged between 16 μg/mL and 0.03 μg/mL, 4 μg/mL and 0.015 μg/mL, 8 μg/mL and 0.015 μg/mL, 8 μg/mL and 0.015 μg/mL and 32 μg/mL and 0.06 μg/mL respectively. From the MIC50 and MIC90 values, it could be deciphered that in the present study, clotrimazole was more active against the test isolates at lower concentrations (0.12-5 μg/mL) when compared to other drugs tested. The results suggest that amongst the tested azole drugs, clotrimazole followed by voriconazole and econazole had lower MICs against moulds isolated from mycotic keratitis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Ibrutinib Dosing Strategies Based on Interaction Potential of CYP3A4 Perpetrators Using Physiologically Based Pharmacokinetic Modeling.

PubMed

de Zwart, L; Snoeys, J; De Jong, J; Sukbuntherng, J; Mannaert, E; Monshouwer, M

2016-11-01

Based on ibrutinib pharmacokinetics and potential sensitivity towards CYP3A4-mediated drug-drug interactions (DDIs), a physiologically based pharmacokinetic approach was developed to mechanistically describe DDI with various CYP3A4 perpetrators in healthy men under fasting conditions. These models were verified using clinical data for ketoconazole (strong CYP3A4 inhibitor) and used to prospectively predict and confirm the inducing effect of rifampin (strong CYP3A4 inducer); DDIs with mild (fluvoxamine, azithromycin) and moderate inhibitors (diltiazem, voriconazole, clarithromycin, itraconazole, erythromycin), and moderate (efavirenz) and strong CYP3A4 inducers (carbamazepine), were also predicted. Ketoconazole increased ibrutinib area under the curve (AUC) by 24-fold, while rifampin decreased ibrutinib AUC by 10-fold; coadministration of ibrutinib with strong inhibitors or inducers should be avoided. The ibrutinib dose should be reduced to 140 mg (quarter of maximal prescribed dose) when coadministered with moderate CYP3A4 inhibitors so that exposures remain within observed ranges at therapeutic doses. Thus, dose recommendations for CYP3A4 perpetrator use during ibrutinib treatment were developed and approved for labeling. © 2016 American Society for Clinical Pharmacology and Therapeutics.

In Vitro Activities of Amphotericin B, Terbinafine, and Azole Drugs against Clinical and Environmental Isolates of Aspergillus terreus Sensu Stricto

PubMed Central

Fernández, Mariana S.; Rojas, Florencia D.; Cattana, María E.; Sosa, María de los Ángeles; Iovannitti, Cristina A.; Giusiano, Gustavo E.

2015-01-01

The antifungal susceptibilities of 40 clinical and environmental isolates of A. terreus sensu stricto to amphotericin B, terbinafine, itraconazole, and voriconazole were determined in accordance with CLSI document M38-A2. All isolates had itraconazole and voriconazole MICs lower than epidemiologic cutoff values, and 5% of the isolates had amphotericin B MICs higher than epidemiologic cutoff values. Terbinafine showed the lowest MICs. No significant differences were found when MICs of clinical and environmental isolates were compared. PMID:25824228

Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation

PubMed Central

Carter, Shelly L.; Walsh, Thomas J.; Kurtzberg, Joanne; Small, Trudy N.; Baden, Lindsey R.; Gersten, Iris D.; Mendizabal, Adam M.; Leather, Helen L.; Confer, Dennis L.; Maziarz, Richard T.; Stadtmauer, Edward A.; Bolaños-Meade, Javier; Brown, Janice; DiPersio, John F.; Boeckh, Michael; Marr, Kieren A.

2010-01-01

Invasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT). This multicenter, randomized, double-blind trial compared fluconazole (N = 295) versus voriconazole (N = 305) for the prevention of IFI in the context of a structured fungal screening program. Patients undergoing myeloablative allogeneic HCT were randomized before HCT to receive study drugs for 100 days, or for 180 days in higher-risk patients. Serum galactomannan was assayed twice weekly for 60 days, then at least weekly until day 100. Positive galactomannan or suggestive signs triggered mandatory evaluation for IFI. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days. Despite trends to fewer IFIs (7.3% vs 11.2%; P = .12), Aspergillus infections (9 vs 17; P = .09), and less frequent empiric antifungal therapy (24.1% vs 30.2%, P = .11) with voriconazole, FFS rates (75% vs 78%; P = .49) at 180 days were similar with fluconazole and voriconazole, respectively. Relapse-free and overall survival and the incidence of severe adverse events were also similar. This study demonstrates that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month FFS and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole. This trial was registered at www.clinicaltrials.gov as NCT00075803. PMID:20826719

In Vitro Activities of Five Antifungal Drugs Against Opportunistic Agents of Aspergillus Nigri Complex.

PubMed

Badali, Hamid; Fakhim, Hamed; Zarei, Fereshteh; Nabili, Mojtaba; Vaezi, Afsane; Poorzad, Nafiseh; Dolatabadi, Somayeh; Mirhendi, Hossein

2016-04-01

Black aspergilli, particularly Aspergillus niger and A. tubingensis, are the most common etiological agents of otomycosis followed by onychomycosis, pulmonary aspergillosis and aspergilloma. However, so far there is no systematic study on their antifungal susceptibility profiles. A collection of 124 clinical and environmental species of black aspergilli consisted of A. niger, A. tubingensis, A. uvarum. A. acidus and A. sydowii were verified by DNA sequencing of the partial β-tubulin gene. MICs of amphotericin B, itraconazole, voriconazole, posaconazole, and MECs of caspofungin were performed based on CLSI M38-A2. Posaconazole and caspofungin had the lowest MIC range (0.016-0.125 µg/ml and 0.008-0.031 µg/ml, respectively), followed by amphotericin B (0.25-4 µg/ml), voriconazole (0.125-16 µg/ml) and itraconazole (0.25 to >16) in an increasing order. Some strains of A. niger showed high MIC value for itraconazole and voriconazole (>16 µg/ml), in contrast only environmental isolates of A. tubingensis had high itraconazole MICs (>16 µg/ml). These results confirm that posaconazole and caspofungin are potential drugs for treatment of aspergillosis due to opportunistic agents of Aspergillus Nigri complex. However, in vivo efficacy remains to be determined.

In vitro synergy of natamycin and voriconazole against clinical isolates of Fusarium, Candida, Aspergillus and Curvularia spp.

PubMed

Sradhanjali, Swatishree; Yein, Bandana; Sharma, Savitri; Das, Sujata

2018-01-01

To determine the minimum inhibitory concentrations (MICs) of voriconazole and natamycin, alone and in combination, against the clinical isolates of Fungus and to evaluate the synergy between the drugs in an experimental in vitro study. In an experimental in vitro study, clinical isolates of Fusarium , Aspergillus , Candida and Curvularia spp were maintained on Sabouraud Dextrose Agar and used for the study. The MICs of natamycin and voriconazole, used alone and in combination, were evaluated by checkerboard microdilution technique based on the standard protocol proposed by the Clinical Laboratory Standards Institute. The interactions were assessed using the fractional inhibitory concentration (FIC) Index model. Tested with all the clinical isolates, the MICs ranged between 0.125 and 8 µg/mL both for natamycin and voriconazole. In descending order, maximum synergism (FIC ≤0.5) was observed in Candida spp (33.3%) followed by Curvularia spp and Fusarium spp (23.1%). Synergism was least for Aspergillus spp (22.2%). However, at 61.5% (8/13), maximum additive effect (>0.5-1) was observed in Aspergillus spp and minimum (33.3%, 2/6) in Candida spp. Indifference (FIC value >1 and≤4) was observed in 22.2% (2/9) of Aspergillus spp, 15.4% (2/13) of Fusarium spp, 33.3% (2/6) of Candida spp and 23.1% (3/13) of Curvularia spp. No cases of antagonism (FIC >4) were observed. Natamycin and voriconazole in combination demonstrated more effective antifungal activity than single-use in vitro treatment in all species tested, which implies that these combinations may be helpful in treating fungal keratitis. There was no antagonism between these two drugs. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Evaluation of Ocular Irritation and Bioavailability of Voriconazole Loaded Microemulsion.

PubMed

Kumar, Rakesh; Sinha, Vivek Ranjan

2017-01-01

Voriconazole (VCZ), a second-generation antifungal with excellent attributes like, broad-spectrum activity, targeted delivery, and tolerability. VCZ loaded microemulsion could be an effective strategy for efficient ocular delivery of the drug. To perform corneal irritation studies and in vivo delivery of VCZ microemulsion to establish its potential as an efficient ocular delivery system. Ocular irritancy was performed by HETCAM (Hen's Egg Test Chorio Allantoic Membrane) assay, corneal histopathology and Draize test. Ex vivo and in vivo studies were performed to determine permeation efficiency of VCZ microemulsion. The irritation studies suggested the non-irritant nature of the microemulsion. The ex vivo studies performed on excised cornea displayed significant enhancement in drug permeation/penetration from microemulsion in contrast to the drug suspension. Further, the in vivo study confirmed the higher availability of VCZ (from microemulsion) in aqueous humor with minimal nasolacrimal drainage (lower plasma drug content) when compared with the drug suspension. The non-irritant nature and high corneal permeation of VCZ encourages the role of microemulsion as a potential ocular delivery system. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Association Between In Vitro Susceptibility to Natamycin and Voriconazole and Clinical Outcomes in Fungal Keratitis

PubMed Central

Sun, Catherine Q.; Lalitha, Prajna; Prajna, N. Venkatesh; Karpagam, Rajarathinam; Geetha, Manoharan; O’Brien, Kieran S.; Oldenburg, Catherine E.; Ray, Kathryn J.; McLeod, Stephen D.; Acharya, Nisha R.; Lietman, Thomas M.

2014-01-01

Purpose To assess the association between minimum inhibitory concentration (MIC) and clinical outcomes in a fungal keratitis clinical trial. Design Experimental study using data from a randomized comparative trial. Participants Of the 323 patients enrolled in the trial, we were able to obtain MIC values from 221 patients with monocular fungal keratitis. Methods The Mycotic Ulcer Treatment Trial I (MUTT I) was a randomized, double-masked clinical trial comparing clinical outcomes of monotherapy with topical natamycin versus voriconazole for the treatment of fungal keratitis. Speciation and determination of MIC to natamycin and voriconazole were performed according to Clinical and Laboratory Standards Institute guidelines. The relationship between MIC and clinical outcome was assessed. Main Outcome Measures The primary outcome was 3-month best spectacle-corrected visual acuity. Secondary outcomes included 3-month infiltrate/scar size, corneal perforation and/or therapeutic penetrating keratoplasty (TPK), and time to re-epithelialization. Results A 2-fold increase in MIC was associated with a larger 3-month infiltrate/scar size (0.21 mm, 95% confidence interval [CI] 0.10–0.31, P <0.001) and increased odds of perforation (odds ratio [OR] 1.32, 95% CI 1.04–1.69, P=0.02). No correlation was found between MIC and 3-month visual acuity. For natamycin-treated cases, an association was found between higher natamycin MIC with larger 3-month infiltrate/scar size (0.29 mm, 95% CI 0.15–0.43, P<0.001) and increased perforations (OR 2.41, 95% CI 1.46–3.97, P<0.001). Among voriconazole-treated cases, the voriconazole MIC did not correlate with any of the measured outcomes in the study. Conclusion Decreased susceptibility to natamycin was associated with increased infiltrate/scar size and increased odds of perforation. There was no association between susceptibility to voriconazole and outcome. PMID:24746358

Association between in vitro susceptibility to natamycin and voriconazole and clinical outcomes in fungal keratitis.

PubMed

Sun, Catherine Q; Lalitha, Prajna; Prajna, N Venkatesh; Karpagam, Rajarathinam; Geetha, Manoharan; O'Brien, Kieran S; Oldenburg, Catherine E; Ray, Kathryn J; McLeod, Stephen D; Acharya, Nisha R; Lietman, Thomas M

2014-08-01

To assess the association between minimum inhibitory concentration (MIC) and clinical outcomes in a fungal keratitis clinical trial. Experimental study using data from a randomized comparative trial. Of the 323 patients enrolled in the trial, we were able to obtain MIC values from 221 patients with monocular fungal keratitis. The Mycotic Ulcer Treatment Trial I was a randomized, double-masked clinical trial comparing clinical outcomes of monotherapy with topical natamycin versus voriconazole for the treatment of fungal keratitis. Speciation and determination of MIC to natamycin and voriconazole were performed according to Clinical and Laboratory Standards Institute guidelines. The relationship between MIC and clinical outcome was assessed. The primary outcome was 3-month best spectacle-corrected visual acuity. Secondary outcomes included 3-month infiltrate or scar size; corneal perforation and/or therapeutic penetrating keratoplasty; and time to re-epithelialization. A 2-fold increase in MIC was associated with a larger 3-month infiltrate or scar size (0.21 mm; 95% confidence interval [CI], 0.10-0.31; P < 0.001) and increased odds of perforation (odds ratio, 1.32; 95% CI, 1.04-1.69; P = 0.02). No correlation was found between MIC and 3-month visual acuity. For natamycin-treated cases, an association was found between higher natamycin MIC with larger 3-month infiltrate or scar size (0.29 mm; 95% CI, 0.15-0.43; P < 0.001) and increased perforations (odds ratio, 2.41; 95% CI, 1.46-3.97; P < 0.001). Among voriconazole-treated cases, the voriconazole MIC did not correlate with any of the measured outcomes in the study. Decreased susceptibility to natamycin was associated with increased infiltrate or scar size and increased odds of perforation. There was no association between susceptibility to voriconazole and outcome. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Refractory sporotrichosis due to Sporothrix brasiliensis in humans appears to be unrelated to in vivo resistance.

PubMed

Almeida-Paes, Rodrigo; Oliveira, Manoel Marques Evangelista; Freitas, Dayvison Francis Saraiva; Valle, Antônio Carlos Francesconi do; Gutierrez-Galhardo, Maria Clara; Zancopé-Oliveira, Rosely Maria

2017-07-01

Sporotrichosis is a subacute to chronic infection caused by members of the Sporothrix schenckii complex. Itraconazole is the first choice antifungal drug for treating this infection, with terbinafine and potassium iodide as alternatives and amphotericin B used in cases of severe infections. Correlation of antifungal susceptibility data with the clinical outcome of the patients is scarce. The aim of this study was to correlate clinical and mycological data in patients with refractory sporotrichosis. In this work, antifungal susceptibilities, determined according to the reference M38-A2 CLSI protocol, of 25 Sporothrix strains, isolated from seven human cases of sporotrichosis with adversities in the treatment, are presented. Tested drugs included itraconazole, ketoconazole, posaconazole, voriconazole, terbinafine, and amphotericin B. Fungi were identified using the T3B PCR fingerprinting. This method identified all strains as Sporothrix brasiliensis and also demonstrated a high degree of similarity between the strains. In general, voriconazole was ineffective against all strains, and elevated minimal inhibitory concentrations (MICs) were observed for amphotericin B. High itraconazole and terbinafine MICs were not observed in S. brasiliensis isolates from patients of this study. Moreover, a significant increase in itraconazole and terbinafine MIC values from strains isolated from the same patient in different periods was not observed. The results suggest that the antifungal susceptibility to terbinafine and itraconazole determined by the reference method does not play an important role in therapeutic failure of sporotrichosis and that acquisition of resistance during prolonged antifungal treatment is not likely to occur in S. brasiliensis. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).

PubMed

Mellinghoff, Sibylle C; Panse, Jens; Alakel, Nael; Behre, Gerhard; Buchheidt, Dieter; Christopeit, Maximilian; Hasenkamp, Justin; Kiehl, Michael; Koldehoff, Michael; Krause, Stefan W; Lehners, Nicola; von Lilienfeld-Toal, Marie; Löhnert, Annika Y; Maschmeyer, Georg; Teschner, Daniel; Ullmann, Andrew J; Penack, Olaf; Ruhnke, Markus; Mayer, Karin; Ostermann, Helmut; Wolf, Hans-H; Cornely, Oliver A

2018-02-01

Immunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. Since the last edition of antifungal prophylaxis recommendations of the German Society for Haematology and Medical Oncology in 2014, seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This update assesses the impact of this additional evidence and effective revisions. Our key recommendations are the following: prophylaxis should be performed with posaconazole delayed release tablets during remission induction chemotherapy for AML and MDS (AI). Posaconazole iv can be used when the oral route is contraindicated or not feasible. Intravenous liposomal amphotericin B did not significantly decrease IFI rates in acute lymphoblastic leukaemia (ALL) patients during induction chemotherapy, and there is poor evidence to recommend it for prophylaxis in these patients (CI). Despite substantial risk of IFI, we cannot provide a stronger recommendation for these patients. There is poor evidence regarding voriconazole prophylaxis in patients with neutropenia (CII). Therapeutic drug monitoring TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of suspicious adverse events or of dose changes of interacting drugs (BIItu). General TDM during posaconazole prophylaxis is not recommended (CIItu), but may be helpful in cases of clinical failure such as breakthrough IFI for verification of compliance or absorption.

Successful treatment of a severe case of fusariomycosis in a beluga whale (Delphinapterus leucas leucas).

PubMed

Naples, Lisa M; Poll, Caryn P; Berzins, Ilze K

2012-09-01

An adult male beluga whale (Delphinapterus leucas leucas) was presented with a 4-cm-diameter, raised, firm nodule on the medial aspect of the left pectoral fin. A fissure developed within the center of the nodule, which formed an ulcerated cyst-like lesion. The lesion rapidly progressed in size, and, with peeling of material present within the cyst, the lesion flattened to a 36 x 25-cm cutaneous ulcer that extended into the axilla. Histopathologic features were consistent with lymphocytic and suppurative dermatitis with intralesional fungi. Fusarium solani was diagnosed by polymerase chain reaction (PCR). Fungal susceptibility testing was performed and revealed drug resistance to multiple antifungal medications tested individually and in combination therapies. Treatments used included serial surgical debridement of affected and surrounding tissue, topical application and regional infusion of various azole, and allylamine antifungals combined with either dimethyl sulfoxide or Tricide for absorption potentiation, and oral voriconazole administration. Although susceptibility testing revealed resistance to voriconazole, visible improvement of the lesion was noted after 6 weeks of oral voriconazole therapy. The voriconazole dosage was tapered based on serum levels and was administered over a 12-mo period. No local recurrence or new lesions were visible by 14 mo from first presentation.

Keratomycosis due to Tintelnotia destructans refractory to common therapy treated successfully with systemic and local terbinafine in combination with polyhexamethylene biguanide.

PubMed

Behrens-Baumann, Wolfgang J; Hofmüller, Wolfram; Tammer, Ina; Tintelnot, Kathrin

2018-04-28

To report on a wearer of rigid gas-permeable contact lenses with a keratomycosis due to Tintelnotia-a new genus of Phaeosphaeriaceae-treated with terbinafine and polyhexamethylene biguanide. Chart review of a patient with fungal keratitis treated additionally with systemic and topical terbinafine 0.25% after symptoms increased under conventional antimycotic therapy with voriconazole. Antifungal susceptibility had been tested in vitro. After starting an additional treatment with systemic and topical terbinafine, the severe corneal infection was sufficiently resolved. The drug was well tolerated without any neurological, dermatological or gastroenterological problems. Terbinafine revealed a marked in vitro antifungal activity of 0.12 µg/ml. The fungus was identified as Tintelnotia destructans. Terbinafine might be considered as a therapeutic option in severe cases of fungal keratitis refractory to common antifungal therapy.

Protothecosis.

PubMed

Mayorga, Jorge; Barba-Gómez, José Fernando; Verduzco-Martínez, Ana Paula; Muñoz-Estrada, Víctor Fernando; Welsh, Oliverio

2012-01-01

Protothecosis is a rare infection caused by achlorophyllic algae that are members of the genus Prototheca. They are ubiquitous in nature in organic material. The clinical manifestations can be acute or chronic and local or disseminated. The disease is classified as cutaneous, causing bursitis or disseminated/systemic, affecting both immunocompetent and immunosuppressed patients, with more severe and disseminated infections occurring in immunocompromised individuals. Prototheca wickerhamii and Prototheca zopfii are the most frequent organisms reported in humans. Diagnosis is made by observing asexual sporangia (thecas) on histopathological examination of tissue. Medical and surgical treatment should be considered. Ketoconazole, itraconazole, fluconazole, voriconazole, posaconazole, and amphotericin B are the most commonly used antifungals. Voriconazole and amphotericin B are highly effective against Prototheca spp. Treatment failure is not uncommon because of the comorbidities that limit the therapeutic outcome. Copyright © 2012. Published by Elsevier Inc.

Pharmacokinetics of voriconazole after oral administration of single and multiple doses in African grey parrots (Psittacus erithacus timneh).

PubMed

Flammer, Keven; Nettifee Osborne, Julie A; Webb, Donna J; Foster, Laura E; Dillard, Stacy L; Davis, Jennifer L

2008-01-01

To determine the pharmacokinetics and safety of orally administered voriconazole in African grey parrots. 20 clinically normal Timneh African grey parrots (Psittacus erithacus timneh). In single-dose trials, 12 parrots were each administered 6, 12, and 18 mg of voriconazole/kg orally and plasma concentrations of voriconazole were determined via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) was administered orally to 6 birds every 12 hours for 9 days; a control group (2 birds) received tap water. Treatment effects were assessed via observation, clinicopathologic analyses (3 assessments), and measurement of trough plasma voriconazole concentrations (2 assessments). Voriconazole's elimination half-life was short (1.1 to 1.6 hours). Higher doses resulted in disproportional increases in the maximum plasma voriconazole concentration and area under the curve. Trough plasma voriconazole concentrations achieved in the multiple-dose trial were lower than those achieved after administration of single doses. Polyuria (the only adverse treatment effect) developed in treated and control birds but was more severe in the treatment group. In African grey parrots, voriconazole has dose-dependent pharmacokinetics and may induce its own metabolism. Oral administration of 12 to 18 mg of voriconazole/kg twice daily is a rational starting dose for treatment of African grey parrots infected with Aspergillus or other fungal organisms that have a minimal inhibitory concentration for voriconazole < or = 0.4 microg/mL. Higher doses may be needed to maintain plasma voriconazole concentrations during long-term treatment. Safety and efficacy of various voriconazole treatment regimens in this species require investigation.

Spotlight on isavuconazole in the treatment of invasive aspergillosis and mucormycosis: design, development, and place in therapy.

PubMed

Jenks, Jeffrey D; Salzer, Helmut Jf; Prattes, Juergen; Krause, Robert; Buchheidt, Dieter; Hoenigl, Martin

2018-01-01

In recent decades, important advances have been made in the diagnosis and treatment of invasive aspergillosis (IA) and mucormycosis. One of these advances has been the introduction of isavuconazole, a second-generation broad spectrum triazole with a favorable pharmacokinetic and safety profile and few drug-drug interactions. Phase III trials in patients with IA and mucormycosis demonstrated that isavuconazole has similar efficacy to voriconazole for the treatment of IA (SECURE trial) and liposomal amphotericin B for the treatment of mucormycosis (VITAL trial with subsequent case-control analysis) and a favorable safety profile with significantly fewer ocular, hepatobiliary, and skin and soft tissue adverse events compared to voriconazole. As a result, recent IA guidelines recommend isavuconazole (together with voriconazole) as gold standard treatment for IA in patients with underlying hematological malignancies. In contrast to liposomal amphotericin B, isavuconazole can be safely administered in patients with reduced renal function and is frequently used for the treatment of mucormycosis in patients with reduced renal function. Updated guidelines on mucormycosis are needed to reflect the current evidence and give guidance on the use of isavuconazole for mucormycosis. Studies are needed to evaluate the role of isavuconazole for 1) anti-mold prophylaxis in high-risk patients, 2) salvage treatment for IA and mucormycosis, and 3) treatment for other mold infections such as Scedosporium apiospermum .

Septic arthritis due to tubercular and Aspergillus co-infection

PubMed Central

Kumar, Mukesh; Thilak, Jai; Zahoor, Adnan; Jyothi, Arun

2016-01-01

Aspergillus septic arthritis is a rare and serious medical and surgical problem. It occurs mainly in immunocompromised patients. Aspergillus fumigatus is the most common causative organism followed by Aspergillus flavus. The most common site affected is knee followed by shoulder, ankle, wrist, hip and sacroiliac joint. Debridement and voriconazole are primary treatment of articular aspergilosis. To the best of our knowledge, there are no reported cases of co-infection of tuberculosis (TB) and Aspergillus infecting joints. We report a case of co-infection of TB and A. flavus of hip and knee of a 60-year-old male, with type 2 diabetes mellitus. He was treated with debridement, intravenous voriconazole, and antitubercular drugs. PMID:27293296

Septic arthritis due to tubercular and Aspergillus co-infection.

PubMed

Kumar, Mukesh; Thilak, Jai; Zahoor, Adnan; Jyothi, Arun

2016-01-01

Aspergillus septic arthritis is a rare and serious medical and surgical problem. It occurs mainly in immunocompromised patients. Aspergillus fumigatus is the most common causative organism followed by Aspergillus flavus. The most common site affected is knee followed by shoulder, ankle, wrist, hip and sacroiliac joint. Debridement and voriconazole are primary treatment of articular aspergilosis. To the best of our knowledge, there are no reported cases of co-infection of tuberculosis (TB) and Aspergillus infecting joints. We report a case of co-infection of TB and A. flavus of hip and knee of a 60-year-old male, with type 2 diabetes mellitus. He was treated with debridement, intravenous voriconazole, and antitubercular drugs.

Histamine H2-receptor antagonists have no clinically significant effect on the steady-state pharmacokinetics of voriconazole

PubMed Central

Purkins, Lynn; Wood, Nolan; Kleinermans, Diane; Nichols, Don

2003-01-01

Aims Voriconazole, a new triazole antifungal agent, is metabolized mainly by cytochrome P450s CYP2C19 and CYP2C9, and also by CYP3A4. The aim of this open-label, placebo-controlled, randomized, three-way crossover study was to determine the effects of cimetidine and ranitidine on the steady-state pharmacokinetics of voriconazole. Methods Twelve healthy male subjects received oral voriconazole 200 mg twice daily plus cimetidine 400 mg twice daily, voriconazole 200 mg twice daily plus ranitidine 150 mg twice daily, and voriconazole 200 mg twice daily plus placebo twice daily. Treatment periods were separated by at least 7 days. Results When cimetidine was administered with voriconazole, the maximum plasma voriconazole concentration (Cmax) and the area under the plasma concentration–time curve of voriconazole (AUCτ) was increased by 18.3% [90% confidence interval (CI) 6.0, 32.0] and 22.5% (90% CI 13.3, 32.5), respectively. Concomitant ranitidine had no significant effect on voriconazole Cmax or AUCτ. Time of Cmax (tmax) elimination half-life (t1/2) or terminal phase rate constant (kel) for voriconazole were similar in all three treatment groups. Most adverse events were mild and transitory; two subjects were withdrawn due to adverse events. Conclusions Coadministration of the histamine H2-receptor antagonists cimetidine or ranitidine does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner. PMID:14616414

Comparison between the Standardized Clinical and Laboratory Standards Institute M38-A2 Method and a 2,3-Bis(2-Methoxy-4-Nitro-5-[(Sulphenylamino)Carbonyl]-2H-Tetrazolium Hydroxide- Based Method for Testing Antifungal Susceptibility of Dermatophytes ▿

PubMed Central

Shehata, Atef S.; Mukherjee, Pranab K.; Ghannoum, Mahmoud A.

2008-01-01

In this study, we determined the utility of a 2,3-bis(2-methoxy-4-nitro-5-[(sulfenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT)-based assay for determining antifungal susceptibilities of dermatophytes to terbinafine, ciclopirox, and voriconazole in comparison to the Clinical and Laboratory Standards Institute (CLSI) M38-A2 method. Forty-eight dermatophyte isolates, including Trichophyton rubrum (n = 15), Trichophyton mentagrophytes (n = 7), Trichophyton tonsurans (n = 11), and Epidermophyton floccosum (n = 13), and two quality control strains, were tested. In the XTT-based method, MICs were determined spectrophotometrically at 490 nm after addition of XTT and menadione. For the CLSI method, the MICs were determined visually. With T. rubrum, the XTT assay revealed MIC ranges of 0.004 to >64 μg/ml, 0.125 to 0.25 μg/ml, and 0.008 to 0.025 μg/ml for terbinafine, ciclopirox, and voriconazole, respectively. Similar MIC ranges were obtained against T. rubrum by using the CLSI method. Additionally, when tested with T. mentagrophytes, T. tonsurans, and E. floccosum isolates, the XTT and CLSI methods resulted in comparable MIC ranges. Both methods revealed similar lowest drug concentrations that inhibited 90% of the isolates for the majority of tested drug-dermatophyte combinations. The levels of agreement within 1 dilution between both methods were as follows: 100% with terbinafine, 97.8% with ciclopirox, and 89.1% with voriconazole. However, the agreement within 2 dilutions between these two methods was 100% for all tested drugs. Our results revealed that the XTT assay can be a useful tool for antifungal susceptibility testing of dermatophytes. PMID:18832129

Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration

PubMed Central

Purkins, Lynn; Wood, Nolan; Ghahramani, Parviz; Love, Edward R; Eve, Malcolm D; Fielding, Anitra

2003-01-01

Aims Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19, and, to a lesser extent, by CYP3A4. Phenytoin is an inducer of CYP3A4 activity, and a substrate and inducer of CYP2C9 and CYP2C19. The present studies investigated the pharmacokinetic interactions of voriconazole and phenytoin when coadministered. Methods Two placebo-controlled parallel-group studies were conducted in healthy male volunteers. Study A was an open-label study and investigated the effect of phenytoin (300 mg once daily) on the steady-state pharmacokinetics of voriconazole (200 mg and 400 mg twice daily). Study B was a double-blind randomized study to investigate the effects of voriconazole (400 mg twice daily) on the steady-state pharmacokinetics of phenytoin (300 mg once daily). Cmax and AUCτ were compared at days 7, 21, and 28 (Study A), and at days 7 and 17 (Study B). All adverse events were recorded. Results Study A: 21 subjects were evaluable (10 voriconazole + phenytoin, 11 voriconazole + placebo). For subjects receiving voriconazole (200 mg twice daily) plus phenytoin, the day 21/day 7 ratios for voriconazole Cmax and AUCτ were 60.7% [90% confidence interval (CI) 50.1, 73.6] and 35.9% (90% CI 29.7, 43.3), respectively. Adjusted for voriconazole + placebo, the ratios between the means were 50.7% (90% CI 38.8, 66.1) and 30.6% (90% CI 23.5, 39.7), respectively. When the dose of voriconazole was increased to 400 mg twice daily, the day 28/day 7 ratios for voriconazole Cmax and AUCτ were 134% (90% CI 89.2, 200) and 139% (90% CI 97.3, 199), respectively. Study B: 15 subjects were evaluable for pharmacokinetic assessments (six phenytoin + voriconazole, nine phenytoin + placebo). The ratios between the means for phenytoin + voriconazole/phenytoin + placebo on day 17 vs. day 7 were: phenytoin Cmax 167% (90% CI 144, 193) and phenytoin AUCτ 181% (90% CI 156, 210). All treatments were well tolerated: most adverse events were mild/moderate and transient. Conclusions Repeat dose administration of phenytoin decreased the mean steady-state Cmax and AUCτ of voriconazole by approximately 50% and 70%, respectively. Increasing the dose of voriconazole from 200 mg to 400 mg b.d. compensated for this effect. Repeat dose administration of 400 mg b.d. voriconazole increased the mean steady-state Cmax and AUCτ of phenytoin by approximately 70% and 80%, respectively. It is therefore recommended that plasma phenytoin concentrations are monitored and the dose adjusted as appropriate when phenytoin is coadministered with voriconazole. PMID:14616412

[In vitro susceptibility of isolates of Paracoccidioides spp complex to systemic antifungals using the microdilution method].

PubMed

Cermehol, Julman R; Alvarado, Primavera; Mendoza, Mireya; Herndndez, Isabel; Cuestal, De

2015-09-01

Broth microdilution, the reference method recommended by the Clinical Laboratory Standards Institute (CLSI), is not available for use with dimorphic fungi, such as those of the Paracoccidioides genus. In this work, in vitro susceptibility of the Paracoccidioides complex (n=19) to systemic antifungals: amphotericin B, 5-flucytosine, ketoconazole, itraconazole, fluconazole, voriconazole and caspofungin, was evaluated using the microdilution method (Document M27-A3, M27-S3), with some modifications such as: culture time in Sabouraud dextrose agar (7-10 days), RPMI 1640 medium supplemented with 2% glucose and the incubation time (7, 8 and 18 days). The sensitivity in vitro was variable; the majority of Paracoccidioides isolates was susceptible to ketoconazol (73.7%), followed by voriconazole (68.4%), itraconazole (63.1%), amphotericin B (52.6%), fluconazole (47.4%), 5-flucytosine (42.1%) and caspofungin (5%). The overall resistance was mainly to caspofungin (94.7%), followed by 5-flucytosine (52.6%) and amphotericin B (47.4%). Fifty-three percent of the isolates were susceptible-dose dependent to fluconazole followed by itraconazole (15.7%) and 5-fluorocytosine (5.3%). Amphotericin B, itraconazole and voriconazole were the most potent antifungal drugs against Paracoccidioides spp (CMI: 0.03-1 microg/mL). Based on these results, we tentatively propose a microdilution assay protocol for susceptibility testing of Paracoccidioides spp to antifungal drugs. This method may be clinically useful to predict resistance, even though further studies are needed.

Susceptibility profile and epidemiological cut-off values of Cryptococcus neoformans species complex from Argentina.

PubMed

Córdoba, Susana; Isla, Maria G; Szusz, Wanda; Vivot, Walter; Altamirano, Rodrigo; Davel, Graciela

2016-06-01

Epidemiological cut-off values (ECVs) based on minimal inhibitory concentration (MIC) distribution have been recently proposed for some antifungal drug/Cryptococcus neoformans combinations. However, these ECVs vary according to the species studied, being serotypes and the geographical origin of strains, variables to be considered. The aims were to define the wild-type (WT) population of the C. neoformans species complex (C. neoformans) isolated from patients living in Argentina, and to propose ECVs for six antifungal drugs. A total of 707 unique C. neoformans isolates obtained from HIV patients suffering cryptococcal meningitis were studied. The MIC of amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole and posaconazole was determined according to the EDef 7.2 (EUCAST) reference document. The MIC distribution, MIC50 , MIC90 and ECV for each of these drugs were calculated. The highest ECV, which included ≥95% of the WT population modelled, was observed for flucytosine and fluconazole (32 μg ml(-1) each). For amphotericin B, itraconazole, voriconazole and posaconazole, the ECVs were: 0.5, 0.5, 0.5 and 0.06 μg ml(-1) respectively. The ECVs determined in this study may aid in identifying the C. neoformans strains circulating in Argentina with decreased susceptibility to the antifungal drugs tested. © 2016 Blackwell Verlag GmbH.

Plasma Fluoride Level as a Predictor of Voriconazole-Induced Periostitis in Patients With Skeletal Pain

PubMed Central

Moon, Woo J.; Scheller, Erica L.; Suneja, Anupam; Livermore, Jacob A.; Malani, Anurag N.; Moudgal, Varsha; Kerr, Lisa E.; Ferguson, Eric; Vandenberg, David M.

2014-01-01

Background. Voriconazole is a triazole antifungal medication used for prophylaxis or to treat invasive fungal infections. Inflammation of the periosteum resulting in skeletal pain, known as periostitis, is a reported side effect of long-term voriconazole therapy. The trifluorinated molecular structure of voriconazole suggests a possible link between excess fluoride and periostitis, as elevated blood fluoride has been reported among patients with periostitis who received voriconazole. Methods. Two hundred sixty-four patients from Michigan were impacted by the multistate outbreak of fungal infections as a result of contaminated methylprednisolone injections. A retrospective study was conducted among 195 patients who received voriconazole therapy at St Joseph Mercy Hospital during this outbreak. Twenty-eight patients who received both bone scan and plasma fluoride measurements for skeletal pain were included in the statistical analyses. Increased tracer uptake on bone scan was considered positive for periostitis. The primary outcome measure was the correlation between plasma fluoride and bone scan results. Results. Blood fluoride (P < .001), alkaline phosphatase (P = .020), daily voriconazole dose (P < .001), and cumulative voriconazole dose (P = .027) were significantly elevated in patients who had periostitis compared with those who did not. Discontinuation or dose reduction of voriconazole resulted in improvement of pain in 89% of patients. Conclusions. High plasma fluoride levels coupled with skeletal pain among patients who are on long-term voriconazole therapy is highly suggestive of periostitis. Initial measurement of fluoride may be considered when bone scan is not readily available. Early detection should be sought, as discontinuation of voriconazole is effective at reversing the disease. PMID:24992954

Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring.

PubMed

Dolton, Michael J; Ray, John E; Marriott, Deborah; McLachlan, Andrew J

2012-06-01

Posaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for other triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. This review examines the available evidence for a relationship between plasma concentration and clinical efficacy for posaconazole, as well as evaluating the utility of TDM and providing provisional target concentrations for posaconazole therapy. Increasing evidence supports an exposure-response relationship for plasma posaconazole concentrations for prophylaxis and treatment of IFIs; a clear relationship has not been identified between posaconazole concentration and toxicity. Intracellular and intrapulmonary concentrations have been studied for posaconazole but have not been correlated to clinical outcomes. In view of the high mortality and cost associated with the treatment of IFIs, increasing evidence of an exposure-response relationship for posaconazole efficacy in the prevention and treatment of IFIs, and the common finding of low posaconazole concentrations in patients, TDM for posaconazole is likely to be of significant clinical utility. In patients with subtherapeutic posaconazole concentrations, increased dose frequency, administration with high-fat meals, and withdrawal of interacting medications from therapy are useful strategies to improve systemic absorption.

[Multicenter Prospective Observational Study of Fungal Keratitis--Identification and Susceptibility Test of Fungi].

PubMed

Sunada, Atsuko; Asari, Seishi; Inoue, Yoshitsugu; Ohashi, Yuichi; Suzuki, Takashi; Shimomura, Yoshikazu; Fukuda, Masahiko; Sotozono, Chie; Hatano, Hiroshi; Eguchi, Hiroshi; Araki-Sasaki, Kaoru; Hoshi, Saichi; Yaguchi, Takashi; Makimura, Koichi; Yokokura, Shunji; Mochizuki, Kiyofumi; Monden, Yu; Nejima, Ryohei

2016-01-01

To investigate the causative fungi of fungal keratitis in Japan and their drug susceptibility. Identification and antifungal susceptibility test for 8 drugs (micafungin, amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole, miconazole and pimaricin) were performed using isolated fungi from patients with fungal keratitis treated at 27 facilities in Japan between November 1, 2011 and October 31, 2013. Fungal strains were detected in 72 (50.7%) out of 142 samples. The major isolates were Fusarium spp. (18), Candida parapsilosis (12), C. albicans (11) and Alternaria spp. (6), in all, fungi of 31 species were identified by gene analysis. In the yeast-like fungi, susceptibility rates were evident for more than 80% in voriconazole, pimaricin, flucytosine, micafungin, amphotericin B and fluconazole. In filamentous fungi, the susceptibility rate was less than 50% except for PMR (90%). Fusarium spp., which were susceptible to amphotericin B and pimaricin, showed lower susceptibility rates compared with other genera. Although various genera and species of fungi cause fungal keratitis, the obtained drug susceptibility data in this study demonstrates the different susceptibility patterns among the major isolates (Fusarium spp., C. parapsilosis, C. albicans and other groups). This is important evidence useful for fungal keratitis treatment.

Use of systemic antifungals in daily clinical practice in the haematology and oncology setting: results of a prospective observational analysis.

PubMed

Metzke, Barbara; Neubauer, Werner Christian; Hieke, Stefanie; Jung, Manfred; Wäsch, Ralph; Engelhardt, Monika

2012-09-01

To assess the role of systemic antifungal drugs as well as the frequency of potential drug interactions and adverse drug events of commonly used antifungals in an unselected haematology/oncology patient cohort. A prospective analysis was performed in our haematology/oncology department between October 2006 and September 2009. Data were obtained from 250 consecutive patients who received treatment and/or prophylaxis with fluconazole (n = 191), liposomal amphotericin B (n = 105), voriconazole (n = 62), caspofungin (n = 27) and/or posaconazole (n = 22). We performed detailed reviews of patient charts and laboratory values in close cooperation with treating physicians and nursing staff and participated regularly in ward and chart rounds. Potential drug interactions were assessed using the electronic database Micromedex® 1.0 (Healthcare Series). In terms of adverse drug events, caspofungin (56%) and voriconazole (58%) revealed a slightly more favourable safety profile than liposomal amphotericin B (66%) and posaconazole (64%). We confirmed frequent nephrotoxic effects with the use of liposomal amphotericin B (20%). Regarding potential drug interactions, 97 (66%) of 147 evaluated patients were exposed to at least 1 of 22 different potentially interacting drug combinations involving systemic antifungal agents. Cyclosporine was the most prevalent potentially interacting drug in our cohort. Systemic antifungal drugs are widely used in the haematology/oncology setting and exhibit numerous potential drug interactions and adverse events in cancer patients. Our results highlight the challenges related to antifungal drugs and should valuably contribute to a safe and efficient application of this increasingly important class of drugs. Copyright © 2012 John Wiley & Sons, Ltd.

Antifungal susceptibilities of Candida glabrata species complex, Candida krusei, Candida parapsilosis species complex and Candida tropicalis causing invasive candidiasis in China: 3 year national surveillance.

PubMed

Xiao, Meng; Fan, Xin; Chen, Sharon C-A; Wang, He; Sun, Zi-Yong; Liao, Kang; Chen, Shu-Lan; Yan, Yan; Kang, Mei; Hu, Zhi-Dong; Chu, Yun-Zhuo; Hu, Tie-Shi; Ni, Yu-Xing; Zou, Gui-Ling; Kong, Fanrong; Xu, Ying-Chun

2015-03-01

To define the antifungal susceptibility patterns of the most common non-albicans Candida spp. in China. We evaluated the susceptibilities to nine antifungal drugs of Candida parapsilosis species complex, Candida tropicalis, Candida glabrata species complex and Candida krusei isolates from patients with invasive candidiasis at 11 hospitals over 3 years. Isolates were identified by MALDI-TOF MS supplemented by DNA sequencing. MICs were determined by Sensititre YeastOne(TM) using current clinical breakpoints/epidemiological cut-off values to assign susceptibility (or WT), and by CLSI M44-A2 disc diffusion for fluconazole and voriconazole. Of 1072 isolates, 392 (36.6%) were C. parapsilosis species complex. C. tropicalis, C. glabrata species complex and C. krusei comprised 35.4%, 24.3% and 3.7% of the isolates, respectively. Over 99.3% of the isolates were of WT phenotype to amphotericin B and 5-flucytosine. Susceptibility/WT rates to azoles among C. parapsilosis species complex were ≥97.5%. However, 11.6% and 9.5% of C. tropicalis isolates were non-susceptible to fluconazole and voriconazole, respectively (7.1% were resistant to both). Approximately 14.3% of C. glabrata sensu stricto isolates (n = 258) were fluconazole resistant, and 11.6% of C. glabrata sensu stricto isolates were cross-resistant to fluconazole and voriconazole. All C. krusei isolates were susceptible/WT to voriconazole, posaconazole and itraconazole. Overall, 97.7%-100% of isolates were susceptible to caspofungin, micafungin and anidulafungin, but 2.3% of C. glabrata were non-susceptible to anidulafungin. There was no azole/echinocandin co-resistance. Disc diffusion and Sensititre YeastOne(TM) methods showed >95% categorical agreement for fluconazole and voriconazole. In summary, reduced azole susceptibility was seen among C. tropicalis. Resistance to echinocandins was uncommon. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Vertebral osteomyelitis and epidural abscess due to Aspergillus nidulans resulting in spinal cord compression: case report and literature review.

PubMed

Jiang, Zheng; Wang, Yunyan; Jiang, Yuquan; Xu, Yonghao; Meng, Bin

2013-04-01

Vertebral osteomyelitis caused by Aspergillus nidulans is rare and usually affects immunocompromised patients. This report presents a case of thoracic vertebral osteomyelitis with epidural abscesses due to A. nidulans in a 40-year-old immunocompetent female who presented with back pain, numbness and weakness of both lower limbs. Magnetic resonance imaging demonstrated osteomyelitis involving the thoracic (T)1-T3 vertebral bodies with epidural abscesses, resulting in spinal compression. The patient underwent a decompression laminectomy of T1-T3 and debridement of the thoracic epidural inflammatory granuloma. Histopathology revealed fungal granulomatous inflammation. The patient received 6 mg/kg voriconazole every 12 h (loading dose on day 1) followed by 4 mg/kg voriconazole twice daily for 1 month, administered intravenously. The patient returned with recurrent back pain 16 months after initial presentation. A. nidulans was identified by fungal culture and polymerase chain reaction. The patient showed no evidence of recurrence 1 year after a 6-month course of oral voriconazole. The key to the effective treatment of Aspergillus osteomyelitis is not to excise the abscess, but to administer systemic antifungal drug therapy.

Elevated Voriconazole Level Associated With Hallucinations and Suicidal Ideation: A Case Report.

PubMed

Jansen, Jeffrey W; Sen, Sumon K; Moenster, Ryan P

2017-01-01

Voriconazole, a broad-spectrum antifungal, has been associated with visual and auditory hallucinations. We report the case of patient being treated with voriconazole for pulmonary aspergillosis who developed visual hallucinations and new suicidal ideation with plan. Voriconazole troughs were supratherapeutic (9.0 mcg/mL) and the patient was positive for the CYP2C19*1/*2 allele.

Saccharomyces cerevisiae biofilm tolerance towards systemic antifungals depends on growth phase.

PubMed

Bojsen, Rasmus; Regenberg, Birgitte; Folkesson, Anders

2014-12-04

Biofilm-forming Candida species cause infections that can be difficult to eradicate, possibly because of antifungal drug tolerance mechanisms specific to biofilms. In spite of decades of research, the connection between biofilm and drug tolerance is not fully understood. We used Saccharomyces cerevisiae as a model for drug susceptibility of yeast biofilms. Confocal laser scanning microscopy showed that S. cerevisiae and C. glabrata form similarly structured biofilms and that the viable cell numbers were significantly reduced by treatment of mature biofilms with amphotericin B but not voriconazole, flucytosine, or caspofungin. We showed that metabolic activity in yeast biofilm cells decreased with time, as visualized by FUN-1 staining, and mature, 48-hour biofilms contained cells with slow metabolism and limited growth. Time-kill studies showed that in exponentially growing planktonic cells, voriconazole had limited antifungal activity, flucytosine was fungistatic, caspofungin and amphotericin B were fungicidal. In growth-arrested cells, only amphotericin B had antifungal activity. Confocal microscopy and colony count viability assays revealed that the response of growing biofilms to antifungal drugs was similar to the response of exponentially growing planktonic cells. The response in mature biofilm was similar to that of non-growing planktonic cells. These results confirmed the importance of growth phase on drug efficacy. We showed that in vitro susceptibility to antifungal drugs was independent of biofilm or planktonic growth mode. Instead, drug tolerance was a consequence of growth arrest achievable by both planktonic and biofilm populations. Our results suggest that efficient strategies for treatment of yeast biofilm might be developed by targeting of non-dividing cells.

[Adequacy of new systemic antifungal agents prescriptions in a teaching hospital].

PubMed

Pavese, P; Ouachi, Z; Vittoz, J-P; Lebeau, B; Foroni, L; Allenet, B; Stahl, J-P; François, P

2007-12-01

The aim of this study was to evaluate the adequacy and the conformity of prescriptions of new systemic antifungal drugs to guidelines and scientific data. Each prescription of liposomal amphotericin B (lip Amb), voriconazole, and caspofungin made between May 2003 and May 2004 in a teaching hospital were reviewed by an infectious diseases specialist. He used criteria based on marketing authorization, national recommendations, and scientific data. One hundred and fifteen files were studied during the 12-month period and 203 prescriptions analyzed. Most patients were immunodepressed. The indication of the treatment was appropriate for 127 prescriptions (62.6%). Dose and drug interactions were compliant with prescription rules for 158 prescriptions (77.8%). Among the causes of misuse, 16.3% concerned combinations of antifungals. Prescriptions of liposomal amphotericin B, voriconazole and caspofungin complied with guidelines respectively in 69.7, 60.6 and 36.8% of the cases. Among the 127 appropriate prescriptions, the use of cheaper molecules with an equivalent clinical effectiveness would have allowed saving 13.6% of the total cost of these prescriptions. This study will lead us to implement policies for new antifungal prescription.

Head-to-Head Comparison of Inhibitory and Fungicidal Activities of Fluconazole, Itraconazole, Voriconazole, Posaconazole, and Isavuconazole against Clinical Isolates of Trichosporon asahii

PubMed Central

Hazirolan, Gulsen; Canton, Emilia; Sahin, Selma

2013-01-01

Treatment of disseminated Trichosporon infections still remains difficult. Amphotericin B frequently displays inadequate fungicidal activity and echinocandins have no meaningful antifungal effect against this genus. Triazoles are currently the drugs of choice for the treatment of Trichosporon infections. This study evaluates the inhibitory and fungicidal activities of five triazoles against 90 clinical isolates of Trichosporon asahii. MICs (μg/ml) were determined according to Clinical and Laboratory Standards Institute microdilution method M27-A3 at 24 and 48 h using two endpoints, MIC-2 and MIC-0 (the lowest concentrations that inhibited ∼50 and 100% of growth, respectively). Minimum fungicidal concentrations (MFCs; μg/ml) were determined by seeding 100 μl of all clear MIC wells (using an inoculum of 104 CFU/ml) onto Sabouraud dextrose agar. Time-kill curves were assayed against four clinical T. asahii isolates and the T. asahii ATCC 201110 strain. The MIC-2 (∼50% reduction in turbidity compared to the growth control well)/MIC-0 (complete inhibition of growth)/MFC values that inhibited 90% of isolates at 48 h were, respectively, 8/32/64 μg/ml for fluconazole, 1/2/8 μg/ml for itraconazole, 0.12/0.5/2 μg/ml for voriconazole, 0.5/2/4 μg/ml for posaconazole, and 0.25/1/4 μg/ml for isavuconazole. The MIC-0 endpoints yielded more consistent MIC results, which remained mostly unchanged when extending the incubation to 48 h (98 to 100% agreement with 24-h values) and are easier to interpret. Based on the time-kill experiments, none of the drugs reached the fungicidal endpoint (99.9% killing), killing activity being shown but at concentrations not reached in serum. Statistical analysis revealed that killing rates are dose and antifungal dependent. The lowest concentration at which killing activity begins was for voriconazole, and the highest was for fluconazole. These results suggest that azoles display fungistatic activity and lack fungicidal effect against T. asahii. By rank order, the most active triazole is voriconazole, followed by itraconazole ∼ posaconazole ∼ isavuconazole > fluconazole. PMID:23877683

Cost-effectiveness evaluation of voriconazole versus liposomal amphotericin B as empirical therapy for febrile neutropenia in Australia.

PubMed

Al-Badriyeh, Daoud; Liew, Danny; Stewart, Kay; Kong, David C M

2009-01-01

A major randomized clinical trial, evaluating voriconazole versus liposomal amphotericin B (LAMB) as empirical therapy in febrile neutropenia, recommended voriconazole as a suitable alternative to LAMB. The current study sought to investigate the health economic impact of using voriconazole and LAMB for febrile neutropenia in Australia. A decision analytic model was constructed to capture downstream consequences of empirical antifungal therapy with each agent. The main outcomes were: success, breakthrough fungal infection, persistent baseline fungal infection, persistent fever, premature discontinuation and death. Underlying transition probabilities and treatment patterns were derived directly from trial data. Resource use was estimated using an expert panel. Cost inputs were obtained from the latest Australian representative published sources. The perspective adopted was that of the Australian hospital. Uncertainty and sensitivity analyses were undertaken via the Monte Carlo simulation. Compared with voriconazole, LAMB was associated with a net cost saving of AU$1422 (2.9%) per patient. A similar trend was observed with the cost per death prevented and successful treatment. LAMB dominated voriconazole as it resulted in higher efficacy and lower costs when compared with voriconazole. The results were most sensitive to the duration of therapy and the alternative therapy used post discontinuations. In uncertainty analysis, LAMB had 99.8% chance of costing less than voriconazole. In this study, which used the current standard five component endpoint to assess the impact of empirical antifungal therapy, LAMB was associated with cost savings relative to voriconazole.

[Mold infections in lung transplants].

PubMed

Solé, Amparo; Ussetti, Piedad

2014-01-01

Invasive infections by molds, mainly Aspergillus infections, account for more than 10% of infectious complications in lung transplant recipients. These infections have a bimodal presentation: an early one, mainly invading bronchial airways, and a late one, mostly focused on lung or disseminated. The Aspergillus colonization at any time in the post-transplant period is one of the major risk factors. Late colonization, together with chronic rejection, is one of the main causes of late invasive forms. A galactomannan value of 0.5 in bronchoalveolar lavage is currently considered a predictive factor of pulmonary invasive infection. There is no universal strategy in terms of prophylaxis. Targeted prophylaxis and preemptive treatment instead of universal prophylaxis, are gaining more followers. The therapeutic drug monitoring level of azoles is highly recommended in the treatment. Monotherapy with voriconazole is the treatment of choice in invasive aspergillosis; combined antifungal therapies are only recommended in severe, disseminated, and other infections due to non-Aspergillus molds. Copyright © 2014 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

Simultaneous determination of five systemic azoles in plasma by high-performance liquid chromatography with ultraviolet detection.

PubMed

Gordien, Jean-Baptiste; Pigneux, Arnaud; Vigouroux, Stephane; Tabrizi, Reza; Accoceberry, Isabelle; Bernadou, Jean-Marc; Rouault, Audrey; Saux, Marie-Claude; Breilh, Dominique

2009-12-05

A simple, specific and automatable HPLC assay was developed for a simultaneous determination of systemic azoles (fluconazole, posaconazole, voriconazole, itraconazole and its metabolite hydroxyl-itraconazole, and ketoconazole) in plasma. The major advantage of this assay was sample preparation by a fully automatable solid phase extraction with Varian Plexa cartridges. C6-phenyl column was used for chromatographic separation, and UV detection was set at a wavelength of 260 nm. Linezolid was used as an internal standard. The assay was specific and linear over the concentration range of 0.05 to 40 microg/ml excepted for fluconazole which was between 0.05 and 100 microg/ml, and itraconazole between 0.1 and 40 microg/ml. Validation data for accuracy and precision for intra- and inter-day were good and satisfied FDA's guidance: CV between 0.24% and 11.66% and accuracy between 93.8% and 108.7% for all molecules. This assay was applied to therapeutic drug monitoring on patients hospitalized in intensive care and onco-hematologic units.

Development and characterization of voriconazole loaded nanoparticles for parenteral delivery.

PubMed

Füredi, Petra; Kovács, Kristóf; Ludányi, Krisztina; Antal, István; Klebovich, Imre

2016-08-20

Human serum albumin (HSA) has attracted the most attention in the last decades as a new nanocarrier system of active pharmaceutical ingredients (API) due to its biocompatibility and high binding capacity to hydrophobic drugs. Voriconazole (VCZ), an antifungal agent with low water solubility, was selected to produce albumin based nanoparticles using nanoparticle albumin-bound technology (nab™-technology). Aim of our study was to study the development process of VCZ-loaded nanoparticles for parenteral drug delivery, such as homogenizing pressure, homogenizing cycle number and drug loading capacity. The main characters of nanoparticles such as particle size distribution and polydispersity index (PDI) were determined by dynamic light scattering. Six homogenization cycles at 1800bar were ensured the acceptable PDI value (lower than 0.3) of the VCZ content nanoparticles. Optimized formulation process produced 81.2±1nm average particle size which meets the requirements of intravenous administration. Furthermore, the encapsulated concentration of VCZ was 69.7±4.2% and the water solubility was over 2 times greater than the API itself which were determined by the developed HPLC method. The in vivo release behavior can be predicted from our applied in vitro dissolution study. Almost 50% of VCZ was liberated from the nanoparticles in the first 60min. Copyright © 2016 Elsevier B.V. All rights reserved.

Complications of hematopoietic stem transplantation: Fungal infections.

PubMed

Omrani, Ali S; Almaghrabi, Reem S

2017-12-01

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of invasive fungal infections, especially during the early neutropenic phase and severe graft-versus-host disease. Mold-active prophylaxis should be limited to the highest risk groups. Empiric antifungal therapy for HSCT with persistent febrile neutropenia is associated with unacceptable response rates, unnecessary antifungal therapy, increased risk of toxicity, and inflated costs. Empiric therapy should not be a substitute for detailed work up to identify the cause of fever in such patients. The improved diagnostic performance of serum biomarkers such as galactomannan and β-D-glucan, as well as polymerase chain reaction assays has allowed the development of diagnostic-driven antifungal therapy strategies for high risk patients. Diagnostic-driven approaches have resulted in reduced unnecessary antifungal exposure, improved diagnosis of invasive fungal disease, and reduced costs without increased risk of mortality. The appropriateness of diagnostic-driven antifungal strategy for individual HSCT centers depends on the availability and turnaround times for diagnostics, multidisciplinary expertise, and the local epidemiology of invasive fungal infections. Echinocandins are the treatment of choice for invasive candidiasis in most HSCT recipients. Fluconazole may be used for the treatment of invasive candidiasis in hemodynamically stable patients with no prior azole exposure. The primary treatment of choice for invasive aspergillosis is voriconazole. Alternatives include isavuconazole and lipid formulations of amphotericin. Currently available evidence does not support routine primary combination antifungal therapy for invasive aspergillosis. However, combination salvage antifungal therapy may be considered in selected patients. Therapeutic drug monitoring is recommended for the majority of HSCT recipients on itraconazole, posaconazole, or voriconazole. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Clinical implications of globally emerging azole resistance in Aspergillus fumigatus

PubMed Central

Verweij, Paul E.

2016-01-01

Aspergillus fungi are the cause of an array of diseases affecting humans, animals and plants. The triazole antifungal agents itraconazole, voriconazole, isavuconazole and posaconazole are treatment options against diseases caused by Aspergillus. However, resistance to azoles has recently emerged as a new therapeutic challenge in six continents. Although de novo azole resistance occurs occasionally in patients during azole therapy, the main burden is the aquisition of resistance through the environment. In this setting, the evolution of resistance is attributed to the widespread use of azole-based fungicides. Although ubiquitously distributed, A. fumigatus is not a phytopathogen. However, agricultural fungicides deployed against plant pathogenic moulds such as Fusarium, Mycospaerella and A. flavus also show activity against A. fumigatus in the environment and exposure of non-target fungi is inevitable. Further, similarity in molecule structure between azole fungicides and antifungal drugs results in cross-resistance of A. fumigatus to medical azoles. Clinical studies have shown that two-thirds of patients with azole-resistant infections had no previous history of azole therapy and high mortality rates between 50% and 100% are reported in azole-resistant invasive aspergillosis. The resistance phenotype is associated with key mutations in the cyp51A gene, including TR34/L98H, TR53 and TR46/Y121F/T289A resistance mechanisms. Early detection of resistance is of paramount importance and if demonstrated, either with susceptibility testing or through molecular analysis, azole monotherapy should be avoided. Liposomal amphotericin B or a combination of voriconazole and an echinocandin are recomended for azole-resistant aspergillosis. This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’. PMID:28080986

The Effectiveness of Voriconazole in Therapy of Candida glabrata's Biofilms Oral Infections and Its Influence on the Matrix Composition and Gene Expression.

PubMed

Rodrigues, Célia F; Gonçalves, Bruna; Rodrigues, Maria Elisa; Silva, Sónia; Azeredo, Joana; Henriques, Mariana

2017-08-01

Candida glabrata is one of most prevalent yeast in fungal infections, especially in immunocompromised patients. Its azole resistance results in a low therapeutic response, particularly when associated with biofilms. The main goal of this work was to study the effectiveness of voriconazole (Vcz) against C. glabrata biofilms oral pathologies, as esophageal or oropharyngeal candidiasis. Antifungal susceptibilities were determined in pre-formed 24-h-biofilms and ERG genes expression was determined by qRT-PCR. Protein quantification was performed using BCA ® Kit, carbohydrate was estimated according to the Dubois assay and β-1,3 glucans concentration were determined using Glucatell ® kit. Finally, ergosterol, Vcz, and fluconazole (Flu) concentrations within the biofilm matrices were determined by RP-HPLC. Results showed that C. glabrata biofilms were more susceptible to Vcz than to Flu and that ERG genes expression evidenced an overexpression of the three ERG genes in the presence of both azoles. The matrix content presented a remarked decrease in proteins and an increase in carbohydrates, namely β-1,3 glucans. Ergosterol was successfully detected and quantified in the biofilm matrices, with no differences in all the considered conditions. Vcz demonstrated better diffusion through the biofilms and better cell penetration capacities, than Flu, indicating that the structure of the drug molecule fully influences its dissemination through the biofilm matrices. This work showed that Vcz is notably more effective than Flu for the treatment of resistant C. glabrata oral biofilms, which demonstrates a clinical relevance in its future use for the treatment of oropharyngeal/esophageal candidiasis caused by this species.

Clinical outcomes of lung-transplant recipients treated by voriconazole and caspofungin combination in aspergillosis.

PubMed

Thomas, A; Korb, V; Guillemain, R; Caruba, T; Boussaud, V; Billaud, E; Prognon, P; Begué, D; Sabatier, B

2010-02-01

Invasive pulmonary aspergillosis (IPA) is a serious cause of death among immune-compromised patients such as organ-transplant recipients. Recently, voriconazole has been approved for first-line therapy in IPA. Theoretically, optimal voriconazole blood level (superior to 1 mg/L according to recent studies) should be reached within 24 h. In practice, a significantly longer time seems to be needed in lung-transplant recipients. Therefore, caspofungin is now used in combination with voriconazole to provide cover against Aspergillus spp. infection during this gap. The first aim of this study was to investigate Aspergillus spp. infection treated with this combination and the atter's tolerability. The median time for attainment of apparently active blood levels in lung transplant recipients were compared between those with cystic fibrosis and those without. Lung-transplant recipients who received a combination of voriconazole and caspofungin between 2002 and 2008 as primary therapy were identified retrospectively. The median number of days to reach active voriconazole blood levels was compared between cystic fibrosis and other patients by Student's t-test. Statistical significance was defined by P-value <0.05. Four patients were treated for Aspergillus colonization before transplantation and their culture were negative at 90 days. Eleven patients were treated for proven or probable invasive aspergillosis and 14 of them had a complete response. Hallucinations (n = 2) and significant hepatic toxicity (n = 2) were reported. Among the 15 studied transplant recipients, a median of 12.3 days was observed for active voriconazole blood levels to be reached. With cystic fibrosis patients, time tended to be longer than with other recipients (14.9 days vs. 8.3 days). Tacrolimus blood levels (between 5 and 15 ng/mL) may have been increased by voriconazole. This retrospective study describes practical experience in the management of this rare and severe disease in a referral centre for cystic fibrosis lung transplantation. Voriconazole and caspofungin combination was acceptably safe and was associated with good clinical outcomes in almost all patients. We showed that in 15 lung-transplant recipients a median of 12.3 days was required for voriconazole to reach high enough blood levels. Caspofungin in combination with voriconazole provides cover against Aspergillus infection during the period when voriconazole may be at subtherapeutic levels with good tolerability.

Antifungal Susceptibility Testing of Aspergillus spp. by Using a Composite Correlation Index (CCI)-Based Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry Method Appears To Not Offer Benefit over Traditional Broth Microdilution Testing

PubMed Central

Gitman, Melissa R.; McTaggart, Lisa; Spinato, Joanna; Poopalarajah, Rahgavi; Lister, Erin; Husain, Shahid

2017-01-01

ABSTRACT Aspergillus spp. cause serious invasive lung infections, and Aspergillus fumigatus is the most commonly encountered clinically significant species. Voriconazole is considered to be the drug of choice for treating A. fumigatus infections; however, rising resistance rates have been reported. We evaluated a matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS)-based method for the differentiation between wild-type and non-wild-type isolates of 20 Aspergillus spp. (including 2 isolates of Aspergillus ustus and 1 of Aspergillus calidoustus that were used as controls due their intrinsic low azole susceptibility with respect to the in vitro response to voriconazole). At 30 and 48 h of incubation, there was complete agreement between Cyp51A sequence analysis, broth microdilution, and MALDI-TOF MS classification of isolates as wild type or non-wild type. In this proof-of-concept study, we demonstrated that MALDI-TOF MS can be used to accurately detect A. fumigatus strains with reduced voriconazole susceptibility. However, rather than proving to be a rapid and simple method for antifungal susceptibility testing, this particular MS-based method showed no benefit over conventional testing methods. PMID:28404678

Antifungal Susceptibility Testing of Aspergillus spp. by Using a Composite Correlation Index (CCI)-Based Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry Method Appears To Not Offer Benefit over Traditional Broth Microdilution Testing.

PubMed

Gitman, Melissa R; McTaggart, Lisa; Spinato, Joanna; Poopalarajah, Rahgavi; Lister, Erin; Husain, Shahid; Kus, Julianne V

2017-07-01

Aspergillus spp. cause serious invasive lung infections, and Aspergillus fumigatus is the most commonly encountered clinically significant species. Voriconazole is considered to be the drug of choice for treating A. fumigatus infections; however, rising resistance rates have been reported. We evaluated a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS)-based method for the differentiation between wild-type and non-wild-type isolates of 20 Aspergillus spp. (including 2 isolates of Aspergillus ustus and 1 of Aspergillus calidoustus that were used as controls due their intrinsic low azole susceptibility with respect to the in vitro response to voriconazole). At 30 and 48 h of incubation, there was complete agreement between Cyp51A sequence analysis, broth microdilution, and MALDI-TOF MS classification of isolates as wild type or non-wild type. In this proof-of-concept study, we demonstrated that MALDI-TOF MS can be used to accurately detect A. fumigatus strains with reduced voriconazole susceptibility. However, rather than proving to be a rapid and simple method for antifungal susceptibility testing, this particular MS-based method showed no benefit over conventional testing methods. © Crown copyright 2017.

Susceptibility testing of terbinafine alone and in combination with amphotericin B, itraconazole, or voriconazole against conidia and hyphae of dematiaceous molds.

PubMed

Biancalana, Fernanda Simas Corrêa; Lyra, Luzia; Moretti, Maria Luiza; Schreiber, Angélica Zaninelli

2011-12-01

Studies have demonstrated excellent in vivo efficacy of terbinafine combined with other antifungal agents against dematiaceous molds; however, there is a lack of in vitro studies. Most studies evaluated conidia inocula, but susceptibility testing of hyphae could mimic the fungal status in infected tissues and might reflect the therapeutic potential of the agent. We investigated the in vitro susceptibility of terbinafine alone and in combination with amphotericin B, itraconazole, or voriconazole against conidia by microdilution and dynamic measurement of hyphae growth of dematiaceous molds. The MIC values for hyphae were, until 3 dilutions, below the MIC obtained for conidia. The results indicated 100% synergistic interactions between terbinafine and azoles or amphotericin B in all tests, but lower MICs for hyphae. In conclusion, our findings allow us to say that the hyphal form of tested dematiaceous molds showed high susceptibility to all antifungal agents evaluated, alone and in combination with terbinafine. Copyright © 2011 Elsevier Inc. All rights reserved.

Severe Skin Toxicity in Pediatric Oncology Patients Treated with Voriconazole and Concomitant Methotrexate

PubMed Central

van Eijkelenburg, Natasha K. A.; Huitema, Alwin D. R.; Schellens, Jan H. M.; Schouten-van Meeteren, Antoinette Y. N.

2013-01-01

We report the occurrence of skin toxicities in pediatric oncology patients on concomitant treatment with voriconazole and methotrexate (MTX). Of 23 patients who received this combination, 11 patients suffered from cheilitis and/or photosensitivity. In contrast, only in 1 of 9 patients who received voriconazole without MTX was photosensitivity observed. A mechanism of action was not able to be identified. We describe two cases with severe skin toxicities. Caution is warranted when using voriconazole and concomitant MTX. PMID:23571545

Antifungal susceptibility profile of diferent yeasts isolates from wild animals, cow's milk with subclinical mastitis and hospital environment.

PubMed

Mendes, J F; Gonçalves, C L; Ferreira, G F; Esteves, I A; Freitas, C H; Villarreal, J P V; Mello, J R B; Meireles, M C A; Nascente, P S

2018-02-01

Yeast infections have acquired great importance due to increasing frequency in immunocompromised patients or patients undergoing invasive diagnostic and therapeutic techniques, and also because of its high morbidity and mortality. At the same time, it has been seen an increase in the emergence of new pathogenic species difficult to diagnose and treat. The aim of this study was to determine the in vitro susceptibility of 89 yeasts from different sources against the antifungals amphotericin B, voriconazole, fluconazole and flucytosine, using the VITEK® 2 Compact system. The antifungal susceptibility was performed automatically by the Vitek® 2 Compact system. The origin of the yeasts was: Group 1 - microbiota of wild animals (W) (26/89), 2 - cow's milk with subclinical mastitis (M) (27/89) and 3 - hospital enviorment (H) (36/89). Of the 89 yeasts submitted to the Vitek® 2 test, 25 (20.9%) were resistant to fluconazole, 11 (12.36%) to amphotericin B, 3 (3.37%) to voriconazole, and no sample was resistant to flucytosine. Regarding the minimum inhibitory concentration (MIC), fluconazole showed an MIC between 1 and 64 mg/mL for the three groups, voriconazole had an MIC between 0.12 and 8 mg/mL, amphotericin B had an MIC between 0.25 and 4 mg/mL for group H and group W respectively, between 0.25 and 16 mg/mL for group M and flucytosine had an MIC equal to 1μg/mL for all groups. The yeasts isolated from the H group showed the highest resistance to fluconazole 12/89 (13.49%), followed by group W (7.87%) and group M (5.62%). The more resistant group to voriconazole was followed by the M and H groups, the W group showed no resistance to this antifungal. Group H was the least resistant (2.25%) to amphotericin.

Safety, Efficacy, and Exposure-Response of Voriconazole in Pediatric Patients With Invasive Aspergillosis, Invasive Candidiasis or Esophageal Candidiasis.

PubMed

Martin, Judith M; Macias-Parra, Mercedes; Mudry, Peter; Conte, Umberto; Yan, Jean L; Liu, Ping; Capparella, M Rita; Aram, Jalal A

2017-01-01

Data on safety and efficacy of voriconazole for invasive aspergillosis (IA) and invasive candidiasis/esophageal candidiasis (IC/EC) in pediatric patients are limited. Patients aged 2-<18 years with IA and IC/EC were enrolled in 2 prospective open-label, non-comparative studies of voriconazole. Patients followed dosing regimens based on age, weight and indication, with adjustments permitted. Treatment duration was 6-12 weeks for IA patients, ≥14 days after last positive Candida culture for IC patients and ≥7 days after signs/symptoms resolution for EC patients. Primary analysis for both the studies was safety and tolerability of voriconazole. Secondary end points included global response success at week 6 and end of treatment (EOT), all-causality mortality and time to death. Voriconazole exposure-response relationship was explored. Of 53 voriconazole-treated pediatric patients (31 IA; 22 IC/EC), 14 had proven/probable IA, 7 had confirmed IC and 10 had confirmed EC. Treatment-related hepatic and visual adverse events, respectively, were reported in 22.6% and 16.1% of IA patients, and 22.7% and 27.3% of IC/EC patients. All-causality mortality in IA patients was 14.3% at week 6; no deaths were attributed to voriconazole. No deaths were reported for IC/EC patients. Global response success rate was 64.3% (week 6 and EOT) in IA patients and 76.5% (EOT) in IC/EC patients. There was no association between voriconazole exposure and efficacy; however, a slight positive association between voriconazole exposure and hepatic adverse events was established. Safety and efficacy outcomes in pediatric patients with IA and IC/EC were consistent with previous findings in adult patients.

Treatment for a eumycetoma infection caused by Aspergillus in an immunocompromised host: a case report.

PubMed

Hopps, S; Roach, A; Yuen, C; Borders, E

2015-02-01

Eumycetoma is a chronic infection of the skin and subcutaneous tissue caused by filamentous fungi, which usually occurs in tropical or subtropical countries. We report a case of an immunocompromised patient presenting with presumed eumycetoma in the United States and his subsequent treatment with voriconazole. The use of voriconazole and liposomal amphotericin B halted the progression and allowed gradual resolution of the infection. The patient will require close monitoring and long-term therapy with voriconazole to obtain a clinical cure. Voriconazole and liposomal amphotericin B are potential initial treatment options, with long-term voriconazole maintenance therapy, for an Aspergillus-induced eumycetoma. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Synergistic anticandidal activity of pure polyphenol curcumin I in combination with azoles and polyenes generates reactive oxygen species leading to apoptosis.

PubMed

Sharma, Monika; Manoharlal, Raman; Negi, Arvind Singh; Prasad, Rajendra

2010-08-01

We have shown previously that pure polyphenol curcumin I (CUR-I) shows antifungal activity against Candida species. By employing the chequerboard method, filter disc and time-kill assays, in the present study we demonstrate that CUR-I at non-antifungal concentration interacts synergistically with azoles and polyenes. For this, pure polyphenol CUR-I was tested for synergy with five azole and two polyene drugs - fluconazole (FLC), miconazole, ketoconazole (KTC), itraconazole (ITR), voriconazole (VRC), nystatin (NYS) and amphotericin B (AMB) - against 21 clinical isolates of Candida albicans with reduced antifungal sensitivity, as well as a drug-sensitive laboratory strain. Notably, there was a 10-35-fold drop in the MIC(80) values of the drugs when CUR-I was used in combination with azoles and polyenes, with fractional inhibitory concentration index (FICI) values ranging between 0.09 and 0.5. Interestingly, the synergistic effect of CUR-I with FLC and AMB was associated with the accumulation of reactive oxygen species, which could be reversed by the addition of an antioxidant such as ascorbic acid. Furthermore, the combination of CUR-I and FLC/AMB triggered apoptosis that could also be reversed by ascorbic acid. We provide the first evidence that pure CUR-I in combination with azoles and polyenes represents a novel therapeutic strategy to improve the activity of common antifungals.

Assessment of carvacrol for control of avian aspergillosis in intratracheally challenged chickens in comparison to voriconazole with a reference on economic impact.

PubMed

Tartor, Y H; Hassan, F A M

2017-11-01

This study was designed to investigate the efficacy of essential oils as an alternative prophylaxis and treatment for avian aspergillosis. The in vitro susceptibility of Aspergillus fumigatus strains to antifungal drugs and carvacrol, thymol, eugenol, thymoquinone and cinnamon was determined using the macrodiffusion and microdilution methods. Carvacrol has antifungal activity in comparison to voriconazole (VCZ) (MIC 0·5, 0·25 μg ml -1 respectively). While cinnamon, euganol, thymol and thymoquinone displayed moderate to weak inhibitory activity. For the efficacy study, five groups of 10-day-old chicks (n = 48) were infected intratracheally either with A. fumigatus conidia or saline (negative control). Chicks in carvacrol prophylactic and treatment (CRPT) group were fed for 10 days beginning from hatch with carvacrol (200 mg kg -1 per diet) supplemented diets. VCZ (VCZT:20 mg kg -1 body weight (BW)), carvacrol treatment (CRT, CRPT) was started upon appearance of the first clinical signs and continued for 10 days. Birds were monitored for an additional 15 days following treatment. Fungal burden and therapeutic efficacy were assessed by survival, BW, quantitative (q) culture (CFU), quantitative real-time PCR (qPCR) and histopathological changes at several time points. Serum biochemical changes were also assessed. VCZT, CRPT, CRT in comparison to the sham-treated (SHAM) group have prolonged survival (87·5, 83·4, 79·2, 41·7% respectively). In VCZT and CRPT, a significant reduction in clinical signs, lesions, CFU and qPCR counts to the limit of detection were observed. CRPT has the lowest BW reduction, economic losses and significant low total cholesterol levels. Carvacrol has a promising potential to be used as a prophylactic and treatment against A. fumigatus. Prognosis of avian aspergillosis is often poor due to delayed diagnosis and treatment failure. However, the widespread uses of azole prophylaxis in birds are thought to be the major driver of azole resistance. These findings create a possibility to develop an effective drug-free alternative strategy for control of avian aspergillosis. © 2017 The Society for Applied Microbiology.

[Comparison of microdilution and disk diffusion methods for the detection of fluconazole and voriconazole susceptibility against clinical Candida glabrata isolates and determination of changing susceptibility with new CLSI breakpoints].

PubMed

Hazırolan, Gülşen; Sarıbaş, Zeynep; Arıkan Akdağlı, Sevtap

2016-07-01

Candida albicans is the most frequently isolated species as the causative agent of Candida infections. However, in recent years, the isolation rate of non-albicans Candida species have increased. In many centers, Candida glabrata is one of the commonly isolated non-albicans species of C.glabrata infections which are difficult-to-treat due to decreased susceptibility to fluconazole and cross-resistance to other azoles. The aims of this study were to determine the in vitro susceptibility profiles of clinical C.glabrata isolates against fluconazole and voriconazole by microdilution and disk diffusion methods and to evaluate the results with both the previous (CLSI) and current species-specific CLSI (Clinical and Laboratory Standards Institute) clinical breakpoints. A total of 70 C.glabrata strains isolated from clinical samples were included in the study. The identification of the isolates was performed by morphologic examination on cornmeal Tween 80 agar and assimilation profiles obtained by using ID32C (BioMérieux, France). Broth microdilution and disk diffusion methods were performed according to CLSI M27-A3 and CLSI M44-A2 documents, respectively. The results were evaluated according to CLSI M27-A3 and M44-A2 documents and new vs. species-specific CLSI breakpoints. By using both previous and new CLSI breakpoints, broth microdilution test results showed that voriconazole has greater in vitro activity than fluconazole against C.glabrata isolates. For the two drugs tested, very major error was not observed with disk diffusion method when microdilution method was considered as the reference method. Since "susceptible" category no more exists for fluconazole vs. C.glabrata, the isolates that were interpreted as susceptible by previous breakpoints were evaluated as susceptible-dose dependent by current CLSI breakpoints. Since species-specific breakpoints remain yet undetermined for voriconazole, comparative analysis was not possible for this agent. The results obtained at 24 hours by disk diffusion method were evaluated by using both previous and current CLSI breakpoints and the agreement rates for fluconazole and voriconazole were 80% and 92.8% with previous CLSI breakpoint, 87.1% and 94.2% with new breakpoints, respectively. The high agreement rates between the two methods obtained by the new breakpoints in particular suggest that disk diffusion appears as a reliable alternative method in general for in vitro susceptibility testing of fluconazole and voriconazole against C.glabrata isolates.

Regression Discontinuity and Randomized Controlled Trial Estimates: An Application to The Mycotic Ulcer Treatment Trials.

PubMed

Oldenburg, Catherine E; Venkatesh Prajna, N; Krishnan, Tiruvengada; Rajaraman, Revathi; Srinivasan, Muthiah; Ray, Kathryn J; O'Brien, Kieran S; Glymour, M Maria; Porco, Travis C; Acharya, Nisha R; Rose-Nussbaumer, Jennifer; Lietman, Thomas M

2018-08-01

We compare results from regression discontinuity (RD) analysis to primary results of a randomized controlled trial (RCT) utilizing data from two contemporaneous RCTs for treatment of fungal corneal ulcers. Patients were enrolled in the Mycotic Ulcer Treatment Trials I and II (MUTT I & MUTT II) based on baseline visual acuity: patients with acuity ≤ 20/400 (logMAR 1.3) enrolled in MUTT I, and >20/400 in MUTT II. MUTT I investigated the effect of topical natamycin versus voriconazole on best spectacle-corrected visual acuity. MUTT II investigated the effect of topical voriconazole plus placebo versus topical voriconazole plus oral voriconazole. We compared the RD estimate (natamycin arm of MUTT I [N = 162] versus placebo arm of MUTT II [N = 54]) to the RCT estimate from MUTT I (topical natamycin [N = 162] versus topical voriconazole [N = 161]). In the RD, patients receiving natamycin had mean improvement of 4-lines of visual acuity at 3 months (logMAR -0.39, 95% CI: -0.61, -0.17) compared to topical voriconazole plus placebo, and 2-lines in the RCT (logMAR -0.18, 95% CI: -0.30, -0.05) compared to topical voriconazole. The RD and RCT estimates were similar, although the RD design overestimated effects compared to the RCT.

Effect of Voriconazole on Candida tropicalis Biofilms: Relation with ERG Genes Expression.

PubMed

Fernandes, Tânia; Silva, Sónia; Henriques, Mariana

2016-10-01

Candida tropicalis has emerged as the third most prevalent fungal pathogens and its ability to form biofilms has been considered one of the most important virulence factors, since biofilms represent high tolerance to antifungal agents. However, the mechanisms of C. tropicalis biofilm resistance to antifungals remain poorly understood. Thus, the main aim of this work was to infer about the effect of voriconazole on the formation and control of C. tropicalis biofilms and disclose its relationship with ERG genes' expression. Planktonic cells tolerance of several C. tropicalis clinical isolates to voriconazole was determined through of antifungal susceptibility test, and the effect of this azole against C. tropicalis biofilm formation and pre-formed biofilms was evaluated by cultivable cells determination and total biomass quantification. ERG genes expression was analyzed by quantitative real-time polymerase chain reaction. This work showed that C. tropicalis resistance to voriconazole is strain dependent and that voriconazole was able to partially control biofilm formation, but was unable to eradicate C. tropicalis pre-formed biofilms. Moreover, C. tropicalis biofilms resistance to voriconazole seems to be associated with alterations of sterol content in the cell membrane, resulting in ERG genes overexpression. Voriconazole is unable to control C. tropicalis biofilms, and the overexpression of ERG genes is a possible mechanism of biofilm resistance.

Pharmacokinetics of a single dose of voriconazole administered orally with and without food to red-tailed hawks (Buteo jamaicensus).

PubMed

Parsley, Ruth A; Tell, Lisa A; Gehring, Ronette

2017-04-01

OBJECTIVE To determine the pharmacokinetics of voriconazole administered PO with or without food to red-tailed hawks (Buteo jamaicensus) and whether any observed variability could be explained by measured covariates to inform dose adjustments. ANIMALS 7 adult red-tailed hawks. PROCEDURES In a crossover study design, hawks were randomly assigned to first receive voriconazole (15 mg/kg, PO) injected into a dead mouse (n = 3; fed birds) or without food (4; unfed birds). Sixteen days later, treatments were reversed. Blood samples were collected at various points to measure plasma voriconazole concentrations by ultraperformance liquid chromatography. Pharmacokinetic data were analyzed by noncompartmental methods and fit to a compartmental model through nonlinear mixed-effects regression, with feeding status and body weight investigated as covariates. RESULTS Voriconazole was well absorbed, with quantifiable plasma concentrations up to 24 hours after administration. Mean plasma half-life was approximately 2 hours in fed and unfed birds. Administration of the voriconazole in food delayed absorption, resulting in a significant delay in time to maximum plasma concentration. The final compartmental model included a categorical covariate to account for this lag in absorption as well as body weight as a covariate of total body clearance (relative to unknown bioavailability). CONCLUSIONS AND CLINICAL RELEVANCE A single dose of voriconazole (15 mg/kg) administered PO to red-tailed hawks resulted in mean plasma voriconazole concentrations greater than the targeted value (1 μg/mL). Additional studies with larger sample sizes and multidose regimens are required before the model developed here can be applied in clinical settings.

Topically applied 1% voriconazole induces dysplastic changes on the ocular surface: animal study.

PubMed

Arikan, Gul; Karatas, Ezgi; Lebe, Banu; Ayhan, Ziya; Utine, Canan Asli; Kutsoylu, Oya Eren; Gunenc, Uzeyir; Yilmaz, Osman

2018-04-26

To identify the risk of inducing ocular surface dysplasia following topical administration of 1% voriconazole eye drop. Fourteen noninflamed healthy eyes of 14 white adult New Zealand rabbits were included in the study. The rabbits were randomly divided into two groups comprised of 7 rabbits each. Group 1 received topical 1% voriconazole and Group 2 received topical saline as the control group. In all animals, right eye was selected for the study. In Group 1 (Voriconazole Group), single drop of voriconazole was instilled every 10 min consecutively for 17 times a day for 60 days. In Group 2 (Control Group), single drop of saline was instilled every 10 min consecutively for 17 times a day for 60 days. At two months, animals were sacrificed and study eyes were enucleated with the eyelids. The specimens were stained with hematoxylin-eosin and histopathologic changes in cornea, bulbar and palpebral conjunctiva were evaluated under light microscope. There were no macroscopically visible lesions on the ocular surface of any rabbits. Histopathological evaluation showed mild to moderate dysplasia localized mainly in the limbus and extending to the adjacent cornea and bulbar conjunctiva in all rabbits in Voriconazole Group. Severe dysplasia or carcinoma in situ was not observed. In the Control Group, dysplasia was not observed, at all. This animal study provides a possible relationship between topically administered 1% voriconazole and ocular surface dysplasia. We recommend ophthalmologists to be aware of the risk of ocular surface dysplasia in patients received voriconazole eye drop.

In Vitro Activities of Eight Antifungal Drugs against 106 Waterborne and Cutaneous Exophiala Species

PubMed Central

Najafzadeh, M. J.; Saradeghi Keisari, M.; Vicente, V. A.; Feng, P.; Shamsian, S. A. A.; Rezaei-Matehkolaei, A.; de Hoog, G. S.; Curfs-Breuker, I.

2013-01-01

The in vitro activities of eight antifungal drugs against 106 clinical and environmental isolates of waterborne and cutaneous Exophiala species were tested. The MICs and minimum effective concentrations for 90% of the strains tested (n = 106) were, in increasing order, as follows: posaconazole, 0.063 μg/ml; itraconazole, 0.25 μg/ml; micafungin, 1 μg/ml; voriconazole, 2 μg/ml; isavuconazole, 4 μg/ml; caspofungin, 8 μg/ml; amphotericin B, 16 μg/ml; fluconazole, 64 μg/ml. PMID:24100491

Spotlight on isavuconazole in the treatment of invasive aspergillosis and mucormycosis: design, development, and place in therapy

PubMed Central

2018-01-01

In recent decades, important advances have been made in the diagnosis and treatment of invasive aspergillosis (IA) and mucormycosis. One of these advances has been the introduction of isavuconazole, a second-generation broad spectrum triazole with a favorable pharmacokinetic and safety profile and few drug–drug interactions. Phase III trials in patients with IA and mucormycosis demonstrated that isavuconazole has similar efficacy to voriconazole for the treatment of IA (SECURE trial) and liposomal amphotericin B for the treatment of mucormycosis (VITAL trial with subsequent case–control analysis) and a favorable safety profile with significantly fewer ocular, hepatobiliary, and skin and soft tissue adverse events compared to voriconazole. As a result, recent IA guidelines recommend isavuconazole (together with voriconazole) as gold standard treatment for IA in patients with underlying hematological malignancies. In contrast to liposomal amphotericin B, isavuconazole can be safely administered in patients with reduced renal function and is frequently used for the treatment of mucormycosis in patients with reduced renal function. Updated guidelines on mucormycosis are needed to reflect the current evidence and give guidance on the use of isavuconazole for mucormycosis. Studies are needed to evaluate the role of isavuconazole for 1) anti-mold prophylaxis in high-risk patients, 2) salvage treatment for IA and mucormycosis, and 3) treatment for other mold infections such as Scedosporium apiospermum. PMID:29750016

Fungal infection of cystic fibrosis patients - single center experience.

PubMed

Garczewska, Barbara; Jarzynka, Sylwia; Kuś, Jan; Skorupa, Wojciech; Augustynowicz-Kopeć, Ewa

2016-01-01

Cystic fibrosis (CF) is the most common monogenetic autosomal recessive disease in the human population. This systemic disease is characterized by changes in multiple organs, mainly in the lung tissue and digestive tract. More than 59% of CF patients become sensitized to fungal spores, mostly Aspergillus fumigatus. 5-15% of CF patients develop allergic bronchopulmonary aspergillosis. The aim of the study was to analyse the occurrence of yeast and filamentous fungi of the respiratory infections in CF patients and evaluation of drug resistance. Between 2006 and 2014, mycological evaluation of 42 patients hospitalized at the National Institute of Tuberculosis and Lung Diseases was carried out. 217 specimens from pulmonary tract were collected from 42 patients with cystic fibrosis. 205 (68%) strains of yeast and 96 (32%) filamentous fungi strains were cultured. The most common mould strain was A. fumigatus - 22,2% (67 species). All isolates of filamentous fungi were in vitro 100% susceptible to itraconazole, voriconazole, posaconazole and amphotericin B. A. fumigatus and C. albicans were the most common etiological agents of fungal respiratory pathogens associated with CF patients. A. fumigatus strains were in vitro 100% susceptible to azole and amphotericin B. Two strains of C. albicans and one strain of C. tropicalis were non-susceptible to azole (fluconazole, itraconazole and voriconazole). Scedosporium apiospermum was resistant to amphotericin B (MIC > 32 mg/l) and susceptible to voriconazole (MIC 0.094 mg/l).

Nebulized voriconazole in infections with Scedosporium apiospermum--case report and review of the literature.

PubMed

Holle, J; Leichsenring, M; Meissner, P E

2014-07-01

Scedosporium infections are rare complications in immunocompromised patients or patients with chronic pulmonary disease. While Scedosporium prolificans is resistant to most antimycotics, Scedosporium apiospermum is usually sensitive to voriconazole and posaconazole. Pharmacokinetics and efficacy of nebulized voriconazole have been described in a murine model previously. We report for the first time the safe and effective use of nebulized voriconazole for the treatment of severe pulmonary infection with Scedosporium apiospermum in an adolescent with cystic fibrosis. Copyright © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Use of Voriconazole in Treatment of Scedosporium apiospermum Infection: Case Report

PubMed Central

Girmenia, Corrado; Luzi, Giovanni; Monaco, Monica; Martino, Pietro

1998-01-01

We report a case of disseminated Scedosporium apiospermum infection in a neutropenic patient with acute myeloid leukemia. Due to progression of the mycosis after 7 days of amphotericin B lipid complex therapy and to high susceptibility of the mold to voriconazole in vitro, the patient was treated with intravenous voriconazole. After a few days of therapy, fever disappeared and skin lesions improved. However, the patient died after 1 month due to intestinal bleeding. Despite a negative outcome, this case seems to indicate a promising role for voriconazole in the treatment of S. apiospermum infections. PMID:9574724

In vitro susceptibility of Candida spp. to fluconazole, itraconazole and voriconazole and the correlation between triazoles susceptibility: Results from a five-year study.

PubMed

Lei, J; Xu, J; Wang, T

2018-06-01

Candida spp. is a common cause of invasive fungal disease. The aim of this study was to examine the susceptibility of Candida spp. to fluconazole, itraconazole and voriconazole and explore the correlation between triazoles susceptibility. The antifungal susceptibility in the present study was measured by ATB Fungus 3 method, and the potential relationship was examined by obtaining the correlation of measured minimal inhibitory concentrations (MICs) of Candida spp. isolates. A total of 2099 clinical isolates of Candida spp. from 1441 patients were analyzed. The organisms included 1435 isolates of Candida albicans, 207 isolates of Candida glabrata, 65 isolates of Candida parapsilosis, 31 isolates of Candida krusei, 268 isolates of Candida tropicalis. Voriconazole and itraconazole were more active than fluconazole and against Candida spp. in vitro. The fluconazole, itraconazole and voriconazole MIC 90 (MIC for 90% of the isolates) for all Candida spp. isolates was 4mg/L, 1mg/L and 0.25mg/L, respectively. There was a moderate correlation between the fluconazole MIC s for Candida spp. isolates and this for voriconazole (R 2 =0.475; P<0.01) and itraconazole (R 2 =0.431; P<0.01). Voriconazole MICs for the Candida spp. isolates also correlated with those for itraconazole (R 2 =0.401; P<0.01). These observations suggest that the in vitro susceptibility of Candida spp. to fluconazole, itraconazole and voriconazole exhibits a moderate correlation. Published by Elsevier Masson SAS.

Voriconazole Exposure and Risk of Cutaneous Squamous Cell Carcinoma, Aspergillus Colonization, Invasive Aspergillosis and Death in Lung Transplant Recipients

PubMed Central

Mansh, M.; Binstock, M.; Williams, K.; Hafeez, F.; Kim, J.; Glidden, D.; Boettger, R.; Hays, S.; Kukreja, J.; Golden, J.; Asgari, M.M.; Chin-Hong, P.; Singer, J.P.; Arron, S.

2015-01-01

Voriconazole is a triazole antifungal used to prevent and treat invasive fungal infections after lung transplantation, but has been associated with an increased risk for developing cutaneous squamous cell carcinoma (SCC). Despite widespread use, there are no clear guidelines for optimal prophylactic regimens that balance its competing risks and benefits. We conducted a retrospective cohort study of all lung transplant recipients at the University of California, San Francisco transplanted between October 1991 and December 2012 (n=455) to investigate whether voriconazole exposure impacted development of SCC, Aspergillus colonization, invasive aspergillosis, and all-cause mortality. Voriconazole exposure was associated with a 73% increased risk for developing SCC (HR=1.73; 95% CI: 1.04–2.88; p=0.03), with each additional 30-day exposure at the standard dose increasing the risk by 3.0% (HR=1.03; 95% CI: 1.02–1.04; p<0.001). Voriconazole exposure reduced risk of Aspergillus colonization by 50% (HR=0.50; 95% CI: 0.34–0.72; p<0.001), but we were underpowered to detect risk reduction for invasive aspergillosis. Voriconazole exposure significantly reduced all-cause mortality among subjects who developed Aspergillus colonization (HR=0.34; 95% CI: 0.13–0.91; p=0.03), but had no significant impact on those without colonization. Physicians should consider patient-specific factors that modify the potential risks and benefits of voriconazole in the care of lung transplant recipients. PMID:26372838

Synergy and antagonism between iron chelators and antifungal drugs in Cryptococcus.

PubMed

Lai, Yu-Wen; Campbell, Leona T; Wilkins, Marc R; Pang, Chi Nam Ignatius; Chen, Sharon; Carter, Dee A

2016-10-01

Fungal infections remain very difficult to treat, and developing new antifungal drugs is difficult and expensive. Recent approaches therefore seek to augment existing antifungals with synergistic agents that can lower the therapeutic dose, increase efficacy and prevent resistance from developing. Iron limitation can inhibit microbial growth, and iron chelators have been employed to treat fungal infections. In this study, chequerboard testing was used to explore combinations of iron chelators with antifungal agents against pathogenic Cryptococcus spp. with the aim of determining how disruption to iron homeostasis affects antifungal susceptibility. The iron chelators ethylenediaminetetraacetic acid (EDTA), deferoxamine (DFO), deferiprone (DFP), deferasirox (DSX), ciclopirox olamine and lactoferrin (LF) were paired with the antifungal agents amphotericin B (AmB), fluconazole, itraconazole, voriconazole and caspofungin. All chelators except for DFO increased the efficacy of AmB, and significant synergy was seen between AmB and LF for all Cryptococcus strains. Addition of exogenous iron rescued cells from the antifungal effect of LF alone but could not prevent inhibition by AmB + LF, indicating that synergy was not due primarily to iron chelation but to other properties of LF that were potentiated in the presence of AmB. Significant synergy was not seen consistently for other antifungal-chelator combinations, and EDTA, DSX and DFP antagonised the activity of azole drugs in strains of Cryptococcus neoformans var. grubii. This study highlights the range of interactions that can be induced by chelators and indicates that most antifungal drugs are not enhanced by iron limitation in Cryptococcus. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Comparison of corneal collagen cross-linking (PACK-CXL) and voriconazole treatments in experimental fungal keratitis.

PubMed

Özdemir, Hüseyin Baran; Kalkancı, Ayşe; Bilgihan, Kamil; Göçün, Pınar Uyar; Öğüt, Betül; Karakurt, Funda; Erdoğan, Merve

2018-06-04

To compare the antifungal efficacy of corneal collagen cross-linking with photoactivated riboflavin (PACK-CXL) and voriconazole in experimental Fusarium solani and Candida albicans keratitis models. Sixty-four corneas of 32 New Zealand rabbits were included and divided into two main groups. Intrastromal injection of Fusarium and Candida suspensions was performed, and it was observed that keratitis was formed on the third day. Both groups were randomly separated into the following four groups: control, PACK-CXL, voriconazole and PACK-CXL combined with voriconazole. PACK-CXL was applied using 0.25% riboflavin in an accelerated Dresden protocol (total ultraviolet A dose 5.4 J/cm²). Voriconazole was applied topically as 7x1/day with a dose of 1% (10 mg/ml). Corneal buttons were excised on the tenth day, and microbiological and pathological examinations were performed. The PACK-CXL and PACK-CXL combined with voriconazole groups each had 100 colony-forming unit (CFU/ml) of reproduced micro-organisms compared with 500 CFU/ml in the voriconazole group and 1500 CFU/ml in the control group (p < 0.001) in the Fusarium keratitis model. The PACK-CXL combined with voriconazole group had 100 CFU/ml, the PACK-CXL group had 150 CFU/ml, and the voriconazole group had 200 CFU/ml of reproduced micro-organisms compared with 4000 CFU/ml in the control group (p < 0.002) in the Candida keratitis model. (p < 0.001). Fewer hyphae and non-specific stromal changes were observed in the pathological cross sections examined in subgroups that used CXL. There was less fungus reproduction and a lower keratitis score for Fusarium solani and Candida albicans in the treatment groups compared to the control groups, especially in groups that used PACK-CXL. These results suggest that it is useful to combine PACK-CXL treatment with medical treatment in the fungal keratitis algorithm at the early stage of the disease. © 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Pharmacokinetics and Tolerability of Letermovir Coadministered With Azole Antifungals (Posaconazole or Voriconazole) in Healthy Subjects.

PubMed

Marshall, William L; McCrea, Jacqueline B; Macha, Sreeraj; Menzel, Karsten; Liu, Fang; van Schanke, Arne; de Haes, Joanna I Udo; Hussaini, Azra; Jordan, Heather R; Drexel, Melissa; Kantesaria, Bhavna S; Tsai, Christine; Cho, Carolyn R; Hulskotte, Ellen G J; Butterton, Joan R; Iwamoto, Marian

2018-03-26

Letermovir is a human cytomegalovirus terminase inhibitor for cytomegalovirus infection prophylaxis in hematopoietic stem cell transplant recipients. Posaconazole (POS), a substrate of glucuronosyltransferase and P-glycoprotein, and voriconazole (VRC), a substrate of CYP2C9/19, are commonly administered to transplant recipients. Because coadministration of these azoles with letermovir is expected, the effect of letermovir on exposure to these antifungals was investigated. Two trials were conducted in healthy female subjects 18 to 55 years of age. In trial 1, single-dose POS 300 mg was administered alone, followed by a 7-day washout; then letermovir 480 mg once daily was given for 14 days with POS 300 mg coadministered on day 14. In trial 2, on day 1 VRC 400 mg was given every 12 hours; on days 2 and 3, VRC 200 mg was given every 12 hours, and on day 4 VRC 200 mg. On days 5 to 8, letermovir 480 mg was given once daily. Days 9 to 12 repeated days 1 to 4 coadministered with letermovir 480 mg once daily. In both trials, blood samples were collected for the assessment of the pharmacokinetic profiles of the antifungals, and safety was assessed. The geometric mean ratios (90%CIs) for POS+letermovir/POS area under the curve and peak concentration were 0.98 (0.83, 1.17) and 1.11 (0.95, 1.29), respectively. Voriconazole+letermovir/VRC area under the curve and peak concentration geometric mean ratios were 0.56 (0.51, 0.62) and 0.61 (0.53, 0.71), respectively. All treatments were generally well tolerated. Letermovir did not affect POS pharmacokinetics to a clinically meaningful extent but decreased VRC exposure. These results suggest that letermovir may be a perpetrator of CYP2C9/19-mediated drug-drug interactions. © 2018, The American College of Clinical Pharmacology.

In Vitro Activity of Voriconazole against Prototheca wickerhamii: Comparative Evaluation of Sensititre and NCCLS M27-A2 Methods of Detection

PubMed Central

Linares, Maria José; Solís, Francisco; Casal, Manuel

2005-01-01

A total of 104 Prototheca wickerhamii isolates and two control strains were tested for susceptibility to voriconazole using the Sensititre YeastOne colorimetric antifungal plate and NCCLS reference method. Voriconazole was highly active against all isolates, with an MIC at which 90% of isolates were inhibited of ≤0.5 μg/ml. Comparison of MICs obtained with the Sensititre product and the NCCLS method demonstrated agreement (100% ± 2 log2 dilutions) between the two methods. Voriconazole may offer an option for the treatment of Prototheca sp. infections, and its efficacy should be established through clinical experience. PMID:15872301

Drug susceptibility profile of Candida glabrata clinical isolates from Iran and genetic resistant mechanisms to caspofungin.

PubMed

Amanloo, Saeid; Shams-Ghahfarokhi, Masoomeh; Ghahri, Mohammad; Razzaghi-Abyaneh, Mehdi

2018-04-20

Candida glabrata is a yeast that can cause hazardous fungal infections with high mortality and drug resistance. The aim of this study was to determine the profile of drug susceptibility in clinical isolates of C. glabrata and review the resistance mechanisms to caspofungin. A total of 50 C. glabrata clinical isolates from Iran were tested for in vitro susceptibilities to amphotericin B, caspofungin, fluconazole and voriconazole. To investigate the mechanism of resistance to caspofungin, hotspot areas of FKS1 and FKS2 genes were sequenced and gene expression profile was evaluated. All the isolates were susceptible to amphotericin B and caspofungin. Fluconazole resistance was exhibited in four isolates. In addition, only one isolate was resistant to voriconazole. FKS2 with 12 point mutations showed more mutations compared to FKS1 that had only two mutations. All substitutions were synonymous. FKS genes were expressed at comparable levels (no statistical significance) in caspofungin-treated and non-treated cultures. The silent mutations in the hotspot areas of FKS genes and inconsiderable changes in gene expression were not associated with increased MIC (0.25μg/ml). Other mechanisms of resistance which include mutations outside the hotspot area of FKS genes could be involved in a slight increase of MIC, and they should be identified through complete FKS gene sequencing. Copyright © 2018 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

In Vitro Antifungal Susceptibility of Neoscytalidium dimidiatum Clinical Isolates from Malaysia.

PubMed

James, Jasper Elvin; Santhanam, Jacinta; Lee, Mei Chen; Wong, Choon Xian; Sabaratnam, Parameswari; Yusoff, Hamidah; Tzar, Mohd Nizam; Razak, Mohd Fuat Abdul

2017-04-01

Neoscytalidium dimidiatum is an opportunistic fungus causing cutaneous infections mostly, which are difficult to treat due to antifungal resistance. In Malaysia, N. dimidiatum is associated with skin and nail infections, especially in the elderly. These infections may be mistaken for dermatophyte infections due to similar clinical appearance. In this study, Neoscytalidium isolates from cutaneous specimens, identified using morphological and molecular methods (28 Neoscytalidium dimidiatum and 1 Neoscytalidium sp.), were evaluated for susceptibility towards antifungal agents using the CLSI broth microdilution (M38-A2) and Etest methods. Amphotericin B, voriconazole, miconazole and clotrimazole showed high in vitro activity against all isolates with MIC ranging from 0.0313 to 1 µg/mL. Susceptibility towards fluconazole and itraconazole was noted in up to 10% of isolates, while ketoconazole was inactive against all isolates. Clinical breakpoints for antifungal drugs are not yet available for most filamentous fungi, including Neoscytalidium species. However, the results indicate that clinical isolates of N. dimidiatum in Malaysia were sensitive towards miconazole, clotrimazole, voriconazole and amphotericin B, in vitro.

[Pharmacology of the antifungals used in the treatment of aspergillosis].

PubMed

Azanza, José Ramón; Sádaba, Belén; Gómez-Guíu, Almudena

2014-01-01

The treatment of invasive aspergillosis requires the use of drugs that characteristically have complex pharmacokinetic properties, the knowledge of which is essential to achieve maximum efficacy with minimal risk to the patient. The lipid-based amphotericin B formulations vary significantly in their pharmacokinetic behaviour, with very high plasma concentrations of the liposomal form, probably related to the presence of cholesterol in their structure. Azoles have a variable absorption profile, particularly in the case of itraconazole and posaconazole, with the latter very dependent on multiple factors. This may also lead to variations in voriconazole, which requires considering the possibility of monitoring plasma concentrations. The aim of this article is to review some of the most relevant aspects of the pharmacology of the antifungals used in the prophylaxis and treatment of the Aspergillus infection. For this reason, it includes the most relevant features of some of the azoles normally prescribed in this infection (itraconazole, posaconazole and voriconazole) and the amphotericin B formulations. Copyright © 2014. Published by Elsevier Espana.

"Soft"or "hard" ionisation? Investigation of metastable gas temperature effect on direct analysis in real-time analysis of Voriconazole.

PubMed

Lapthorn, Cris; Pullen, Frank

2009-01-01

The performance of the direct analysis in real-time (DART) technique was evaluated across a range of metastable gas temperatures for a pharmaceutical compound, Voriconazole, in order to investigate the effect of metastable gas temperature on molecular ion intensity and fragmentation. The DART source has been used to analyse a range of analytes and from a range of matrices including drugs in solid tablet form and preparations, active ingredients in ointment, naturally occurring plant alkaloids, flavours and fragrances, from thin layer chromatography (TLC) plates, melting point tubes and biological matrices including hair, urine and blood. The advantages of this technique include rapid analysis time (as little as 5 s), a reduction in sample preparation requirements, elimination of mobile phase requirement and analysis of samples not typically amenable to atmospheric pressure ionisation (API) techniques. This technology has therefore been proposed as an everyday tool for identification of components in crude organic reaction mixtures.

In Vitro Drug Interaction Modeling of Combinations of Azoles with Terbinafine against Clinical Scedosporium prolificans Isolates

PubMed Central

Meletiadis, Joseph; Mouton, Johan W.; Meis, Jacques F. G. M.; Verweij, Paul E.

2003-01-01

The in vitro interaction between terbinafine and the azoles voriconazole, miconazole, and itraconazole against five clinical Scedosporium prolificans isolates after 48 and 72 h of incubation was tested by a microdilution checkerboard (eight-by-twelve) technique. The antifungal effects of the drugs alone and in combination on the fungal biomass as well as on the metabolic activity of fungi were measured using a spectrophotometric method and two colorimetric methods, based on the lowest drug concentrations showed 75 and 50% growth inhibition (MIC-1 and MIC-2, respectively). The nature and the intensity of the interactions were assessed using a nonparametric approach (fractional inhibitory concentration [FIC] index model) and a fully parametric response surface approach (Greco model) of the Loewe additivity (LA) no-interaction theory as well as a nonparametric (Prichard model) and a semiparametric response surface approaches of the Bliss independence (BI) no-interaction theory. Statistically significant synergy was found between each of the three azoles and terbinafine in all cases, although with different intensities. A 27- to 64-fold and 16- to 90-fold reduction of the geometric mean of the azole and terbinafine MICs, respectively, was observed when they were combined, resulting in FIC indices of <1 to 0.02. Using the MIC-1 higher levels of synergy were obtained, , which were more consistent between the two incubation periods than using the MIC-2. The strongest synergy among the azoles was found with miconazole using the BI-based models and with voriconazole using the LA-based models. The synergistic effects both on fungal growth and metabolic activity were more potent after 72 h of incubation. Fully parametric approaches in combination with the modified colorimetric method might prove useful for testing the in vitro interaction of antifungal drugs against filamentous fungi. PMID:12499177

Molecular typing and in vitro antifungal susceptibility of Cryptococcus spp from patients in Midwest Brazil.

PubMed

Favalessa, Olivia Cometti; de Paula, Daphine Ariadne Jesus; Dutra, Valeria; Nakazato, Luciano; Tadano, Tomoko; Lazera, Marcia dos Santos; Wanke, Bodo; Trilles, Luciana; Walderez Szeszs, Maria; Silva, Dayane; Hahn, Rosane Christine

2014-08-13

Cryptococcosis is a systemic fungal infection that affects humans and animals, mainly due to Cryptococcus neoformans and Cryptococcus gattii. Following the epidemic of acquired immunodeficiency syndrome (AIDS), fungal infections by C. neoformans have become more common among immunocompromised patients. Cryptococcus gattii has primarily been isolated as a primary pathogen in healthy hosts and occurs endemically in northern and northeastern Brazil. We to perform genotypic characterization and determine the in vitro susceptibility profile to antifungal drugs of the Cryptococcus species complex isolated from HIV-positive and HIV-negative patients attended at university hospitals in Cuiabá, MT, in the Midwestern region of Brazil. Micromorphological features, chemotyping with canavanine-glycine-bromothymol blue (CGB) agar and genotyping by URA5-RFLP were used to identify the species. The antifungal drugs tested were amphotericin B, fluconazole, flucytosine, itraconazole and voriconazole. Minimum inhibitory concentrations (MICs) were determined according to the CLSI methodology M27-A3. Analysis of samples yelded C. neoformans AFLP1/VNI (17/27, 63.0%) and C. gattii AFLP6/VGII (10/27, 37.0%). The MICs ranges for the antifungal drugs were: amphotericin B (0.5-1 mg/L), fluconazole (1-16 mg/L), flucytosine (1-16 mg/L), itraconazole (0.25-0.12 mg/L) and voriconazole (0.06-0.5 mg/L). Isolates of C. neoformans AFLP1/VNI were predominant in patients with HIV/AIDS, and C. gattii VGII in HIV-negative patients. The genotypes identified were susceptible to the antifungal drugs tested. It is worth emphasizing that AFLP6/VGII is a predominant genotype affecting HIV-negative individuals in Cuiabá. These findings serve as a guide concerning the molecular epidemiology of C. neoformans and C. gattii in the State of Mato Grosso.

Pharmacodynamics of Voriconazole in Children: Further Steps along the Path to True Individualized Therapy

PubMed Central

Huurneman, Luc J.; Neely, Michael; Veringa, Anette; Docobo Pérez, Fernando; Ramos-Martin, Virginia; Tissing, Wim J.; Alffenaar, Jan-Willem C.

2016-01-01

Voriconazole is the agent of choice for the treatment of invasive aspergillosis in children at least 2 years of age. The galactomannan index is a routinely used diagnostic marker for invasive aspergillosis and can be useful for following the clinical response to antifungal treatment. The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) mathematical model that links the pharmacokinetics of voriconazole with the galactomannan readout in children. Twelve children receiving voriconazole for treatment of proven, probable, and possible invasive fungal infections were studied. A previously published population PK model was used as the Bayesian prior. The PK-PD model was used to estimate the average area under the concentration-time curve (AUC) in each patient and the resultant galactomannan-time profile. The relationship between the ratio of the AUC to the concentration of voriconazole that induced half maximal killing (AUC/EC50) and the terminal galactomannan level was determined. The voriconazole concentration-time and galactomannan-time profiles were both highly variable. Despite this variability, the fit of the PK-PD model was good, enabling both the pharmacokinetics and pharmacodynamics to be described in individual children. (AUC/EC50)/15.4 predicted terminal galactomannan (P = 0.003), and a ratio of >6 suggested a lower terminal galactomannan level (P = 0.07). The construction of linked PK-PD models is the first step in developing control software that enables not only individualized voriconazole dosages but also individualized concentration targets to achieve suppression of galactomannan levels in a timely and optimally precise manner. Controlling galactomannan levels is a first critical step to maximizing clinical response and survival. PMID:26833158

[Cerebral aspergillosis].

PubMed

Tattevin, P; Jauréguiberry, S; Gangneux, J-P

2004-05-01

The brain is almost always a localization of invasive aspergillosis, after hematogenous spread from pulmonary aspergillosis. Brain aspergilosis is not rare and is one of the worst prognosis factors of invasive aspergillosis. The incidence of this severe mycosis is currently on the rise due to the development of major immunosuppressive treatments. Brain aspergillosis is noteworthy for its vascular tropism, leading to infectious cerebral vasculitis, mainly involving thalamoperforating and lenticulostriate arteries, with a high frequency of thalamic or basal nuclei lesions. Extra-neurologic features that suggest this diagnosis are: i) risk factors for invasive aspergillosis (major or prolonged neutropenia, hematologic malignancies, prolonged corticosteroid treatment, bone marrow or solid organ transplant, AIDS); ii) persistent fever not responding to presumptive antibacterial treatment; iii) respiratory signs (brain aspergillosis is associated with pulmonary aspergillosis in 80 to 95 p. 100 of cases). Perspectives. Two recent major improvements in brain aspergillosis management must be outlined: i) for diagnostic purposes, the development of testing for Aspergillus antigenemia (a non-invasive procedure with good diagnostic value for invasive aspergillosis); ii) for therapeutic purposes, the demonstration that voriconazole is better than amphotericin B in terms of clinical response, tolerance and survival, for all types of invasive aspergillosis, the benefit being probably even greater in case of brain aspergillosis because of the good diffusion of voriconazole into the central nervous system. Brain aspergillosis is a severe emerging opportunistic infection for which diagnostic and therapeutic tools have recently improved. Thus, this diagnostic must be suspected early, especially in the immunocompromised patient, in the event of respiratory symptoms and when the brain lesions are localized in the central nuclei and the thalamus.

Luliconazole, an alternative antifungal agent against Aspergillus terreus.

PubMed

Zargaran, M; Taghipour, S; Kiasat, N; Aboualigalehdari, E; Rezaei-Matehkolaei, A; Zarei Mahmoudabadi, A; Shamsizadeh, F

2017-09-01

Aspergillus terreus is the fourth leading cause of invasive and non-invasive aspergillosis and one of the causative agents of morbidity and mortality among immunocompromised and high-risk patients. A. terreus appears to have increased as a cause of opportunistic fungal infections from superficial to serious invasive infections. Although, invasive aspergillosis is often treated empirically with amphotericin B, most A. terreus isolates are resistant both in vivo and in vitro to some antifungal drugs. In this study, we aimed to evaluate antifungals susceptibility profiles of the different strains of A. terreus against amphotericin B, caspofungin, fluconazole, voriconazole, posaconazole and luliconazole. Forty A. terreus strains originating from environmental sources (air and soil) were identified using by macroscopic and microscopic features. Six antifungals including, amphotericin B, caspofungin, fluconazole, voriconazole, posaconazole and luliconazole were applied for susceptibility tests. Our results show that tested isolates had different susceptibility to antifungals. The lowest MIC GM related to luliconazole (0.00236μg/ml), followed by posaconazole (0.18621μg/ml), voriconazole (0.22925μg/ml), caspofungin (0.86μg/ml), fluconazole (8μg/ml) and amphotericin B (11.12μg/ml). This study demonstrated that luliconazole had an excellent in vitro activity against all tested isolates of A. terreus, with MIC GM 0.00236μg/mL than other tested antifungals. As a result, luliconazole could be a possible alternative antifungal for the treatment of aspergillosis due to A. terreus. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hargrove, Tatiana Y.; Garvey, Edward P.; Hoekstra, William J.

ABSTRACT Within the past few decades, the incidence and complexity of human fungal infections have increased, and therefore, the need for safer and more efficient, broad-spectrum antifungal agents is high. In the study described here, we characterized the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14α-demethylase (CYP51B) from the filamentous fungusAspergillus fumigatus. VT-1598 displayed a high affinity of binding to the enzyme in solution (dissociation constant, 13 ± 1 nM) and in the reconstituted enzymatic reaction was revealed to have an inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole,more » ketoconazole, and posaconazole. The X-ray structure of the VT-1598/A. fumigatusCYP51 complex was determined and depicts the distinctive binding mode of the inhibitor in the enzyme active site, suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His374, the CYP51 residue that is highly conserved across fungal pathogens and fungus specific. Comparative structural analysis ofA. fumigatusCYP51/voriconazole andCandida albicansCYP51/VT-1161 complexes supports the role of H bonding in fungal CYP51/inhibitor complexes and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using twoA. fumigatusstrains (strains 32820 and 1022) displayed a direct correlation between the effects of the drugs on CYP51B activity and fungal growth inhibition, indicating the noteworthy anti-A. fumigatuspotency of VT-1598 and confirming its promise as a broad-spectrum antifungal agent.« less

Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity

PubMed Central

Hargrove, Tatiana Y.; Garvey, Edward P.; Hoekstra, William J.; Yates, Christopher M.; Wawrzak, Zdzislaw; Rachakonda, Girish; Villalta, Fernando

2017-01-01

ABSTRACT Within the past few decades, the incidence and complexity of human fungal infections have increased, and therefore, the need for safer and more efficient, broad-spectrum antifungal agents is high. In the study described here, we characterized the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14α-demethylase (CYP51B) from the filamentous fungus Aspergillus fumigatus. VT-1598 displayed a high affinity of binding to the enzyme in solution (dissociation constant, 13 ± 1 nM) and in the reconstituted enzymatic reaction was revealed to have an inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/A. fumigatus CYP51 complex was determined and depicts the distinctive binding mode of the inhibitor in the enzyme active site, suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His374, the CYP51 residue that is highly conserved across fungal pathogens and fungus specific. Comparative structural analysis of A. fumigatus CYP51/voriconazole and Candida albicans CYP51/VT-1161 complexes supports the role of H bonding in fungal CYP51/inhibitor complexes and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using two A. fumigatus strains (strains 32820 and 1022) displayed a direct correlation between the effects of the drugs on CYP51B activity and fungal growth inhibition, indicating the noteworthy anti-A. fumigatus potency of VT-1598 and confirming its promise as a broad-spectrum antifungal agent. PMID:28461309

Genetic diversity of Aspergillus species isolated from onychomycosis and Aspergillus hongkongensis sp. nov., with implications to antifungal susceptibility testing.

PubMed

Tsang, Chi-Ching; Hui, Teresa W S; Lee, Kim-Chung; Chen, Jonathan H K; Ngan, Antonio H Y; Tam, Emily W T; Chan, Jasper F W; Wu, Andrea L; Cheung, Mei; Tse, Brian P H; Wu, Alan K L; Lai, Christopher K C; Tsang, Dominic N C; Que, Tak-Lun; Lam, Ching-Wan; Yuen, Kwok-Yung; Lau, Susanna K P; Woo, Patrick C Y

2016-02-01

Thirteen Aspergillus isolates recovered from nails of 13 patients (fingernails, n=2; toenails, n=11) with onychomycosis were characterized. Twelve strains were identified by multilocus sequencing as Aspergillus spp. (Aspergillus sydowii [n=4], Aspergillus welwitschiae [n=3], Aspergillus terreus [n=2], Aspergillus flavus [n=1], Aspergillus tubingensis [n=1], and Aspergillus unguis [n=1]). Isolates of A. terreus, A. flavus, and A. unguis were also identifiable by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The 13th isolate (HKU49(T)) possessed unique morphological characteristics different from other Aspergillus spp. Molecular characterization also unambiguously showed that HKU49(T) was distinct from other Aspergillus spp. We propose the novel species Aspergillus hongkongensis to describe this previously unknown fungus. Antifungal susceptibility testing showed most Aspergillus isolates had low MICs against itraconazole and voriconazole, but all Aspergillus isolates had high MICs against fluconazole. A diverse spectrum of Aspergillus species is associated with onychomycosis. Itraconazole and voriconazole are probably better drug options for Aspergillus onychomycosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Activity of voriconazole (UK-109,496) against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive pulmonary aspergillosis.

PubMed Central

Murphy, M; Bernard, E M; Ishimaru, T; Armstrong, D

1997-01-01

Voriconazole, a new azole antifungal agent, showed potent activity against clinical isolates of Aspergillus spp. in vitro. For A. fumigatus, the MIC range was < 0.03 to 0.5 microgram/ml and the MIC at which 90% of isolates are inhibited was 0.25 microgram/ml. In an experimental model of invasive pulmonary aspergillosis which mimics infection in humans, oral voriconazole at dosages of 30 mg/kg of body weight per day significantly delayed or prevented mortality. PMID:9056016

Aspergillus spondylodiscitis after multivisceral transplantation.

PubMed

Gerlach, Undine A; Kohler, Sven; Sauer, Igor M; Joerres, Dinah; Kandziora, Frank; Neuhaus, Peter; Pratschke, Johann; Pascher, Andreas

2009-01-01

Although spondylodiscitis is rare, it is increasingly described in patients with compromised immunity due to malignancy, chemotherapy or immunosuppression. Typical pathogens are staphylococcus aureus and enterobacteria; fungal spondylodiscitis is uncommon. We present a case of aspergillus spondylodiscitis following pulmonary aspergillosis in a patient with multivisceral and kidney transplantation. Due to irreversible disc destruction, surgical restoration by autologous iliac crest graft was required in addition to intravenous antifungal therapy, which consisted of voriconazole, caspofungin and liposomal amphotericin B. Aspergillus spondylodiscitis is a diagnostic and therapeutic challenge, a combination of surgical debridement and antifungal therapy is inevitable to prevent rapid progression of invasive aspergillosis and neurological damage.

[In vitro activity of voriconazole and three other antifungal agents against dermatophytes].

PubMed

Serrano-Martino, María del Carmen; Chávez-Caballero, Mónica; Valverde-Conde, Anastasio; Claro, Rosa María; Pemán, Javier; Martín-Mazuelos, Estrella

2003-11-01

The increase in infections due to dermatophytes in recent years led us to study the effectiveness of new antifungal formulations against these microorganisms. The in vitro activity of a new antifungal agent, voriconazole, was compared with three other antifungal agents, itraconazole, fluconazole and terbinafine, against 120 dermatophytes belonging to four species (61 Trichophyton mentagrophytes, 34 Microsporum canis, 13 M. gypseum and 12 T. rubrum). A broth microdilution method was used following the recommendations of the NCCLS document M38-P with some modifications. Terbinafine was the most active agent against the dermatophytes studied (MIC90 < or = 0.03 mg/ml), followed by voriconazole (MIC90, 0.25 micro g/ml) and itraconazole (MIC90, 0.5 micro g/ml). Fluconazole was the least active antifungal agent. The most susceptible species was M. canis. Voriconazole was found to have effective activity against dermatophytes.

Use of prophylactic voriconazole for three months after lung transplantation does not reduce infection with Aspergillus: a retrospective study of 147 patients.

PubMed

Tofte, Nete; Jensen, Claus; Tvede, Michael; Andersen, Claus B; Carlsen, Jørn; Iversen, Martin

2012-11-01

This was a retrospective study analyzing the mortality and incidence of Aspergillus infection and invasive disease, comparing patients given voriconazole for 3 months following transplantation to patients not given prophylaxis. All consecutive patients (n = 147) transplanted at Copenhagen University Hospital, Rigshospitalet from 2002 to 2006 were included in the study; the study period included the 2 years before the initiation of fungal prophylaxis (88 patients) and the 2 years after (59 patients). Eight patients transplanted in this period were excluded leaving 139 patients in the study. No effect of voriconazole on the incidence of Aspergillus infection (colonization, or superficial or invasive infection) or on the time from transplantation to the first sign of infection was seen when the 2 groups of patients were compared. The cumulated incidence of infection was 45% without and 49% with prophylaxis, and in both groups approximately half of the infections occurred in the first 3 months, the time during which prophylaxis was given. There were significantly more cystic fibrosis (CF) patients among the Aspergillus-infected patients compared to other diagnoses, and the effect of prophylaxis was the same as in non-CF patients. There was a significantly lower mortality in the voriconazole-treated group compared to the non-prophylaxis group, but in an isolated analysis of Aspergillus-infected patients this difference no longer existed; hence, the difference in mortality must be attributable to a time effect and not to voriconazole prophylaxis. Routine use of voriconazole treatment for prophylaxis against Aspergillus infection in lung transplant recipients does not appear to be warranted.

In vitro susceptibility testing of Aspergillus spp. against voriconazole, itraconazole, posaconazole, amphotericin B and caspofungin.

PubMed

Shi, Jun-yan; Xu, Ying-chun; Shi, Yi; Lü, Huo-xiang; Liu, Yong; Zhao, Wang-sheng; Chen, Dong-mei; Xi, Li-yan; Zhou, Xin; Wang, He; Guo, Li-na

2010-10-01

During recent years, the incidence of serious infections caused by opportunistic fungi has increased dramatically due to alterations of the immune status of patients with hematological diseases, malignant tumors, transplantations and so forth. Unfortunately, the wide use of triazole antifungal agents to treat these infections has lead to the emergence of Aspergillus spp. resistant to triazoles. The present study was to assess the in vitro activities of five antifungal agents (voriconazole, itraconazole, posaconazole, amphotericin B and caspofungin) against different kinds of Aspergillus spp. that are commonly encountered in the clinical setting. The agar-based Etest MIC method was employed. One hundred and seven strains of Aspergillus spp. (5 species) were collected and prepared according to Etest Technique Manuel. Etest MICs were determined with RPMI agar containing 2% glucose and were read after incubation for 48 hours at 35°C. MIC(50), MIC(90) and MIC range were acquired by Whonet 5.4 software. The MIC(90) of caspofungin against A. fumigatus, A. flavus and A. nidulans was 0.094 µg/ml whereas the MIC(90) against A. niger was 0.19 µg/ml. For these four species, the MIC(90) of caspofungin was the lowest among the five antifungal agents. For A. terrus, the MIC(90) of posaconazole was the lowest. For A. fumigatus and A. flavus, the MIC(90) in order of increasing was caspofungin, posaconazole, voriconazole, itraconazole, and amphotericin B. The MIC of amphotericin B against A. terrus was higher than 32 µg/ml in all 7 strains tested. The in vitro antifungal susceptibility test shows the new drug caspofungin, which is a kind of echinocandins, has good activity against the five species of Aspergillus spp. and all the triazoles tested have better in vitro activity than traditional amphotericin B.

A rapid MCM-41 dispersive micro-solid phase extraction coupled with LC/MS/MS for quantification of ketoconazole and voriconazole in biological fluids.

PubMed

Yahaya, Noorfatimah; Sanagi, Mohd Marsin; Abd Aziz, Noorizan; Wan Ibrahim, Wan Aini; Nur, Hadi; Loh, Saw Hong; Kamaruzaman, Sazlinda

2017-02-01

A rapid dispersive micro-solid phase extraction (D-μ-SPE) combined with LC/MS/MS method was developed and validated for the determination of ketoconazole and voriconazole in human urine and plasma samples. Synthesized mesoporous silica MCM-41 was used as sorbent in d-μ-SPE of the azole compounds from biological fluids. Important D-μ-SPE parameters, namely type desorption solvent, extraction time, sample pH, salt addition, desorption time, amount of sorbent and sample volume were optimized. Liquid chromatographic separations were carried out on a Zorbax SB-C 18 column (2.1 × 100 mm, 3.5 μm), using a mobile phase of acetonitrile-0.05% formic acid in 5 mm ammonium acetate buffer (70:30, v/v). A triple quadrupole mass spectrometer with positive ionization mode was used for the determination of target analytes. Under the optimized conditions, the calibration curves showed good linearity in the range of 0.1-10,000 μg/L with satisfactory limit of detection (≤0.06 μg/L) and limit of quantitation (≤0.3 μg/L). The proposed method also showed acceptable intra- and inter-day precisions for ketoconazole and voriconazole from urine and human plasma with RSD ≤16.5% and good relative recoveries in the range 84.3-114.8%. The MCM-41-D-μ-SPE method proved to be rapid and simple and requires a small volume of organic solvent (200 μL); thus it is advantageous for routine drug analysis. Copyright © 2016 John Wiley & Sons, Ltd.

Bone and joint infections by Mucorales, Scedosporium, Fusarium and even rarer fungi.

PubMed

Koehler, Philipp; Tacke, Daniela; Cornely, Oliver A

2016-01-01

Mucorales, Scedosporium and Fusarium species are rarely considered as cause for bone and joint infections. However, these moulds are emerging as important fungal pathogens in immunocompromised and immunocompetent patients. Typical pre-disposing host conditions are immunosuppression and diabetes. Most common causative pathogens are Mucorales followed by Scedosporium and Fusarium. Acremonium and Phialemonium species are rare but some case reports exist. MRI is the gold standard imaging technique. Tissue specimens obtained as aspirates, imaging guided biopsy or open surgery need mycological and histopathological work-up for genus and species identification. Multimodal treatment strategies combine surgical debridement, drainage of joints or abscesses, removal of infected prosthetic joints and systemic antifungals. The treatment of mucormycosis is polyene based and may be combined with either posaconazole or - in rare cases - caspofungin. As Scedosporium species are intrinsically resistant to polyenes and azoles show absence of in vitro activity, voriconazole plus synergistic treatment regimens become the therapeutic standard. In fusariosis, fungal susceptibility is virtually impossible to predict, so that combination treatment of voriconazole and lipid-based amphotericin B should be the first-line strategy while susceptibility results are pending. In the absence of randomized controlled trials, infections due to the above moulds should be registered, e.g. in the registries of the European Confederation of Medical Mycology (ECMM).

A novel vesicular carrier, transethosome, for enhanced skin delivery of voriconazole: characterization and in vitro/in vivo evaluation.

PubMed

Song, Chung Kil; Balakrishnan, Prabagar; Shim, Chang-Koo; Chung, Suk-Jae; Chong, Saeho; Kim, Dae-Duk

2012-04-01

This study describes a novel carrier, transethosome, for enhanced skin delivery of voriconazole. Transethosomes (TELs) are composed of phospholipid, ethanol, water and edge activator (surfactants) or permeation enhancer (oleic acid). Characterization of the TELs was based on results from recovery, particle size, transmission electron microscopy (TEM), zeta potential and elasticity studies. In addition, skin permeation profile was obtained using static vertical diffusion Franz cells and hairless mouse skin treated with TELs containing 0.3% (w/w) voriconazole, and compared with those of ethosomes (ELs), deformable liposomes (DLs), conventional liposomes (CLs) and control (polyethylene glycol, PG) solutions. The recovery of the studied vesicles was above 90% in all vesicles, as all of them contained ethanol (7-30%). There was no significant difference in the particles size of all vesicles. The TEM study revealed that the TELs were in irregular spherical shape, implying higher fluidity due to perturbed lipid bilayer compared to that of other vesicles which were of spherical shape. The zeta potential of vesicles containing sodium taurocholate or oleic acid showed higher negative value compared to other vesicles. The elasticities of ELs and TELs were much higher than that of CLs and DLs. Moreover, TELs dramatically enhanced the skin permeation of voriconazole compared to the control and other vesicles (p<0.05). Moreover, the TELs enhanced both in vitro and in vivo skin deposition of voriconazole in the dermis/epidermis region compared to DLs, CLs and control. Therefore, based on the current study, the novel carrier TELs could serve as an effective dermal delivery for voriconazole. Copyright © 2011 Elsevier B.V. All rights reserved.

Scedosporium prolificans Osteomyelitis in an Immunocompetent Child Treated with Voriconazole and Caspofungin, as Well as Locally Applied Polyhexamethylene Biguanide

PubMed Central

Steinbach, William J.; Schell, Wiley A.; Miller, Jackie L.; Perfect, John R.

2003-01-01

Scedosporium species are increasingly isolated from immunocompromised and immunocompetent patients. Unfortunately, Scedosporium infections are generally resistant to amphotericin B, and Scedosporium prolificans strains are particularly resistant to the antifungal agents now in use. We report here on an immunocompetent child with S. prolificans-associated osteomyelitis successfully treated with debridement, local irrigation with polyhexamethylene biguanide, and the systemic administration of voriconazole and caspofungin despite poor in vitro activity of voriconazole alone against the isolate. We also review the treatments and outcomes of 28 reported cases of osteomyelitis or septic arthritis caused by Scedosporium species in immunocompetent patients. PMID:12904435

Differential effects of antifungal agents on expression of genes related to formation of Candida albicans biofilms.

PubMed

Chatzimoschou, Athanasios; Simitsopoulou, Maria; Antachopoulos, Charalampos; Walsh, Thomas J; Roilides, Emmanuel

2016-01-01

The purpose of this study was to analyse specific molecular mechanisms involved in the intrinsic resistance of C. albicans biofilms to antifungals. We investigated the transcriptional profile of three genes (BGL2, SUN41, ECE1) involved in Candida cell wall formation in response to voriconazole or anidulafungin after the production of intermediate and mature biofilms. C. albicans M61, a well-documented biofilm producer strain, was used for the development of intermediate (12 h and 18 h) and completely mature biofilms (48 h). After exposure of cells from each biofilm growth mode to voriconazole (128 and 512 mg l(-1)) or anidulafungin (0.25 and 1 mg l(-1)) for 12-24 h, total RNA samples extracted from biofilm cells were analysed by RT-PCR. The voriconazole and anidulafungin biofilm MIC was 512 and 0.5 mg l(-1) respectively. Anidulafungin caused significant up-regulation of SUN41 (3.7-9.3-fold) and BGL2 (2.2-2.8 fold) in intermediately mature biofilms; whereas, voriconazole increased gene expression in completely mature biofilms (SUN41 2.3-fold, BGL2 2.1-fold). Gene expression was primarily down-regulated by voriconazole in intermediately, but not completely mature biofilms. Both antifungals caused down-regulation of ECE1 in intermediately mature biofilms. © 2015 Blackwell Verlag GmbH.

The Effective Treatment of Lung Infection Due to Scedosporium prolificans with Voriconazole and Surgery

PubMed Central

Masukane, Seiya; Kitahara, Yoshihiro; Okumoto, Joe; Sasaki, Keisuke; Nakano, Kikuo

2017-01-01

Scedosporium prolificans is a fungus that has demonstrated resistance against most currently available antifungal agents and which causes a rapidly disseminating and potentially fatal infection. A 68-year-old woman presented with a fever and consolidation in the lung field. Her symptoms and inflammatory reaction did not improve despite treatment with tazobactam/piperacillin, meropenem, and micafungin. Scedosporium prolificans was detected from the patient's bronchial lavage fluid, and we initiated treatment with voriconazole. Voriconazole was effective in shrinking the consolidation and suppressing the inflammatory reaction. The residual lesion was surgically resected because of the risk of systemic dissemination. The patient is currently alive without relapse or dissemination. PMID:28420849

The Effective Treatment of Lung Infection Due to Scedosporium prolificans with Voriconazole and Surgery.

PubMed

Masukane, Seiya; Kitahara, Yoshihiro; Okumoto, Joe; Sasaki, Keisuke; Nakano, Kikuo

2017-01-01

Scedosporium prolificans is a fungus that has demonstrated resistance against most currently available antifungal agents and which causes a rapidly disseminating and potentially fatal infection. A 68-year-old woman presented with a fever and consolidation in the lung field. Her symptoms and inflammatory reaction did not improve despite treatment with tazobactam/piperacillin, meropenem, and micafungin. Scedosporium prolificans was detected from the patient's bronchial lavage fluid, and we initiated treatment with voriconazole. Voriconazole was effective in shrinking the consolidation and suppressing the inflammatory reaction. The residual lesion was surgically resected because of the risk of systemic dissemination. The patient is currently alive without relapse or dissemination.

Microdilution Susceptibility Testing of Amphotericin B, Itraconazole, and Voriconazole against Clinical Isolates of Aspergillus and Fusarium Species

PubMed Central

Arikan, Sevtap; Lozano-Chiu, Mario; Paetznick, Victor; Nangia, Sunaina; Rex, John H.

1999-01-01

We compared the activities of amphotericin B, itraconazole, and voriconazole against clinical Aspergillus (n = 82) and Fusarium (n = 22) isolates by a microdilution method adopted from the National Committee for Clinical Laboratory Standards (NCCLS-M27A). RPMI 1640 (RPMI), RPMI 1640 supplemented to 2% glucose (RPMI-2), and antibiotic medium 3 supplemented to 2% glucose (AM3) were used as test media. MICs were determined after 24, 48, and 72 h. A narrow range of amphotericin B MICs was observed for Aspergillus isolates, with minor variations among species. MICs for Fusarium isolates were higher than those for Aspergillus isolates. MICs of itraconazole were prominently high for two previously defined itraconazole-resistant Aspergillus fumigatus isolates and Fusarium solani. Voriconazole showed good in vitro activity against itraconazole-resistant isolates, but the MICs of voriconazole for F. solani were high. RPMI was the most efficient medium for detection of itraconazole-resistant isolates, followed by RPMI-2. While the significance remains unclear, AM3 lowered the MICs, particularly those of amphotericin B. PMID:10565912

Effect of Media Modified To Mimic Cystic Fibrosis Sputum on the Susceptibility of Aspergillus fumigatus, and the Frequency of Resistance at One Center

PubMed Central

Moss, Richard B.; Hernandez, Cathy; Clemons, Karl V.; Martinez, Marife

2016-01-01

Studies of cystic fibrosis (CF) patient exacerbations attributed to Pseudomonas aeruginosa infection have indicated a lack of correlation of outcome with in vitro susceptibility results. One explanation is that the media used for testing do not mimic the airway milieu, resulting in incorrect conclusions. Therefore, media have been devised to mimic CF sputum. Aspergillus fumigatus is the leading fungal pathogen in CF, and susceptibility testing is also used to decide therapeutic choices. We assessed whether media designed to mimic CF sputa would give different fungal susceptibility results than those of classical methods, assaying voriconazole, the most utilized anti-Aspergillus drug in this setting, and 30 CF Aspergillus isolates. The frequency of marked resistance (defined as an MIC of >4 μg/ml) in our CF unit by classical methods is 7%. Studies performed with classical methods and with digested sputum medium, synthetic sputum medium, and artificial sputum medium revealed prominent differences in Aspergillus susceptibility results, as well as growth rate, with each medium. Clinical correlative studies are required to determine which results are most useful in predicting outcome. Comparison of MICs with non-CF isolates also indicated the CF isolates were generally more resistant. PMID:26810647

Invasive Sino-Orbital Mycosis in an Aplastic Anemia Patient Caused by Neosartorya laciniosa

PubMed Central

Malejczyk, Kathy; Sigler, Lynne; Gibas, Connie Fe C.

2013-01-01

We report the first case of Neosartorya laciniosa invasive sinusitis involving the orbit in an immunocompromised male with aplastic anemia. Treatment included surgical debridement with enucleation of the eye and combination voriconazole and micafungin therapy followed by voriconazole alone. The fungus was identified using sequencing of partial benA and calmodulin genes. PMID:23345294

Trichosporon faecale invasive infection in a patient with severe aplastic anemia: Efficacy of voriconazole and liposomal amphotericin B before neutrophil recovery

PubMed Central

Pérard, Baptiste; Rougeron, Amandine; Favre, Simon; Accoceberry, Isabelle; Vigouroux, Stéphane; Mohr, Catherine; Milpied, Noël

2015-01-01

We report a case of a 51-year old man with a severe aplastic anemia who developed an invasive trichosporonosis to Trichosporon faecale with fungemia and skin lesions during severe neutropenia. The treatment was successful before neutrophil recovery with a combination of voriconazole and liposomal amphotericin B. PMID:26199866

Trichosporon faecale invasive infection in a patient with severe aplastic anemia: Efficacy of voriconazole and liposomal amphotericin B before neutrophil recovery.

PubMed

Pérard, Baptiste; Rougeron, Amandine; Favre, Simon; Accoceberry, Isabelle; Vigouroux, Stéphane; Mohr, Catherine; Milpied, Noël

2015-09-01

We report a case of a 51-year old man with a severe aplastic anemia who developed an invasive trichosporonosis to Trichosporon faecale with fungemia and skin lesions during severe neutropenia. The treatment was successful before neutrophil recovery with a combination of voriconazole and liposomal amphotericin B.

Intensive care unit drug costs in the context of total hospital drug expenditures with suggestions for targeted cost containment efforts.

PubMed

Altawalbeh, Shoroq M; Saul, Melissa I; Seybert, Amy L; Thorpe, Joshua M; Kane-Gill, Sandra L

2018-04-01

To assess costs of intensive care unit (ICU) related pharmacotherapy relative to hospital drug expenditures, and to identify potential targets for cost-effectiveness investigations. We offer the unique advantage of comparing ICU drug costs with previously published data a decade earlier to describe changes over time. Financial transactions for all ICU patients during fiscal years (FY) 2009-2012 were retrieved from the hospital's data repository. ICU drug costs were evaluated for each FY. ICU departments' charges were also retrieved and calculated as percentages of total ICU charges. Albumin, prismasate (dialysate), voriconazole, factor VII and alteplase denoted the highest percentages of ICU drug costs. ICU drug costs contributed to an average of 31% (SD 1.0%) of the hospital's total drug costs. ICU drug costs per patient day increased by 5.8% yearly versus 7.8% yearly for non-ICU drugs. This rate was higher for ICU drugs costs at 12% a decade previous. Pharmacy charges contributed to 17.7% of the total ICU charges. Growth rates of costs per year have declined but still drug expenditures in the ICU are consistently a significant driver in this resource intensive environment with a high impact on hospital drug expenditures. Copyright © 2017 Elsevier Inc. All rights reserved.

Fungal keratitis.

PubMed

Tuli, Sonal S

2011-01-01

What is the most appropriate management of fungal keratitis? Traditionally, topical Natamycin is the most commonly used medication for filamentous fungi while Amphotericin B is most commonly used for yeast. Voriconazole is rapidly becoming the drug of choice for all fungal keratitis because of its wide spectrum of coverage and increased penetration into the cornea. Repeated debridement of the ulcer is recommended for the penetration of topical medications. While small, peripheral ulcers may be treated in the community, larger or central ulcers, especially if associated with signs suggestive of anterior chamber penetration should be referred to a tertiary center. Prolonged therapy for approximately four weeks is usually necessary.

Breakthrough mucormycosis after voriconazole use in a case of invasive fungal rhinosinusitis due to Curvularia lunata.

PubMed

Gupta, Nitin; Kumar, Arvind; Singh, Gagandeep; Ratnakar, Gogineni; Vinod, Kutty Sharada; Wig, Naveet

2017-01-01

Invasive fungal rhinosinusitis (FRS) is a potentially fatal illness requiring early diagnosis and aggressive treatment with surgery and antifungals. We report a case of chronic FRS in a recently diagnosed diabetic individual due to Curvularia lunata. Imaging revealed extension into the right orbit and right basifrontal lobe. This was further complicated by development of nosocomial mucormycosis which was attributed to voriconazole therapy. The patient responded well to debridement and amphotericin B based therapy. To our knowledge, there are no reported cases of invasive FRS due to Curvularia lunata. Also, breakthrough mucormycosis on voriconazole therapy is rarely seen in non-malignancy, non-transplant settings. The possibility of rare fungal infections (community and nosocomial) should be entertained in developing settings where fungal spores are ubiquitous.

Time-Kill Kinetics and In Vitro Antifungal Susceptibility of Non-fumigatus Aspergillus Species Isolated from Patients with Ocular Mycoses.

PubMed

Öz, Yasemin; Özdemir, Havva Gül; Gökbolat, Egemen; Kiraz, Nuri; Ilkit, Macit; Seyedmousavi, Seyedmojtaba

2016-04-01

Aspergillus species can cause ocular morbidity and blindness, and thus, appropriate antifungal therapy is needed. We investigated the in vitro activity of itraconazole, voriconazole, posaconazole, caspofungin, anidulafungin, and amphotericin B against 14 Aspergillus isolates obtained from patients with ocular mycoses, using the CLSI reference broth microdilution methodology. In addition, time-kill assays were performed, exposing each isolate separately to 1-, 4-, and 16-fold concentrations above the minimum inhibitory concentration (MIC) of each antifungal agent. A sigmoid maximum-effect (E max) model was used to fit the time-kill curve data. The drug effect was further evaluated by measuring an increase/decrease in the killing rate of the tested isolates. The MICs of amphotericin B, itraconazole, voriconazole, and posaconazole were 0.5-1.0, 1.0, 0.5-1.0, and 0.25 µg/ml for A. brasiliensis, A. niger, and A. tubingensis isolates, respectively, and 2.0-4.0, 0.5, 1.0 for A. flavus, and 0.12-0.25 µg/ml for A. nomius isolates, respectively. A. calidoustus had the highest MIC range for the azoles (4.0-16.0 µg/ml) among all isolates tested. The minimum effective concentrations of caspofungin and anidulafungin were ≤0.03-0.5 µg/ml and ≤0.03 µg/ml for all isolates, respectively. Posaconazole demonstrated maximal killing rates (E(max) = 0.63 h(-1), r(2) = 0.71) against 14 ocular Aspergillus isolates, followed by amphotericin B (E(max) = 0.39 h(-1), r(2) = 0.87), voriconazole (E(max) = 0.35 h(-1), r(2) = 0.098), and itraconazole (E(max) = 0.01 h(-1), r(2) = 0.98). Overall, the antifungal susceptibility of the non-fumigatus Aspergillus isolates tested was species and antifungal agent dependent. Analysis of the kinetic growth assays, along with consideration of the killing rates, revealed that posaconazole was the most effective antifungal against all of the isolates.

Equine keratomycosis in Switzerland: a retrospective evaluation of 35 horses (January 2000-August 2011).

PubMed

Voelter-Ratson, K; Pot, S A; Florin, M; Spiess, B M

2013-09-01

Keratomycosis is a severe disease in horses. Geographical differences in fungi causing keratomycosis and susceptibility of the organisms to antifungal drugs exist but few previous publications on this disease originate from Europe. To retrospectively compare the clinical data of 36 eyes with keratomycosis, diagnosed in 35 horses between January 2000 and August 2011 at the Vetsuisse Faculty of Switzerland. Case history, season, prior treatment, clinical appearance, surgical and medical treatment, treatment duration, and globe survival were evaluated. Retrospective case series. Medical records of horses with a definitive cytological or histological diagnosis of keratomycosis were reviewed. Thirty-one of 36 eyes (86.1%) presented with ulcerative keratitis, 2/36 (5.55%) had diffuse corneal infiltration, 2/36 (5.55%) had superficial punctate keratitis and 1/36 (2.8%) had a fluorescein-negative fungal plaque. Two of 6 fungal cultures produced Aspergillus spp. Thirty eyes received medical and surgical treatment, while 3 eyes were treated medically only. In 3 horses the globe was removed at the time of first presentation. Sex, age, prior treatment with antimicrobials or steroids, or type of surgical approach did not significantly influence the outcome. Twenty-three of 36 eyes (63.9%) were at least partially visual, 11/36 eyes (30.5%) were enucleated and 2 horses (2/36 eyes, 5.6%) were subjected to euthanasia. Treatment protocols were compared in the 31 eyes with ulcerative keratitis. In this group, 3/31 globes were immediately enucleated, 16/31 eyes were treated topically with voriconazole or voriconazole/fluconazole and 12/31 with other antifungal drug combinations. The different medication protocols did not significantly affect the outcome. There were no significant differences in outcome between different medical treatment protocols or types of surgical approach. Future studies in central Europe should focus on the identification of fungal pathogens, susceptibility patterns and the efficacy of antifungal drug therapies. © 2013 EVJ Ltd.

Species distribution and susceptibility profile to fluconazole, voriconazole and MXP-4509 of 551 clinical yeast isolates from a Romanian multi-centre study.

PubMed

Minea, B; Nastasa, V; Moraru, R F; Kolecka, A; Flonta, M M; Marincu, I; Man, A; Toma, F; Lupse, M; Doroftei, B; Marangoci, N; Pinteala, M; Boekhout, T; Mares, M

2015-02-01

This is the first multi-centre study regarding yeast infections in Romania. The aim was to determine the aetiological spectrum and susceptibility pattern to fluconazole, voriconazole and the novel compound MXP-4509. The 551 isolates were identified using routine laboratory methods, matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and DNA sequence analysis. Susceptibility testing was performed using the European Committee for Antimicrobial Susceptibility Testing (EUCAST) method and breakpoints. The yeasts originated from superficial infections (SUP, 51.5 %), bloodstream infections (BSI, 31.6 %) and deep-seated infections (DEEP, 16.9 %), from patients of all ages. Nine genera and 30 species were identified. The 20 Candida species accounted for 94.6 % of all isolates. C. albicans was the overall leading pathogen (50.5 %). Lodderomyces elongisporus is reported for the first time as a fungaemia cause in Europe. C. glabrata and Saccharomyces cerevisiae, as well as the non-Candida spp. and non-albicans Candida spp. groups, showed decreased fluconazole susceptibility (<75 %). The overall fluconazole resistance was 10.2 %. C. krusei accounted for 27 of the 56 fluconazole-resistant isolates. The overall voriconazole resistance was 2.5 % and was due mainly to C. glabrata and C. tropicalis isolates. Fluconazole resistance rates for the three categories of infection were similar to the overall value; voriconazole resistance rates differed: 4 % for BSI, 3.2 % for DEEP and 1.4 % for SUP. The antifungal activity of MXP-4509 was superior to voriconazole against C. glabrata and many fluconazole-resistant isolates. There was a large percentage of non-albicans Candida isolates. A large part of the high fluconazole resistance was not acquired but intrinsic, resulting from the high percentage of C. krusei.

Comparative Study of the Effects of Fluconazole and Voriconazole on Candida glabrata, Candida parapsilosis and Candida rugosa Biofilms.

PubMed

Madhavan, Priya; Jamal, Farida; Pei, Chong Pei; Othman, Fauziah; Karunanidhi, Arunkumar; Ng, Kee Peng

2018-06-01

Infections by non-albicans Candida species are a life-threatening condition, and formation of biofilms can lead to treatment failure in a clinical setting. This study was aimed to demonstrate the in vitro antibiofilm activity of fluconazole (FLU) and voriconazole (VOR) against C. glabrata, C. parapsilosis and C. rugosa with diverse antifungal susceptibilities to FLU and VOR. The antibiofilm activities of FLU and VOR in the form of suspension as well as pre-coatings were assessed by XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] reduction assay. Morphological and intracellular changes exerted by the antifungal drugs on Candida cells were examined by scanning electron microscope (SEM) and transmission electron microscope (TEM). The results of the antibiofilm activities showed that FLU drug suspension was capable of killing C. parapsilosis and C. rugosa at minimum inhibitory concentrations (MICs) of 4× MIC FLU and 256× MIC FLU, respectively. While VOR MICs ranging from 2× to 32× were capable of killing the biofilms of all Candida spp tested. The antibiofilm activities of pre-coated FLU were able to kill the biofilms at ¼× MIC FLU and ½× MIC FLU for C. parapsilosis and C. rugosa strains, respectively. While pre-coated VOR was able to kill the biofilms, all three Candida sp at ½× MIC VOR. SEM and TEM examinations showed that FLU and VOR treatments exerted significant impact on Candida cell with various degrees of morphological changes. In conclusion, a fourfold reduction in MIC 50 of FLU and VOR towards ATCC strains of C. glabrata, C. rugosa and C. rugosa clinical strain was observed in this study.

Synergistic effects of tacrolimus and azole antifungal compounds in fluconazole-susceptible and fluconazole-resistant Candida glabrata isolates.

PubMed

Denardi, Laura Bedin; Mario, Débora Alves Nunes; Loreto, Érico Silva; Santurio, Janio Morais; Alves, Sydney Hartz

2015-03-01

In vitro interaction between tacrolimus (FK506) and four azoles (fluconazole, ketoconazole, itraconazole and voriconazole) against thirty clinical isolates of both fluconazole susceptible and -resistant Candida glabrata were evaluated by the checkerboard microdilution method. Synergistic, indifferent or antagonism interactions were found for combinations of the antifungal agents and FK506. A larger synergistic effect was observed for the combinations of FK506 with itraconazole and voriconazole (43%), followed by that of the combination with ketoconazole (37%), against fluconazole-susceptible isolates. For fluconazole-resistant C. glabrata , a higher synergistic effect was obtained from FK506 combined with ketoconazole (77%), itraconazole (73%), voriconazole (63%) and fluconazole (60%). The synergisms that we observed in vitro , notably against fluconazole-resistant C. glabrata isolates, are promising and warrant further analysis of their applications in experimental in vivo studies.

Antifungal activities of diphenyl diselenide and ebselen alone and in combination with antifungal agents against Fusarium spp.

PubMed

Venturini, Tarcieli Pozzebon; Chassot, Francieli; Loreto, Érico Silva; Keller, Jéssica Tairine; Azevedo, Maria Izabel; Zeni, Gilson; Santurio, Janio Morais; Alves, Sydney Hartz

2016-07-01

Herein, we describe the in vitro activity of a combination of the organoselenium compounds diphenyl diselenide and ebselen alone and in combination with amphotericin B, caspofungin, itraconazole, and voriconazole against 25 clinical isolates of Fusarium spp. For this analysis, we used the broth microdilution method based on the M38-A2 technique and checkerboard microdilution method. Diphenyl diselenide (MIC range = 4-32 μg/ml) and ebselen (MIC range = 2-8 μg/ml) showed in vitro activity against the isolates tested. The most effective combinations were (synergism rates): ebselen + amphotericin B (88%), ebselen + voriconazole (80%), diphenyl diselenide + amphotericin B (72%), and diphenyl diselenide + voriconazole (64%). Combination with caspofungin resulted in low rates of synergism: ebselen + caspofungin, 36%, and diphenyl diselenide + caspofungin, 28%; combination with itraconazole demonstrated indifferent interactions. Antagonistic effects were not observed for any of the combinations tested. Our findings suggest that the antifungal potential of diphenyl diselenide and ebselen deserves further investigation in in vivo experimental models, especially in combination with amphotericin B and voriconazole. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Assessment of posaconazole salvage therapy in chronic pulmonary aspergillosis by using predefined response criteria.

PubMed

Rodriguez-Goncer, Isabel; Harris, Chris; Kosmidis, Chris; Muldoon, Eavan G; Newton, Pippa J; Denning, David W

2018-06-12

Chronic pulmonary aspergillosis (CPA) is a progressive infection that destroys lung tissue in non-immunocompromised patients. First line therapies for CPA (itraconazole and/or voriconazole) are often curtailed due to toxicity or the development of drug resistance. Posaconazole is a potential alternative for these patients. Use of posaconazole was funded by the NHS Highly Specialised National Commissioners on an individual basis for patients who failed or did not tolerate first line therapy; those who met predefined criteria for improvement at 4 and 6 months (weight gain and/or improvement in St George's Respiratory Questionnaire) continued posaconazole long-term. We recorded response, failure, discontinuation rates, and adverse events. Seventy-eight patients received posaconazole as salvage therapy. Thirty-four (44%) achieved targets for continuation of therapy. Fourteen (18%) failed therapy; 5 (36%) patients did not achieve clinical targets at 4 or 6 months of assessment and 9 (64%) developed clinical and/or radiological failure. Twenty-eight (36%) discontinued their trial early; 8 (29%) died and 20 (71%) had significant side effects. One patient was non-compliant and another was lost to follow up. Establishing criteria for therapeutic success offered a clear, safe and sustainable method of identifying patients who benefit from additional therapy, and minimised continuation of ineffective therapy in those who did not. Copyright © 2018. Published by Elsevier B.V.

Liquid and vapour-phase antifungal activities of essential oils against Candida albicans and non-albicans Candida.

PubMed

Mandras, Narcisa; Nostro, Antonia; Roana, Janira; Scalas, Daniela; Banche, Giuliana; Ghisetti, Valeria; Del Re, Simonetta; Fucale, Giacomo; Cuffini, Anna Maria; Tullio, Vivian

2016-08-30

The management of Candida infections faces many problems, such as a limited number of antifungal drugs, toxicity, resistance of Candida to commonly antifungal drugs, relapse of Candida infections, and the high cost of antifungal drugs. Though azole antifungal agents and derivatives continue to dominate as drugs of choice against Candida infections, there are many available data referring to the anticandidal activity of essential oils. Since we have previous observed a good antimicrobial activity of some essential oils against filamentous fungi, the aim of this study was to extend the research to evaluate the activity of the same oils on Candida albicans, C.glabrata and C.tropicalis clinical strains, as well as the effects of related components. Essential oils selection was based both on ethnomedicinal use and on proved antibacterial and/or antifungal activity of some of these oils. Fluconazole and voriconazole were used as reference drugs. The minimum inhibitory concentration (MIC) and the minimal fungicidal concentration (MFC) of essential oils (thyme red, fennel, clove, pine, sage, lemon balm, and lavender) and their major components were investigated by the broth microdilution method (BM) and the vapour contact assay (VC). Using BM, pine oil showed the best activity against all strains tested, though C.albicans was more susceptible than C.glabrata and C.tropicalis (MIC50-MIC90 = 0.06 %, v/v). On the contrary, sage oil displayed a weak activity (MIC50-MIC90 = 1 %, v/v). Thyme red oil (MIC50-MIC90 ≤ 0.0038 %, v/v for C.albicans and C.tropicalis, and 0.0078- < 0.015 %, v/v for C.glabrata), followed by lemon balm, lavender and sage were the most effective by VC. Carvacrol and thymol showed the highest activity, whereas linalyl acetate showed the lowest activity both by two methods. α-pinene displayed a better activity by BM than VC. Results show a good activity of essential oils, mainly thymus red and pine oils, and their components carvacrol, thymol and α-pinene against Candida spp., including fluconazole/voriconazole resistant strains. These data encourage adequately controlled and randomized clinical investigations. The use in vapour phase could have additional advantages without requiring direct contact, resulting in easy of environmental application such as in hospital, and/or in school.

Saprochaete clavata invasive infection in a patient with severe aplastic anemia: Efficacy of voriconazole and liposomal amphotericin B with adjuvant granulocyte transfusions before neutrophil recovery following allogeneic bone marrow transplantation.

PubMed

Favre, Simon; Rougeron, Amandine; Levoir, Laure; Pérard, Baptiste; Milpied, Noël; Accoceberry, Isabelle; Gabriel, Frédéric; Vigouroux, Stéphane

2016-03-01

We report a case of a 27-year old man with severe aplastic anemia who developed a Saprochaete clavata (Geotrichum clavatum) disseminated invasive infection shortly prior a scheduled allogeneic bone marrow transplantation. Treatment with a combination of voriconazole, liposomal amphotericin B and adjuvant granulocyte transfusions was successful before neutrophil recovery.

High-risk cutaneous squamous cell carcinoma in a Japanese allogeneic bone marrow transplant recipient on long-term voriconazole.

PubMed

Ng, William; Takahashi, Akira; Muto, Yusuke; Yamazaki, Naoya

2017-10-01

Cutaneous squamous cell carcinomas arise as secondary cancers in hematopoietic stem cell transplant survivors. They have been documented primarily in Western cohorts and relatively little is known about their occurrence in Asian hematopoietic stem cell transplant recipients, with no reports of squamous cell carcinomas with high-risk features in Asian patients. We describe a case of a cutaneous squamous cell carcinoma with high-risk features on the scalp of a Japanese bone marrow transplant recipient approximately 6.5 years post-transplant, who was on long-term voriconazole. The history of a photodistributed erythema followed by the appearance of multiple actinic keratoses and solar lentigines, together with the rarity of cutaneous squamous cell carcinomas in Asian hematopoietic stem cell transplant cohorts revealed in our literature review, suggest that voriconazole use contributed to the development of high-risk squamous cell carcinoma in our patient. © 2017 Japanese Dermatological Association.

Comparison of the Vitek 2 yeast susceptibility system with CLSI microdilution for antifungal susceptibility testing of fluconazole and voriconazole against Candida spp., using new clinical breakpoints and epidemiological cutoff values.

PubMed

Pfaller, Michael A; Diekema, Daniel J; Procop, Gary W; Rinaldi, Michael G

2013-09-01

A commercially available, fully automated yeast susceptibility test system (Vitek 2; bioMérieux, Marcy d'Etoile, France) was compared in 3 different laboratories with the Clinical and Laboratory Standards Institute (CLSI) reference microdilution (BMD) method by testing 2 quality control strains, 10 reproducibility strains, and 425 isolates of Candida spp. against fluconazole and voriconazole. Reference CLSI BMD MIC endpoints and Vitek 2 MIC endpoints were read after 24 hours and 9.1-27.1 hours incubation, respectively. Excellent essential agreement (within 2 dilutions) between the reference and Vitek 2 MICs was observed for fluconazole (97.9%) and voriconazole (96.7%). Categorical agreement (CA) between the 2 methods was assessed using the new species-specific clinical breakpoints (CBPs): susceptible (S) ≤2 μg/mL, susceptible dose-dependent (SDD) 4 μg/mL, and resistant (R) ≥8 μg/mL for fluconazole and Candida albicans, Candida tropicalis, and Candida parapsilosis and ≤32 μg/mL (SDD), ≥64 μg/mL (R) for Candida glabrata; S ≤0.12 μg/mL, SDD 0.25-0.5 μg/mL, R ≥1 μg/mL for voriconazole and C. albicans, C. tropicalis, and C. parapsilosis, and ≤0.5 μg/mL (S), 1 μg/mL (SDD), ≥2 μg/mL (R) for Candida krusei. The epidemiological cutoff value (ECV) of 0.5 μg/mL for voriconazole and C. glabrata was used to differentiate wild-type (WT; MIC ≤ ECV) from non-WT (MIC > ECV) strains of this species. Due to the lack of CBPs for the less common species, the ECVs for fluconazole and voriconazole, respectively, were used for Candida lusitaniae (2 μg/mL and 0.03 μg/mL), Candida dubliniensis (0.5 μg/mL and 0.03 μg/mL), Candida guilliermondii (8 μg/mL and 0.25 μg/mL), and Candida pelliculosa (4 μg/mL and 0.25 μg/mL) to categorize isolates of these species as WT and non-WT. CA between the 2 methods was 96.8% for fluconazole and 96.5% for voriconazole with less than 1% very major errors and 1.3-3.0% major errors. The Vitek 2 yeast susceptibility system remains comparable to the CLSI BMD reference method for testing the susceptibility of Candida spp. when using the new (lower) CBPs and ECVs. © 2013.

Fungal keratitis

PubMed Central

Tuli, Sonal S

2011-01-01

Clinical question: What is the most appropriate management of fungal keratitis? Results: Traditionally, topical Natamycin is the most commonly used medication for filamentous fungi while Amphotericin B is most commonly used for yeast. Voriconazole is rapidly becoming the drug of choice for all fungal keratitis because of its wide spectrum of coverage and increased penetration into the cornea. Implementation: Repeated debridement of the ulcer is recommended for the penetration of topical medications. While small, peripheral ulcers may be treated in the community, larger or central ulcers, especially if associated with signs suggestive of anterior chamber penetration should be referred to a tertiary center. Prolonged therapy for approximately four weeks is usually necessary. PMID:21468333

Multilocus Phylogeny and Antifungal Susceptibility of Aspergillus Section Circumdati from Clinical Samples and Description of A. pseudosclerotiorum sp. nov.

PubMed Central

Siqueira, J. P. Z.; Sutton, D. A.; García, D.; Wiederhold, N.; Peterson, S. W.; Guarro, J.

2017-01-01

ABSTRACT A multilocus phylogenetic study was carried out to assess species identity of a set of 34 clinical isolates from Aspergillus section Circumdati from the United States and to determine their in vitro antifungal susceptibility against eight antifungal drugs. The genetic markers used were the internal transcribed spacer (ITS) region, and fragments of the beta-tubulin (BenA), calmodulin (CaM), and RNA polymerase II second largest subunit (RPB2) genes. The drugs tested were amphotericin B, itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin, micafungin, and terbinafine. The most common species sampled was A. westerdijkiae (29.4%), followed by a novel species, which was described here as A. pseudosclerotiorum (23.5%). Other species identified were A. sclerotiorum (17.6%), A. ochraceus (8.8%), A. subramanianii (8.8%), and A. insulicola and A. ochraceopetaliformis, with two isolates (5.9%) of each. The drugs that showed the most potent activity were caspofungin, micafungin, and terbinafine, while amphotericin B showed the least activity. PMID:28053212

Multilocus Phylogeny and Antifungal Susceptibility of Aspergillus Section Circumdati from Clinical Samples and Description of A. pseudosclerotiorum sp. nov.

PubMed

Siqueira, J P Z; Sutton, D A; Gené, J; García, D; Wiederhold, N; Peterson, S W; Guarro, J

2017-03-01

A multilocus phylogenetic study was carried out to assess species identity of a set of 34 clinical isolates from Aspergillus section Circumdati from the United States and to determine their in vitro antifungal susceptibility against eight antifungal drugs. The genetic markers used were the internal transcribed spacer (ITS) region, and fragments of the beta-tubulin ( BenA ), calmodulin ( CaM ), and RNA polymerase II second largest subunit ( RPB2 ) genes. The drugs tested were amphotericin B, itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin, micafungin, and terbinafine. The most common species sampled was A. westerdijkiae (29.4%), followed by a novel species, which was described here as A. pseudosclerotiorum (23.5%). Other species identified were A. sclerotiorum (17.6%), A. ochraceus (8.8%), A. subramanianii (8.8%), and A. insulicola and A. ochraceopetaliformis , with two isolates (5.9%) of each. The drugs that showed the most potent activity were caspofungin, micafungin, and terbinafine, while amphotericin B showed the least activity. Copyright © 2017 American Society for Microbiology.

Results from the PharmaSat Nanosatellite Mission: Dose Dependence of Growth and Metabolic Parameters for S. cerevisiae Grown in Microgravity and Challenged by Voriconazole

NASA Astrophysics Data System (ADS)

Ricco, Antonio; Parra, Macarena; Niesel, David; Ly, Diana; Kudlicki, Andrzej; McGinnis, Michael; Hines, John

We report cellular growth and metabolic activity results for Saccharomyces cerevisiae grown aboard PharmaSat, a 5.0-kg autonomous, self-contained biological nanosatellite launched as a secondary payload in May of 2009 and presently in Earth orbit at 450 km. The response of S. cerevisiae to three dose levels bracketing the minimum inhibitory concentration (MIC) of the antifungal voriconazole was monitored in microgravity using 3-color absorbance to measure metabolic activity and turbidity (cell number), which were characterized chiefly by two param-eters: (1) the doubling time and (2) the time delay before the onset of rapid growth. Growth was conducted in forty-eight 100-L microwells containing the yeast—one fluidically separate bank of 12 wells for each voriconazole concentration, plus a control bank. Yeast were main-tained in stasis until the satellite had been deployed, the orbit stabilized, the communications links established, and the growth temperature of 27 ° C stabilized. To re-initiate yeast growth, RPMI growth medium was added. The S. cerevisiae were grown for approximately 12 hr, at which time they were challenged with varying concentrations (0, 0.25xMIC, MIC, 4xMIC) of voriconazole; the optical density and the color change of the redox-based viability indicator alamar blue were recorded as growth proceeded for an additional 84 hr. Results telemetered to the ground reveal a 33 percent longer lag time in microgravity and 60 percent longer dou-bling time than identical ground control experiments. Lag and doubling times are essentially unaffected by voriconazole at 0.125 g/mL in either environment; they lengthen similarly at 0.5 g/mL, voriconazole's MIC. At four times MIC, ground controls show no significant growth nor metabolic activity as tracked by alamar blue; in space, while there was also no measurable cellu-lar growth, remarkably, metabolic activity was clearly present (n = 12 wells). Explanations for the differences in metabolic activity and population growth in microgravity vs. terrestrial grav-ity will be presented and ramifications for future space studies of microorganisms in spaceflight explored. This study highlights the increasing capability of small satellites to enable important biological space studies at reasonable cost, allowing for the possibility of repeat missions.

Postantifungal effect of the combination of caspofungin with voriconazole and amphotericin B against clinical Candida krusei isolates.

PubMed

Oz, Yasemin; Kiremitci, Abdurrahman; Dag, Ilknur; Metintas, Selma; Kiraz, Nuri

2013-01-01

We evaluated the postantifungal effects (PAFEs) of caspofungin (CAS), voriconazole (VOR), amphotericin B (AmB), and the combinations of CAS + VOR and CAS + AmB against 30 clinical Candida krusei isolates at 0.25, 1 and 4 times the MIC of each individually and in the indicated combinations. Antifungals were removed after 1 hour and colony counts were performed at 0, 2, 6, 24, and 48 h. VOR did not display any measurable PAFE regardless of antifungal concentrations, while AmB and CAS exhibited dose-dependent PAFE. The most effective agent producing a prolonged PAFE in this study was CAS. Although the combination of CAS with VOR generated longer PAFEs at 0.25 and 1 times their respective MICs in comparison with CAS alone, this combination was indifferent rather than synergistic. However, the combination of CAS with AmB at 4 times their MICs exhibited the best performance, reducing the colony counts during the 48 h after removal of drugs and resulted in synergic interaction in respect to 20 (67%) isolates. Consequently, CAS has a prolonged PAFE in vitro against C. krusei isolates, and the combination of AmB + CAS may increase significantly the efficacy of CAS. Our data may be useful in optimizing dosing regimens for these agents and their combinations, although further studies are needed to explore the clinical usefulness of our results.

Evaluation of the Effects of Ketoconazole and Voriconazole on the Pharmacokinetics of Oxcarbazepine and Its Main Metabolite MHD in Rats by UPLC-MS-MS.

PubMed

Chen, Xinxin; Gu, Ermin; Wang, Shuanghu; Zheng, Xiang; Chen, Mengchun; Wang, Li; Hu, Guoxin; Cai, Jian-ping; Zhou, Hongyu

2016-03-01

Oxcarbazepine (OXC), a second-generation antiepileptic drug, undergoes rapid reduction with formation of the active metabolite 10,11-dihydro-10-hydroxy-carbazepine (MHD) in vivo. In this study, a method for simultaneous determination of OXC and MHD in rat plasma using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS-MS) was developed and validated. Under given chromatographic conditions, OXC, MHD and internal standard diazepam were separated well and quantified by electrospray positive ionization mass spectrometry in the multiple reaction monitoring transitions mode. The method validation demonstrated good linearity over the range of 10-2,000 ng/mL for OXC and 5-1,000 ng/mL for MHD. The lower limit of quantification was 5 ng/mL for OXC and 2.5 ng/mL for MHD, respectively. The method was successfully applied to the evaluation of the pharmacokinetics of OXC and MHD in rats, with or without pretreatment by ketoconazole (KET) and voriconazole (VOR). Statistics indicated that KET and VOR significantly affected the disposition of OXC and MHD in vivo, whereas VOR predominantly interfered with the disposition of MHD. This method is suitable for pharmacokinetic study in small animals. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

In vitro antifungal susceptibility and molecular identity of 99 clinical isolates of the opportunistic fungal genus Curvularia.

PubMed

da Cunha, Keith C; Sutton, Deanna A; Fothergill, Annette W; Gené, Josepa; Cano, Josep; Madrid, Hugo; Hoog, Sybren de; Crous, Pedro W; Guarro, Josep

2013-06-01

The in vitro antifungal susceptibility of a set of 99 clinical isolates of Curvularia was tested against 9 drugs using a reference microdilution method. The isolates had been identified previously to species level by comparing their ITS rDNA and glyceraldehyde-3-phosphate dehydrogenase gene sequences with those of reference strains. We were able to reliably identify 73.2% of the isolates, the most frequent species being Curvularia aeria, Curvularia geniculata/Curvularia senegalensis, Curvularia lunata, Curvularia inaequalis, Curvularia verruculosa, and Curvularia borreriae. Most of these isolates had been recovered from nasal sinus, which is generally considered one of the most frequent sites of infection by these fungi. In addition, at least 3 phylogenetic species that have not yet been formally described were detected. The most active drugs were the echinocandins, amphotericin B, and posaconazole, whereas voriconazole and itraconazole showed poor activity. Copyright © 2013 Elsevier Inc. All rights reserved.

PharmaSat: drug dose response in microgravity from a free-flying integrated biofluidic/optical culture-and-analysis satellite

NASA Astrophysics Data System (ADS)

Ricco, Antonio J.; Parra, Macarena; Niesel, David; Piccini, Matthew; Ly, Diana; McGinnis, Michael; Kudlicki, Andrzej; Hines, John W.; Timucin, Linda; Beasley, Chris; Ricks, Robert; McIntyre, Michael; Friedericks, Charlie; Henschke, Michael; Leung, Ricky; Diaz-Aguado, Millan; Kitts, Christopher; Mas, Ignacio; Rasay, Mike; Agasid, Elwood; Luzzi, Ed; Ronzano, Karolyn; Squires, David; Yost, Bruce

2011-02-01

We designed, built, tested, space-qualified, launched, and collected telemetered data from low Earth orbit from Pharma- Sat, a 5.1-kg free flying "nanosatellite" that supported microbial growth in 48 microfluidic wells, dosed microbes with multiple concentrations of a pharmaceutical agent, and monitored microbial growth and metabolic activity using a dedicated 3-color optical absorbance system at each microwell. The PharmaSat nanosatellite comprised a structure approximately 10 x 10 x 35 cm, including triple-junction solar cells, bidirectional communications, power-generation and energy- storage system, and a sealed payload 1.2-L containment vessel that housed the biological organisms along with the fluidic, optical, thermal, sensor, and electronic subsystems. Growth curves for S. cerevisiae (Brewer's yeast) were obtained for multiple concentrations of the antifungal drug voriconazole in the microgravity conditions of low Earth orbit. Corresponding terrestrial control experiments were conducted for comparison.

In Vitro Activities of Four Novel Triazoles against Scedosporium spp.

PubMed Central

Carrillo, A. J.; Guarro, J.

2001-01-01

In order to develop new approaches to the treatment of the severe and usually fatal infections caused by Scedosporium spp., the in vitro antifungal activities of four novel triazoles (posaconazole, ravuconazole, voriconazole, and UR-9825) and some current antifungals (amphotericin B, ketoconazole, itraconazole, and nystatin) were determined. The latter group was clearly ineffective against the two species tested. The four new antifungals showed activity against Scedosporium apiospermum, and UR-9825 and voriconazole were active against S. prolificans. PMID:11408242

Voriconazole for the treatment of refractory Aspergillus fumigatus keratitis

PubMed Central

Mehta, Hitendra B; Garg, Prashant; Kodial, Harish

2008-01-01

We report a case of Aspergillus fumigatus keratitis in a 53-year-old, well-controlled diabetic female who did not respond to standard antifungal treatment. She was started on topical natamycin eye drops, but the infiltrate continued to progress. Topical amphotericin B and systemic ketoconazole was added, however, there was no response and the infiltrate increased further. She was then switched to topical and systemic voriconazole. Steady resolution of the infiltrate was noted within 2 weeks of therapy. PMID:18417831

Cost-effectiveness analysis of combination antifungal therapy with voriconazole and anidulafungin versus voriconazole monotherapy for primary treatment of invasive aspergillosis in Spain

PubMed Central

Grau, Santiago; Azanza, Jose Ramon; Ruiz, Isabel; Vallejo, Carlos; Mensa, Josep; Maertens, Johan; Heinz, Werner J; Barrueta, Jon Andoni; Peral, Carmen; Mesa, Francisco Jesús; Barrado, Miguel; Charbonneau, Claudie; Rubio-Rodríguez, Darío; Rubio-Terrés, Carlos

2017-01-01

Objective According to a recent randomized, double-blind clinical trial comparing the combination of voriconazole and anidulafungin (VOR+ANI) with VOR monotherapy for invasive aspergillosis (IA) in patients with hematologic disease or with hematopoietic stem cell transplant, mortality was lower after 6 weeks with VOR+ANI than with VOR monotherapy in a post hoc analysis of patients with galactomannan-based IA. The objective of this study was to compare the cost-effectiveness of VOR+ANI with VOR, from the perspective of hospitals in the Spanish National Health System. Methods An economic model with deterministic and probabilistic analyses was used to determine costs per life-year gained (LYG) for VOR+ANI versus VOR in patients with galactomannan-based IA. Mortality, adverse event rates, and life expectancy were obtained from clinical trial data. The costs (in 2015 euros [€]) of the drugs and the adverse event-related costs were obtained from Spanish sources. A Tornado plot and a Monte Carlo simulation (1,000 iterations) were used to assess uncertainty of all model variables. Results According to the deterministic analysis, for each patient treated with VOR+ANI compared with VOR monotherapy, there would be a total of 0.348 LYG (2.529 vs 2.181 years, respectively) at an incremental cost of €5,493 (€17,902 vs €12,409, respectively). Consequently, the additional cost per LYG with VOR+ANI compared with VOR would be €15,785. Deterministic sensitivity analyses confirmed the robustness of these findings. In the probabilistic analysis, the cost per LYG with VOR+ANI was €15,774 (95% confidence interval: €15,763–16,692). The probability of VOR+ANI being cost-effective compared with VOR was estimated at 82.5% and 91.9%, based on local cost-effectiveness thresholds of €30,000 and €45,000, respectively. Conclusion According to the present economic study, combination therapy with VOR+ANI is cost-effective as primary therapy of IA in galactomannan-positive patients in Spain who have hematologic disease or hematopoietic stem cell transplant, compared with VOR monotherapy. PMID:28115858

Microsporidial Stromal Keratitis: Successful Treatment with Topical Voriconazole and Oral Itraconazole

PubMed Central

Kim, James; Shenoy, Sudhir; Chévez-Barrios, Patricia; Kapur, Manuj

2016-01-01

We report a case of microsporidial stromal keratitis successfully treated with topical voriconazole and oral itraconazole. A 30-year-old Hispanic male construction worker who wears contacts lenses presented with left eye erythematous, epiphora, and mild pain increasing over few days after failing previous antibiotics treatment. His best corrected visual acuity in the left eye was count fingers at three feet, and the slit lamp examination showed 3+ conjunctival injection, a circular central corneal ulcer 3.2 mm in diameter, stromal thinning, and an anterior chamber with white cells, flair, and 0.1 mm hypopyon. A cornea punch biopsy identified microsporidial organisms with some features suggestive of Vittaforma corneae. After treatment with topical voriconazole and oral itraconazole for eight weeks, the patient had complete resolution with no recurrence for over 12 months of follow-up. To our knowledge, this is the first reported case of successful treatment of microsporidial stromal keratitis with antifungals. PMID:28123915

[Isolation of Scedosporium apiospermum (teleomorph: Pseudallescheria apiosperma) from an acute myeloid leukemia patient].

PubMed

Ergin, Cağrı; Kutlu, Murat; Arıkan Akdağlı, Sevtap; Sarıbaş, Zeynep; Aydeniz Ozansoy, Fatma; Sarı, Ismail; Dursunoğlu, Neşe

2013-04-01

Scedosporium apiospermum is an emerging opportunistic pathogen that may lead to life-threatening infections especially in immunosuppressive individuals. In this report, S.apiospermum infection in a 62 year old male patient with acute myeloid leukemia was presented. During remission-induction chemotherapy, piperacillin-tazobactam therapy was started for febrile neutropenia. Since fever had continued, treatment was switched to imipenem and also amphotericin B deoxycholate was added to the treatment protocol. Because of allergic reaction to amphotericin B, caspofungin was started at the fifth day of neutropenic fever. Following imaging studies with high resolution computerized thorasic tomography, antifungal therapy was changed to voriconazole due to findings suggestive of invasive aspergillosis. Since galactomannan antigen was found negative at the first day of voriconazole therapy, bronchoalveolar lavage material from apical segment of the left lower lobe was cultured onto various microbiologic media. S.apiospermum (Teleomorph: Pseudallescheria apiosperma) was isolated on the fourth day of cultivation. According to CLSI M38-A2 microdilution procedure, minimum inhibitory concentrations (MIC) of voriconazole, caspofungin, amphotericin B and posaconazole were found as 0.06, 2, 8 and 4 µg/ml, respectively. Since neutropenia was resolved, the patient was discharged with continued voriconazole therapy. It was concluded that antifungal susceptibility tests should be performed for Scedosporium species and the results should be compared to the clinical response. The determination of MIC breakpoints may provide useful information for the recommendation and use of optimal choices for the treatment of Scedosporium infections.

Susceptibility of 100 filamentous fungi: comparison of two diffusion methods, Neo-Sensitabs and E-test, for amphotericin B, caspofungin, itraconazole, voriconazole and posaconazole.

PubMed

Colosi, Ioana A; Faure, Odile; Dessaigne, Bérangére; Bourdon, Cécile; Lebeau, Bernadette; Colosi, Horaţiu A; Pelloux, Hervé

2012-05-01

We compared the E-test method to that of the Neo-Sensitabs tablet diffusion assay for evaluating the in vitro susceptibility of 100 clinical isolates of filamentous fungi (Aspergillus spp., Fusarium spp., Scedosporium spp., zygomycetes and other molds) to amphotericin B, itraconazole, voriconazole, caspofungin, and posaconazole. We determined the categorical agreement level between E-test minimum inhibitory concentrations (MIC) and tablet end-points, as opposed to the following disagreement parameters: very major error - resistant parameter (R) in E-test and susceptible (S) in tablet; major error - S by E-test and R by tablet; minor error - shifts between S and susceptible dose-dependent (S-DD) or S-DD and R. We also performed linear regression analyses and computed Pearson's correlation coefficients (R values) between the log transforms of MICs and the inhibition zone diameters of the five studied antifungal agents. For itraconazole we obtained 97% categorical agreement and R = -0.727. Categorical agreement for caspofungin and voriconazole was 96% and R =-0.821 and R = -0.789, respectively. For posaconazole the categorical agreement was 94% and R =-0.743. Amphotericin B exhibited a lower degree of agreement (76%, R = -0.672), especially in studies of Aspergillus spp. Our results suggest a potential value of the Neo-Sensitabs assay for in vitro susceptibility testing of molds to itraconazole, voriconazole, caspofungin and posaconazole, while amphotericin B exhibited an overall lower degree of agreement.

Predictors of Corneal Perforation or Need for Therapeutic Keratoplasty in Severe Fungal Keratitis: A Secondary Analysis of the Mycotic Ulcer Treatment Trial II.

PubMed

Prajna, N Venkatesh; Krishnan, Tiruvengada; Rajaraman, Revathi; Patel, Sushila; Shah, Ranjeet; Srinivasan, Muthiah; Das, Manoranjan; Ray, Kathryn J; Oldenburg, Catherine E; McLeod, Stephen D; Zegans, Michael E; Acharya, Nisha R; Lietman, Thomas M; Rose-Nussbaumer, Jennifer

2017-09-01

Identifying patients with infectious keratitis who are at risk of experiencing a poor outcome may be useful to allocate resources toward high-risk patients, particularly in resource-poor settings. To determine baseline patient and ulcer characteristics that predict a high risk of developing corneal perforation and/or the need to undergo therapeutic penetrating keratoplasty (TPK). This is a secondary analysis of Mycotic Ulcer Treatment Trial II, a multicenter, double-masked, placebo-controlled randomized clinical trial that enrolled 240 patients with smear-positive filamentous fungal corneal ulcers who enrolled between May 2010 and August 2015. Participants had a baseline visual acuity of 20/400 or worse and were randomized to receive oral voriconazole or a placebo (all participants received topical voriconazole, 1%). After 39 participants (16.3%) were enrolled, topical natamycin, 5%, was also added. The primary outcome of this secondary analysis was the rate of corneal perforation or the need to undergo TPK. The mean (SD) age at enrollment was 49 (13) years, 104 participants (43.3%) were women, and all were of Southeast Asian descent. The presence of hypopyon at baseline indicated 2.28 times the odds of the patient developing corneal perforation and/or needing TPK (95% CI, 1.18-4.40; P = .01). Study participants whose infiltrate involved the posterior one-third had a 71.4% risk of developing corneal perforation and/or needing TPK. For each 1-mm increase in the geometric mean of the infiltrate, there was 1.37 (95% CI, 1.12-1.67; P = .002) increased odds of developing perforation and/or needing TPK. Other clinical features such as visual acuity, baseline culture positivity, type of filamentous fungal organism and duration of symptoms, and demographic characteristics, such as sex and occupation, were not significant predictors in the multivariable regression analysis. These results suggest that risk stratification from baseline ulcer characteristics can identify those at highest risk for developing corneal perforation and/or needing TPK. clinicaltrials.gov Identifier: NCT00996736.

Interaction between caspofungin or voriconazole and cefoperazone-sulbactam or piperacillin-tazobactam by in vitro and in vivo methods.

PubMed

Keçeli, Sema Aşkin; Willke, Ayse; Tamer, Gulden Sonmez; Boral, Ozden Buyukbaba; Sonmez, Nese; Cağatay, Penbe

2014-05-01

Immunosuppressive patients are at risk of fungal and bacterial infections. Therefore, these patients receive prophylactic, preemptive, empirical or target antifungal and concomitant antibiotic therapy. To this end, caspofungin (CAS) or voriconazole (VRC) antifungals and cefoperazone-sulbactam (CPZ/SAM) or piperacillin-tazobactam (PIP/TAZ) antibiotics may be used. Here, we aimed to investigate the interaction between these antifungals and antibiotics by in vitro and in vivo methods. The interaction was tested by chequerboard analysis and fractional inhibitory concentration index (FICI). It was also tested in a neutropenic mice-invasive candidiasis model and evaluated by fungal burden in kidney tissue of infected animals from the first day to the fifth day of treatment with 24 h intervals. A synergism was detected between CAS and CPZ/SAM (FICI = 0.1) and PIP/TAZ (FICI = 0.3). Fungal burden in tissues of drug-treated mice was reduced compared with controls in a time-dependent manner. In comparison with CAS-alone treated group, there were 1.32 log10 reductions of fungal burden in CAS + CPZ/SAM (p = 0.002) and in CAS + PIP/TAZ group (p = 0.14). The same interactions were not found with VRC and antibiotics. CPZ/SAM had stronger synergistic interaction with CAS than PIP/TAZ. The mechanism of synergism is not well understood. This is most likely due to an increase in the anticandidal effect of CAS plus antibiotics. © 2013 APMIS. Published by John Wiley & Sons Ltd.

D-Cateslytin: a new antifungal agent for the treatment of oral Candida albicans associated infections.

PubMed

Dartevelle, Pauline; Ehlinger, Claire; Zaet, Abdurraouf; Boehler, Christian; Rabineau, Morgane; Westermann, Benoit; Strub, Jean-Marc; Cianferani, Sarah; Haïkel, Youssef; Metz-Boutigue, Marie-Hélène; Marban, Céline

2018-06-18

The excessive use of antifungal agents, compounded by the shortage of new drugs being introduced into the market, is causing the accumulation of multi-resistance phenotypes in many fungal strains. Consequently, new alternative molecules to conventional antifungal agents are urgently needed to prevent the emergence of fungal resistance. In this context, Cateslytin (Ctl), a natural peptide derived from the processing of Chromogranin A, has already been described as an effective antimicrobial agent against several pathogens including Candida albicans. In the present study, we compared the antimicrobial activity of two conformations of Ctl, L-Ctl and D-Ctl against Candida albicans. Our results show that both D-Ctl and L-Ctl were potent and safe antifungal agents. However, in contrast to L-Ctl, D-Ctl was not degraded by proteases secreted by Candida albicans and was also stable in saliva. Using video microscopy, we also demonstrated that D-Ctl can rapidly enter C. albicans, but is unable to spread within a yeast colony unless from a mother cell to a daughter cell during cellular division. Besides, we revealed that the antifungal activity of D-Ctl could be synergized by voriconazole, an antifungal of reference in the treatment of Candida albicans related infections. In conclusion, D-Ctl can be considered as an effective, safe and stable antifungal and could be used alone or in a combination therapy with voriconazole to treat Candida albicans related diseases including oral candidosis.

Antimicrobials and the risk of torsades de pointes: the contribution from data mining of the US FDA Adverse Event Reporting System.

PubMed

Poluzzi, Elisabetta; Raschi, Emanuel; Motola, Domenico; Moretti, Ugo; De Ponti, Fabrizio

2010-04-01

Drug-induced torsades de pointes (TdP) is a complex regulatory and clinical problem due to the rarity of this sometimes fatal adverse event. In this context, the US FDA Adverse Event Reporting System (AERS) is an important source of information, which can be applied to the analysis of TdP liability of marketed drugs. To critically evaluate the risk of antimicrobial-induced TdP by detecting alert signals in the AERS, on the basis of both quantitative and qualitative analyses. Reports of TdP from January 2004 through December 2008 were retrieved from the public version of the AERS. The absolute number of cases and reporting odds ratio as a measure of disproportionality were evaluated for each antimicrobial drug (quantitative approach). A list of drugs with suspected TdP liability (provided by the Arizona Centre of Education and Research on Therapeutics [CERT]) was used as a reference to define signals. In a further analysis, to refine signal detection, we identified TdP cases without co-medications listed by Arizona CERT (qualitative approach). Over the 5-year period, 374 reports of TdP were retrieved: 28 antibacterials, 8 antifungals, 1 antileprosy and 26 antivirals were involved. Antimicrobials more frequently reported were levofloxacin (55) and moxifloxacin (37) among the antibacterials, fluconazole (47) and voriconazole (17) among the antifungals, and lamivudine (8) and nelfinavir (6) among the antivirals. A significant disproportionality was observed for 17 compounds, including several macrolides, fluoroquinolones, linezolid, triazole antifungals, caspofungin, indinavir and nelfinavir. With the qualitative approach, we identified the following additional drugs or fixed dose combinations, characterized by at least two TdP cases without co-medications listed by Arizona CERT: ceftriaxone, piperacillin/tazobactam, cotrimoxazole, metronidazole, ribavirin, lamivudine and lopinavir/ritonavir. Disproportionality for macrolides, fluoroquinolones and most of the azole antifungals should be viewed as 'expected' according to Arizona CERT list. By contrast, signals were generated by linezolid, caspofungin, posaconazole, indinavir and nelfinavir. Drugs detected only by the qualitative approach should be further investigated by increasing the sensitivity of the method, e.g. by searching also for the TdP surrogate marker, prolongation of the QT interval. The freely available version of the FDA AERS database represents an important source to detect signals of TdP. In particular, our analysis generated five signals among antimicrobials for which further investigations and active surveillance are warranted. These signals should be considered in evaluating the benefit-risk profile of these drugs.

Corneal Cross-Linking Has No Effect on Matrix Metalloproteinase 9 and 13 Levels During Fungal Keratitis on the Early Stage.

PubMed

Kalkanci, Ayse; Bilgihan, Kamil; Ozdemir, Huseyin Baran; Yar Saglam, Atiye Seda; Karakurt, Funda; Erdogan, Merve

2018-04-01

The aim of our study was to investigate matrix metalloproteinases, MMP-9 and MMP-13 levels, in the rabbit model of Fusarium and Candida keratitis treated by corneal cross-linking (PACK-CXL). Rabbit corneas were inoculated with fungal inoculum for keratitis. Each group divided into four subgroups, including un-treated group, PACK-CXL group, voriconazole group and PACK-CXL plus voriconazole group. PACK-CXL was applied with 0.25% riboflavin in accelerated Dresden protocol, and 0.1% voriconazole drops were administered. All corneal buttons excised at tenth day after ophthalmological examination. Fungal cell counts and Scheiber scores were determined in all groups. Corneal tissue MMP mRNA levels were evaluated quantitative reverse transcriptase PCR. The difference in MMP-9 and MMP-13 levels at all groups was not statistically significant (p > 0.05). PACK-CXL with 0.25% riboflavin either alone or combined with antifungal drops was unable to provide decline in inflammatory findings in both macroscopic and microscopic levels similar to medical antifungal treatment.

Fungal keratitis secondary to Scedosporium apiospermum infection and successful treatment with surgical and medical intervention.

PubMed

Kepez Yildiz, Burcin; Hasanreisoglu, Murat; Aktas, Zeynep; Aksu, Gulsah; Kocak, Burcak Comert; Akata, Fikret

2014-04-01

To report a rare case of severe fungal keratitis caused by Scedosporium apiospermum, which was treated with a penetrating tectonic keratoplasty and aggressive medical treatment. A 62-year-old woman with a history of soil contamination of the right eye while planting vegetables presented with a severe corneal abscess and ocular pain. The patient received medical treatment and underwent tectonic keratoplasty. Both corneal scrapings and the corneal button were evaluated microscopically. The samples were sent for aerobic and anaerobic bacterial and fungal cultures. Microbiological examinations showed S. apiospermum. The isolate was sensitive to amphoterycine B, caspofungin, voriconazole, and resistant to fluconazole. No clinical improvement was achieved with topical voriconazole, vancomycin, ceftazidime, and systemic voriconazole. A penetrating tectonic keratoplasty and lensectomy with continuation of anti-fungal therapy achieved satisfactory results. A fungal etiology should be suspected in a progressive and untreatable corneal abscess. Microbiological investigation is very important in early diagnosis. Despite early diagnosis and aggressive treatment, in selected cases removing the infected tissue surgically is vital in preserving the ocular globe and vision.

Considerations for a Pediatric Biopharmaceutics Classification System (BCS): application to five drugs.

PubMed

Gandhi, Shivani V; Rodriguez, William; Khan, Mansoor; Polli, James E

2014-06-01

It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development program. However, we are unaware of efforts to classify drugs into a Biopharmaceutics Classification System (BCS) framework for pediatric patients. The objective was to classify five drugs into a potential BCS. These five drugs were selected since both oral and intravenous pharmacokinetic data were available for each drug, and covered the four BCS classes in adults. Literature searches for each drug were conducted using Medline and applied to classify drugs with respect to solubility and permeability in pediatric subpopulations. Four pediatric subpopulations were considered: neonates, infants, children, and adolescents. Regarding solubility, dose numbers were calculated using a volume for each subpopulation based on body surface area (BSA) relative to 250 ml for a 1.73 m(2) adult. Dose numbers spanned a range of values, depending upon the pediatric dose formula and subpopulation. Regarding permeability, pharmacokinetic literature data required assumptions and decisions about data collection. Using a devised pediatric BCS framework, there was agreement in adult and pediatric BCS class for two drugs, azithromycin (class 3) and ciprofloxacin (class 4). There was discordance for the three drugs that have high adult permeability since all pediatric permeabilities were low: dolasetron (class 3 in pediatric), ketoprofen (class 4 in pediatric), and voriconazole (class 4 in pediatric). A main contribution of this work is the identification of critical factors required for a pediatric BCS.

Continuous infusion of amphotericin B deoxycholate: an innovative, low-cost strategy in antifungal treatment.

PubMed

Falci, Diego R; dos Santos, Rodrigo P; Wirth, Fernanda; Goldani, Luciano Z

2011-03-01

The combination of amphotericin B and sodium deoxycholate is the formulation most used in clinical practice. The development of new agents such as amphotericin with lipid formulations, caspofungin, voriconazole and other azolic derivatives, promoted alternatives to amphotericin B deoxycholate. However, because of the high cost of these new drugs, their use is difficult in a scenario of limited resources. A few strategies have been devised to make the use of amphotericin B deoxycholate less toxic. In this review, we seek to describe the accumulated knowledge about this molecule, with focus on its use in continuous infusion, which appears to be an alternative to reduce toxicity, while maintaining its clinical efficacy. © 2009 Blackwell Verlag GmbH.

Successful treatment of Beauveria bassiana fungal keratitis with topical voriconazole.

PubMed

Ogawa, Akiko; Matsumoto, Yukihiro; Yaguchi, Takashi; Shimmura, Shigeto; Tsubota, Kazuo

2016-04-01

We describe a 66-year-old woman who suffered from fungal keratitis after corneal transplantation. The causative organism was identified as Beauveria bassiana on the basis of morphological characteristics and the sequence of the internal transcribed spacer region of the ribosomal RNA gene. The patient was successfully treated with topical voriconazole (VRCZ) use only. We, hereby, present the first report of a case with B. bassiana fungal keratitis that responded to topical antifungal VRCZ treatment. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Curvularia lunata endophthalmitis.

PubMed

Berbel, Rodrigo Fabri; Casella, Antonio Marcelo Barbante; de Freitas, Denise; Höfling-Lima, Ana Luisa

2011-10-01

The aim of this study was to report a case of a 52-year-old man with a rare fungal endophthalmitis after penetrating ocular trauma with a fish hook. The patient was submitted to wound repair and hook extraction. Three weeks after the trauma, a cataract extraction with phacoemulsification and in-the-bag intraocular lens implantation was performed. After the development of endophthalmitis, vitrectomy and lens explantation with positive culture for Curvularia lunata were carried out. The infection was controlled with the administration of systemic itraconazole and intraocular voriconazole. The use of intravitreal voriconazole injection is a viable option in cases of Curvularia fungal endophthalmitis.

Successful Treatment of Combined Aspergillus and Cytomegalovirus Abscess in Brain and Lung After Liver Transplant for Toxic Fulminant Hepatitis.

PubMed

Kim, Tae-Seok; Ahn, Keun Soo; Kim, Yong Hoon; Kim, Hyoung Tae; Jang, Byoung Kuk; Hwang, Jae Seok; Kim, Il-Man; Kang, Yu Na; Kang, Koo Jeong

2017-02-01

Invasive aspergillosis is one of the most important and fatal complications after liver transplant, especially in patients with involvement of the central nervous system. We present a case of a patient who developed cerebral and pulmonary aspergillosis, coinfected with cytomegalovirus, after liver transplant for toxic fulminant hepatitis. The patient was treated successfully with neurosurgical intervention and voriconazole. Voriconazole is considered more effective in cerebral aspergillosis than other anti-fungal agents due to the greater penetration into central nervous system and higher cerebrospinal fluid and brain tissue levels.

Chronic Invasive Aspergillus Sinusitis and Otitis with Meningeal Extension Successfully Treated with Voriconazole.

PubMed

Morgand, Marjolaine; Rammaert, Blandine; Poirée, Sylvain; Bougnoux, Marie-Elisabeth; Tran, Hugo; Kania, Romain; Chrétien, Fabrice; Jouvion, Gregory; Lortholary, Olivier

2015-12-01

Invasive aspergillosis (IA) is a severe disseminated fungal disease that occurs mostly in immunocompromised patients. However, central nervous system IA, combining meningitis and skull base involvement, does not occur only in groups with classic risk factors for IA; patients with chronic renal failure and diabetes mellitus are also at risk for more chronic forms. In both of our proven IA cases, voriconazole monotherapy was effective without surgery, and cerebrospinal fluid and serum 1,3-β-d-glucan test results were initially positive, in contrast to galactomannan antigen results. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Functionalised isocoumarins as antifungal compounds: Synthesis and biological studies.

PubMed

Simic, Milena; Paunovic, Nikola; Boric, Ivan; Randjelovic, Jelena; Vojnovic, Sandra; Nikodinovic-Runic, Jasmina; Pekmezovic, Marina; Savic, Vladimir

2016-01-01

A series of novel 3-substituted isocoumarins was prepared via Pd-catalysed coupling processes and screened in vitro for antifungal activity against Candida species. The study revealed antifungal potential of isocoumarins possessing the azole substituents, which, in some cases, showed biological properties equal to those of clinically used voriconazole. Selected compounds were also screened against voriconazole resistant Candida krusei 6258 and a clinical isolate Candida parapsilosis CA-27. Although the activity against these targets needs to be improved further, the results emphasise additional potential of this new class of antifungal compounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

Risk factors for low vision related functioning in the Mycotic Ulcer Treatment Trial: a randomised trial comparing natamycin with voriconazole

PubMed Central

Rose-Nussbaumer, Jennifer; Prajna, N Venkatesh; Krishnan, Tiruvengada; Mascarenhas, Jeena; Rajaraman, Revathi; Srinivasan, Muthiah; Raghavan, Anita; Oldenburg, Catherine E; O’Brien, Kieran S; Ray, Kathryn J; Porco, Travis C; McLeod, Stephen D; Acharya, Nisha R; Keenan, Jeremy D; Lietman, Thomas M

2016-01-01

Background/aims The Mycotic Ulcer Treatment Trial I (MUTT I) was a double-masked, multicentre, randomised controlled trial, which found that topical natamycin is superior to voriconazole for the treatment of filamentous fungal corneal ulcers. In this study, we determine risk factors for low vision-related quality of life in patients with fungal keratitis. Methods The Indian visual function questionnaire (IND-VFQ) was administered to MUTT I study participants at 3 months. Associations between patient and ulcer characteristics and IND-VFQ subscale score were assessed using generalised estimating equations. Results 323 patients were enrolled in the trial, and 292 (90.4%) completed the IND-VFQ at 3 months. Out of a total possible score of 100, the average VFQ score for all participants was 81.3 (range 0–100, SD 23.6). After correcting for treatment arm, each logMAR line of worse baseline visual acuity in the affected eye resulted in an average 1.2 points decrease on VFQ at 3 months (95% CI −1.8 to 0.6, p<0.001). Those who required therapeutic penetrating keratoplasty had an average of 25.2 points decrease on VFQ after correcting for treatment arm (95% CI −31.8 to −18.5, p<0.001). Study participants who were unemployed had on average 28.5 points decrease on VFQ (95% CI −46.9 to −10.2, p=0.002) after correcting for treatment arm. Conclusions Monocular vision loss from corneal opacity due to fungal keratitis reduced vision-related quality of life. Given the relatively high worldwide burden of corneal opacity, improving treatment outcomes of corneal infections should be a public health priority. Trial registration number Clinicaltrials.gov Identifier: NCT00996736. PMID:26531051

Single and multidose ocular kinetics and stability analysis of extemporaneous formulation of topical voriconazole in humans.

PubMed

Senthilkumari, Srinivasan; Lalitha, Prajna; Prajna, Namperumalsamy Venkatesh; Haripriya, Aravind; Nirmal, Jeyabalan; Gupta, Pankaj; Velpandian, Thirumurthy

2010-11-01

The purpose of the present study was to evaluate the kinetics of single and multiple doses of topical, non-preserved voriconazole (VZ) in human eyes. For single dose kinetics, 119 patients undergoing cataract surgery were divided into group I and group II and each group received a single drop (30 µl) of either 1% or 0.1% VZ formulation. Aqueous humor was collected at designated time intervals. For multidose kinetics, a single drop of 1% VZ was instilled 5 times either hourly or every 2 hr. The aqueous humor was tested for VZ at the 5th hr and 9th hr, respectively, after initial instillation. The stability and efficacy of the reconstituted VZ formulations were also evaluated after 30 days. Single dose ocular kinetics of 1% VZ resulted in a maximum mean aqueous concentration of 3.333 ± 1.61 µg/ml in 30 min whereas 0.1% showed a maximum mean aqueous concentration of 0.817 ±.36 µg/ml. In the multidose kinetic study, hourly and bi-hourly dosing resulted in mean aqueous concentrations of 7.47 ± 2.14 µg/ml and 4.69 ± 2.7 µg/ml, respectively. The reconstituted VZ formulations were stable at all studied temperatures, and their efficacy was maintained throughout the study period. The present study showed that the achieved mean concentration of VZ in both single dose and multi dose kinetic studies satisfactorily met the MIC(90) for almost all causative fungal organisms. The frequency of instillation may be designed for an "every 2 hr regimen" to maintain a therapeutic concentration for successful therapy.

In Vitro Antifungal Susceptibility of Yeast and Mold Phases of Isolates of Dimorphic Fungal Pathogen Emergomyces africanus (Formerly Emmonsia sp.) from HIV-Infected South African Patients

PubMed Central

Britz, Erika; Zulu, Thokozile G.; Mpembe, Ruth S.; Naicker, Serisha D.; Schwartz, Ilan S.

2017-01-01

ABSTRACT Disseminated emmonsiosis is an important AIDS-related mycosis in South Africa that is caused by Emergomyces africanus, a newly described and renamed dimorphic fungal pathogen. In vitro antifungal susceptibility data can guide management. Identification of invasive clinical isolates was confirmed phenotypically and by sequencing of the internal transcribed spacer region. Yeast and mold phase MICs of fluconazole, voriconazole, itraconazole, posaconazole, caspofungin, anidulafungin, micafungin, and flucytosine were determined with custom-made frozen broth microdilution (BMD) panels in accordance with Clinical and Laboratory Standards Institute recommendations. MICs of amphotericin B, itraconazole, posaconazole, and voriconazole were determined by Etest. Fifty unique E. africanus isolates were tested. The yeast and mold phase geometric mean (GM) BMD and Etest MICs of itraconazole were 0.01 mg/liter. The voriconazole and posaconazole GM BMD MICs were 0.01 mg/liter for both phases, while the GM Etest MICs were 0.001 and 0.002 mg/liter, respectively. The fluconazole GM BMD MICs were 0.18 mg/liter for both phases. The GM Etest MICs of amphotericin B, for the yeast and mold phases were 0.03 and 0.01 mg/liter. The echinocandins and flucytosine had very limited in vitro activity. Treatment and outcome data were available for 37 patients; in a multivariable model including MIC data, only isolation from blood (odds ratio [OR], 8.6; 95% confidence interval [CI], 1.3 to 54.4; P = 0.02) or bone marrow (OR, 12.1; 95% CI, 1.2 to 120.2; P = 0.03) (versus skin biopsy) was associated with death. In vitro susceptibility data support the management of disseminated emmonsiosis with amphotericin B, followed by itraconazole, voriconazole, or posaconazole. Fluconazole was a relatively less potent agent. PMID:28356416

Invasive candidiasis in intensive care units in China: in vitro antifungal susceptibility in the China-SCAN study.

PubMed

Liu, Wei; Tan, Jingwen; Sun, Jimei; Xu, Zhijiang; Li, Min; Yang, Qing; Shao, Haifeng; Zhang, Liyan; Liu, Weixia; Wan, Zhe; Cui, Wei; Zang, Bin; Jiang, Dongpo; Fang, Qiang; Qin, Bingyu; Qin, Tiehe; Li, Weiqin; Guo, Fengmei; Liu, Dawei; Guan, Xiandong; Yu, Kaijiang; Qiu, Haibo; Li, Ruoyu

2014-01-01

The objectives of this study were to determine species distribution and in vitro antifungal susceptibility of Candida isolates identified in the multicentre China-SCAN study of invasive Candida infection (ICI) in intensive care units (ICUs) across China. Candida isolates from patients in the China-SCAN study with documented ICI were evaluated by a central laboratory. Species were identified using chromogenic culture media or the API 20C AUX kit. Susceptibility to fluconazole, voriconazole, itraconazole, caspofungin and amphotericin B was determined using the CLSI broth microdilution method (M27-A3) and updated clinical breakpoints or epidemiological cut-off values. A total of 389 isolates from 244 patients were analysed. Species identified most frequently were Candida albicans (40.1%), Candida parapsilosis (21.3%), Candida tropicalis (17.2%) and Candida glabrata (12.9%). Rarer species such as Lodderomyces elongisporus and Candida ernobii were also identified. Fluconazole susceptibility was evident in 85.9% (134/156) of C. albicans, 62.7% (42/67) of C. tropicalis and 48.2% (40/83) of C. parapsilosis isolates. Susceptibility to voriconazole was ≥ 90% among all species. All isolates were susceptible to amphotericin B and caspofungin except C. glabrata [86.0% (43/50) susceptible to caspofungin]. Cross-resistance between fluconazole and voriconazole was observed for C. parapsilosis and C. glabrata. Although C. albicans was the predominant single species, non-albicans species constituted >50% of isolates. Fluconazole susceptibility was lower in most non-albicans species, indicating that fluconazole resistance should be closely monitored. Susceptibility to voriconazole, amphotericin B and caspofungin is encouraging. Differences between these data and those from other regions emphasize the importance of assessing regional variations.

[Invasive aspergillosis in hematooncological patients: advantages and disadvantages of various diagnostic methods, treatment options and financial costs of therapy].

PubMed

Rácil, Z; Mayer, J; Kocmanová, I; Wagnerová, B; Winterová, J; Folber, F; Lengerová, M; Moulis, M; Zácková, D; Smardová, L; Janíková, A; Navrátil, M; Dvoráková, D; Vorlícek, J

2008-02-01

Invasive aspergillosis (IA) is a leading invasive fungal infection in hematooncological patients. The aim of this study was to analyse the incidence, diagnostic procedures and treatment of IA in hematooncological department in large hospital in the Czech Republic. A retrospective analysis of medical and laboratory records from patients hospitalised in our department with proven/probable IA between January 2000 and December 2006 was performed. 52 cases of IA in 51 patients were identified (17.3% proven IA/82.7% probable IA). Number of IA cases notably increased during study period (1 case of IA in 2000 vs 21 cases of IA in 2006) and majority of them was of nosocomial origin (61.5%). Pulmonary aspergillosis was diagnosed in 46 cases (88.5%). Patients treated for acute leukemia or undergoing allogeneic stem cell transplantation represent the group at the highest risk of IA (in total 52% of cases). Fever and signs of pulmonary involvement were the most common clinical signs of infection (presented in 92.3% and 69.2 cases respectively). Conventional diagnostic methods including autopsy were able to diagnose only 15 cases of IA (28.8%). In all other cases (71.2%) the diagnosis was done by detection of galactomannan (GM) in serum. Introduction of GM monitoring enabled erlier initiation of antifungal treatment by 4 days. Initial therapy of IA led to the treatment response (partial and complete) in 18 (34.6%) of infections--the highest percentage of response has been seen in voriconazole monotherapy group (42%) and when combination of voriconazole and caspofungin has been used (83%). Salvage therapy was initiated due to the failure of initial treatment in 21 (40.3%) of cases. Patients were treated mostly with combination ofvoriconazole and caspofungin and/or monotherapy with voriconazole has been used with treatment response 55% and 50% respectively. Introduction of new antifungal drugs together with increased number of patients with IA led to the marked increase of total costs spent on treatment of IA per year--from 11,5 thousands CZK in 2000 to 6,2 millions CZK in 2006. IA is the most frequent cause of infection-related mortality in patients with haematological malignancies. Routine use of non-culture base methods in diagnosis of IA together with treatment using new, effective antifungals can improve prognosis of patients with this life threatening infection.

Antifungal Susceptibility and Phylogeny of Opportunistic Members of the Order Mucorales

PubMed Central

Vitale, Roxana G.; de Hoog, G. Sybren; Schwarz, Patrick; Dannaoui, Eric; Deng, Shuwen; Machouart, Marie; Voigt, Kerstin; van de Sande, Wendy W. J.; Dolatabadi, Somayeh; Meis, Jacques F.

2012-01-01

The in vitro susceptibilities of 66 molecularly identified strains of the Mucorales to eight antifungals (amphotericin B, terbinafine, itraconazole, posaconazole, voriconazole, caspofungin, micafungin, and 5-fluorocytosine) were tested. Molecular phylogeny was reconstructed based on the nuclear ribosomal large subunit to reveal taxon-specific susceptibility profiles. The impressive phylogenetic diversity of the Mucorales was reflected in susceptibilities differing at family, genus, and species levels. Amphotericin B was the most active drug, though somewhat less against Rhizopus and Cunninghamella species. Posaconazole was the second most effective antifungal agent but showed reduced activity in Mucor and Cunninghamella strains, while voriconazole lacked in vitro activity for most strains. Genera attributed to the Mucoraceae exhibited a wide range of MICs for posaconazole, itraconazole, and terbinafine and included resistant strains. Cunninghamella also comprised strains resistant to all azoles tested but was fully susceptible to terbinafine. In contrast, the Lichtheimiaceae completely lacked strains with reduced susceptibility for these antifungals. Syncephalastrum species exhibited susceptibility profiles similar to those of the Lichtheimiaceae. Mucor species were more resistant to azoles than Rhizopus species. Species-specific responses were obtained for terbinafine where only Rhizopus arrhizus and Mucor circinelloides were resistant. Complete or vast resistance was observed for 5-fluorocytosine, caspofungin, and micafungin. Intraspecific variability of in vitro susceptibility was found in all genera tested but was especially high in Mucor and Rhizopus for azoles and terbinafine. Accurate molecular identification of etiologic agents is compulsory to predict therapy outcome. For species of critical genera such as Mucor and Rhizopus, exhibiting high intraspecific variation, susceptibility testing before the onset of therapy is recommended. PMID:22075600

Antifungal susceptibility and phylogeny of opportunistic members of the order mucorales.

PubMed

Vitale, Roxana G; de Hoog, G Sybren; Schwarz, Patrick; Dannaoui, Eric; Deng, Shuwen; Machouart, Marie; Voigt, Kerstin; van de Sande, Wendy W J; Dolatabadi, Somayeh; Meis, Jacques F; Walther, Grit

2012-01-01

The in vitro susceptibilities of 66 molecularly identified strains of the Mucorales to eight antifungals (amphotericin B, terbinafine, itraconazole, posaconazole, voriconazole, caspofungin, micafungin, and 5-fluorocytosine) were tested. Molecular phylogeny was reconstructed based on the nuclear ribosomal large subunit to reveal taxon-specific susceptibility profiles. The impressive phylogenetic diversity of the Mucorales was reflected in susceptibilities differing at family, genus, and species levels. Amphotericin B was the most active drug, though somewhat less against Rhizopus and Cunninghamella species. Posaconazole was the second most effective antifungal agent but showed reduced activity in Mucor and Cunninghamella strains, while voriconazole lacked in vitro activity for most strains. Genera attributed to the Mucoraceae exhibited a wide range of MICs for posaconazole, itraconazole, and terbinafine and included resistant strains. Cunninghamella also comprised strains resistant to all azoles tested but was fully susceptible to terbinafine. In contrast, the Lichtheimiaceae completely lacked strains with reduced susceptibility for these antifungals. Syncephalastrum species exhibited susceptibility profiles similar to those of the Lichtheimiaceae. Mucor species were more resistant to azoles than Rhizopus species. Species-specific responses were obtained for terbinafine where only Rhizopus arrhizus and Mucor circinelloides were resistant. Complete or vast resistance was observed for 5-fluorocytosine, caspofungin, and micafungin. Intraspecific variability of in vitro susceptibility was found in all genera tested but was especially high in Mucor and Rhizopus for azoles and terbinafine. Accurate molecular identification of etiologic agents is compulsory to predict therapy outcome. For species of critical genera such as Mucor and Rhizopus, exhibiting high intraspecific variation, susceptibility testing before the onset of therapy is recommended.

In vitro susceptibility of antifungal drugs against Sporothrix brasiliensis recovered from cats with sporotrichosis in Brazil.

PubMed

Brilhante, Raimunda Sâmia Nogueira; Rodrigues, Anderson Messias; Sidrim, José Júlio Costa; Rocha, Marcos Fábio Gadelha; Pereira, Sandro Antonio; Gremião, Isabella Dib Ferreira; Schubach, Tânia Maria Pacheco; de Camargo, Zoilo Pires

2016-03-01

Sporotrichosis is an important subcutaneous mycosis of humans and animals. Classically, the disease is acquired upon traumatic inoculation of Sporothrix propagules from contaminated soil and plant debris. In addition, the direct horizontal transmission of Sporothrix among animals and the resulting zoonotic infection in humans highlight an alternative and efficient rout of transmission through biting and scratching. Sporothrix brasiliensis is the most virulent species of the Sporothrix schenckii complex and is responsible for the long-lasting outbreak of feline sporotrichosis in Brazil. However, antifungal susceptibility data of animal-borne isolates is scarce. Therefore, this study evaluated the in vitro activity of amphotericin B, caspofungin, itraconazole, voriconazole, fluconazole, and ketoconazole against animal-borne isolates of S. brasiliensis. The susceptibility tests were performed through broth microdilution (M38-A2). The results show the relevant activity of itraconazole, amphotericin B, and ketoconazole against S. brasiliensis, with the following MIC ranges: 0.125-2, 0.125-4 and 0.0312-2 μg/ml, respectively. Caspofungin was moderately effective, displaying higher variation in MIC values (0.25-64 μg/ml). Voriconazole (2-64 μg/ml) and fluconazole (62.5-500 μg/ml) showed low activity against S. brasiliensis strains. This study contributed to the characterization of the in vitro antifungal susceptibility of strains of S. brasiliensis recovered from cats with sporotrichosis, which have recently been considered the main source of human infections. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Susceptibility Testing of Common and Uncommon Aspergillus Species against Posaconazole and Other Mold-Active Antifungal Azoles Using the Sensititre Method.

PubMed

Mello, Enrica; Posteraro, Brunella; Vella, Antonietta; De Carolis, Elena; Torelli, Riccardo; D'Inzeo, Tiziana; Verweij, Paul E; Sanguinetti, Maurizio

2017-06-01

We tested 59 common and 27 uncommon Aspergillus species isolates for susceptibility to the mold-active azole antifungal agents itraconazole, voriconazole, and posaconazole using the Sensititre method. The overall essential agreement with the CLSI reference method was 96.5% for itraconazole and posaconazole and was 100% for voriconazole. By the Sensititre method as well as the CLSI reference method, all of 10 A. fumigatus isolates with a cyp51 mutant genotype were classified as being non-wild-type isolates (MIC > epidemiological cutoff value [ECV]) with respect to triazole susceptibility. Copyright © 2017 American Society for Microbiology.

Susceptibility Testing of Common and Uncommon Aspergillus Species against Posaconazole and Other Mold-Active Antifungal Azoles Using the Sensititre Method

PubMed Central

Mello, Enrica; Posteraro, Brunella; Vella, Antonietta; De Carolis, Elena; Torelli, Riccardo; D'Inzeo, Tiziana; Verweij, Paul E.

2017-01-01

ABSTRACT We tested 59 common and 27 uncommon Aspergillus species isolates for susceptibility to the mold-active azole antifungal agents itraconazole, voriconazole, and posaconazole using the Sensititre method. The overall essential agreement with the CLSI reference method was 96.5% for itraconazole and posaconazole and was 100% for voriconazole. By the Sensititre method as well as the CLSI reference method, all of 10 A. fumigatus isolates with a cyp51 mutant genotype were classified as being non-wild-type isolates (MIC > epidemiological cutoff value [ECV]) with respect to triazole susceptibility. PMID:28416538

Vision-Related Quality-of-Life Outcomes in the Mycotic Ulcer Treatment Trial I: A Randomized Clinical Trial.

PubMed

Rose-Nussbaumer, Jennifer; Prajna, N Venkatesh; Krishnan, K Tiruvengada; Mascarenhas, Jeena; Rajaraman, Revathi; Srinivasan, Muthiah; Raghavan, Anita; Oldenburg, Catherine E; O'Brien, Kieran S; Ray, Kathryn J; McLeod, Stephen D; Porco, Travis C; Lietman, Thomas M; Acharya, Nisha R; Keenan, Jeremy D

2015-06-01

Given the limitations in health care resources, quality-of-life measures for interventions have gained importance. To determine whether vision-related quality-of-life outcomes were different between the natamycin and voriconazole treatment arms in the Mycotic Ulcer Treatment Trial I, as measured by an Indian Vision Function Questionnaire. Secondary analysis (performed October 11-25, 2014) of a double-masked, multicenter, randomized, active comparator-controlled, clinical trial at multiple locations of the Aravind Eye Care System in South India that enrolled patients with culture- or smear-positive filamentous fungal corneal ulcers who had a baseline visual acuity of 20/40 to 20/400 (logMAR of 0.3-1.3). Study participants were randomly assigned to topical voriconazole, 1%, or topical natamycin, 5%. Subscale score on the Indian Vision Function Questionnaire from each of the 4 subscales (mobility, activity limitation, psychosocial impact, and visual function) at 3 months. A total of 323 patients were enrolled in the trial, and 292 (90.4%) completed the Indian Vision Function Questionnaire at 3 months. The majority of study participants had subscale scores consistent with excellent function. After adjusting for baseline visual acuity and organism, we found that study participants in the natamycin-treated group scored, on average, 4.3 points (95% CI, 0.1-8.5) higher than study participants in the voriconazole-treated group (P = .046). In subgroup analyses looking at ulcers caused by Fusarium species and adjusting for baseline best spectacle-corrected visual acuity, the natamycin-treated group scored 8.4 points (95% CI, 1.9-14.9) higher than the voriconazole-treated group (P = .01). Differences in quality of life were not detected for patients with Aspergillus or other non-Fusarium species as the causative organism (1.5 points [95% CI, -3.9 to 6.9]; P = .52). We found evidence of improvement in vision-related quality of life among patients with fungal ulcers who were randomly assigned to natamycin compared with those randomly assigned to voriconazole, and especially among patients with Fusarium species as the causative organism. Incorporation of quality-of-life measures in clinical trials is important to fully evaluate the effect of the studied interventions. clinicaltrials.gov Identifier:NCT00996736.

Vision-Related Quality-of-Life Outcomes in the Mycotic Ulcer Treatment Trial I

PubMed Central

Rose-Nussbaumer, Jennifer; Prajna, N. Venkatesh; Krishnan, K. Tiruvengada; Mascarenhas, Jeena; Rajaraman, Revathi; Srinivasan, Muthiah; Raghavan, Anita; Oldenburg, Catherine E.; O’Brien, Kieran S.; Ray, Kathryn J.; McLeod, Stephen D.; Porco, Travis C.; Lietman, Thomas M.; Acharya, Nisha R.; Keenan, Jeremy D.

2016-01-01

IMPORTANCE Given the limitations in health care resources, quality-of-life measures for interventions have gained importance. OBJECTIVE To determine whether vision-related quality-of-life outcomes were different between the natamycin and voriconazole treatment arms in the Mycotic Ulcer Treatment Trial I, as measured by an Indian Vision Function Questionnaire. DESIGN, SETTING, AND PARTICIPANTS Secondary analysis (performed October 11–25, 2014) of a double-masked, multicenter, randomized, active comparator–controlled, clinical trial at multiple locations of the Aravind Eye Care System in South India that enrolled patients with culture- or smear-positive filamentous fungal corneal ulcers who had a baseline visual acuity of 20/40 to 20/400 (logMAR of 0.3–1.3). INTERVENTIONS Study participants were randomly assigned to topical voriconazole, 1%, or topical natamycin, 5%. MAIN OUTCOMES AND MEASURES Subscale score on the Indian Vision Function Questionnaire from each of the 4 subscales (mobility, activity limitation, psychosocial impact, and visual function) at 3 months. RESULTS A total of 323 patients were enrolled in the trial, and 292 (90.4%) completed the Indian Vision Function Questionnaire at 3 months. The majority of study participants had subscale scores consistent with excellent function. After adjusting for baseline visual acuity and organism, we found that study participants in the natamycin-treated group scored, on average, 4.3 points (95% CI, 0.1–8.5) higher than study participants in the voriconazole-treated group (P = .046). In subgroup analyses looking at ulcers caused by Fusarium species and adjusting for baseline best spectacle–corrected visual acuity, the natamycin-treated group scored 8.4 points (95% CI, 1.9–14.9) higher than the voriconazole-treated group (P = .01). Differences in quality of life were not detected for patients with Aspergillus or other non-Fusarium species as the causative organism (1.5 points [95% CI, −3.9 to 6.9]; P = .52). CONCLUSIONS AND RELEVANCE We found evidence of improvement in vision-related quality of life among patients with fungal ulcers who were randomly assigned to natamycin compared with those randomly assigned to voriconazole, and especially among patients with Fusarium species as the causative organism. Incorporation of quality-of-life measures in clinical trials is important to fully evaluate the effect of the studied interventions. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00996736 PMID:25764482

Antifungal activity of amphotericin B and voriconazole against the biofilms and biofilm-dispersed cells of Candida albicans employing a newly developed in vitro pharmacokinetic model.

PubMed

El-Azizi, Mohamed; Farag, Noha; Khardori, Nancy

2015-04-03

Candida albicans is a common cause of a variety of superficial and invasive disseminated infections the majority of which are associated with biofilm growth on implanted devices. The aim of the study is to evaluate the activity of amphotericin B and voriconazole against the biofilm and the biofilm-dispersed cells of Candida albicans using a newly developed in vitro pharmacokinetic model which simulates the clinical situation when the antifungal agents are administered intermittently. RPMI medium containing 1-5 X 10(6) CFU/ml of C. albicans was continuously delivered to the device at 30 ml/h for 2 hours. The planktonic cells were removed and biofilms on the catheter were kept under continuous flow of RPMI medium at 10 ml/h. Five doses of amphotericin B or voriconazole were delivered to 2, 5 and 10 day-old biofilms at initial concentrations (2 and 3 μg/ml respectively) that were exponentially diluted. Dispersed cells in effluents from the device were counted and the adherent cells on the catheter were evaluated after 48 h of the last dose. The minimum inhibitory concentration of voriconazole and amphotericin B against the tested isolate was 0.0325 and 0.25 μg/ml respectively. Amphotericin B significantly reduced the dispersion of C. albicans cells from the biofilm. The log10 reduction in the dispersed cells was 2.54-3.54, 2.30-3.55, and 1.94-2.50 following addition of 5 doses of amphotericin B to 2-, 5- and 10-day old biofilms respectively. The number of the viable cells within the biofilm was reduced by 18 (±7.63), 5 and 4% following addition of the 5 doses of amphotericin B to the biofilms respectively. Voriconazole showed no significant effect on the viability of C. albicans within the biofilm. Both antifungal agents failed to eradicate C. albicans biofilm or stop cell dispersion from them and the resistance progressed with maturation of the biofilm. These findings go along with the need for removal of devices in spite of antifungal therapy in patients with device-related infection. This is the first study which investigates the effects of antifungal agents on the biofilm and biofilm-dispersion of C. albicans in an in vitro pharmacokinetic biofilm model.

In Vitro Interactions between Non-Steroidal Anti-Inflammatory Drugs and Antifungal Agents against Planktonic and Biofilm Forms of Trichosporon asahii

PubMed Central

Cong, Lin; Lu, Xuelian

2016-01-01

Increasing drug resistance has brought enormous challenges to the management of Trichosporon spp. infections. The in vitro antifungal activities of non-steroidal anti-inflammatory drugs (NSAIDs) against Candida spp. and Cryptococcus spp. were recently discovered. In the present study, the in vitro interactions between three NSAIDs (aspirin, ibuprofen and diclofenac sodium) and commonly used antifungal agents (fluconazole, itraconazole, voriconazole, caspofungin and amphotericin B) against planktonic and biofilm cells of T. asahii were evaluated using the checkerboard microdilution method. The spectrophotometric method and the XTT reduction assay were used to generate data on biofilm cells. The fractional inhibitory concentration index (FICI) and the ΔE model were compared to interpret drug interactions. Using the FICI, the highest percentages of synergistic effects against planktonic cells (86.67%) and biofilm cells (73.33%) were found for amphotericin B/ibuprofen, and caspofungin/ibuprofen showed appreciable percentages (73.33% for planktonic form and 60.00% for biofilm) as well. We did not observe antagonism. The ΔE model gave consistent results with FICI (86.67%). Our findings suggest that amphotericin B/ibuprofen and caspofungin/ibuprofen combinations have potential effects against T. asahii. Further in vivo and animal studies to investigate associated mechanisms need to be conducted. PMID:27275608

In vitro antifungal activity of antipsychotic drugs and their combinations with conventional antifungals against Scedosporium and Pseudallescheria isolates.

PubMed

Homa, Mónika; Galgóczy, László; Tóth, Eszter; Tóth, Liliána; Papp, Tamás; Chandrasekaran, Muthusamy; Kadaikunnan, Shine; Alharbi, Naiyf S; Vágvölgyi, Csaba

2015-11-01

In the present study, in vitro antifungal activities of five antipsychotic drugs (i.e., chlorpromazine hydrochloride, CPZ; trifluoperazine hydrochloride, TPZ; amantadine hydrochloride; R-(-)-deprenyl hydrochloride, and valproic acid sodium salt) and five conventional antifungal drugs (i.e., amphotericin B, AMB; caspofungin, CSP; itraconazole; terbinafine, TRB and voriconazole, VRC) were investigated in broth microdilution tests against four clinical and five environmental Scedosporium and Pseudallescheria isolates. When used alone, phenothiazines CPZ and TPZ exerted remarkable antifungal effects. Thus, their in vitro combinations with AMB, CSP, VRC, and TRB were also examined against the clinical isolates. In combination with antifungal agents, CPZ was able to act synergistically with AMB and TRB in cases of one and two isolates, respectively. In all other cases, indifferent interactions were revealed. Antagonism was not observed between the tested agents. These combinations may establish a more effective and less toxic therapy after further in vitro and in vivo studies for Scedosporium and Pseudallescheria infections. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Copper-based metal coordination complexes with Voriconazole ligand: Syntheses, structures and antimicrobial properties

NASA Astrophysics Data System (ADS)

Zhao, Yan-Ming; Tang, Gui-Mei; Wang, Yong-Tao; Cui, Yue-Zhi; Ng, Seik Weng

2018-03-01

Three new chiral metal coordination complexes, namely, [Cu(FZ)2(CH3COO)2(H2O)]·2H2O (1), [Cu(FZ)2(NO3)2] (2), and [Cu2(FZ)2 (H2O)8](SO4)2·4H2O (3) [FZ = (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidiny)-1-(1H-1,2,4-triazol-1-yl)-2-butanol) (Voriconazole)] have been obtained by the reaction of Cu(II) salts and the free ligand FZ at room temperature. Complexes 1-3 were structurally characterized by X-ray single-crystal diffraction, IR, UV-vis, powder X-ray diffraction (PXRD), and thermogravimetric analysis (TGA). Complex 1 crystallizes in the chiral space group C2, which exhibits a mono-nuclear structure. Both complexes 2 and 3 display a one-dimensional (1D) tape structure, which crystallize in chiral space group P21212 and P212121, respectively. Among these complexes, there exist a variety of hydrogen bonds and stacking interactions, through which a three-dimensional supramolecular architecture will be generated. Compared with the standard (Voriconazole), these Cu-based complexes show the more potent inhibiting efficiency against the species of Candida and Aspergillus. Moreover, among these complexes, complex 1 shows the most excellent efficiency.

Prevalence, virulence factors and antifungal susceptibility of Candida spp. isolated from bloodstream infections in a tertiary care hospital in Brazil.

PubMed

Canela, Heliara Maria Spina; Cardoso, Bárbara; Vitali, Lucia Helena; Coelho, Harnoldo Colares; Martinez, Roberto; Ferreira, Márcia Eliana da Silva

2018-01-01

Candida spp. are responsible for 80% of all systemic fungal infections and are associated with high mortality rates. This study characterised 79 bloodstream isolates of C. albicans, C. glabrata, C. orthopsilosis, C. parapsilosis and C. tropicalis from patients in a Brazilian hospital. The susceptibility to amphotericin B, caspofungin, fluconazole and voriconazole was determined; virulence factor production was assessed based on haemolysin, phospholipase and proteinase activities, and the patients' clinical characteristics were analysed. C. albicans was the predominant species (44%), followed by C. glabrata (19%), C. tropicalis (19%), C. parapsilosis (14%) and C. orthopsilosis (4%). The candidemia incidence was 1.52 per 1000 admissions, and the crude mortality rate was 52%. One C. albicans isolate was resistant to fluconazole and voriconazole. Moreover, 20.2%, 2.5% and 3.8% of the isolates exhibited dose-dependent susceptibility to fluconazole, voriconazole and caspofungin, respectively. In conclusion, although the C. glabrata incidence was higher than that usually described in Brazil, its increase was previously observed in studies conducted worldwide. Furthermore, the azole resistance of the C. albicans isolate could be due to previous exposure to these antifungals. These results highlight the importance of epidemiological studies and will facilitate an improved understanding of candidemia in the studied hospital. © 2017 Blackwell Verlag GmbH.

Severe infections in children with acute leukemia undergoing intensive chemotherapy can successfully be prevented by ciprofloxacin, voriconazole, or micafungin prophylaxis.

PubMed

Yeh, Ting-Chi; Liu, Hsi-Che; Hou, Jen-Yin; Chen, Kuan-Hao; Huang, Ting-Huan; Chang, Ching-Yi; Liang, Der-Cherng

2014-04-15

The purpose of the current study was to prevent bloodstream infection and invasive fungal infection (IFI) by administering prophylactic antibiotic and antifungal agents during intensive chemotherapy in patients being treated for acute leukemia. Prophylaxis treatment was administered during intensive chemotherapy in children with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) from January 1, 2010 to December 31, 2012. Oral ciprofloxacin (at a dose of 300 mg/m(2) /12 hours) was administered after chemotherapy when a patient with AML or ALL became neutropenic and > 7 days of neutropenia was expected. Voriconazole (at a dose of 4 mg/kg/12 hours) was initiated at the onset of neutropenia in patients with AML and after 7 days of neutropenia in patients with ALL. Micafungin (at a dose of 2 mg/kg/day) was substituted for voriconazole when patients with ALL received vincristine. Prophylaxis treatment was discontinued when the absolute neutrophil count recovered to > 100/μL. All episodes of bloodstream infection, IFI, febrile neutropenia, and intensive care unit stays related to severe infection occurring between January 1, 2005 and December 31, 2012 were recorded. During the preprophylaxis period, 62 children with ALL and 24 children with AML experienced a total of 44 episodes of bloodstream infection and 22 episodes of IFI. Seven patients died of severe infection. In contrast, in the prophylaxis period, 10 episodes of bloodstream infection occurred and no IFIs were reported to occur in 51 patients with ALL and 14 patients with AML. Moreover, no patient died of severe infection. Episodes of febrile neutropenia and intensive care unit stay were significantly reduced during the prophylaxis period. Prophylaxis with ciprofloxacin and voriconazole or micafungin was found to reduce the rates of bloodstream infection and IFI in children with acute leukemia undergoing intensive chemotherapy. © 2013 American Cancer Society.

In Vitro Antifungal Susceptibility of Yeast and Mold Phases of Isolates of Dimorphic Fungal Pathogen Emergomyces africanus (Formerly Emmonsia sp.) from HIV-Infected South African Patients.

PubMed

Maphanga, Tsidiso G; Britz, Erika; Zulu, Thokozile G; Mpembe, Ruth S; Naicker, Serisha D; Schwartz, Ilan S; Govender, Nelesh P

2017-06-01

Disseminated emmonsiosis is an important AIDS-related mycosis in South Africa that is caused by Emergomyces africanus , a newly described and renamed dimorphic fungal pathogen. In vitro antifungal susceptibility data can guide management. Identification of invasive clinical isolates was confirmed phenotypically and by sequencing of the internal transcribed spacer region. Yeast and mold phase MICs of fluconazole, voriconazole, itraconazole, posaconazole, caspofungin, anidulafungin, micafungin, and flucytosine were determined with custom-made frozen broth microdilution (BMD) panels in accordance with Clinical and Laboratory Standards Institute recommendations. MICs of amphotericin B, itraconazole, posaconazole, and voriconazole were determined by Etest. Fifty unique E. africanus isolates were tested. The yeast and mold phase geometric mean (GM) BMD and Etest MICs of itraconazole were 0.01 mg/liter. The voriconazole and posaconazole GM BMD MICs were 0.01 mg/liter for both phases, while the GM Etest MICs were 0.001 and 0.002 mg/liter, respectively. The fluconazole GM BMD MICs were 0.18 mg/liter for both phases. The GM Etest MICs of amphotericin B, for the yeast and mold phases were 0.03 and 0.01 mg/liter. The echinocandins and flucytosine had very limited in vitro activity. Treatment and outcome data were available for 37 patients; in a multivariable model including MIC data, only isolation from blood (odds ratio [OR], 8.6; 95% confidence interval [CI], 1.3 to 54.4; P = 0.02) or bone marrow (OR, 12.1; 95% CI, 1.2 to 120.2; P = 0.03) (versus skin biopsy) was associated with death. In vitro susceptibility data support the management of disseminated emmonsiosis with amphotericin B, followed by itraconazole, voriconazole, or posaconazole. Fluconazole was a relatively less potent agent. Copyright © 2017 American Society for Microbiology.

Network Meta-analysis and Pharmacoeconomic Evaluation of Fluconazole, Itraconazole, Posaconazole, and Voriconazole in Invasive Fungal Infection Prophylaxis

PubMed Central

Zhao, Ying Jiao; Tan, Gloria; Teng, Monica; Tee, Caroline; Tan, Ban Hock; Ong, Benjamin; Lim, Boon Peng; Chai, Louis Yi Ann

2015-01-01

Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting. PMID:26525782

Aspergillus fumigatus carrying TR34/L98H resistance allele causing complicated suppurative otitis media in Tanzania: Call for improved diagnosis of fungi in sub-Saharan Africa.

PubMed

Mushi, Martha F; Buname, Gustave; Bader, Oliver; Groß, Uwe; Mshana, Stephen E

2016-09-02

Suppurative otitis media (SOM) is a major public health concern worldwide and is associated with increased morbidity. Cases of fungal suppurative otitis media were studied to establish the effect of fungi in otitis media. Ear swabs from 410 patients were collected aseptically using sterile cotton swabs from discharging ear through perforated tympanic membrane. Swabs were subjected to microscopic and culture investigations. The species of fungal growing on Sabouraud's agar were identified using MALDI-TOF MS. For moulds broth micro dilution method following EUCAST guidelines was employed to determine susceptibility patterns against itraconazole, voriconazole and posaconazole. A total of 44 (10.74 %) cases with positive fungal culture growth were studied. The median age of patients with fungal infection was 29.5 (IQR 16-43) years. Of 44 patients; 35 (79.6 %) had pure growth of one type of fungal. Candida albicans was the most common fungus isolated (n = 13; 29.6 %) followed by Aspergillus versicolor (n = 8; 18.2 %). A total of 7 (15.9 %) patients had disease complication at time of enrollment; of them 6 (13.6 %) had hearing loss. On follow up 7 (15.9 %) had poor treatment outcome. All five Aspergillus fumigatus strains resistant itraconazole with reduced susceptibility to voriconazole and posaconazole carried carrying TR34/L98H resistance allele. In addition, all Penicillium citrinum isolates were resistant to voriconazole while all Penicillium sumatrense were resistant to both itraconazole and voriconazole. There were non-significant association of poor treatment outcome and female gender, being HIV positive and being infected with moulds. Fungal infections play a significant role in SOM pathology in our setting. Diagnosis of fungal infections in developing countries should be improved so that appropriate management can be initiated on time to prevent associated complications.

Network Meta-analysis and Pharmacoeconomic Evaluation of Fluconazole, Itraconazole, Posaconazole, and Voriconazole in Invasive Fungal Infection Prophylaxis.

PubMed

Zhao, Ying Jiao; Khoo, Ai Leng; Tan, Gloria; Teng, Monica; Tee, Caroline; Tan, Ban Hock; Ong, Benjamin; Lim, Boon Peng; Chai, Louis Yi Ann

2016-01-01

Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Epidemiology and antifungal susceptibility of bloodstream Candida isolates in Quebec: Report on 453 cases between 2003 and 2005

PubMed Central

St-Germain, Guy; Laverdière, Michel; Pelletier, René; René, Pierre; Bourgault, Anne-Marie; Lemieux, Claude; Libman, Michael

2008-01-01

BACKGROUND Between May 2003 and April 2005, a population-based surveillance of Candida bloodstream infections was conducted in Quebec. A total of 453 episodes of candidemia (464 yeast isolates) from 54 participating hospitals were studied. RESULTS The annual incidence rate was three per 100,000 population. Global hospital mortality was 38%. The most common predisposing factors were the presence of an intravascular catheter (80%), use of antibacterial therapy (67%), stay in an intensive care unit (49%), use of parenteral nutrition (32%) and intra-abdominal surgery (31%). Fluconazole alone or in association with other antifungals was used for treatment in over 80% of cases. Candida albicans comprised 62% of isolates, followed by Candida glabrata (17%), Candida parapsilosis (9%), Candida tropicalis (5%), Candida lusitaniae (3%) and Candida krusei (3%). Of the 288 C albicans isolates, seven (2%) were resistant to flucytosine, one to fluconazole and none to itraconazole or voriconazole. Of the 75 non-C albicans species isolates with reduced susceptibility to fluconazole (minimum inhibitory concentration [MIC] 16 μg/mL or greater), none were susceptible to itraconazole (MIC 0.12 mg/L or lower), whereas 71 (95%) were susceptible to voriconazole (MIC 1 μg/mL or lower). However, only five of 12 (42%) fluconazole-resistant isolates were susceptible to voriconazole. Posaconazole, ravuconazole and caspofungin displayed a broad spectrum of activity against these isolates, with MICs of 1 mg/L or lower in 56%, 92% and 100% of isolates, respectively. Overall, a correlation (r2>0.87) was observed among increasing fluconazole MICs and the geometric mean MICs of itraconazole, voriconazole, posaconazole and ravuconazole. CONCLUSIONS These surveillance results when compared with those of the 1993 to 1995 survey confirm little variation in the distribution of species causing invasive Candida infection over a 10-year period in Quebec, as well as the continuous excellent overall in vitro activity of fluconazole. PMID:19145263

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

PubMed Central

Krasowski, Matthew D.

2010-01-01

In the past twenty years, 14 new antiepileptic drugs have been approved for use in the United States and/or Europe. These drugs are eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. In general, the clinical utility of therapeutic drug monitoring has not been established in clinical trials for these new anticonvulsants, and clear guidelines for drug monitoring have yet to be defined. The antiepileptic drugs with the strongest justifications for drug monitoring are lamotrigine, oxcarbazepine, stiripentol, and zonisamide. Stiripentol and tiagabine are strongly protein bound and are candidates for free drug monitoring. Therapeutic drug monitoring has lower utility for gabapentin, pregabalin, and vigabatrin. Measurement of salivary drug concentrations has potential utility for therapeutic drug monitoring of lamotrigine, levetiracetam, and topiramate. Therapeutic drug monitoring of the new antiepileptic drugs will be discussed in managing patients with epilepsy. PMID:20640233

The relation between promotional spending on drugs and their therapeutic gain: a cohort analysis

PubMed Central

Lexchin, Joel

2017-01-01

Background: Whether drug promotion helps or hinders appropriate prescribing by physicians is debated. This study examines the most heavily promoted drugs and the therapeutic value of those drugs to help determine whether doctors should be using promotional material to inform themselves about drugs. Methods: Lists were constructed of the 50 most heavily promoted drugs (amount of money spent on journal advertisements and visits by sales representatives) and the 50 top-selling drugs (by dollar value) for 2013, 2014 and 2015. Therapeutic gain was determined by examining ratings from the Patented Medicine Prices Review Board and the French drug bulletin Prescrire International and was categorized as major, moderate or little to none. For each of the 3 years, the number of drugs in the 3 therapeutic categories for drugs in both groups was compared. The amount and proportion of money spent on promotion for drugs in each of the 3 therapeutic categories for the 3 years was also determined. Results: Therapeutic ratings were available for 42 of 79 of the most heavily promoted drugs over the 3 years and for 40 of 61 of the top-selling drugs. Nearly all the money spent on promotion in each of the 3 years went to drugs with little to no therapeutic gain. The distribution of therapeutic gain for drugs in both groups was statistically significantly different only in 2013 (p = 0.04). Interpretation: Most of the money spent on promotion went to drugs that offer little to no therapeutic gain. This result calls into question whether doctors should read journal advertisements or see sales representatives to acquire information about important medical therapies. PMID:28912143

The patterns of colonization and antifungal susceptibility of Candida, isolated from preterm neonates in Khorramabad, South West of Iran.

PubMed

Kooshki, P; Rezaei-Matehkolaei, A; Mahmoudabadi, A Z

2018-06-01

Usually, 7-20% of preterm neonates colonized by Candida species present invasive candidiasis. Candida albicans, and several non-albicans species cause invasive infection with C. albicans being the most dominant agent. In the last two decades, infection due to non-albicans have been increased dramatically due to their low sensitivity to antifungal drugs such as fluconazole. The aim of present study was to evaluate Candida colonization pattern and antifungal susceptibility among preterm neonates from Khorramabad, South west of Iran. Samples were collected from 80 preterm neonates, cultured on CHROMagar Candida and incubated at 37°C. All recovered isolates were primarily screened based on classical methods and identified by PCR-RFLP targeting the ITS-rDNA regions. Antifungal susceptibility testing of all isolates was performed according to the CLSI method against amphotericin B, caspofungin, itraconazole, fluconazole and voriconazole. Totally 23 isolates of Candida species were recovered from 20 patients (female: male, 50:50) including, C. albicans (18), C. parapsilosis (2) and C. glabrata (1). Furthermore, the blood cultures from two patients were yielded C. albicans and C. parapsilosis so that patient with C. albicans died after five days. Generally, in this study, 9 (39.1%) isolates were resistant to amphotericin B including; 7 (30.4%) C. albicans and 2 (8.7%) C. parapsilosis. In addition, 2 (8.7%) and 4 (17.4%) isolates were also resistant to itraconazole and caspofungin, respectively. In conclusion, Candida colonization among preterm neonates is still an important issue in hospitals. In addition, in spite of a significant amphotericin B resistant Candida, voriconazole, fluconazole, and itraconazole are valuable antifungals, due to fully sensitivity to Candida. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Pediatric Obesity: Pharmacokinetic Alterations and Effects on Antimicrobial Dosing.

PubMed

Natale, Stephanie; Bradley, John; Nguyen, William Huy; Tran, Tri; Ny, Pamela; La, Kirsten; Vivian, Eva; Le, Jennifer

2017-03-01

Limited data exist for appropriate drug dosing in obese children. This comprehensive review summarizes pharmacokinetic (PK) alterations that occur with age and obesity, and these effects on antimicrobial dosing. A thorough comparison of different measures of body weight and specific antimicrobial agents including cefazolin, cefepime, ceftazidime, daptomycin, doripenem, gentamicin, linezolid, meropenem, piperacillin-tazobactam, tobramycin, vancomycin, and voriconazole is presented. PubMed (1966-July 2015) and Cochrane Library searches were performed using these key terms: children, pharmacokinetic, obesity, overweight, body mass index, ideal body weight, lean body weight, body composition, and specific antimicrobial drugs. PK studies in obese children and, if necessary, data from adult studies were summarized. Knowledge of PK alterations stemming from physiologic changes that occur with age from the neonate to adolescent, as well as those that result from increased body fat, become an essential first step toward optimizing drug dosing in obese children. Excessive amounts of adipose tissue contribute significantly to body size, total body water content, and organ size and function that may modify drug distribution and clearance. PK studies that evaluated antimicrobial dosing primarily used total (or actual) body weight (TBW) for loading doses and TBW or adjusted body weight for maintenance doses, depending on the drugs' properties and dosing units. PK studies in obese children are imperative to elucidate drug distribution, clearance, and, consequently, the dose required for effective therapy in these children. Future studies should evaluate the effects of both age and obesity on drug dosing because the incidence of obesity is increasing in pediatric patients. © 2017 Pharmacotherapy Publications, Inc.

Albumin Enhances Caspofungin Activity against Aspergillus Species by Facilitating Drug Delivery to Germinating Hyphae

PubMed Central

Ioannou, Petros; Andrianaki, Aggeliki; Akoumianaki, Tonia; Kyrmizi, Irene; Albert, Nathaniel; Perlin, David; Samonis, George

2015-01-01

The modest in vitro activity of echinocandins against Aspergillus implies that host-related factors augment the action of these antifungal agents in vivo. We found that, in contrast to the other antifungal agents (voriconazole, amphotericin B) tested, caspofungin exhibited a profound increase in activity against various Aspergillus species under conditions of cell culture growth, as evidenced by a ≥4-fold decrease in minimum effective concentrations (MECs) (P = 0. 0005). Importantly, the enhanced activity of caspofungin against Aspergillus spp. under cell culture conditions was strictly dependent on serum albumin and was not observed with the other two echinocandins, micafungin and anidulafungin. Of interest, fluorescently labeled albumin bound preferentially on the surface of germinating Aspergillus hyphae, and this interaction was further enhanced upon treatment with caspofungin. In addition, supplementation of cell culture medium with albumin resulted in a significant, 5-fold increase in association of fluorescently labeled caspofungin with Aspergillus hyphae (P < 0.0001). Collectively, we found a novel synergistic interaction between albumin and caspofungin, with albumin acting as a potential carrier molecule to facilitate antifungal drug delivery to Aspergillus hyphae. PMID:26643329

Novel fluconazole derivatives with promising antifungal activity.

PubMed

Thamban Chandrika, Nishad; Shrestha, Sanjib K; Ngo, Huy X; Howard, Kaitlind C; Garneau-Tsodikova, Sylvie

2018-02-01

The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action. Copyright © 2017 Elsevier Ltd. All rights reserved.

Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis

PubMed Central

Hargrove, Tatiana Y.; Friggeri, Laura; Wawrzak, Zdzislaw; Qi, Aidong; Hoekstra, William J.; Schotzinger, Robert J.; York, John D.; Guengerich, F. Peter; Lepesheva, Galina I.

2017-01-01

With some advances in modern medicine (such as cancer chemotherapy, broad exposure to antibiotics, and immunosuppression), the incidence of opportunistic fungal pathogens such as Candida albicans has increased. Cases of drug resistance among these pathogens have become more frequent, requiring the development of new drugs and a better understanding of the targeted enzymes. Sterol 14α-demethylase (CYP51) is a cytochrome P450 enzyme required for biosynthesis of sterols in eukaryotic cells and is the major target of clinical drugs for managing fungal pathogens, but some of the CYP51 key features important for rational drug design have remained obscure. We report the catalytic properties, ligand-binding profiles, and inhibition of enzymatic activity of C. albicans CYP51 by clinical antifungal drugs that are used systemically (fluconazole, voriconazole, ketoconazole, itraconazole, and posaconazole) and topically (miconazole and clotrimazole) and by a tetrazole-based drug candidate, VT-1161 (oteseconazole: (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol). Among the compounds tested, the first-line drug fluconazole was the weakest inhibitor, whereas posaconazole and VT-1161 were the strongest CYP51 inhibitors. We determined the X-ray structures of C. albicans CYP51 complexes with posaconazole and VT-1161, providing a molecular mechanism for the potencies of these drugs, including the activity of VT-1161 against Candida krusei and Candida glabrata, pathogens that are intrinsically resistant to fluconazole. Our comparative structural analysis outlines phylum-specific CYP51 features that could direct future rational development of more efficient broad-spectrum antifungals. PMID:28258218

Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis.

PubMed

Hargrove, Tatiana Y; Friggeri, Laura; Wawrzak, Zdzislaw; Qi, Aidong; Hoekstra, William J; Schotzinger, Robert J; York, John D; Guengerich, F Peter; Lepesheva, Galina I

2017-04-21

With some advances in modern medicine (such as cancer chemotherapy, broad exposure to antibiotics, and immunosuppression), the incidence of opportunistic fungal pathogens such as Candida albicans has increased. Cases of drug resistance among these pathogens have become more frequent, requiring the development of new drugs and a better understanding of the targeted enzymes. Sterol 14α-demethylase (CYP51) is a cytochrome P450 enzyme required for biosynthesis of sterols in eukaryotic cells and is the major target of clinical drugs for managing fungal pathogens, but some of the CYP51 key features important for rational drug design have remained obscure. We report the catalytic properties, ligand-binding profiles, and inhibition of enzymatic activity of C. albicans CYP51 by clinical antifungal drugs that are used systemically (fluconazole, voriconazole, ketoconazole, itraconazole, and posaconazole) and topically (miconazole and clotrimazole) and by a tetrazole-based drug candidate, VT-1161 (oteseconazole: ( R )-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol). Among the compounds tested, the first-line drug fluconazole was the weakest inhibitor, whereas posaconazole and VT-1161 were the strongest CYP51 inhibitors. We determined the X-ray structures of C. albicans CYP51 complexes with posaconazole and VT-1161, providing a molecular mechanism for the potencies of these drugs, including the activity of VT-1161 against Candida krusei and Candida glabrata , pathogens that are intrinsically resistant to fluconazole. Our comparative structural analysis outlines phylum-specific CYP51 features that could direct future rational development of more efficient broad-spectrum antifungals. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Therapeutic Duplicates in a Cohort of Hospitalized Elderly Patients: Results from the REPOSI Study.

PubMed

Pasina, Luca; Astuto, Sarah; Cortesi, Laura; Tettamanti, Mauro; Franchi, Carlotta; Marengoni, Alessandra; Mannucci, Pier Mannuccio; Nobili, Alessandro

2016-09-01

Explicit criteria for potentially inappropriate prescriptions in the elderly are recommended to avoid prescriptions of duplicate drug classes and to optimize monotherapy within a single drug class before a new agent is considered. Duplicate drug class prescription (or therapeutic duplicates) puts the patient at increased risk of adverse drug reactions with no additional therapeutic benefits. To our knowledge, the prevalence of elderly inpatients receiving therapeutic duplicates has never been studied. Our objective was to assess the prevalence of therapeutic duplicates at admission, discharge, and 3-month follow-up of hospitalized elderly patients. This cross-sectional prospective study was conducted in 97 Italian internal medicine and geriatric wards. Therapeutic duplicates were defined as at least two drugs of the same therapeutic class prescribed simultaneously to a patient. A patient's drug therapy at admission relates to prescriptions from general practitioners, whereas prescriptions at discharge are those from hospital internists or geriatricians. The study sample comprised 5821 admitted and 4983 discharged patients. In all, 143 therapeutic duplicates were found at admission and 170 at discharge. The prevalence of patients exposed to at least one therapeutic duplicate rose significantly from hospital admission (2.5 %) to discharge (3.4 %; p = 0.0032). Psychotropic drugs and drugs for peptic ulcer or gastroesophageal reflux disease were the most frequently involved. A total of 86.8 % of patients discharged with at least one therapeutic duplicate were still receiving them at 3-month follow-up. Hospitalization and drugs prescribed by internists and geriatricians are both factors associated with a small but definite increase in overall therapeutic duplicates in elderly patients admitted to internal medicine and geriatric wards. More attention should be paid to the indications for each drug prescribed, because therapeutic duplicates are not supported by evidence and increase both the risk of adverse drug reactions and costs. Identification of unnecessary therapeutic duplicates is essential for the optimization of polypharmacy.

In Vitro Activity of Posaconazole against Talaromyces marneffei by Broth Microdilution and Etest Methods and Comparison to Itraconazole, Voriconazole, and Anidulafungin

PubMed Central

Lam, Clare S. K.; Ngan, Antonio H. Y.; Wu, Alan K. L.; Tsang, Dominic N. C.; Tse, Cindy W. S.; Que, Tak-Lun; Tang, Bone S. F.

2016-01-01

ABSTRACT We determined the susceptibilities of 57 Talaromyces marneffei strains to anidulafungin, itraconazole, voriconazole, and posaconazole with MICs of 2 to 8, 0.002 to 0.004, 0.016 to 0.063, and 0.001 to 0.002 μg/ml by broth microdilution and >32, ≤0.002 to 0.008, ≤0.002 to 0.008, and ≤0.002 μg/ml by Etest, respectively, at yeast phase; MICs at mycelial phase for anidulafungin and posaconazole were 1 to 2 and 0.004 to 0.063 μg/ml, respectively. The results suggest promising activities of posaconazole. Etest can be used for testing of azoles against T. marneffei. PMID:28031205

A review on therapeutic drug monitoring of immunosuppressant drugs.

PubMed

Mohammadpour, Niloufar; Elyasi, Sepideh; Vahdati, Naser; Mohammadpour, Amir Hooshang; Shamsara, Jamal

2011-11-01

: Immunosuppressants require therapeutic drug monitoring because of their narrow therapeutic index and significant inter-individual variability in blood concentrations. This variability can be because of factors like drug-nutrient interactions, drug-disease interactions, renal-insufficiency, inflammation and infection, gender, age, polymorphism and liver mass. Drug monitoring is widely practiced especially for cyclosporine, tacrolimus, sirolimus and mycophenolic acid. CYCLOSPORINE: Therapeutic monitoring of immunosuppressive therapy with cyclosporine is a critical requirement because of intra- and inter-patient variability of drug absorption, narrow therapeutic window and drug induced nephrotoxicity. MYCOPHENOLIC ACID MPA: Some reasons for therapeutic drug monitoring of MPA during post-transplant period include: relationship between MPA pharmacokinetic parameters and clinical outcomes, Inter-patient pharmacokinetic variability for MPA despite fixed MMF doses, alternations of MPA pharmacokinetics during the first months after transplantation, drug- drug interaction and influence of kidney function on MPA pharmacokinetic. SIROLIMUS: A recent review of the pharmacokinetics of sirolimus suggested a therapeutic range of 5 to 10 μg l(-1) in whole blood. However, the only consensus guidelines published on the therapeutic monitoring of sirolimus concluded that there was not enough information available about the clinical use of the drug to make recommendations. TACROLIMUS: Sudies have shown, in kidney and liver transplant patients, significant associations of low tacrolimus concentrations with rejection and of high concentrations with nephrotoxicity. Although the feasibility of a limited sampling scheme to predict AUC has been demonstrated, as yet, trough, or pre-dose, whole blood concentration monitoring is still the method of choice.

Therapeutic drug levels

MedlinePlus

... medlineplus.gov/ency/article/003430.htm Therapeutic drug levels To use the sharing features on this page, please enable JavaScript. Therapeutic drug levels are lab tests to look for the presence ...

Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms.

PubMed

Garcia-Rubio, Rocio; Alcazar-Fuoli, Laura; Monteiro, Maria Candida; Monzon, Sara; Cuesta, Isabel; Pelaez, Teresa; Mellado, Emilia

2018-06-01

Triazole antifungal compounds are the first treatment choice for invasive aspergillosis. However, in the last decade the rate of azole resistance among Aspergillus fumigatus strains has increased notoriously. The main resistance mechanisms are well defined and mostly related to point mutations of the azole target, 14-α sterol demethylase ( cyp51A ), with or without tandem repeat integrations in the cyp51A promoter. Furthermore, different combinations of five Cyp51A mutations (F46Y, M172V, N248T, D255E, and E427K) have been reported worldwide in about 10% of all A. fumigatus isolates tested. The azole susceptibility profile of these strains shows elevated azole MICs, although on the basis of the azole susceptibility breakpoints, these strains are not considered azole resistant. The purpose of the study was to determine whether these cyp51A polymorphisms (single nucleotide polymorphisms [SNPs]) are responsible for the azole susceptibility profile and whether they are reflected in a poorer azole treatment response in vivo that could compromise patient treatment and outcome. A mutant with a cyp51A deletion was generated and became fully susceptible to all azoles tested. Also, three cyp51A gene constructions with different combinations of SNPs were generated and reintroduced into an azole-susceptible wild-type (WT) strain (the Δ akuB KU80 strain). The alternative model host Galleria mellonella was used to compare the virulence and voriconazole response of G. mellonella larvae infected with A. fumigatus strains with WT cyp51A or cyp51A with SNPs. All strains were pathogenic in G. mellonella larvae, although they did not respond similarly to voriconazole therapeutic doses. Finally, the full genomes of these strains were sequenced and analyzed in comparison with those of A. fumigatus WT strains, revealing that they belong to different strain clusters or lineages. Copyright © 2018 American Society for Microbiology.

Risk factors for low vision related functioning in the Mycotic Ulcer Treatment Trial: a randomised trial comparing natamycin with voriconazole.

PubMed

Rose-Nussbaumer, Jennifer; Prajna, N Venkatesh; Krishnan, Tiruvengada; Mascarenhas, Jeena; Rajaraman, Revathi; Srinivasan, Muthiah; Raghavan, Anita; Oldenburg, Catherine E; O'Brien, Kieran S; Ray, Kathryn J; Porco, Travis C; McLeod, Stephen D; Acharya, Nisha R; Keenan, Jeremy D; Lietman, Thomas M

2016-07-01

The Mycotic Ulcer Treatment Trial I (MUTT I) was a double-masked, multicentre, randomised controlled trial, which found that topical natamycin is superior to voriconazole for the treatment of filamentous fungal corneal ulcers. In this study, we determine risk factors for low vision-related quality of life in patients with fungal keratitis. The Indian visual function questionnaire (IND-VFQ) was administered to MUTT I study participants at 3 months. Associations between patient and ulcer characteristics and IND-VFQ subscale score were assessed using generalised estimating equations. 323 patients were enrolled in the trial, and 292 (90.4%) completed the IND-VFQ at 3 months. Out of a total possible score of 100, the average VFQ score for all participants was 81.3 (range 0-100, SD 23.6). After correcting for treatment arm, each logMAR line of worse baseline visual acuity in the affected eye resulted in an average 1.2 points decrease on VFQ at 3 months (95% CI -1.8 to 0.6, p<0.001). Those who required therapeutic penetrating keratoplasty had an average of 25.2 points decrease on VFQ after correcting for treatment arm (95% CI -31.8 to -18.5, p<0.001). Study participants who were unemployed had on average 28.5 points decrease on VFQ (95% CI -46.9 to -10.2, p=0.002) after correcting for treatment arm. Monocular vision loss from corneal opacity due to fungal keratitis reduced vision-related quality of life. Given the relatively high worldwide burden of corneal opacity, improving treatment outcomes of corneal infections should be a public health priority. Clinicaltrials.gov Identifier: NCT00996736. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Environmental isolation, biochemical identification, and antifungal drug susceptibility of Cryptococcus species.

PubMed

Teodoro, Valter Luis Iost; Gullo, Fernanda Patrícia; Sardi, Janaína de Cássia Orlandi; Torres, Edson Maria; Fusco-Almeida, Ana Marisa; Mendes-Giannini, Maria José Soares

2013-01-01

The incidence of opportunistic fungal infections has increased in recent years and is considered an important public health problem. Among systemic and opportunistic mycoses, cryptococcosis is distinguished by its clinical importance due to the increased risk of infection in individuals infected by human immunodeficiency virus. To determine the occurrence of pathogenic Cryptococcus in pigeon excrement in the City of Araraquara, samples were collected from nine environments, including state and municipal schools, abandoned buildings, parks, and a hospital. The isolates were identified using classical tests, and susceptibility testing for the antifungal drugs (fluconazole, itraconazole, voriconazole, and amphotericin B) independently was also performed. After collection, the excrement samples were plated on Niger agar and incubated at room temperature. A total of 87 bird dropping samples were collected, and 66.6% were positive for the genus Cryptococcus. The following species were identified: Cryptococcus neoformans (17.2%), Cryptococcus gattii (5.2%), Cryptococcus ater (3.5%), Cryptococcus laurentti (1.7%), and Cryptococcus luteolus (1.7%). A total of 70.7% of the isolates were not identified to the species level and are referred to as Cryptococcus spp. throughout the manuscript. Although none of the isolates demonstrated resistance to antifungal drugs, the identification of infested areas, the proper control of birds, and the disinfection of these environments are essential for the epidemiological control of cryptococcosis.

[Susceptibility to antifungal agents of Candida sp. and biofilm formation].

PubMed

Ciok-Pater, Emilia; Białucha, Agata; Gospodarek, Eugenia; Ostafin, Agnieszka

2011-01-01

In recent years the increase in frequency of fungal infections with Candida sp. was noticed. These infections are connected with ability of Candida sp. to form biofilm on surfaces of biomaterials used in medicine. Furthermore fungal infections make serious therapeutic problems because ofbiofilm resistance to antifungal agents actually. The aim of the study was to evaluate the susceptibility to antifungal agents of Candida sp. and their ability to form biofilm on different biomaterials. 50 strains of Candida sp. isolated from patients of University Hospital No. 1 of dr A. Jurasz in Bydgoszcz were examined. API Candida (bioMérieux) tests were used to identify Candida sp. strains. The susceptibility of the yeast strains to antifungal agents was evaluated by ATB FUNGUS 2 INT (bioMérieux) tests. The susceptibility of examined strains to voriconazole, posaconazole, caspofungin and anidulafungin was assessed by means ofEtests (AB BIODISK) method employing drug concentrations from 0,002 to 32 microg/ml. All analysed strains were susceptible to amphotericin B and caspofungin. Biofilm formation on different biomaterials (silicon, latex, polychloride vinyl, polypropylene, nylon) was measured after 72 hour incubation at 37 degrees C. All examined yeasts formed biofilm on all analysed biomaterials. The highest number of strains formed biofilm on surface of polychloride vinyl: 23 (92,0%) by C. albicans strains and 24 (96,0%) Candida non-albicans strains. The lowest number of the strains formed biofilm on the surface of nylon: 12 (48,0%) of C. albicans strains and 9 (36,0%) of Candida non-albicans strains. The studied strains resistant to azoles and anidulafungin display stronger ability to form biofilm on surfaces of all analysed biomaterials.

Species distribution and antifungal susceptibility of Candida spp. isolated from superficial candidiasis in outpatients in Iran.

PubMed

Razzaghi-Abyaneh, M; Sadeghi, G; Zeinali, E; Alirezaee, M; Shams-Ghahfarokhi, M; Amani, A; Mirahmadi, R; Tolouei, R

2014-06-01

Candidiasis is the most prevalent fungal infection affecting human and animals all over the world. This study represents the epidemiological aspects of superficial candidiasis in outpatients and in vitro antifungal susceptibility of etiologic Candida species. Clinical samples were taken from 173 patients including skin and nail scrapings (107; 61.8%), vaginal discharge (28; 16.2%), sputum (20; 11.6%), oral swabs (7; 4.0%), bronchoalveolar lavage (6; 3.5%) and 1 specimen (0.6%) of each eye tumor, gastric juice, urine, biopsy and urinary catheter and confirmed as candidiasis by direct microscopy, culture and histopathology. Susceptibility patterns of the isolated Candida species were determined using the disk diffusion and broth microdilution methods. Among 173 Candida isolates, C. albicans (72.3%) was the most prevalent species followed by C. parapsilosis (11.5%). Other identified species were C. glabrata, C. krusei, C. tropicalis, C. guilliermondii, C. intermedia and C. sake. Majority of the Candida isolates were susceptible to fluconazole (95.4%) followed by 5-flucytosine (89.6%), voriconazole (78.6%) itraconazole (48.0%) and ketoconazole (42.8%). Caspofungin was the most potent antifungal drug against C. albicans (MICs; 0.062-1 μg/mL), ketoconazole for C. parapsilosis and C. tropicalis (MICs; 0.031-0.25 μg/mL) and itraconazole for C. krusei, C. glabrata and C. guilliermondii (MICs; 0.031-1 μg/mL). This study reinforces the significance of superficial candidiasis as an important fungal infection with multiple clinical presentations. Our results further indicate that susceptibility testing to commonly used antifungals is crucial in order to select the appropriate therapeutic strategies which minimize complications while improving patients' life. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

In vitro antifungal susceptibility testing of Scopulariopsis brevicaulis strains using agar diffusion method.

PubMed

Skóra, Magdalena; Macura, Anna B

2011-01-01

The genus Scopulariopsis is a common soil saprotroph and has been isolated from air, organic waste and also from plant, animal and human tissues. Scopulariopsis has mainly been associated in humans with superficial mycoses, but it has also been described as the cause of subcutaneous and invasive infections. The most common aetiological agent of infections in humans is Scopulariopsis brevicaulis. This species has been reported to be resistant in vitro to broad-spectrum antifungal agents available today. The aim of the study was to establish in vitro antifungal susceptibility of 35 S. brevicaulis strains against amphotericin B (AMB), flucytosine (FC), caspofungin (CAS), terbinafine (TER), ciclopirox (CIC), voriconazole (VOR), clotrimazole (CTR), miconazole (MCZ), econazole (ECO), ketoconazole (KET), itraconazole (ITR), and fluconazole (FLU). Antifungal susceptibility tests were evaluated by an agar diffusion method (Neo-Sensitabs, Rosco, Denmark). AMB, FC, CAS, ITR and FLU showed no antifungal activity against S. brevicaulis. TER, CIC, CTR, KET, VOR, ECO, and MCZ revealed inhibitory activity for S. brevicaulis, but it varied for each of the drugs. The best antifungal effect was observed for TER and CIC. All isolates had large inhibition zones for TER and CIC. CTR was also inhibitory for all tested S. brevicaulis isolates, but the diameters of inhibition zones were smaller than for TER and CIC. Nearly 89% isolates showed inhibition zones for KET and the mean diameter of the inhibition zone was comparable to CTR. The least antifungal activity exhibited VQR, ECO and MCZ. Because of the multiresistance of S. brevicaulis, infections due to this species may not respond to particular antifungal treatment and other therapeutic approaches should be considered, e.g., combined therapy and/or surgery.

21 CFR 890.5660 - Therapeutic massager.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Therapeutic massager. 890.5660 Section 890.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5660 Therapeutic...

21 CFR 890.5660 - Therapeutic massager.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Therapeutic massager. 890.5660 Section 890.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5660 Therapeutic...

21 CFR 890.5660 - Therapeutic massager.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Therapeutic massager. 890.5660 Section 890.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5660 Therapeutic...

21 CFR 890.5660 - Therapeutic massager.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Therapeutic massager. 890.5660 Section 890.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5660 Therapeutic...

21 CFR 890.5660 - Therapeutic massager.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Therapeutic massager. 890.5660 Section 890.5660 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5660 Therapeutic...

21 CFR 890.5975 - Therapeutic vibrator.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Therapeutic vibrator. 890.5975 Section 890.5975 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5975 Therapeutic...

21 CFR 890.5975 - Therapeutic vibrator.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Therapeutic vibrator. 890.5975 Section 890.5975 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES PHYSICAL MEDICINE DEVICES Physical Medicine Therapeutic Devices § 890.5975 Therapeutic...

Quantifying Components of Drug Expenditure Inflation: The British Columbia Seniors' Drug Benefit Plan

PubMed Central

Morgan, Steven G

2002-01-01

Objective To quantify the relative and absolute importance of different factors contributing to increases in per capita prescription drug costs for a population of Canadian seniors. Data Sources/Study Setting Data consist of every prescription claim from 1985 to 1999 for the British Columbia Pharmacare Plan A, a tax-financed public drug plan covering all community-dwelling British Columbians aged 65 and older. Study Design Changes in per capita prescription drug expenditures are attributed to changes to four components of expenditure inflation: (1) the pattern of exposure to drugs across therapeutic categories; (2) the mix of drugs used within therapeutic categories; (3) the rate of generic drug product selection; and (4) the prices of unchanged products. Data Collection/Extraction Methods Data were extracted from administrative claims files housed at the UBC Centre for Health Services and Policy Research. Principal Findings Changes in drug prices, the pattern of exposure to drugs across therapeutic categories, and the mix of drugs used within therapeutic categories all caused spending per capita to increase. Incentives for generic substitution and therapeutic reference pricing policies temporarily slowed the cost-increasing influence of changes in product selection by encouraging the use of generic drug products and/or cost-effective brand-name products within therapeutic categories. Conclusions The results suggest that drug plans (and patients) would benefit from more concerted efforts to evaluate the relative cost-effectiveness of competing products within therapeutic categories of drugs. PMID:12479495

Aspergillus felis sp. nov., an Emerging Agent of Invasive Aspergillosis in Humans, Cats, and Dogs

PubMed Central

Barrs, Vanessa R.; van Doorn, Tineke M.; Houbraken, Jos; Kidd, Sarah E.; Martin, Patricia; Pinheiro, Maria Dolores; Richardson, Malcolm; Varga, Janos; Samson, Robert A.

2013-01-01

We describe a novel heterothallic species in Aspergillus section Fumigati, namely A. felis (neosartorya-morph) isolated from three host species with invasive aspergillosis including a human patient with chronic invasive pulmonary aspergillosis, domestic cats with invasive fungal rhinosinusitis and a dog with disseminated invasive aspergillosis. Disease in all host species was often refractory to aggressive antifungal therapeutic regimens. Four other human isolates previously reported as A. viridinutans were identified as A. felis on comparative sequence analysis of the partial β-tubulin and/or calmodulin genes. A. felis is a heterothallic mold with a fully functioning reproductive cycle, as confirmed by mating-type analysis, induction of teleomorphs within 7 to 10 days in vitro and ascospore germination. Phenotypic analyses show that A. felis can be distinguished from the related species A. viridinutans by its ability to grow at 45°C and from A. fumigatus by its inability to grow at 50°C. Itraconazole and voriconazole cross-resistance was common in vitro. PMID:23798996

Voriconazole

MedlinePlus

... is also used to treat esophageal candidiasis (a yeast [a type of fungus] infection that may cause ... patching in the mouth and throat) and other yeast infections of the skin, stomach, kidney, bladder, and ...

Scedosporium prolificans fungaemia in a patient with acute lymphoblastic leukaemia.

PubMed

Kubisiak-Rzepczyk, H; Gil, L; Zawirska, A; Kubisiak-Michalska, A; Mol, A; Reich, A; Komarnicki, M; Adamski, Z

2013-12-01

Aggressive chemotherapy and immunosuppressive treatment may prolong patients' life, but influence the risk of severe, life-threatening infections. Here, we report the case of a 21-year-old caucasian female who developed a disseminated infection of Scedosporium prolificans after allogenic stem cell transplantation performed for treatment of relapsed acute lymphoblastic leukaemia. The pathogen was isolated from the blood and identified on the basis of its macroscopic and microscopic morphological features. The empirical treatment with amphotericin B provided no improvement. However, introduction of intravenous voriconazole resulted in amelioration of fever. Unfortunately, the patient died due to progression of underlying disease and multiorgan failure. However, this case report indicates a possible relevance of voriconazole-based treatment regimens in invasive S. prolificans infections. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Drug Delivery Systems, CNS Protection, and the Blood Brain Barrier

PubMed Central

Upadhyay, Ravi Kant

2014-01-01

Present review highlights various drug delivery systems used for delivery of pharmaceutical agents mainly antibiotics, antineoplastic agents, neuropeptides, and other therapeutic substances through the endothelial capillaries (BBB) for CNS therapeutics. In addition, the use of ultrasound in delivery of therapeutic agents/biomolecules such as proline rich peptides, prodrugs, radiopharmaceuticals, proteins, immunoglobulins, and chimeric peptides to the target sites in deep tissue locations inside tumor sites of brain has been explained. In addition, therapeutic applications of various types of nanoparticles such as chitosan based nanomers, dendrimers, carbon nanotubes, niosomes, beta cyclodextrin carriers, cholesterol mediated cationic solid lipid nanoparticles, colloidal drug carriers, liposomes, and micelles have been discussed with their recent advancements. Emphasis has been given on the need of physiological and therapeutic optimization of existing drug delivery methods and their carriers to deliver therapeutic amount of drug into the brain for treatment of various neurological diseases and disorders. Further, strong recommendations are being made to develop nanosized drug carriers/vehicles and noninvasive therapeutic alternatives of conventional methods for better therapeutics of CNS related diseases. Hence, there is an urgent need to design nontoxic biocompatible drugs and develop noninvasive delivery methods to check posttreatment clinical fatalities in neuropatients which occur due to existing highly toxic invasive drugs and treatment methods. PMID:25136634

[The place of a new drug in the therapeutic strategy].

PubMed

Castaigne, A; Goehrs, J M; Ravoire, S

A therapeutic strategy is a hierarchical set of appropriate measures to provide an answer to a pathological state. A drug is a part of this set (together with the diagnosis, the environment and the other medicinal interventions or not). A new drug's place in a therapeutic strategy can be evaluated according to one or several referential(s) when it (or they) exist, referentials which express the state of knowledge before launch of the new drug. The drug's profile (indication or contraindication, etc.), at the point when the marketing authorization is given, is purely theoretical. One must evaluate the real place of the drug under its real conditions of use (pragmatic trials, observable surveys). A new drugs' place in a therapeutic strategy can only be evaluated in the course of time unless a therapeutic revolution occurs.

A Case Report of Penile Infection Caused by Fluconazole- and Terbinafine-Resistant Candida albicans.

PubMed

Hu, Yongxuan; Hu, Yanqing; Lu, Yan; Huang, Shiyun; Liu, Kangxing; Han, Xue; Mao, Zuhao; Wu, Zhong; Zhou, Xianyi

2017-04-01

Candida albicans is the most common pathogen that causes balanoposthitis. It often causes recurrence of symptoms probably due to its antifungal resistance. A significant number of balanitis Candida albicans isolates are resistant to azole and terbinafine antifungal agents in vitro. However, balanoposthitis caused by fluconazole- and terbinafine-resistant Candida albicans has rarely been reported. Here, we describe a case of a recurrent penile infection caused by fluconazole- and terbinafine-resistant Candida albicans, as well as the treatments administered to this patient. The isolate from the patient was tested for drug susceptibility in vitro. It was sensitive to itraconazole, voriconazole, clotrimazole and amphotericin B, but not to terbinafine and fluconazole. Thus, oral itraconazole was administrated to this patient with resistant Candida albicans penile infection. The symptoms were improved, and mycological examination result was negative. Follow-up treatment of this patient for 3 months showed no recurrence.

Orbital Apex Syndrome Caused by Invasive Aspergillosis as an Adverse Effect of Systemic Chemotherapy for Metastatic Colorectal Cancer: a Case Report.

PubMed

Miyamoto, Yuji; Sakamoto, Yasuo; Ohuchi, Mayuko; Tokunaga, Ryuma; Shigaki, Hironobu; Kurashige, Junji; Iwatsuki, Masaaki; Baba, Yoshifumi; Yoshida, Naoya; Watanabe, Masayuki; Baba, Hideo

2016-02-01

Continuous therapy with cytotoxic drugs suppresses humoral immune function and may result in local infection. We present a case of orbital apex syndrome caused by Aspergillus infection during chemotherapy for metastatic colorectal cancer. A 74-year-old man with colorectal liver metastases under long-term continuous systemic chemotherapy presented with painful, progressive orbital apex syndrome. Magnetic resonance imaging disclosed a small enhancing lesion around the right ethmoid sinus. We initially diagnosed colorectal cancer metastasis and he underwent biopsy via the endoscopic endonasal transethmoid approach. However, pathological examination of the cultured specimen revealed Aspergillus fumigatus. The patient was treated with voriconazole and the orbital apex syndrome resolved after 1 month. Orbital aspergillosis is a life-threatening disease and should be listed as a differential diagnosis of uncommon local infections during continuous chemotherapy. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Activities of E1210 and comparator agents tested by CLSI and EUCAST broth microdilution methods against Fusarium and Scedosporium species identified using molecular methods.

PubMed

Castanheira, Mariana; Duncanson, Frederick P; Diekema, Daniel J; Guarro, Josep; Jones, Ronald N; Pfaller, Michael A

2012-01-01

Fusarium (n = 67) and Scedosporium (n = 63) clinical isolates were tested by two reference broth microdilution (BMD) methods against a novel broad-spectrum (active against both yeasts and molds) antifungal, E1210, and comparator agents. E1210 inhibits the inositol acylation step in glycophosphatidylinositol (GPI) biosynthesis, resulting in defects in fungal cell wall biosynthesis. Five species complex organisms/species of Fusarium (4 isolates unspeciated) and 28 Scedosporium apiospermum, 7 Scedosporium aurantiacum, and 28 Scedosporium prolificans species were identified by molecular techniques. Comparator antifungal agents included anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B. E1210 was highly active against all of the tested isolates, with minimum effective concentration (MEC)/MIC(90) values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B, respectively, for Fusarium of 0.12, >16, >16, >8, >8, 8, and 4 μg/ml. E1210 was very potent against the Scedosporium spp. tested. The E1210 MEC(90) was 0.12 μg/ml for S. apiospermum, but 1 to >8 μg/ml for other tested agents. Against S. aurantiacum, the MEC(50) for E1210 was 0.06 μg/ml versus 0.5 to >8 μg/ml for the comparators. Against S. prolificans, the MEC(90) for E1210 was only 0.12 μg/ml, compared to >4 μg/ml for amphotericin B and >8 μg/ml for itraconazole, posaconazole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparator agents. The essential agreement (EA; ±2 doubling dilutions) was >93% for all comparisons, with the exception of posaconazole and F. oxysporum species complex (SC) (60%), posaconazole and S. aurantiacum (85.7%), and voriconazole and S. aurantiacum (85.7%). In conclusion, E1210 exhibited very potent and broad-spectrum antifungal activity against azole- and amphotericin B-resistant strains of Fusarium spp. and Scedosporium spp. Furthermore, in vitro susceptibility testing of E1210 against isolates of Fusarium and Scedosporium may be accomplished using either of the CLSI or EUCAST BMD methods, each producing very similar results.

Activities of E1210 and Comparator Agents Tested by CLSI and EUCAST Broth Microdilution Methods against Fusarium and Scedosporium Species Identified Using Molecular Methods

PubMed Central

Duncanson, Frederick P.; Diekema, Daniel J.; Guarro, Josep; Jones, Ronald N.; Pfaller, Michael A.

2012-01-01

Fusarium (n = 67) and Scedosporium (n = 63) clinical isolates were tested by two reference broth microdilution (BMD) methods against a novel broad-spectrum (active against both yeasts and molds) antifungal, E1210, and comparator agents. E1210 inhibits the inositol acylation step in glycophosphatidylinositol (GPI) biosynthesis, resulting in defects in fungal cell wall biosynthesis. Five species complex organisms/species of Fusarium (4 isolates unspeciated) and 28 Scedosporium apiospermum, 7 Scedosporium aurantiacum, and 28 Scedosporium prolificans species were identified by molecular techniques. Comparator antifungal agents included anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B. E1210 was highly active against all of the tested isolates, with minimum effective concentration (MEC)/MIC90 values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B, respectively, for Fusarium of 0.12, >16, >16, >8, >8, 8, and 4 μg/ml. E1210 was very potent against the Scedosporium spp. tested. The E1210 MEC90 was 0.12 μg/ml for S. apiospermum, but 1 to >8 μg/ml for other tested agents. Against S. aurantiacum, the MEC50 for E1210 was 0.06 μg/ml versus 0.5 to >8 μg/ml for the comparators. Against S. prolificans, the MEC90 for E1210 was only 0.12 μg/ml, compared to >4 μg/ml for amphotericin B and >8 μg/ml for itraconazole, posaconazole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparator agents. The essential agreement (EA; ±2 doubling dilutions) was >93% for all comparisons, with the exception of posaconazole and F. oxysporum species complex (SC) (60%), posaconazole and S. aurantiacum (85.7%), and voriconazole and S. aurantiacum (85.7%). In conclusion, E1210 exhibited very potent and broad-spectrum antifungal activity against azole- and amphotericin B-resistant strains of Fusarium spp. and Scedosporium spp. Furthermore, in vitro susceptibility testing of E1210 against isolates of Fusarium and Scedosporium may be accomplished using either of the CLSI or EUCAST BMD methods, each producing very similar results. PMID:22083469

Quantitative Analysis of Therapeutic Drugs in Dried Blood Spot Samples by Paper Spray Mass Spectrometry: An Avenue to Therapeutic Drug Monitoring

NASA Astrophysics Data System (ADS)

Manicke, Nicholas Edward; Abu-Rabie, Paul; Spooner, Neil; Ouyang, Zheng; Cooks, R. Graham

2011-09-01

A method is presented for the direct quantitative analysis of therapeutic drugs from dried blood spot samples by mass spectrometry. The method, paper spray mass spectrometry, generates gas phase ions directly from the blood card paper used to store dried blood samples without the need for complex sample preparation and separation; the entire time for preparation and analysis of blood samples is around 30 s. Limits of detection were investigated for a chemically diverse set of some 15 therapeutic drugs; hydrophobic and weakly basic drugs, such as sunitinib, citalopram, and verapamil, were found to be routinely detectable at approximately 1 ng/mL. Samples were prepared by addition of the drug to whole blood. Drug concentrations were measured quantitatively over several orders of magnitude, with accuracies within 10% of the expected value and relative standard deviation (RSD) of around 10% by prespotting an internal standard solution onto the paper prior to application of the blood sample. We have demonstrated that paper spray mass spectrometry can be used to quantitatively measure drug concentrations over the entire therapeutic range for a wide variety of drugs. The high quality analytical data obtained indicate that the technique may be a viable option for therapeutic drug monitoring.

Species distribution and antifungal susceptibility patterns of Candida isolates from a public tertiary teaching hospital in the Eastern Cape Province, South Africa.

PubMed

Mnge, P; Okeleye, B I; Vasaikar, S D; Apalata, T

2017-05-15

Candida species are the leading cause of invasive fungal infections, and over the past decade there has been an increased isolation of drug resistant Candida species. This study aimed to identify the species distribution of Candida isolates and to determine their unique antifungal susceptibility and resistance patterns. During a cross-sectional study, 209 Candida isolates (recovered from 206 clinical samples) were collected and their species distribution was determined using ChromAgar Candida. The Vitek-2 system (Biomerieux, South Africa) was used to determine minimum inhibitory concentrations (MICs) to azoles (fluconazole, voriconazole), echinocandins (caspofungin, micafungin), polyenes (amphotericin B) and flucytosine. Four species of Candida were isolated, of which C. albicans was the most frequent, isolated in 45.4% (95/209) of the isolates, followed by C. glabrata: 31.1% (65/209). The MICs of the different antifungal drugs varied amongst the species of Candida. From the 130 isolates tested for MICs, 90.77% (112/130) were susceptible to all antifungal drugs and 6.9% (9/130) of the isolates were multi-drug resistant. C. dubliniensis (n=2) isolates were susceptible to all the above mentioned antifungal drugs. There was no significant difference in species distribution amongst clinical specimens and between patients' genders (P>0.05). An increase in MIC values for fluconazole and flucytosine towards the resistance range was observed. To our knowledge, this is the first report on surveillance of Candida species distribution and antifungal susceptibility at a public tertiary teaching hospital in Eastern Cape, South Africa.

Therapeutic indications and other use-case-driven updates in the drug ontology: anti-malarials, anti-hypertensives, opioid analgesics, and a large term request.

PubMed

Hogan, William R; Hanna, Josh; Hicks, Amanda; Amirova, Samira; Bramblett, Baxter; Diller, Matthew; Enderez, Rodel; Modzelewski, Timothy; Vasconcelos, Mirela; Delcher, Chris

2017-03-03

The Drug Ontology (DrOn) is an OWL2-based representation of drug products and their ingredients, mechanisms of action, strengths, and dose forms. We originally created DrOn for use cases in comparative effectiveness research, primarily to identify historically complete sets of United States National Drug Codes (NDCs) that represent packaged drug products, by the ingredient(s), mechanism(s) of action, and so on contained in those products. Although we had designed DrOn from the outset to carefully distinguish those entities that have a therapeutic indication from those entities that have a molecular mechanism of action, we had not previously represented in DrOn any particular therapeutic indication. In this work, we add therapeutic indications for three research use cases: resistant hypertension, malaria, and opioid abuse research. We also added mechanisms of action for opioid analgesics and added 108 classes representing drug products in response to a large term request from the Program for Resistance, Immunology, Surveillance and Modeling of Malaria in Uganda (PRISM) project. The net result is a new version of DrOn, current to May 2016, that represents three major therapeutic classes of drugs and six new mechanisms of action. A therapeutic indication of a drug product is represented as a therapeutic function in DrOn. Adverse effects of drug products, as well as other therapeutic uses for which the drug product was not designed are dispositions. Our work provides a framework for representing additional therapeutic indications, adverse effects, and uses of drug products beyond their design. Our work also validated our past modeling decisions for specific types of mechanisms of action, namely effects mediated via receptor and/or enzyme binding. DrOn is available at: http://purl.obolibrary.org/obo/dron.owl . A smaller version without NDCs is available at: http://purl.obolibrary.org/obo/dron/dron-lite.owl.

Albumin Enhances Caspofungin Activity against Aspergillus Species by Facilitating Drug Delivery to Germinating Hyphae.

PubMed

Ioannou, Petros; Andrianaki, Aggeliki; Akoumianaki, Tonia; Kyrmizi, Irene; Albert, Nathaniel; Perlin, David; Samonis, George; Kontoyiannis, Dimitrios P; Chamilos, Georgios

2015-12-07

The modest in vitro activity of echinocandins against Aspergillus implies that host-related factors augment the action of these antifungal agents in vivo. We found that, in contrast to the other antifungal agents (voriconazole, amphotericin B) tested, caspofungin exhibited a profound increase in activity against various Aspergillus species under conditions of cell culture growth, as evidenced by a ≥4-fold decrease in minimum effective concentrations (MECs) (P = 0. 0005). Importantly, the enhanced activity of caspofungin against Aspergillus spp. under cell culture conditions was strictly dependent on serum albumin and was not observed with the other two echinocandins, micafungin and anidulafungin. Of interest, fluorescently labeled albumin bound preferentially on the surface of germinating Aspergillus hyphae, and this interaction was further enhanced upon treatment with caspofungin. In addition, supplementation of cell culture medium with albumin resulted in a significant, 5-fold increase in association of fluorescently labeled caspofungin with Aspergillus hyphae (P < 0.0001). Collectively, we found a novel synergistic interaction between albumin and caspofungin, with albumin acting as a potential carrier molecule to facilitate antifungal drug delivery to Aspergillus hyphae. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Photodynamic Therapy Combined with Terbinafine Against Chromoblastomycosis and the Effect of PDT on Fonsecaea monophora In Vitro

PubMed Central

Hu, Yongxuan; Huang, Xiaowen; Lu, Sha; Hamblin, Michael R.; Mylonakis, Eleftherios; Zhang, Junmin

2014-01-01

Chromoblastomycosis, a chronic fungal infection of skin and subcutaneous tissue caused by dematiaceous fungi, is associated with low cure and high relapse rates. Among all factors affecting clinical outcome, etiological agents have an important position. In southern China, Fonsecaea pedrosoi and Fonsecaea monophora are main causative agents causing Chromoblastomycosis. We treated one case of chromoblastomycosis by photodynamic therapy (PDT) of 5-aminolevulinic acid (ALA) irradiation combined with terbinafine 250 mg a day. The lesions were improved after two sessions of ALA-PDT treatment, each including nine times, at an interval of 1 week, combined with terbinafine 250 mg/day oral, and clinical improvement could be observed. In the following study, based on the clinical treatment, the effect of PDT and antifungal drugs on this isolate was detected in vitro. It showed sensitivity to terbinafine, itraconazole or voriconazole, and PDT inhibited the growth. Both the clinic and experiments in vitro confirm the good outcome of ALA-PDT applied in the inhibition of F. monophora. It demonstrated that combination of antifungal drugs with ALA-PDT arises as a promising alternative method for the treatment of these refractory cases of chromoblastomycosis. PMID:25366276

Exploring the associations between drug side-effects and therapeutic indications.

PubMed

Wang, Fei; Zhang, Ping; Cao, Nan; Hu, Jianying; Sorrentino, Robert

2014-10-01

Drug therapeutic indications and side-effects are both measurable patient phenotype changes in response to the treatment. Inferring potential drug therapeutic indications and identifying clinically interesting drug side-effects are both important and challenging tasks. Previous studies have utilized either chemical structures or protein targets to predict indications and side-effects. In this study, we compared drug therapeutic indication prediction using various information including chemical structures, protein targets and side-effects. We also compared drug side-effect prediction with various information sources including chemical structures, protein targets and therapeutic indication. Prediction performance based on 10-fold cross-validation demonstrates that drug side-effects and therapeutic indications are the most predictive information source for each other. In addition, we extracted 6706 statistically significant indication-side-effect associations from all known drug-disease and drug-side-effect relationships. We further developed a novel user interface that allows the user to interactively explore these associations in the form of a dynamic bipartitie graph. Many relationship pairs provide explicit repositioning hypotheses (e.g., drugs causing postural hypotension are potential candidates for hypertension) and clear adverse-reaction watch lists (e.g., drugs for heart failure possibly cause impotence). All data sets and highly correlated disease-side-effect relationships are available at http://astro.temple.edu/∼tua87106/druganalysis.html. Copyright © 2014 Elsevier Inc. All rights reserved.

Issues in formulary management: therapeutic interchange. The value, cost, and quality of therapeutic interchange.

PubMed

Mahoney, C D

1992-10-01

Therapeutic interchange is a process of substituting a prescribed medication with one that offers therapeutic and cost benefits. The practice not only provides short-term savings but also is associated with decreases in lengths of stay in hospitals and total hospital drug expenses. There may be medicolegal implications when FDA-approved indications differ for interchanged drugs. The potential for liability is decreased when a standard of care is met, but since standards can change, guidelines should be reviewed regularly. High-tech, high-cost drugs are sometimes appropriate for therapeutic interchange. Pharmacy and therapeutics committees should assure best value by considering indirect expenses, quality, and therapeutic outcome, as well as product cost. Therapeutic interchange programs enable pharmacy managers to neutralize or at least slow the rate of drug cost increases, ensuring appropriate utilization of resources and more favorable patient outcomes.

Therapeutic effects of drug-nutrient interactions in the elderly.

PubMed

Roe, D A

1985-02-01

The elderly are the major drug users both because they need specific prescription drugs for control of chronic diseases and because they make excessive use of over-the-counter (OTC) drugs. Therapeutic drugs that are required may be discontinued because the individuals suffer side effects or because the drug is ineffective. Adverse drug reactions in the elderly may result from drug overuse or misuse, slowed drug metabolism or elimination secondary to aging or to age-related chronic disease, intake of alcohol, food-drug incompatibilities, or nutrient-drug interactions. The timing of drug intake in relation to food intake is an important determinant of therapeutic efficacy in the elderly. Food-drug interactions in the gastrointestinal tract may reduce drug absorption. Enteral formula feeding may also interfere with drug absorption. Conversely, absorption of certain drugs (e.g., thiazides) may be promoted by meal-induced slowing of gastric emptying time. Therapeutic diet prescription can influence drug responses in the elderly because the protein composition of the diet influences the rate of drug metabolism. Nutrient depletion secondary to the effect of drugs may be recognized as an important and often avoidable type of adverse drug reaction.

An innovative and highly drug-tolerant approach for detecting neutralizing antibodies directed to therapeutic antibodies.

PubMed

Sloan, John H; Conway, Richard G; Pottanat, Thomas G; Troutt, Jason S; Higgs, Richard E; Konrad, Robert J; Qian, Yue-Wei

2016-10-01

Immunogenicity testing of biotherapeutic drugs is a regulatory requirement. Herein, we describe a drug-tolerant assay for detecting neutralizing antibodies against a therapeutic antibody. Excess target of the therapeutic antibody was incorporated into the detection step of an affinity capture elution assay. Signal generated from binding of antidrug antibody (ADA) to the therapeutic antibody was compared with signal from binding of ADA to the therapeutic antibody preincubated with its target. The results demonstrated that the target blocked binding of the therapeutic antibody to neutralizing monkey ADA and to two anti-idiotypic antibodies. This highly drug-tolerant novel approach enables the detection of neutralizing antibodies and allows for one basic assay format to achieve complete characterization of ADA responses.

Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment.

PubMed

Phi, Lan Thi Hanh; Sari, Ita Novita; Yang, Ying-Gui; Lee, Sang-Hyun; Jun, Nayoung; Kim, Kwang Seock; Lee, Yun Kyung; Kwon, Hyog Young

2018-01-01

Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are suggested to be responsible for drug resistance and cancer relapse due in part to their ability to self-renew themselves and differentiate into heterogeneous lineages of cancer cells. Thus, it is important to understand the characteristics and mechanisms by which CSCs display resistance to therapeutic agents. In this review, we highlight the key features and mechanisms that regulate CSC function in drug resistance as well as recent breakthroughs of therapeutic approaches for targeting CSCs. This promises new insights of CSCs in drug resistance and provides better therapeutic rationales to accompany novel anticancer therapeutics.

A reinforcement-based therapeutic workplace for the treatment of drug abuse: six-month abstinence outcomes.

PubMed

Silverman, K; Svikis, D; Robles, E; Stitzer, M L; Bigelow, G E

2001-02-01

This study evaluated a novel drug abuse treatment, the Therapeutic Workplace. In this treatment, patients are paid to perform jobs or to participate in job training. Salary is linked to abstinence by requiring patients to provide drug-free urine samples to gain access to the workplace. Pregnant and postpartum drug abuse patients (N = 40) were randomly assigned to a Therapeutic Workplace or usual care control group. Therapeutic Workplace participants were invited to work 3 hr every weekday for 6 months and could earn up to $4,030 in vouchers for abstinence, workplace attendance, and performance. On average, 45% of participants attended the workplace per day. Relative to controls, the Therapeutic Workplace nearly doubled patients' abstinence from opiates and cocaine (33% vs. 59% of thrice-weekly urine samples drug negative, respectively, p < .05). The Therapeutic Workplace can effectively treat heroin and cocaine abuse in pregnant and postpartum women.

[Customizing dosage drugs what contribution in therapeutic drug monitoring?].

PubMed

Abdessadek, Mohammed; Magoul, Rabia; Amarti, Afaf; El Ouezzani, Seloua; Khabbal, Youssef

2014-01-01

Drug response is often variable from an individual to another: the same dose of drug administered to different patients could cause variable pharmacological effects in nature and intensity. Those effects are often the result of variability in drugs pharmacokinetics (absorption, distribution, metabolism and elimination) which alter their bioavailability. In fact, two factors should be taken into account: the disease(s) from which the patient suffers, and the associated drugs, because many drug interactions may alter their pharmacokinetics causing consequently quite enough of different therapeutic effects. The choice of the assay of the drug subject in monitoring is crucial, it allows quantifying the in vivo dose of the drug and the quality of compliance thereof, the pharmacokinetic characteristics allows the clinician to adjust the dosage by different approaches so that plasma concentrations are included in the therapeutic range. Therapeutic monitoring aims to increase clinical efficacy and to minimize toxicity.

Chicanoizing the Therapeutic Community

ERIC Educational Resources Information Center

Aron, William S.; And Others

1974-01-01

Focusing on the drug addiction problem and its antecedent conditions in a Chicano population, the article examines several therapeutic interventions suggested by these conditions and indicates how they might be incorporated into a drug addiction Therapeutic Community treatment program designed to meet the needs of Chicano drug addicts. (Author/NQ)

The role of drug efflux pumps in Malassezia pachydermatis and Malassezia furfur defence against azoles.

PubMed

Iatta, Roberta; Puttilli, Maria Rita; Immediato, Davide; Otranto, Domenico; Cafarchia, Claudia

2017-03-01

This study aims to evaluate the effect of efflux pump modulators (EPMs) on the minimal inhibitory concentration (MIC) of fluconazole (FLZ) and voriconazole (VOR) in Malassezia furfur and Malassezia pachydermatis. The in vitro efficacy of azoles, in combination with EPMs (ie haloperidol-HAL, promethazine-PTZ and cyclosporine A-CYS), against 21 M. furfur from bloodstream infection patients and 14 M. pachydermatis from the skin of dogs with dermatitis, was assessed using a broth microdilution chequerboard analysis. Data were analysed using the model-fractional inhibitory concentration index (FICI) method. The MIC of FLZ and VOR of Malassezia spp. decreased in the presence of sub-inhibitory concentrations of HAL and/or PTZ. The synergic effect was observed only in strains with FLZ MIC≥128 μg/mL for M. furfur, FLZ MIC≥64 μg/mL for M. pachydermatis and VOR MIC≥4 μg/mL in both Malassezia spp. These results suggest that the drug efflux pumps are involved as defence mechanisms to azole drugs in Malassezia yeast. The synergism might be related to an increased expression of efflux pump genes, eventually resulting in azole resistance phenomena. Finally, the above FLZ and VOR MIC values might be considered the cut-off to discriminate susceptible and resistant strains. © 2016 Blackwell Verlag GmbH.

Recent Progress in Functional Micellar Carriers with Intrinsic Therapeutic Activities for Anticancer Drug Delivery.

PubMed

Qu, Ying; Chu, BingYang; Shi, Kun; Peng, JinRong; Qian, ZhiYong

2017-12-01

Polymeric micelles have presented superior delivery properties for poorly water-soluble chemotherapeutic agents. However, it remains discouraging that there may be some additional short or long-term toxicities caused by the metabolites of high quantities of carriers. If carriers had simultaneous therapeutic effects with the drug, these issues would not be a concern. For this, carriers not only simply act as drug carriers, but also exert an intrinsic therapeutic effect as a therapeutic agent. The functional micellar carriers would be beneficial to maximize the anticancer effect, overcome the drug resistance and reduce the systemic toxicity. In this review, we aim to summarize the recent progress on the development of functional micellar carriers with intrinsic anticancer activities for the delivery of anticancer drugs. This review focuses on the design strategies, properties of carriers and the drug loading behavior. In addition, the combinational therapeutic effects between carriers and chemotherapeutic agents are also discussed.

Predictors of therapeutic engagement in prison-based drug treatment.

PubMed

Welsh, Wayne N; McGrain, Patrick N

2008-08-01

Few studies to date have examined predictors of therapeutic engagement (TE) or other indicators of responsiveness to prison drug treatment. Subjects were 347 inmates participating in a 12-month modified therapeutic community (TC) drug treatment program at a specialized treatment prison for convicted, drug-involved offenders. Data were obtained through correctional databases and the administration of the TCU Drug Screen II, the Resident Evaluation of Self and Treatment (REST), and the Counselor Rating of Client (CRC) form. Three main hypotheses were supported: (1) baseline motivation predicted therapeutic engagement net of other inmate characteristics; (2) critical dimensions of the treatment experience (e.g., peer support, counselor rapport) also predicted therapeutic engagement; and (3) dynamic predictors and programmatic characteristics became more important over time. Implications for research, theory and policy are discussed.

Bridging Services: Drug Abuse, Human Services and the Therapeutic Community. Proceedings of the World Conference of Therapeutic Communities (9th, San Francisco, California, September 1-6, 1985).

ERIC Educational Resources Information Center

Acampora, Alfonso P., Ed.; Nebelkopf, Ethan, Ed.

The World Federation of Therapeutic Communities is an international association of drug treatment centers that use the "Therapeutic Community" (TC) to combat chemical dependency and drug addiction. Their 1985 conference focused on bridging services between the TC and the traditional human service systems. A total of 85 separate papers were…

Anticonvulsants

NASA Astrophysics Data System (ADS)

Kabra, Pokar M.; Stafford, Brian E.; McDonald, Donna M.; Marton, Laurence J.

Until recently, it was difficult to explain why an identical drug dosage may exert a toxic effect in one patient and a therapeutic, or no, response in another patient. It has now been demonstrated that the concentration of drug at the tissue receptor site is the most important parameter for adjusting drug dosage. However, the concentration of drug at the receptor site cannot be measured directly, and must therefore be correlated with the concentration of drug in body fluids in contact with these tissue receptors. The ability to correlate plasma drug concentration with tissue concentrations and with therapeutic or toxic effects has enabled those interested in optimizing drug dosages to generate much of the information needed to make useful therapeutic decisions. The exact nature of drug-receptor interactions is not firmly established. It is, however, known that the concentration of free drug correlates best with therapeutic effect. The free drug in plasma is in equilibrium with protein-bound drug and, because of this relationship, it is important to understand to what extent a particular drug is protein-bound. Various attempts to measure free drug concentration in saliva (1) and cerebrospinal fluid (2) have been reported.

A Comparative Study on the Cost of New Antibiotics and Drugs of Other Therapeutic Categories

PubMed Central

Falagas, Matthew E.; Fragoulis, Konstantinos N.; Karydis, Ioannis

2006-01-01

Background Drug treatment is becoming more expensive due to the increased cost for the introduction of new drugs, and there seems to be an uneven distribution of medication cost for different therapeutic categories. We hypothesized that the cost of new antimicrobial agents may differ from that of other therapeutic categories and this may play a role in the stagnation of development of new antibiotics. Methodology/Principal Findings We performed a pharmaco-economical comparative analysis of the drug cost of treatment for new agents introduced in the United States drug market in various therapeutic categories. We calculated the drug cost (in US dollars) of a ten-day treatment of all new drugs approved by the FDA during the period between January 1997 and July 2003, according to the 2004 Red Book Pharmacy's Fundamental Reference. New anti-neoplastic agents were found to be the most expensive drugs in comparison to all other therapeutic categories, with a median ten-day drug-treatment cost of US$848 compared to the median ten-day drug-treatment costs of all other categories ranging from US$29 to US$301. On the other hand, new antimicrobial drugs were found to be much less expensive, with a median ten-day drug-treatment cost of US$137 and $US85 for all anti-microbial agents and for anti-microbial agents excluding anti-HIV medications, respectively. Conclusions/Significance The drug-treatment cost of new medications varies considerably by different therapeutic categories. This fact may influence industry decisions regarding the development of new drugs and may play a role in the shortage of new antimicrobial agents in the fight against the serious problem of antimicrobial resistance. PMID:17183637

A comparative study on the cost of new antibiotics and drugs of other therapeutic categories.

PubMed

Falagas, Matthew E; Fragoulis, Konstantinos N; Karydis, Ioannis

2006-12-20

Drug treatment is becoming more expensive due to the increased cost for the introduction of new drugs, and there seems to be an uneven distribution of medication cost for different therapeutic categories. We hypothesized that the cost of new antimicrobial agents may differ from that of other therapeutic categories and this may play a role in the stagnation of development of new antibiotics. We performed a pharmaco-economical comparative analysis of the drug cost of treatment for new agents introduced in the United States drug market in various therapeutic categories. We calculated the drug cost (in US dollars) of a ten-day treatment of all new drugs approved by the FDA during the period between January 1997 and July 2003, according to the 2004 Red Book Pharmacy's Fundamental Reference. New anti-neoplastic agents were found to be the most expensive drugs in comparison to all other therapeutic categories, with a median ten-day drug-treatment cost of US$848 compared to the median ten-day drug-treatment costs of all other categories ranging from US$29 to US$301. On the other hand, new antimicrobial drugs were found to be much less expensive, with a median ten-day drug-treatment cost of US$137 and $US85 for all anti-microbial agents and for anti-microbial agents excluding anti-HIV medications, respectively. The drug-treatment cost of new medications varies considerably by different therapeutic categories. This fact may influence industry decisions regarding the development of new drugs and may play a role in the shortage of new antimicrobial agents in the fight against the serious problem of antimicrobial resistance.

Epidemiology of candidemia and antifungal susceptibility in invasive Candida species in the Asia-Pacific region.

PubMed

Wang, He; Xu, Ying-Chun; Hsueh, Po-Ren

2016-10-01

In the Asia-Pacific region, Candida albicans is the predominant Candida species causing invasive candidiasis/candidemia in Australia, Japan, Korea, Hong Kong, Malaysia, Singapore and Thailand whereas C. tropicalis is the most frequently encountered Candida species in Pakistan and India. Invasive isolates of C. albicans, C. parapsilosis complex and C. tropicalis remain highly susceptible to fluconazole (>90% susceptible). Fluconazole resistance (6.8-15%), isolates with the non-wild-type phenotype for itraconazole susceptibility (3.9-10%) and voriconazole (5-17.8%), and echinocandin resistance (2.1-2.2% in anidulafungin and 2.2% in micafungin) among invasive C. glabrata complex isolates are increasing in prevalence. Moreover, not all isolates of C. tropicalis have been shown to be susceptible to fluconazole (nonsusceptible rate, 5.7-11.6% in China) or voriconazole (nonsusceptible rate, 5.7-9.6% in China).

Management of Aspergillus osteomyelitis: report of failure of liposomal amphotericin B and response to voriconazole in an immunocompetent host and literature review.

PubMed

Stratov, I; Korman, T M; Johnson, P D R

2003-05-01

Presented here is a case of Aspergillus osteomyelitis in an immunocompetent patient that progressed despite surgery and prolonged treatment with liposomal amphotericin B; the report is followed by a review of the literature. The review of this case and 41 similar cases found an overall cure rate of 69%. The importance of surgery when amphotericin B is used as first-line therapy is indicated by a 14% cure rate when amphotericin B is used alone compared to 75% when combined with surgery. When therapy is failing or surgery is contraindicated, dose escalation using a lipid formulation was not effective. On review, the addition of another agent, in particular 5-fluorocytosine, appears to be more beneficial. The patient reported here responded rapidly to voriconazole, a promising new antifungal agent for Aspergillus infections.

TR34/L98H Mutation in CYP51A Gene in Aspergillus fumigatus Clinical Isolates During Posaconazole Prophylaxis: First Case in Korea.

PubMed

Lee, Hyeon-Jeong; Cho, Sung-Yeon; Lee, Dong-Gun; Park, Chulmin; Chun, Hye-Sun; Park, Yeon-Joon

2018-06-01

Azole resistance in Aspergillus fumigatus is an emerging problem, especially in immunocompromised patients. It has been reported worldwide, including in Asia, but has not yet been reported in Korea. Here, we report a case of invasive pulmonary aspergillosis (IPA) caused by azole-resistant A. fumigatus that developed in a hematopoietic stem cell transplantation recipient during posaconazole prophylaxis for immunosuppressive therapy of graft-versus-host diseases. We identified TR34/L98H/S297T/F495L mutation in the CYP51A gene of A. fumigatus clinical isolate obtained from bronchial washing fluid. Minimal inhibitory concentrations for itraconazole, voriconazole, and posaconazole were > 16, 1, and 4 μg/mL, respectively. While IPA improved partially under voriconazole treatment, the patient died from carbapenemase-producing Klebsiella pneumoniae bacteremia. Further epidemiological surveillance studies are warranted.

21 CFR 884.5940 - Powered vaginal muscle stimulator for therapeutic use.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Powered vaginal muscle stimulator for therapeutic use. 884.5940 Section 884.5940 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... for therapeutic use in increasing muscular tone and strength in the treatment of sexual dysfunction...

21 CFR 884.5940 - Powered vaginal muscle stimulator for therapeutic use.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Powered vaginal muscle stimulator for therapeutic use. 884.5940 Section 884.5940 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... for therapeutic use in increasing muscular tone and strength in the treatment of sexual dysfunction...

21 CFR 884.5940 - Powered vaginal muscle stimulator for therapeutic use.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Powered vaginal muscle stimulator for therapeutic use. 884.5940 Section 884.5940 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... for therapeutic use in increasing muscular tone and strength in the treatment of sexual dysfunction...

21 CFR 884.5940 - Powered vaginal muscle stimulator for therapeutic use.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Powered vaginal muscle stimulator for therapeutic use. 884.5940 Section 884.5940 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... for therapeutic use in increasing muscular tone and strength in the treatment of sexual dysfunction...

21 CFR 884.5940 - Powered vaginal muscle stimulator for therapeutic use.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Powered vaginal muscle stimulator for therapeutic use. 884.5940 Section 884.5940 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... for therapeutic use in increasing muscular tone and strength in the treatment of sexual dysfunction...

Double loaded self-decomposable SiO2 nanoparticles for sustained drug release

NASA Astrophysics Data System (ADS)

Zhao, Saisai; Zhang, Silu; Ma, Jiang; Fan, Li; Yin, Chun; Lin, Ge; Li, Quan

2015-10-01

Sustained drug release for a long duration is a desired feature of modern drugs. Using double-loaded self-decomposable SiO2 nanoparticles, we demonstrated sustained drug release in a controllable manner. The double loading of the drugs was achieved using two different mechanisms--the first one via a co-growth mechanism, and the second one by absorption. A two-phase sustained drug release was firstly revealed in an in vitro system, and then further demonstrated in mice. After a single intravenous injection, the drug was controllably released from the nanoparticles into blood circulation with a Tmax of about 8 h, afterwards a long lasting release pattern was achieved to maintain drug systemic exposure with a plasma elimination half-life of approximately 28 h. We disclosed that the absorbed drug molecules contributed to the initial fast release for quickly reaching the therapeutic level with relatively higher plasma concentrations, while the ``grown-in'' drugs were responsible for maintaining the therapeutic level via the later controlled slow and sustained release. The present nanoparticle carrier drug configuration and the loading/maintenance release mechanisms provide a promising platform that ensures a prolonged therapeutic effect by controlling drug concentrations within the therapeutic window--a sustained drug delivery system with a great impact on improving the management of chronic diseases.Sustained drug release for a long duration is a desired feature of modern drugs. Using double-loaded self-decomposable SiO2 nanoparticles, we demonstrated sustained drug release in a controllable manner. The double loading of the drugs was achieved using two different mechanisms--the first one via a co-growth mechanism, and the second one by absorption. A two-phase sustained drug release was firstly revealed in an in vitro system, and then further demonstrated in mice. After a single intravenous injection, the drug was controllably released from the nanoparticles into blood circulation with a Tmax of about 8 h, afterwards a long lasting release pattern was achieved to maintain drug systemic exposure with a plasma elimination half-life of approximately 28 h. We disclosed that the absorbed drug molecules contributed to the initial fast release for quickly reaching the therapeutic level with relatively higher plasma concentrations, while the ``grown-in'' drugs were responsible for maintaining the therapeutic level via the later controlled slow and sustained release. The present nanoparticle carrier drug configuration and the loading/maintenance release mechanisms provide a promising platform that ensures a prolonged therapeutic effect by controlling drug concentrations within the therapeutic window--a sustained drug delivery system with a great impact on improving the management of chronic diseases. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr03029c

Azole-Resistance in Aspergillus terreus and Related Species: An Emerging Problem or a Rare Phenomenon?

PubMed

Zoran, Tamara; Sartori, Bettina; Sappl, Laura; Aigner, Maria; Sánchez-Reus, Ferran; Rezusta, Antonio; Chowdhary, Anuradha; Taj-Aldeen, Saad J; Arendrup, Maiken C; Oliveri, Salvatore; Kontoyiannis, Dimitrios P; Alastruey-Izquierdo, Ana; Lagrou, Katrien; Cascio, Giuliana Lo; Meis, Jacques F; Buzina, Walter; Farina, Claudio; Drogari-Apiranthitou, Miranda; Grancini, Anna; Tortorano, Anna M; Willinger, Birgit; Hamprecht, Axel; Johnson, Elizabeth; Klingspor, Lena; Arsic-Arsenijevic, Valentina; Cornely, Oliver A; Meletiadis, Joseph; Prammer, Wolfgang; Tullio, Vivian; Vehreschild, Jörg-Janne; Trovato, Laura; Lewis, Russell E; Segal, Esther; Rath, Peter-Michael; Hamal, Petr; Rodriguez-Iglesias, Manuel; Roilides, Emmanuel; Arikan-Akdagli, Sevtap; Chakrabarti, Arunaloke; Colombo, Arnaldo L; Fernández, Mariana S; Martin-Gomez, M Teresa; Badali, Hamid; Petrikkos, Georgios; Klimko, Nikolai; Heimann, Sebastian M; Uzun, Omrum; Roudbary, Maryam; de la Fuente, Sonia; Houbraken, Jos; Risslegger, Brigitte; Lass-Flörl, Cornelia; Lackner, Michaela

2018-01-01

Objectives: Invasive mold infections associated with Aspergillus species are a significant cause of mortality in immunocompromised patients. The most frequently occurring aetiological pathogens are members of the Aspergillus section Fumigati followed by members of the section Terrei . The frequency of Aspergillus terreus and related (cryptic) species in clinical specimens, as well as the percentage of azole-resistant strains remains to be studied. Methods: A global set ( n = 498) of A. terreus and phenotypically related isolates was molecularly identified (beta-tubulin), tested for antifungal susceptibility against posaconazole, voriconazole, and itraconazole, and resistant phenotypes were correlated with point mutations in the cyp51A gene. Results: The majority of isolates was identified as A. terreus (86.8%), followed by A. citrinoterreus (8.4%), A. hortai (2.6%), A. alabamensis (1.6%), A. neoafricanus (0.2%), and A. floccosus (0.2%). One isolate failed to match a known Aspergillus sp., but was found most closely related to A. alabamensis . According to EUCAST clinical breakpoints azole resistance was detected in 5.4% of all tested isolates, 6.2% of A. terreus sensu stricto (s.s.) were posaconazole-resistant. Posaconazole resistance differed geographically and ranged from 0% in the Czech Republic, Greece, and Turkey to 13.7% in Germany. In contrast, azole resistance among cryptic species was rare 2 out of 66 isolates and was observed only in one A. citrinoterreus and one A. alabamensis isolate. The most affected amino acid position of the Cyp51A gene correlating with the posaconazole resistant phenotype was M217, which was found in the variation M217T and M217V. Conclusions: Aspergillus terreus was most prevalent, followed by A. citrinoterreus . Posaconazole was the most potent drug against A. terreus , but 5.4% of A. terreus sensu stricto showed resistance against this azole. In Austria, Germany, and the United Kingdom posaconazole-resistance in all A. terreus isolates was higher than 10%, resistance against voriconazole was rare and absent for itraconazole.

Azole-Resistance in Aspergillus terreus and Related Species: An Emerging Problem or a Rare Phenomenon?

PubMed Central

Zoran, Tamara; Sartori, Bettina; Sappl, Laura; Aigner, Maria; Sánchez-Reus, Ferran; Rezusta, Antonio; Chowdhary, Anuradha; Taj-Aldeen, Saad J.; Arendrup, Maiken C.; Oliveri, Salvatore; Kontoyiannis, Dimitrios P.; Alastruey-Izquierdo, Ana; Lagrou, Katrien; Cascio, Giuliana Lo; Meis, Jacques F.; Buzina, Walter; Farina, Claudio; Drogari-Apiranthitou, Miranda; Grancini, Anna; Tortorano, Anna M.; Willinger, Birgit; Hamprecht, Axel; Johnson, Elizabeth; Klingspor, Lena; Arsic-Arsenijevic, Valentina; Cornely, Oliver A.; Meletiadis, Joseph; Prammer, Wolfgang; Tullio, Vivian; Vehreschild, Jörg-Janne; Trovato, Laura; Lewis, Russell E.; Segal, Esther; Rath, Peter-Michael; Hamal, Petr; Rodriguez-Iglesias, Manuel; Roilides, Emmanuel; Arikan-Akdagli, Sevtap; Chakrabarti, Arunaloke; Colombo, Arnaldo L.; Fernández, Mariana S.; Martin-Gomez, M. Teresa; Badali, Hamid; Petrikkos, Georgios; Klimko, Nikolai; Heimann, Sebastian M.; Uzun, Omrum; Roudbary, Maryam; de la Fuente, Sonia; Houbraken, Jos; Risslegger, Brigitte; Lass-Flörl, Cornelia; Lackner, Michaela

2018-01-01

Objectives: Invasive mold infections associated with Aspergillus species are a significant cause of mortality in immunocompromised patients. The most frequently occurring aetiological pathogens are members of the Aspergillus section Fumigati followed by members of the section Terrei. The frequency of Aspergillus terreus and related (cryptic) species in clinical specimens, as well as the percentage of azole-resistant strains remains to be studied. Methods: A global set (n = 498) of A. terreus and phenotypically related isolates was molecularly identified (beta-tubulin), tested for antifungal susceptibility against posaconazole, voriconazole, and itraconazole, and resistant phenotypes were correlated with point mutations in the cyp51A gene. Results: The majority of isolates was identified as A. terreus (86.8%), followed by A. citrinoterreus (8.4%), A. hortai (2.6%), A. alabamensis (1.6%), A. neoafricanus (0.2%), and A. floccosus (0.2%). One isolate failed to match a known Aspergillus sp., but was found most closely related to A. alabamensis. According to EUCAST clinical breakpoints azole resistance was detected in 5.4% of all tested isolates, 6.2% of A. terreus sensu stricto (s.s.) were posaconazole-resistant. Posaconazole resistance differed geographically and ranged from 0% in the Czech Republic, Greece, and Turkey to 13.7% in Germany. In contrast, azole resistance among cryptic species was rare 2 out of 66 isolates and was observed only in one A. citrinoterreus and one A. alabamensis isolate. The most affected amino acid position of the Cyp51A gene correlating with the posaconazole resistant phenotype was M217, which was found in the variation M217T and M217V. Conclusions: Aspergillus terreus was most prevalent, followed by A. citrinoterreus. Posaconazole was the most potent drug against A. terreus, but 5.4% of A. terreus sensu stricto showed resistance against this azole. In Austria, Germany, and the United Kingdom posaconazole-resistance in all A. terreus isolates was higher than 10%, resistance against voriconazole was rare and absent for itraconazole. PMID:29643840

[Analysis of the pathogenic characteristics of 162 severely burned patients with bloodstream infection].

PubMed

Gong, Y L; Yang, Z C; Yin, S P; Liu, M X; Zhang, C; Luo, X Q; Peng, Y Z

2016-09-20

To analyze the distribution and drug resistance of pathogen isolated from severely burned patients with bloodstream infection, so as to provide reference for the clinical treatment of these patients. Blood samples of 162 severely burned patients (including 120 patients with extremely severe burn) with bloodstream infection admitted into our burn ICU from January 2011 to December 2014 were collected. Pathogens were cultured by fully automatic blood culture system, and API bacteria identification panels were used to identify pathogen. Kirby-Bauer paper disk diffusion method was used to detect the drug resistance of major Gram-negative and -positive bacteria to 37 antibiotics including ampicillin, piperacillin and teicoplanin, etc. (resistance to vancomycin was detected by E test), and drug resistance of fungi to 5 antibiotics including voriconazole and amphotericin B, etc. Modified Hodge test was used to further identify imipenem and meropenem resistant Klebsiella pneumonia. D test was used to detect erythromycin-induced clindamycin resistant Staphylococcus aureus. The pathogen distribution and drug resistance rate were analyzed by WHONET 5.5. Mortality rate and infected pathogens of patients with extremely severe burn and patients with non-extremely severe burn were recorded. Data were processed with Wilcoxon rank sum test. (1) Totally 1 658 blood samples were collected during the four years, and 339 (20.4%) strains of pathogens were isolated. The isolation rate of Gram-negative bacteria, Gram-positive bacteria, and fungi were 68.4% (232/339), 24.5% (83/339), and 7.1% (24/339), respectively. The top three pathogens with isolation rate from high to low were Acinetobacter baumannii, Staphylococcus aureus, and Pseudomonas aeruginosa in turn. (2) Except for the low drug resistance rate to polymyxin B and minocycline, drug resistance rate of Acinetobacter baumannii to the other antibiotics were relatively high (81.0%-100.0%). Pseudomonas aeruginosa was sensitive to polymyxin B but highly resistant to other antibiotics (57.7%-100.0%). Enterobacter cloacae was sensitive to imipenem and meropenem, while its drug resistance rates to ciprofloxacin, levofloxacin, cefoperazone/sulbactam, cefepime, piperacillin/tazobactam were 25.0%-49.0%, and those to the other antibiotics were 66.7%-100.0%. Drug resistance rates of Klebsiella pneumoniae to cefoperazone/sulbactam, imipenem, and meropenem were low (5.9%-15.6%, two imipenem- and meropenem-resistant strains were identified by modified Hodge test), while its drug resistance rates to amoxicillin/clavulanic acid, piperacillin/tazobactam, cefepime, cefoxitin, amikacin, levofloxacin were 35.3%-47.1%, and those to the other antibiotics were 50.0%-100.0%. (3) Drug resistance rates of methicillin-resistant Staphylococcus aureus (MRSA) to most of the antibiotics were higher than those of the methicillin-sensitive Staphylococcus aureus (MSSA). MRSA was sensitive to linezolid, vancomycin, and teicoplanin, while its drug resistance rates to compound sulfamethoxazole, clindamycin, minocycline, and erythromycin were 5.3%-31.6%, and those to the other antibiotics were 81.6%-100.0%. Except for totally resistant to penicillin G and tetracycline, MSSA was sensitive to the other antibiotics. Fourteen Staphylococcus aureus strains were resistant to erythromycin-induced clindamycin. Enterococcus was sensitive to vancomycin and teicoplanin, while its drug resistance rates to linezolid, chloramphenicol, nitrofurantoin, and high unit gentamicin were low (10.0%-30.0%), and those to ciprofloxacin, erythromycin, minocycline, and ampicillin were high (60.0%-80.0%). Enterococcus was fully resistant to rifampicin. (4) Fungi was sensitive to amphotericin B, and drug resistance rates of fungi to voriconazole, fluconazole, itraconazole, and ketoconazole were 7.2%-12.5%. (5) The mortality of patients with extremely severe burn was higher than that of patients with non-extremely severe burn. The variety of infected pathogens in patients with extremely severe burn significantly outnumbered that in patients with non-extremely severe burn (Z=-2.985, P=0.005). The variety of pathogen in severely burned patients with bloodstream infection is wide, with the main pathogens as Acinetobacter baumannii, Staphylococcus aureus, and Pseudomonas aeruginosa, and the drug resistance situation is grim. The types of infected pathogen in patients with extremely severe burn are more complex, and the mortality of these patients is higher when compared with that of patients with non-extremely severe burn.

Recent Progress in Nanomedicine: Therapeutic, Diagnostic and Theranostic Applications

PubMed Central

Rizzo, Larissa Y.; Theek, Benjamin; Storm, Gert; Kiessling, Fabian; Lammers, Twan

2013-01-01

In recent years, the use of nanomedicine formulations for therapeutic and diagnostic applications has increased exponentially. Many different systems and strategies have been developed for drug targeting to pathological sites, as well as for visualizing and quantifying important (patho-) physiological processes. In addition, ever more efforts have been undertaken to combine diagnostic and therapeutic properties within a single nanomedicine formulation. These so-called nanotheranostics are able to provide valuable information on drug delivery, drug release and drug efficacy, and they are considered to be highly useful for personalizing nanomedicine-based (chemo-) therapeutic interventions. PMID:23578464

The Therapeutic Effect of the Antitumor Drug 11beta and Related Molecules on Polycystic Kidney Disease

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-15-1-0364 TITLE: The Therapeutic Effect of the Antitumor Drug 11beta and Related Molecules on Polycystic Kidney Disease...SUBTITLE The Therapeutic Effect of the Antitumor Drug 11beta and Related Molecules on Polycystic Kidney Disease 5a. CONTRACT NUMBER 5b. GRANT NUMBER...synthetic multifunctional compounds as therapeutics for polycystic kidney disease (PKD). In collaboration with the Essigmann lab at MIT, we have

Human tumor xenografts in mouse as a model for evaluating therapeutic efficacy of monoclonal antibodies or antibody-drug conjugate targeting receptor tyrosine kinases.

PubMed

Feng, Liang; Wang, Wei; Yao, Hang-Ping; Zhou, Jianwei; Zhang, Ruiwen; Wang, Ming-Hai

2015-01-01

Targeting receptor tyrosine kinases by therapeutic monoclonal antibodies and antibody-drug conjugates has met with tremendous success in clinical oncology. Currently, numerous therapeutic monoclonal antibodies are under preclinical development. The potential for moving candidate antibodies into clinical trials relies heavily on therapeutic efficacy validated by human tumor xenografts in mice. Here we describe methods used to determine therapeutic efficacy of monoclonal antibodies or antibody-drug conjugates specific to human receptor tyrosine kinase using human tumor xenografts in mice as the model. The end point of the study is to determine whether treatment of tumor-bearing mice with a monoclonal antibody or antibody-drug conjugates results in significant delay of tumor growth.

Factors influencing neonatal therapeutic effect of anti-MRSA drugs.

PubMed

Hayashi, H; Matsuzaki, T; Saito, A; Shimizu, M; Matsumoto, Y

2005-07-01

Factors influencing the neonatal therapeutic effect of anti-MRSA (methicillin-resistant Staphylococcus aureus) drugs are investigated. This study took place over a two-year period from April 1998 to March 2000. We calculated the non-adjusted odds ratio for each influential factor to determine the therapeutic effect of anti-MRSA drugs. Significant factors for therapeutic effect were found to be platelet count, urea nitrogen, creatinine, and CRP, each measured before starting administration of anti-MRSA drugs; whether blood drug concentration was measured; and whether pneumonia or septicemia was present. There was a tendency where a better therapeutic effect was gained when the total protein and albumin values were high. We applied multivariate logistic regression analysis to these factors, and found the following independent significant factors: CRP (odds ratio (OR) = 1.582), albumin (OR = 3.079), Cre (OR -0.213), whether blood drug concentration was measured (OR = 3.767), and presence of pneumonia or septicemia (OR = 0.216). This result suggests that consideration should be given to these five important factors when treating MRSA patients.

Environmental pollution with antimicrobial agents from bulk drug manufacturing industries in Hyderabad, South India, is associated with dissemination of extended-spectrum beta-lactamase and carbapenemase-producing pathogens.

PubMed

Lübbert, Christoph; Baars, Christian; Dayakar, Anil; Lippmann, Norman; Rodloff, Arne C; Kinzig, Martina; Sörgel, Fritz

2017-08-01

High antibiotic and antifungal concentrations in wastewater from anti-infective drug production may exert selection pressure for multidrug-resistant (MDR) pathogens. We investigated the environmental presence of active pharmaceutical ingredients and their association with MDR Gram-negative bacteria in Hyderabad, South India, a major production area for the global bulk drug market. From Nov 19 to 28, 2016, water samples were collected from the direct environment of bulk drug manufacturing facilities, the vicinity of two sewage treatment plants, the Musi River, and habitats in Hyderabad and nearby villages. Samples were analyzed for 25 anti-infective pharmaceuticals with liquid chromatography-tandem mass spectrometry and for MDR Gram-negative bacteria using chromogenic culture media. In addition, specimens were screened with PCR for bla VIM , bla KPC , bla NDM , bla IMP-1 , and bla OXA-48 resistance genes. All environmental specimens from 28 different sampling sites were contaminated with antimicrobials. High concentrations of moxifloxacin, voriconazole, and fluconazole (up to 694.1, 2500, and 236,950 µg/L, respectively) as well as increased concentrations of eight other antibiotics were found in sewers in the Patancheru-Bollaram industrial area. Corresponding microbiological analyses revealed an extensive presence of extended-spectrum beta-lactamase and carbapenemase-producing Enterobacteriaceae and non-fermenters (carrying mainly bla OXA-48 , bla NDM , and bla KPC ) in more than 95% of the samples. Insufficient wastewater management by bulk drug manufacturing facilities leads to unprecedented contamination of water resources with antimicrobial pharmaceuticals, which seems to be associated with the selection and dissemination of carbapenemase-producing pathogens. The development and global spread of antimicrobial resistance present a major challenge for pharmaceutical producers and regulatory agencies.

Epidemiological and Genomic Landscape of Azole Resistance Mechanisms in Aspergillus Fungi

PubMed Central

Hagiwara, Daisuke; Watanabe, Akira; Kamei, Katsuhiko; Goldman, Gustavo H.

2016-01-01

Invasive aspergillosis is a life-threatening mycosis caused by the pathogenic fungus Aspergillus. The predominant causal species is Aspergillus fumigatus, and azole drugs are the treatment of choice. Azole drugs approved for clinical use include itraconazole, voriconazole, posaconazole, and the recently added isavuconazole. However, epidemiological research has indicated that the prevalence of azole-resistant A. fumigatus isolates has increased significantly over the last decade. What is worse is that azole-resistant strains are likely to have emerged not only in response to long-term drug treatment but also because of exposure to azole fungicides in the environment. Resistance mechanisms include amino acid substitutions in the target Cyp51A protein, tandem repeat sequence insertions at the cyp51A promoter, and overexpression of the ABC transporter Cdr1B. Environmental azole-resistant strains harboring the association of a tandem repeat sequence and punctual mutation of the Cyp51A gene (TR34/L98H and TR46/Y121F/T289A) have become widely disseminated across the world within a short time period. The epidemiological data also suggests that the number of Aspergillus spp. other than A. fumigatus isolated has risen. Some non-fumigatus species intrinsically show low susceptibility to azole drugs, imposing the need for accurate identification, and drug susceptibility testing in most clinical cases. Currently, our knowledge of azole resistance mechanisms in non-fumigatus Aspergillus species such as A. flavus, A. niger, A. tubingensis, A. terreus, A. fischeri, A. lentulus, A. udagawae, and A. calidoustus is limited. In this review, we present recent advances in our understanding of azole resistance mechanisms particularly in A. fumigatus. We then provide an overview of the genome sequences of non-fumigatus species, focusing on the proteins related to azole resistance mechanisms. PMID:27708619

MACROMOLECULAR THERAPEUTICS

PubMed Central

Yang, Jiyuan; Kopeček, Jindřich

2014-01-01

This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines – (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. PMID:24747162

Advances of molecular clinical pharmacology in gastroenterology and hepatology.

PubMed

Prandota, Joseph

2010-01-01

During developmental age, differences in pharmacodynamic reactions to several drugs may reflect polymorphisms of genes encoding drug-transporting proteins, receptors, drug targets, and gene products, whose disturbed activity sometimes plays an important role in certain diseases. Administration of drugs with a narrow therapeutic index may quite easily be associated with changes in pharmacokinetics and development of adverse drug reactions, which occasionally may cause fatalities. In such cases, polypragmasy and resulting drug interactions may enhance effects of changes in drug-metabolizing enzymes' activities. Phenotyping and genotyping of patients slowly are finding their place in some therapeutic regimens used in clinical gastroenterology and hepatology. At present, some assays to measure, for example, thiopurine S-methyltransferase activity are already commercially available. Polymorphisms of CYP450 enzymes, interleukins, and altered gene expression play an important role in some patients' various gastrointestinal tract and liver diseases. Herbal drugs also affect proinflammatory and antiinflammatory cytokine and nitric oxide balance in the body. Therapeutic use of recombined proteins, such as infliximab, natalizumab, onercept, humanized antibody to integrin α-4 β-7, or IFN-β in some large-bowel diseases increased therapeutic efficacy. IFN-α used in the patients with chronic hepatitis C improved cellular immunity in these subjects and exerted antiviral activity. Practical application of progress in pharmacogenetics, pharmacokinetics, pharmacodynamics, and use of bioproducts in novel therapeutic regimens has opened therapeutic frontiers and increased clinical safety.

[Fungal keratitis caused by Scedosporium apiospermum: first report from Turkey].

PubMed

Kalkan Akçay, Emine; Açıkgöz, Ziya Cibali; Can, Mehmet Erol; Celikbilek, Nevreste; Dereli Can, Gamze; Cağıl, Nurullah

2013-10-01

Fungal keratitis, an eye infection with poor prognosis, is difficult to treat and can lead to loss of vision. Among filamentous fungi Scedosporium spp. rarely lead to fungal keratitis. Here we present a case of keratitis caused by Scedosporium apiospermum. A 61-year-old female patient was admitted to our hospital with the complaints of right eye pain and decreased vision after a foreign body trauma to the right eye. The patient was diagnosed as keratitis by biomicroscopic examination. Conjunctival swabs collected from both eyes were inoculated onto sheep blood agar, chocolate agar, eosin methylene blue agar and Sabouraud dextrose agar. Corneal scrapings from the right eye were inoculated onto the same solid media by "C-streak" method, and in brain-heart-infusion broth by immersion. While gram-stained smears of conjunctival swabs showed no significant finding, smears of corneal scrapings revealed abundant neutrophils and profuse septate hyphae. Fungal keratitis was diagnosed and topical enhanced amphotericin B (0.5 mg/ml) therapy was initiated with netilmicin sulfate and oxytetracycline HCl plus polymyxin B sulfate. At the 10th day of therapy a mold growth was detected in corneal scraping cultures and was identified microscopically as S.apiospermum. Based on the relevant literature, therapy was changed to enhanced topical voriconazole (2 mg/ml) applied hourly, plus systemic voriconazole administration. At the third day of treatment, reduction of epithelial defect and decline in the focus of keratitis were observed. In the following days, however, a progression occurred in the focus of keratitis and 5% natamycin ophthalmic suspension was added to the therapy. Since the patient did not respond to any of the medical treatments, therapeutic penetrating keratoplasty was planned; yet, the patient refused the operation and was discharged with her own request. As far as the local literature was concerned, this is the first report of keratitis caused by S.apiospermum in Turkey. Though a very rare causative agent of keratitis, S.apiospermum is generally resistant to antifungal therapy and often require surgical treatment. Especially in patients with predisposing factors, this organism should be kept in mind as a potential causative agent and relevant microbiological examinations should be performed.

Combination therapeutics in complex diseases.

PubMed

He, Bing; Lu, Cheng; Zheng, Guang; He, Xiaojuan; Wang, Maolin; Chen, Gao; Zhang, Ge; Lu, Aiping

2016-12-01

The biological redundancies in molecular networks of complex diseases limit the efficacy of many single drug therapies. Combination therapeutics, as a common therapeutic method, involve pharmacological intervention using several drugs that interact with multiple targets in the molecular networks of diseases and may achieve better efficacy and/or less toxicity than monotherapy in practice. The development of combination therapeutics is complicated by several critical issues, including identifying multiple targets, targeting strategies and the drug combination. This review summarizes the current achievements in combination therapeutics, with a particular emphasis on the efforts to develop combination therapeutics for complex diseases. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

A Therapeutic Workplace for the Long-Term Treatment of Drug Addiction and Unemployment: Eight-Year Outcomes of a Social Business Intervention

PubMed Central

Aklin, Will M.; Wong, Conrad J.; Hampton, Jacqueline; Svikis, Dace S.; Stitzer, Maxine L.; Bigelow, George E.; Silverman, Kenneth

2014-01-01

This study evaluated the long-term effects of a Therapeutic Workplace social business on drug abstinence and employment. Pregnant and postpartum women (N=40) enrolled in methadone treatment were randomly assigned to a Therapeutic Workplace or Usual Care Control group. Therapeutic Workplace participants could work weekdays in training and then as employees of a social business, but were required to provide drug-free urine samples to work and maintain maximum pay. Three-year outcomes were reported previously. This paper reports 4- to 8- year outcomes. During year 4 when the business was open, Therapeutic Workplace participants provided significantly more cocaine- and opiate-negative urine samples than controls; reported more days employed, higher employment income, and less money spent on drugs. During the 3 years after the business closed, Therapeutic Workplace participants only reported higher income than controls. A Therapeutic Workplace social business can maintain long-term abstinence and employment, but additional intervention may be required to sustain effects. PMID:25124257

[Therapeutic drug monitoring of levetiracetam].

PubMed

Dailly, Eric; Bouquié, Régis; Bentué-Ferrer, Danièle

2010-01-01

Levetiracetam is an anticonvulsant drug used to treat partial seizures, myoclonic seizures of juvenile myoclonic epilepsy and primary generalized tonic-clonic seizures. A review of the literature with an evidence-based medicine method highlighted parameters (age, renal failure, pregnancy, combination with other anticonvulsant drugs) which affect levetiracetam pharmacokinetics but no significant relationship between plasma concentration of levetiracetam and efficacy or toxicity. Concentrations usually observed in therapeutics is from 6 to 18 mg/L. However, the determination of an individual therapeutic concentration, associated with an effective and well tolerated therapy, could be recommended particularly before pregnancy. Consequently, therapeutic drug monitoring of levetiracetam which is not currently recommended could be possibly useful in specific clinical situations.

Clinical differences among nonsteroidal antiinflammatory drugs: implications for therapeutic substitution in ambulatory patients.

PubMed

Levy, R A; Smith, D L

1989-01-01

The practice of therapeutic substitution, i.e., replacing one drug with another chemically different drug from the same therapeutic class, represents an important therapeutic modification with potential clinical significance far beyond that of generic substitution. Adverse consequences following therapeutic substitution of nonsteroidal antiinflammatory drugs (NSAID) is of special concern because of substantial differences among these agents in pharmacokinetic, pharmacological, and clinical properties. Therapeutic substitution of NSAID for ambulatory patients may result in compromised clinical outcome because (1) patient response is unpredictable and selection of the optimal agent must be tailored for each patient; (2) substantial differences exist in adverse reaction profiles; (3) drug interaction studies are lacking; and (4) selection of an agent must be individualized to ensure compliance with the dosing regimen. Cost savings achieved through therapeutic substitution of NSAID may be lost by additional overall treatment costs due to adverse reactions or suboptimal therapy. The occurrence of adverse or suboptimal effects in ambulatory patients is more likely if NSAID are substituted without full knowledge of the patient's medical history and clinical status. Communication between the pharmacy and prescribing physician regarding a patient's specific needs is essential for rational substitution among NSAID.

Macromolecular therapeutics.

PubMed

Yang, Jiyuan; Kopeček, Jindřich

2014-09-28

This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines - (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. Copyright © 2014 Elsevier B.V. All rights reserved.

Targeted nanomedicine for cancer therapeutics: Towards precision medicine overcoming drug resistance.

PubMed

Bar-Zeev, Maya; Livney, Yoav D; Assaraf, Yehuda G

2017-03-01

Intrinsic anticancer drug resistance appearing prior to chemotherapy as well as acquired resistance due to drug treatment, remain the dominant impediments towards curative cancer therapy. Hence, novel targeted strategies to overcome cancer drug resistance constitute a key aim of cancer research. In this respect, targeted nanomedicine offers innovative therapeutic strategies to overcome the various limitations of conventional chemotherapy, enabling enhanced selectivity, early and more precise cancer diagnosis, individualized treatment as well as overcoming of drug resistance, including multidrug resistance (MDR). Delivery systems based on nanoparticles (NPs) include diverse platforms enabling a plethora of rationally designed therapeutic nanomedicines. Here we review NPs designed to enhance antitumor drug uptake and selective intracellular accumulation using strategies including passive and active targeting, stimuli-responsive drug activation or target-activated release, triggered solely in the cancer cell or in specific organelles, cutting edge theranostic multifunctional NPs delivering drug combinations for synergistic therapy, while facilitating diagnostics, and personalization of therapeutic regimens. In the current paper we review the recent findings of the past four years and discuss the advantages and limitations of the various novel NPs-based drug delivery systems. Special emphasis is put on in vivo study-based evidences supporting significant therapeutic impact in chemoresistant cancers. A future perspective is proposed for further research and development of complex targeted, multi-stage responsive nanomedical drug delivery systems for personalized cancer diagnosis and efficacious therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Therapeutic drug monitoring of antimetabolic cytotoxic drugs

PubMed Central

Lennard, L

1999-01-01

Therapeutic drug monitoring is not routinely used for cytotoxic agents. There are several reasons, but one major drawback is the lack of established therapeutic concentration ranges. Combination chemotherapy makes the establishment of therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as that when the drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centres, and some of these protocols are now part of large multicentre trials. Nonetheless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite therapy, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic enzyme activities or genotype in addition to, or instead of, the more traditional measurement of parent drug or drug metabolites. The cytotoxic activities of mercaptopurine and fluorouracil are regulated by thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. Lack of TPMT functional activity produces life-threatening mercaptopurine myelotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioavailability, pharmacokinetics, toxicity and efficacy of their substrate drugs. PMID:10190647

Dual delivery of biological therapeutics for multimodal and synergistic cancer therapies.

PubMed

Jang, Bora; Kwon, Hyokyoung; Katila, Pramila; Lee, Seung Jin; Lee, Hyukjin

2016-03-01

Cancer causes >8.2 million deaths annually worldwide; thus, various cancer treatments have been investigated over the past decades. Among them, combination drug therapy has become extremely popular, and treatment with more than one drug is often necessary to achieve appropriate anticancer efficacy. With the development of nanoformulations and nanoparticulate-based drug delivery, researchers have explored the feasibility of dual delivery of biological therapeutics to overcome the current drawbacks of cancer therapy. Compared with the conventional single drug therapy, dual delivery of therapeutics has provided various synergistic effects in addition to offering multimodality to cancer treatment. In this review, we highlight and summarize three aspects of dual-delivery systems for cancer therapy. These include (1) overcoming drug resistance by the dual delivery of chemical drugs with biological therapeutics for synergistic therapy, (2) targeted and controlled drug release by the dual delivery of drugs with stimuli-responsive nanomaterials, and (3) multimodal theranostics by the dual delivery of drugs and molecular imaging probes. Furthermore, recent developments, perspectives, and new challenges regarding dual-delivery systems for cancer therapy are discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

Recent advances in (therapeutic protein) drug development

PubMed Central

Lagassé, H.A. Daniel; Alexaki, Aikaterini; Simhadri, Vijaya L.; Katagiri, Nobuko H.; Jankowski, Wojciech; Sauna, Zuben E.; Kimchi-Sarfaty, Chava

2017-01-01

Therapeutic protein drugs are an important class of medicines serving patients most in need of novel therapies. Recently approved recombinant protein therapeutics have been developed to treat a wide variety of clinical indications, including cancers, autoimmunity/inflammation, exposure to infectious agents, and genetic disorders. The latest advances in protein-engineering technologies have allowed drug developers and manufacturers to fine-tune and exploit desirable functional characteristics of proteins of interest while maintaining (and in some cases enhancing) product safety or efficacy or both. In this review, we highlight the emerging trends and approaches in protein drug development by using examples of therapeutic proteins approved by the U.S. Food and Drug Administration over the previous five years (2011–2016, namely January 1, 2011, through August 31, 2016). PMID:28232867

Phylogeny of the Clinically Relevant Species of the Emerging Fungus Trichoderma and Their Antifungal Susceptibilities

PubMed Central

Sandoval-Denis, Marcelo; Sutton, Deanna A.; Cano-Lira, José F.; Fothergill, Annette W.; Wiederhold, Nathan P.; Guarro, Josep

2014-01-01

A set of 73 isolates of the emerging fungus Trichoderma isolated from human and animal clinical specimens were characterized morphologically and molecularly using a multilocus sequence analysis that included the internal transcribed spacer (ITS) regions of the nuclear ribosomal DNA and fragments of the translation elongation factor 1 alpha (Tef1), endochitinase CHI18-5 (Chi18-5), and actin 1 (Act1) genes. The most frequent species was Trichoderma longibrachiatum (26%), followed by Trichoderma citrinoviride (18%), the Hypocrea lixii/Trichoderma harzianum species complex (15%), the newly described species Trichoderma bissettii (12%), and Trichoderma orientale (11%). The most common anatomical sites of isolation in human clinical specimens were the respiratory tract (40%), followed by deep tissue (30%) and superficial tissues (26%), while all the animal-associated isolates were obtained from superficial tissue samples. Susceptibilities of the isolates to eight antifungal drugs in vitro showed mostly high MICs, except for voriconazole and the echinocandins. PMID:24719448

Candida Endophthalmitis After Descemet Stripping Automated Endothelial Keratoplasty With Grafts From Both Eyes of a Donor With Possible Systemic Candidiasis.

PubMed

Palioura, Sotiria; Sivaraman, Kavitha; Joag, Madhura; Sise, Adam; Batlle, Juan F; Miller, Darlene; Espana, Edgar M; Amescua, Guillermo; Yoo, Sonia H; Galor, Anat; Karp, Carol L

2018-04-01

To report 2 cases with late postoperative Candida albicans interface keratitis and endophthalmitis after Descemet stripping automated endothelial keratoplasty (DSAEK) with corneal grafts originating from a single donor with a history of presumed pulmonary candidiasis. Two patients underwent uncomplicated DSAEK by 2 corneal surgeons at different surgery centers but with tissue from the same donor and were referred to the Bascom Palmer Eye Institute with multifocal infiltrates at the graft-host cornea interface 6 to 8 weeks later, and anterior chamber cultures that were positive for the same genetic strain of C. albicans. Immediate explantation of DSAEK lenticules and daily intracameral and instrastromal voriconazole and amphotericin injections failed to control the infection. Thus, both patients underwent therapeutic penetrating keratoplasty with intraocular lens explantation, pars plana vitrectomy, and serial postoperative intraocular antifungal injection. Both patients are doing well at 2 years postoperatively with best-corrected vision of 20/20 and 20/30+ with rigid gas permeable lenses. One patient required repeat optical penetrating keratoplasty and glaucoma tube implantation 1 year after the original surgery. Literature review reveals that donor lenticule explantation and intraocular antifungals are often inadequate to control fungal interface keratitis, and a therapeutic graft is commonly needed. Interface fungal keratitis and endophthalmitis due to infected donor corneal tissue is difficult to treat, and both recipients of grafts originating from the same donor are at risk of developing this challenging condition.

IMPACT web portal: oncology database integrating molecular profiles with actionable therapeutics.

PubMed

Hintzsche, Jennifer D; Yoo, Minjae; Kim, Jihye; Amato, Carol M; Robinson, William A; Tan, Aik Choon

2018-04-20

With the advancement of next generation sequencing technology, researchers are now able to identify important variants and structural changes in DNA and RNA in cancer patient samples. With this information, we can now correlate specific variants and/or structural changes with actionable therapeutics known to inhibit these variants. We introduce the creation of the IMPACT Web Portal, a new online resource that connects molecular profiles of tumors to approved drugs, investigational therapeutics and pharmacogenetics associated drugs. IMPACT Web Portal contains a total of 776 drugs connected to 1326 target genes and 435 target variants, fusion, and copy number alterations. The online IMPACT Web Portal allows users to search for various genetic alterations and connects them to three levels of actionable therapeutics. The results are categorized into 3 levels: Level 1 contains approved drugs separated into two groups; Level 1A contains approved drugs with variant specific information while Level 1B contains approved drugs with gene level information. Level 2 contains drugs currently in oncology clinical trials. Level 3 provides pharmacogenetic associations between approved drugs and genes. IMPACT Web Portal allows for sequencing data to be linked to actionable therapeutics for translational and drug repurposing research. The IMPACT Web Portal online resource allows users to query genes and variants to approved and investigational drugs. We envision that this resource will be a valuable database for personalized medicine and drug repurposing. IMPACT Web Portal is freely available for non-commercial use at http://tanlab.ucdenver.edu/IMPACT .

Polymer therapeutics: concepts and applications.

PubMed

Haag, Rainer; Kratz, Felix

2006-02-13

Polymer therapeutics encompass polymer-protein conjugates, drug-polymer conjugates, and supramolecular drug-delivery systems. Numerous polymer-protein conjugates with improved stability and pharmacokinetic properties have been developed, for example, by anchoring enzymes or biologically relevant proteins to polyethylene glycol components (PEGylation). Several polymer-protein conjugates have received market approval, for example the PEGylated form of adenosine deaminase. Coupling low-molecular-weight anticancer drugs to high-molecular-weight polymers through a cleavable linker is an effective method for improving the therapeutic index of clinically established agents, and the first candidates have been evaluated in clinical trials, including, N-(2-hydroxypropyl)methacrylamide conjugates of doxorubicin, camptothecin, paclitaxel, and platinum(II) complexes. Another class of polymer therapeutics are drug-delivery systems based on well-defined multivalent and dendritic polymers. These include polyanionic polymers for the inhibition of virus attachment, polycationic complexes with DNA or RNA (polyplexes), and dendritic core-shell architectures for the encapsulation of drugs. In this Review an overview of polymer therapeutics is presented with a focus on concepts and examples that characterize the salient features of the drug-delivery systems.

Therapeutic Engagement as a Predictor of Retention in Adolescent Therapeutic Community Treatment

ERIC Educational Resources Information Center

Abdel-Salam, Sami; Gunter, Whitney D.

2014-01-01

The adolescent drug problem places a huge toll on society and a heavy burden on the criminal justice system. Research regarding the benefits of therapeutic community (TC) treatment for adolescents has shown it to be effective. Despite the ability of therapeutic communities to lower drug relapse and reduce criminality, a great deal remains unknown…

The Holy Grail of Polymer Therapeutics for Cancer Therapy: An Overview on the Pharmacokinetics and Bio Distribution.

PubMed

Dyawanapelly, Sathish; Junnuthula, Vijayabhaskar Reddy; Singh, AkhileshVikram

2015-01-01

In recent years, multifaceted clinical benefits of polymeric therapeutics have been reported. Over the past decades, cancer has been one of the leading causes of mortality in the world. Many clinically approved chemotherapeutics encounter potential challenges against deadly cancer. Moreover, safety and efficacy of anticancer agents have been limited by undesirable pharmacokinetics and biodistribution. To address these limitations, various polymer drug conjugates are being studied and developed to improve the antitumor efficacy. Among other therapeutics, polymer therapeutics are well established platforms that circumvent anticancer therapeutics from enzymatic metabolism via direct conjugation to therapeutic molecules. Interestingly, polymer therapeutics meets an unmet need of small molecules. Further clinical study showed that polymer-drug conjugation can achieve desired pharmacokinetics and biodistribution properties of several anticancer drugs. The present retrospective review mainly enlightens the most recent preclinical and clinical studies include safety, stability, pharmacokinetic behavior and distribution of polymer therapeutics.

Phenotypic and molecular identification of Fonsecaea pedrosoi strains isolated from chromoblastomycosis patients in Mexico and Venezuela.

PubMed

Carolina Rojas, O; León-Cachón, Rafael B R; Pérez-Maya, Antonio Alí; Aguirre-Garza, Marcelino; Moreno-Treviño, María G; González, Gloria M

2015-05-01

Chromoblastomycosis is a chronic granulomatous disease caused frequently by fungi of the Fonsecaea genus. The objective of this study was the phenotypic and molecular identification of F. pedrosoi strains isolated from chromoblastomycosis patients in Mexico and Venezuela. Ten strains were included in this study. For phenotypic identification, we used macroscopic and microscopic morphologies, carbohydrate assimilation test, urea hydrolysis, cixcloheximide tolerance, proteolitic activity and the thermotolerance test. The antifungal activity of five drugs was evaluated against the isolates. Molecular identification was performed by sequencing the internal transcribed spacer (ITS) ribosomal DNA regions of the isolated strains. The physiological analysis and morphological features were variable and the precise identification was not possible. All isolates were susceptible to itraconazole, terbinafine, voriconazole and posaconazole. Amphotericin B was the least effective drug. The alignment of the 559-nucleotide ITS sequences from our strains compared with sequences of GenBank revealed high homology with F. pedrosoi (EU285266.1). In this study, all patients were from rural areas, six from Mexico and four from Venezuela. Ten isolates were identified by phenotypic and molecular analysis, using ITS sequence and demonstrated that nine isolates from Mexico and Venezuela were 100% homologous and one isolate showed a small genetic distance. © 2015 Blackwell Verlag GmbH.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2003-06-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: AdGVVEGF121.10, anakinra, andolast, anidulafungin, APC-2059, l-arginine hydrochloride, aripiprazole, arzoxifene hydrochloride, asimadoline; Bexarotene, bimatoprost, bimosiamose, bizelesin, BMS-188667, botulinum toxin type B, bromfenac sodium, bryostatin 1; Cannabidiol, cariporide mesilate, CCI-1004, CDP-571, cerivastatin sodium, clevudine; Dalbavancin, darbepoetin alfa, decitabine, deligoparin sodium, diethylnorspermine, drotrecogin alfa (activated), DTaP-HBV-IPV/Hib-vaccine; E-5564, eculizumab, edodekin alfa, emtricitabine, enfuvirtide, (-)-epigallocatechin gallate, eplerenone, esomeprazole magnesium, etaquine, etoricoxib, ezetimibe; Fesoterodine, fipamezole hydrochloride, fondaparinux sodium, fosamprenavir calcium, frovatriptan, fulvestrant; Gadofosveset sodium, galiximab, ghrelin (human), glufosfamide; Homoharringtonine; Idraparinux sodium, imatinib mesylate, INS-37217; KRN-7000; L-651582, lafutidine, lanthanum carbonate, lenercept, levetiracetam, lusupultide; Magnesium sulfate, melatonin, mepolizumab, midostaurin, morphine hydrochloride, mozavaptan; Natalizumab, nesiritide; OPC-51803, oregovomab, oritavancin; Peginterferon alfa-2(a), pleconaril, plevitrexed, prasterone, pregabalin; Ranibizumab, Ro-31-7453, roxifiban acetate, rubitecan; SCV-07, SHL-749, sho-saiko-to, soblidotin, solifenacin succinate; Tegaserod maleate, telithromycin, tenecteplase, theraCIM, tipifarnib, travoprost; Valdecoxib, vardenafil hydrochloride hydrate, voriconazole; Ximelagatran; Ziprasidone hydrochloride, ZYC-00101. (c) 2003 Prous Science. All rights reserved.

Bimetallic redox nanoprobe enhances the therapeutic efficacy of hyperthermia in drug-resistant cancer cells

NASA Astrophysics Data System (ADS)

Vishwakarma, Sandeep Kumar; Lakkireddy, Chandrakala; Marjan, Tuba; Fatima, Anjum; Bardia, Avinash; Paspala, Syed Ameer Basha; Habeeb, Md. Aejaz; Khan, Aleem Ahmed

2018-05-01

Cancer nanotheranostics has emerged as one of the most promising fields of medicine wherein nano-sized molecules/agents are used for combined diagnosis and treatment of cancer. Despite promises of novel cancer therapeutic approaches, several crucial challenges have remained to be overcome for successful clinical translation of such agents. Hence, the present study has been aimed to investigate the therapeutic efficacy of bimetallic gadolinium super-paramagnetic iron oxide nanoformulation of ascorbic acid in synergism with hyperthermia on ascorbic acid-resistant breast cancer cells. This particular strategy provides real-time MRI-based non-invasive imaging of drug loading in resistant cancer cells along with highly enhanced therapeutic efficacy. This unique redox nanoprobe is capable of reversing drug-resistance mechanism in cancer cells and offers better therapeutic possibilities in targeted and effective destruction of drug-resistant cancer cells.

Therapeutic drug monitoring of vedolizumab in inflammatory bowel disease: current data and future directions.

PubMed

Ward, Mark G; Sparrow, Miles P; Roblin, Xavier

2018-01-01

The introduction of vedolizumab, a lymphocyte adhesion inhibitor, has expanded the relatively limited therapeutic armamentarium available for Crohn's disease and ulcerative colitis. Despite its effectiveness, both primary nonresponse and secondary loss of response to vedolizumab do occur, as is observed with the use of anti-tumour necrosis factor (TNF) therapy. Further, in a proportion, onset of efficacy may be relatively slow. A large body of data support an exposure-response relationship with anti-TNF drug levels, which has led to therapeutic drug monitoring becoming incorporated into everyday clinical management. The influence of patient and disease factors on the pharmacokinetics of anti-TNF levels, including immunogenicity, has also been examined. The role of therapeutic drug monitoring with vedolizumab is less clear. This review summarizes the available evidence on the pharmacokinetics and pharmacodynamics of vedolizumab in inflammatory bowel disease and how drug levels, immunogenicity and other factors influence clinical outcomes. Vedolizumab clearance is increased with very high body weight and hypoalbuminaemia, but is not influenced by the addition of an immunomodulator. Immunogenicity is uncommon. α4β7 receptor saturation occurs at low serum vedolizumab drug levels, and measuring it alone is insufficient to predict clinical outcomes. Using quartile analysis of vedolizumab drug levels, there appears to be a modest exposure-response relationship during induction. Drug levels at week 6 of approximately >20 μg/ml have been shown to be associated with improved clinical outcomes, including subsequent mucosal healing rates during maintenance and avoiding the need to dose escalate due to lack of response. There are currently insufficient data to support the routine use of therapeutic drug monitoring during maintenance therapy. Further studies to elucidate the role of therapeutic drug monitoring of vedolizumab are needed.

Comparison of Drug Benefits Provided by Veterans Affairs Canada and the Canadian Forces Health Services Group.

PubMed

Chow, Matthew; Wicks, Charles J; Ma, Janice; Grenier, Sylvain

2017-05-23

Drug benefits are provided at public expense to all actively serving Canadian Armed Forces (CAF) personnel, with ongoing drug coverage offered by Veterans Affairs Canada (VAC) for selected conditions following termination of employment. Differences in drug coverage between these programs could introduce risks for treatment disruption. Work was undertaken to establish a process that would allow systematic comparison of the entire VAC and CAF formularies, and to identify and explain discordant listings in 14 therapeutic categories that pose risk of adverse outcomes with sudden treatment interruption. Lists of medications were created for each program, including regular benefit and restricted use drugs, using files obtained from the claims processor in January 2015. Products were coded using the Anatomic-Therapeutic-Chemical (ATC) system. Degree of alignment within therapeutic categories was assessed based on the percentage of fifth-level ATCs that were covered in common. Discordantly listed drugs in 14 categories of concern were reviewed to identify similarities in product characteristics. A total of 1124 medications were identified in 80 therapeutic categories. Coverage of medications was identical in 11 categories, and overall, almost three-quarters of identified drugs (73.4%, n = 825) were covered in common by both plans. Many discordant listings reflected known differences in the programs' operating procedures. A number of discrepancies were also identified in newer therapeutic categories. There is significant overlap in the medications covered by the CAF and VAC drug benefit programs. Application of the ATC coding system allowed for discrepancies to be readily identified across the entire formulary, and in specific therapeutic categories of concern. © 2017 Journal of Population Therapeutics and Clinical Pharmacology. All rights reserved.

Antifungal susceptibility of Malassezia furfur, Malassezia sympodialis, and Malassezia globosa to azole drugs and amphotericin B evaluated using a broth microdilution method.

PubMed

Rojas, Florencia D; Sosa, María de los A; Fernández, Mariana S; Cattana, María E; Córdoba, Susana B; Giusiano, Gustavo E

2014-08-01

We studied the in vitro activity of fluconazole (FCZ), ketoconazole (KTZ), miconazole (MCZ), voriconazole (VCZ), itraconazole (ITZ) and amphotericin B (AMB) against the three major pathogenic Malassezia species, M. globosa, M. sympodialis, and M. furfur. Antifungal susceptibilities were determined using the broth microdilution method in accordance with Clinical and Laboratory Standards Institute reference document M27-A3. To support lipid-dependent yeast development, glucose, peptone, ox bile, malt extract, glycerol, and Tween supplements were added to Roswell Park Memorial Institute RPMI 1640 medium. The supplemented medium allowed good growth of all three species studied. The minimal inhibitory concentrations (MICs) were recorded after 72 h of incubation at 32ºC. The three species showed different susceptibility profiles for the drugs tested. Malassezia sympodialis was the most susceptible and M. furfur the least susceptible species. KTZ, ITZ, and VCZ were the most active drugs, showing low variability among isolates of the same species. FCZ, MCZ, and AMB showed high MICs and wide MIC ranges. Differences observed emphasize the need to accurately identify and evaluate antifungal susceptibility of Malassezia species. Further investigations and collaborative studies are essential for correlating in vitro results with clinical outcomes since the existing limited data do not allow definitive conclusions. © The Author 2014. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Distribution and Drug Susceptibility of Candida spp. Associated With Female Genital Tract Infection, Chongqing, China

PubMed Central

Luo, Xiaodong; Dong, Xiaojing; Pen, Zhi

2015-01-01

Background Vulvovaginal candidiasis is defined as vulvovaginitis associated with vaginal carriage of Candida spp. and is a common problem with a high rate of morbidity. Objectives To investigate the distribution of Candida spp. and evaluate the corresponding antifungal susceptibility in women with genital tract infection in Chongqing, southwestern China. Patients and Methods Samples (n = 2.129) were obtained from female patients with symptoms of genital tract infection. Candida spp. were isolated from the specimens and were identified using a coloration medium and the VITEK 2 Compact automatic microbial identification system. Antifungal susceptibility testing was performed using the ATB FUNGUS drug susceptibility testing system. Results From 2,129 samples, 478 (22.45%) isolates of Candida were isolated, of which 395 (82.64%) were Candida albicans, 39 (8.16%) were C. glabrata, 21 (4.39%) were C. tropicalis, 9 (1.88%) were C. parapsilosis, and 14 (2.93%) were other Candida spp. The resistance of C. albicans, C. glabrata, and C. tropicalis to 5 antifungal drugs (amphotericin B, voriconazole, fluconazole, 5-fluorocytosine, and itraconazole) ranged from 0.5% to 6.4%, 0% to 7.7%, and 0% to 9.6%, respectively. Conclusions Candida albicans was the major pathogen associated with candidiasis of the female genital tract in patients in Chongqing. The results of the antifungal sensitivity of the isolates suggest that it is important for clinicians to administer appropriate antifungals for the treatment of Candida spp. infections. PMID:28138369

Preclinical models used for immunogenicity prediction of therapeutic proteins.

PubMed

Brinks, Vera; Weinbuch, Daniel; Baker, Matthew; Dean, Yann; Stas, Philippe; Kostense, Stefan; Rup, Bonita; Jiskoot, Wim

2013-07-01

All therapeutic proteins are potentially immunogenic. Antibodies formed against these drugs can decrease efficacy, leading to drastically increased therapeutic costs and in rare cases to serious and sometimes life threatening side-effects. Many efforts are therefore undertaken to develop therapeutic proteins with minimal immunogenicity. For this, immunogenicity prediction of candidate drugs during early drug development is essential. Several in silico, in vitro and in vivo models are used to predict immunogenicity of drug leads, to modify potentially immunogenic properties and to continue development of drug candidates with expected low immunogenicity. Despite the extensive use of these predictive models, their actual predictive value varies. Important reasons for this uncertainty are the limited/insufficient knowledge on the immune mechanisms underlying immunogenicity of therapeutic proteins, the fact that different predictive models explore different components of the immune system and the lack of an integrated clinical validation. In this review, we discuss the predictive models in use, summarize aspects of immunogenicity that these models predict and explore the merits and the limitations of each of the models.

Five-year National Surveillance of Invasive Candidiasis: Species Distribution and Azole Susceptibility from the China Hospital Invasive Fungal Surveillance Net (CHIF-NET) Study.

PubMed

Xiao, Meng; Sun, Zi-Yong; Kang, Mei; Guo, Da-Wen; Liao, Kang; Chen, Sharon C-A; Kong, Fanrong; Fan, Xin; Cheng, Jing-Wei; Hou, Xin; Zhou, Meng-Lan; Li, Ying; Yu, Shu-Ying; Huang, Jing-Jing; Wang, He; Xu, Ying-Chun

2018-05-09

Data on the epidemiology of invasive candidiasis (IC) and antifungal susceptibility of Candida isolates in China are still limited. Here we report surveillance for IC from the China Hospital Invasive Fungal Surveillance Net (CHIF-NET) Study. Sixty-five tertiary hospitals collected 8,829 Candida isolates from August 1, 2009 to July 31, 2014. Matrix-assisted laser desorption/ionization -time of flight mass spectrometry supplemented by rDNA sequencing was used to define species, and fluconazole and voriconazole susceptibilities determined by the Clinical and Laboratory Standards Institute disk diffusion method. A total of 32 Candida species were identified. C. albicans was the most common species (44.9%) followed by C. parapsilosis complex (20.0%), C. tropicalis (17.2%) and C. glabrata complex (10.8%), with other species comprising <3%. However, in candidemia, the proportion of cases caused by C. albicans was only 32.3%. C. albicans and C. parapsilosis complex isolates were susceptible to fluconazole and voriconazole (<6% resistance), while fluconazole- and azole cross-resistant rates were high in C. tropicalis (13.3% and 12.9%), C. glabrata complex (18.7% and 14%) and uncommon Candida species (44.1% and 10.3%) isolates. Moreover, from year 1 to 5 of the study, there was a significant increase in resistant rates amongst C. glabrata complex isolates to fluconazole (12.2% to 24.0%), and amongst C. tropicalis isolates to both fluconazole (5.7% to 21.0%) and voriconazole (5.7% to 21.4%) (all P<0.01). Geographic variations in causative species and susceptibilities were noted. Our findings indicated that antifungal resistance have become noteworthy in China, and enhanced surveillance is warranted. Copyright © 2018 American Society for Microbiology.

Surveillance for azole resistance in clinical and environmental isolates of Aspergillus fumigatus in Australia and cyp51A homology modelling of azole-resistant isolates.

PubMed

Talbot, Jessica J; Subedi, Shradha; Halliday, Catriona L; Hibbs, David E; Lai, Felcia; Lopez-Ruiz, Francisco J; Harper, Lincoln; Park, Robert F; Cuddy, William S; Biswas, Chayanika; Cooley, Louise; Carter, Dee; Sorrell, Tania C; Barrs, Vanessa R; Chen, Sharon C-A

2018-05-29

The prevalence of azole resistance in Aspergillus fumigatus is uncertain in Australia. Azole exposure may select for resistance. We investigated the frequency of azole resistance in a large number of clinical and environmental isolates. A. fumigatus isolates [148 human, 21 animal and 185 environmental strains from air (n = 6) and azole-exposed (n = 64) or azole-naive (n = 115) environments] were screened for azole resistance using the VIPcheck™ system. MICs were determined using the Sensititre™ YeastOne YO10 assay. Sequencing of the Aspergillus cyp51A gene and promoter region was performed for azole-resistant isolates, and cyp51A homology protein modelling undertaken. Non-WT MICs/MICs at the epidemiological cut-off value of one or more azoles were observed for 3/148 (2%) human isolates but not amongst animal, or environmental, isolates. All three isolates grew on at least one azole-supplemented well based on VIPcheck™ screening. For isolates 9 and 32, the itraconazole and posaconazole MICs were 1 mg/L (voriconazole MICs 0.12 mg/L); isolate 129 had itraconazole, posaconazole and voriconazole MICs of >16, 1 and 8 mg/L, respectively. Soil isolates from azole-exposed and azole-naive environments had similar geometric mean MICs of itraconazole, posaconazole and voriconazole (P > 0.05). A G54R mutation was identified in the isolates exhibiting itraconazole and posaconazole resistance, and the TR34/L98H mutation in the pan-azole-resistant isolate. cyp51A modelling predicted that the G54R mutation would prevent binding of itraconazole and posaconazole to the haem complex. Azole resistance is uncommon in Australian clinical and environmental A. fumigatus isolates; further surveillance is indicated.

Evaluation of Candida species and antifungal susceptibilities among children with invasive candidiasis

PubMed Central

Sütçü, Murat; Acar, Manolya; Genç, Gonca Erköse; Kökçü, İlknur; Aktürk, Hacer; Atay, Gürkan; Törun, Selda Hançerli; Salman, Nuran; Erturan, Zayre; Somer, Ayper

2017-01-01

Aim Non-albicans Candida species and resistant microorganisms have been more commonly isolated in invasive candidiasis in recent years. The aim of this study was to evaluate the distrubution of Candida spp and antifungal resistance in our clinic. Material and Methods Fifty-four Candida isolates and antifungal susceptibility results obtained from patients diagnosed as having invasive candidiasis between December 2012 and June 2016 were included. Clinical and laboratory data were retrospectively analyzed. E-test method was used in order to determine antifungal susceptibilities of Candida spp for amphotericin B, fluconazole, voriconazole, ketoconazole, itraconazole, anidulafungin, caspofungin, and flucytosine. Results The clinical diagnoses of the patients were candidemia (n=27, 50%), catheter-related blood stream infection (n=1, 1.8%), urinary tract infection (n=13, 24%), surgical site infection (n=4, 7.4%), intraabdominal infection (n=3, 5.5%), empyema (n=2, 3.7%), and pneumonia (n=4, 7.4%). The most common isolated agent was C. albicans (n=27, 50%) and the others were C. parapsilosis (n=13, 24%), C. tropicalis (n=6, 11.1%), C. glabrata (n=3, 5.6%), C. lusitaniae (n=2, 3.7%), and unspecified Candida spp. (n=3, 5.6%). Fluconazole resistance was 7.4% among all isolates. Resistance against itraconazole, ketoconazole, anidulafungin, voriconazole and caspofungin were 33.3%, 12.5%, 11.1%, 5%, and 2.5%, respectively. Isolates presented intermediate resistance against itraconazole (41.7%), voriconazole (5.6%), and amphotericin B (3.7%) to varying extents. All of the isolates were susceptible to flucytosine. Conclusions In our clinic, C. albicans and non-albicans Candida species were equally distributed and antifungal susceptibilities against major antifungal agents such as fluconazole, amphotericin B, and caspofungin were found considerably high. PMID:29062248

Análisis de Costo Efectividad de Estrategias de Tratamiento Antimicótico en Pacientes con Neutropenia Febril Persistente y Tratamiento Antibiótico de Amplio Espectro.

PubMed

Gamboa Garay, Oscar Andrés; Fuentes Pachón, Juan Camilo; Cuervo Maldonado, Sonia Isabel; Gómez Rincón, Julio Cesar; Castillo Londoño, Juan Sebastian

2012-12-01

To assess cost-effectiveness of antifungal treatment on patients with persistent fever neutropenia: empiric antifungal therapy (EAT) vs. anticipated antifungal therapy (AAT). A decision model was performed to evaluate the cost-effectiveness of antifungal treatment strategies in patients with febrile neutropenia not responding to a broad spectrum antibiotic treatment. The strategies included were: 1) EAT with amphotericin B deoxycholate; 2) EAT with liposomal amphotericin B; 3) EAT with caspofungin; and 4) AAT with voriconazole and amphotericin B deoxycholate or liposomal amphotericin B or caspofungin in patients who initiate treatment despite having negative CT scan and galactomannan or fail to voriconazole. Effectiveness was measured as the number of deaths averted. Cost-effectiveness and incremental cost-effectiveness ratios were calculated. Deterministic and probabilistic sensitivity analyzes were performed. EAT with Amphotericin B deoxycholate was the least expensive and least effective strategy. The EAT with caspofungin was the most effective. The cost per death averted for caspofungin when compared with amphotericin B deoxycholate was $17,011,073.83, which would indicate that this strategy would be cost-effective for the country if the willingness to pay per death averted is equal to or greater than this value. EAT with liposomal amphotericin B and AAT with voriconazole were dominated by AET with caspofungin, which is less costly and more effective. EAT with caspofungin would be cost-effective for Colombia if the threshold per death averted is greater to $18.000.000. If the threshold is lesser the EAT with amphotericin B deoxycholate would be the election. Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Microdose study of a P-glycoprotein substrate, fexofenadine, using a non-radioisotope-labelled drug and LC/MS/MS.

PubMed

Yamazaki, A; Kumagai, Y; Yamane, N; Tozuka, Z; Sugiyama, Y; Fujita, T; Yokota, S; Maeda, M

2010-04-01

Fexofenadine is a P-glycoprotein substrate of low bioavailability. It is primarily excreted into faeces as a parent drug via biliary excretion. The predictability from microdose data for the drug absorbed via transporters such as P-glycoprotein is not known. Therefore, this study assessed the predictability of therapeutic-dose pharmacokinetics of fexofenadine from microdosing data using non-radioisotope-labelled drug and liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). In a single dose, randomized, two-way crossover study, eight subjects received a microdose (100 microg) or a therapeutic dose (60 mg) of fexofenadine. Blood samples were collected until 12 h after dosing, and assayed using LC/MS/MS. Plasma concentration-time curves of fexofenadine between microdose and therapeutic dose were similar. The mean +/- SD of C(max) normalized to 60 mg dose after microdose and therapeutic dose were 379 +/- 147 and 275 +/- 145 ng/mL respectively. The mean AUC(last) normalized to 60 mg dose after microdose and therapeutic dose were 1914 +/- 738 and 1431 +/- 432 ng/h/mL respectively. The mean dose-adjusted C(max) and AUC(last) after microdose were higher compared with those after therapeutic dose. Individual plots of C(max) and AUC(last) normalized to 60 mg dose, were similar for microdose and therapeutic dose. None of the pharmacokinetic parameters were statistically different using anova. Overall, the microdose pharmacokinetics profile was similar to, and hence predictive of, that of the therapeutic dose. For the P-glycoprotein substrate fexofenadine, the predictability of therapeutic-dose pharmacokinetics from microdose data was good. A microdose study using a non-radioisotope-labelled drug and LC/MS/MS is convenient, and has the potential to aid the early selection of drug candidates.

A therapeutic workplace for the long-term treatment of drug addiction and unemployment: eight-year outcomes of a social business intervention.

PubMed

Aklin, Will M; Wong, Conrad J; Hampton, Jacqueline; Svikis, Dace S; Stitzer, Maxine L; Bigelow, George E; Silverman, Kenneth

2014-01-01

This study evaluated the long-term effects of a therapeutic workplace social business on drug abstinence and employment. Pregnant and postpartum women (N = 40) enrolled in methadone treatment were randomly assigned to a therapeutic workplace or usual care control group. Therapeutic workplace participants could work weekdays in training and then as employees of a social business, but were required to provide drug-free urine samples to work and maintain maximum pay. Three-year outcomes were reported previously. This paper reports 4- to 8-year outcomes. During year 4 when the business was open, therapeutic workplace participants provided significantly more cocaine- and opiate-negative urine samples than controls; reported more days employed, higher employment income, and less money spent on drugs. During the 3 years after the business closed, therapeutic workplace participants only reported higher income than controls. A therapeutic workplace social business can maintain long-term abstinence and employment, but additional intervention may be required to sustain effects. Copyright © 2014 Elsevier Inc. All rights reserved.

Drug convertarule.

PubMed

Brodie, M J; Robson, A; Murray, T

1983-04-09

A convenient pocket ruler has been developed that allows conversion between metric and molar measurements of many of the drugs for which therapeutic monitoring in the circulation is commonly used. The ruler also gives information to the clinician on suggested therapeutic ranges for the incorporated drugs.

Equivalence and interchangeability of narrow therapeutic index drugs in organ transplantation

PubMed Central

Johnston, Atholl

2013-01-01

The calcineurin inhibitors (CNIs), ciclosporin and tacrolimus, are the mainstay of immunosuppression in solid organ transplantation. Generic formulations of these drugs are now available. With increasing pressure on healthcare budgets and the consequent need to match health expectations to available resources, substitution with a generic product appears an attractive option to reduce costs. Approval of generic products differs from innovator drugs, and narrow therapeutic index drugs (NTIs; including CNIs) bring their own particular considerations. With NTIs, small variations in drug exposure could result in reduced immunosuppression or drug toxicity with potentially adverse effects on patient outcomes. NTIs are subject to stricter regulatory approval versus many other generic drugs. However, different generic formulations may still not necessarily be therapeutically equivalent in individuals, raising the possibility of significant differences in exposure between products. Although regional recommendations vary, many guidelines emphasise the need for NTI drug substitution to be initiated by the transplant physician, thus ensuring careful therapeutic monitoring and reduced negative patient impact. The need for therapeutic monitoring during generic substitution has important implications for the overall costs of generic treatment as these costs have to be factored in to the potential savings made from using generic formulations. The reduced acquisition costs of generic products may not necessarily translate into lower overall healthcare costs. This article examines the issue of equivalence and interchangeability of NTI drugs used in organ transplantation, the implications of the approval process for generic drugs on treatment efficacy and safety, and the effective management of substitutions between products. PMID:24089632

Epidemiological and mycological characteristics of candidemia in patients with hematological malignancies attending a tertiary-care center in India.

PubMed

Dewan, Eshani; Biswas, Debasis; Kakati, Barnali; Verma, S K; Kotwal, Aarti; Oberoi, Aroma

2015-09-01

We undertook the present study to ascertain the contributing risk factors and explore the epidemiological and mycological characteristics of opportunistic candidemia among patients with hematological malignancies. Observational cross-sectional study in a tertiary care center. Consecutive patients with hematological malignancies reporting to the collaborating medical and pediatric units with a febrile episode were recruited and screened for candidemia by blood culture. Recovered Candida isolates were speciated and antifungal susceptibility testing was performed as per Clinical and Laboratory Standards Institute guideline (CLSI) guidelines M44-A. Further analysis was done for potential risk factors and compared between culture positive and negative patients. Of 150 patients recruited, the majority (n=27) were between 51 and 60 years and the male to female ratio was 1.63:1. Fifteen patients (10%) were culture positive. The culture positivity was significantly higher in acute lymphocytic leukemia (ALL) than in non-ALL patients (p=0.03). There was significant association of candidaemia with leucopenia, chemotherapeutic drugs, corticosteroids and presence of indwelling devices. Duration of disease (p=0.032) and duration of hospitalization (p=0.003) were significantly prolonged in culture positive patients. C. tropicalis was the commonest isolate (46.67%), with non- Candida albicans outnumbering C. albicans in all categories of hematological malignancies (2.75:1). All isolates of C. albicans were uniformly sensitive to all the azoles, but only 50% were sensitive to amphotericin B and none to nystatin and flucytosine. This observational study identifies ALL and chronic lymphocytic leukemia (CLL) as the forms of hematological malignancy predominantly associated with candidemia; specifies risk factors and chemotherapeutic agents predisposing patients towards its occurrence; reports a preponderance of C. tropicalis among the causative agents and finds voriconazole to be the most effective antifungal agent against the recovered isolates. This information could assist in tailoring prophylactic and therapeutic antifungal practices for this infection, according to local epidemiological and mycological characteristics. Copyright © 2015. Published by Elsevier B.V.

Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds.

PubMed

Würth, Roberto; Thellung, Stefano; Bajetto, Adriana; Mazzanti, Michele; Florio, Tullio; Barbieri, Federica

2016-01-01

Drug repositioning is gaining increasing attention in drug discovery because it represents a smart way to exploit new molecular targets of a known drug or target promiscuity among diverse diseases, for medical uses different from the one originally considered. In this review, we focus on known non-oncological drugs with new therapeutic applications in oncology, explaining the rationale behind this approach and providing practical evidence. Moving from incompleteness of the knowledge of drug-target interactions, particularly for older molecules, we highlight opportunities for repurposing compounds as cancer therapeutics, underling the biologically and clinically relevant affinities for new targets. Ideal candidates for repositioning can contribute to the therapeutically unmet need for more-efficient anticancer agents, including drugs that selectively target cancer stem cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

Selenium nanoparticles: potential in cancer gene and drug delivery.

PubMed

Maiyo, Fiona; Singh, Moganavelli

2017-05-01

In recent decades, colloidal selenium nanoparticles have emerged as exceptional selenium species with reported chemopreventative and therapeutic properties. This has sparked widespread interest in their use as a carrier of therapeutic agents with results displaying synergistic effects of selenium with its therapeutic cargo and improved anticancer activity. Functionalization remains a critical step in selenium nanoparticles' development for application in gene or drug delivery. In this review, we highlight recent developments in the synthesis and functionalization strategies of selenium nanoparticles used in cancer drug and gene delivery systems. We also provide an update of recent preclinical studies utilizing selenium nanoparticles in cancer therapeutics.

Methadone: The Drug and Its Therapeutic Uses In the Treatment of Addiction. Series 31, No. 1.

ERIC Educational Resources Information Center

Gamage, James R.; Zerkin, E. Lief

This fact sheet from the National Clearinghouse for Drug Abuse Information discusses methadone, a therapeutic drug for the treatment of narcotic addiction. It reviews the pharmacology of the drug as well as physiological and psychological effects, patterns of use, and adverse effects (toxicity and poisoning). It examines the success rates of…

Liposomal Drug Delivery System for Cancer Therapy: Advancement and Patents.

PubMed

Jha, Sheetal; Sharma, Pramod K; Malviya, Rishabha

2016-01-01

In this review article, authors reviewed about the liposomes which are amongst various drug delivering systems for the delivery of the therapeutic agents at the target site. Advances in liposomal drug delivery systems for the cancer therapy have enhanced the therapeutic levels of the anticancer moieties. Liposomes show promising action on the tumor by incorporating less amount of drug at the target site, with minimum toxic effect and maximum therapeutic effect and thereby enhancing the bioavailability. Liposome-based drug delivery systems provide the potential to elevate the effect of drug concentration in tumor cells. Manuscript briefly describes the role of liposomes in cancer therapy and various patents based on the same. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Inferences of drug responses in cancer cells from cancer genomic features and compound chemical and therapeutic properties

PubMed Central

Wang, Yongcui; Fang, Jianwen; Chen, Shilong

2016-01-01

Accurately predicting the response of a cancer patient to a therapeutic agent is a core goal of precision medicine. Existing approaches were mainly relied primarily on genomic alterations in cancer cells that have been treated with different drugs. Here we focus on predicting drug response based on integration of the heterogeneously pharmacogenomics data from both cell and drug sides. Through a systematical approach, named as PDRCC (Predict Drug Response in Cancer Cells), the cancer genomic alterations and compound chemical and therapeutic properties were incorporated to determine the chemotherapeutic response in cancer patients. Using the Cancer Cell Line Encyclopedia (CCLE) study as the benchmark dataset, all pharmacogenomics data exhibited their roles in inferring the relationships between cancer cells and drugs. When integrating both genomic resources and compound information, the prediction coverage was significantly increased. The validity of PDRCC was also supported by its effective in uncovering the unknown cell-drug associations with database and literature evidences. It set the stage for clinical testing of novel therapeutic strategies, such as the sensitive association between cancer cell ‘A549_LUNG’ and compound ‘Topotecan’. In conclusion, PDRCC offers the possibility for faster, safer, and cheaper the development of novel anti-cancer therapeutics in the early-stage clinical trails. PMID:27645580

Inferences of drug responses in cancer cells from cancer genomic features and compound chemical and therapeutic properties

NASA Astrophysics Data System (ADS)

Wang, Yongcui; Fang, Jianwen; Chen, Shilong

2016-09-01

Accurately predicting the response of a cancer patient to a therapeutic agent is a core goal of precision medicine. Existing approaches were mainly relied primarily on genomic alterations in cancer cells that have been treated with different drugs. Here we focus on predicting drug response based on integration of the heterogeneously pharmacogenomics data from both cell and drug sides. Through a systematical approach, named as PDRCC (Predict Drug Response in Cancer Cells), the cancer genomic alterations and compound chemical and therapeutic properties were incorporated to determine the chemotherapeutic response in cancer patients. Using the Cancer Cell Line Encyclopedia (CCLE) study as the benchmark dataset, all pharmacogenomics data exhibited their roles in inferring the relationships between cancer cells and drugs. When integrating both genomic resources and compound information, the prediction coverage was significantly increased. The validity of PDRCC was also supported by its effective in uncovering the unknown cell-drug associations with database and literature evidences. It set the stage for clinical testing of novel therapeutic strategies, such as the sensitive association between cancer cell ‘A549_LUNG’ and compound ‘Topotecan’. In conclusion, PDRCC offers the possibility for faster, safer, and cheaper the development of novel anti-cancer therapeutics in the early-stage clinical trails.

Biomedical applications of microneedles in therapeutics: recent advancements and implications in drug delivery.

PubMed

Rejinold, N Sanoj; Shin, Ju-Hyung; Seok, Hae Yong; Kim, Yeu-Chun

2016-01-01

The skin, as the largest organ, is a better option for drug delivery in many diseases. However, most transdermal delivery is difficult due to the low permeability of therapeutics across the various skin layers. There have been many innovations in transdermal drug delivery to enhance the therapeutic efficacy of the drugs administered. Microneedles (MN), micron sized needles, are of great interest to scientists as a new therapeutic vehicle through transdermal routes, especially for vaccines, drugs, small molecules, etc. This review covers new insights into different types of MNs such as solid, hollow, coated and dissolving MNs (SMNs, HMNs, CMNs, and DMNs) for selected biomedical applications in detail. Specific focus has been given to CMNs and DMNs for vaccine and drug delivery applications with recent developments in new MNs covered. This review explores the feasibility of innovative MNs used as a drug delivery carrier. Because most of the SMNs and HMNs have many limitations, it is difficult to achieve therapeutic efficacy. Therefore, many scientists are investigating functional modifications of MNs through covalent and non-covalent methods, especially for CMNs and DMNs. The biomedical applications of MNs are growing and new exciting improvements could be achieved, thus resulting in better micro/nano technologies in the near future.

Inferences of drug responses in cancer cells from cancer genomic features and compound chemical and therapeutic properties.

PubMed

Wang, Yongcui; Fang, Jianwen; Chen, Shilong

2016-09-20

Accurately predicting the response of a cancer patient to a therapeutic agent is a core goal of precision medicine. Existing approaches were mainly relied primarily on genomic alterations in cancer cells that have been treated with different drugs. Here we focus on predicting drug response based on integration of the heterogeneously pharmacogenomics data from both cell and drug sides. Through a systematical approach, named as PDRCC (Predict Drug Response in Cancer Cells), the cancer genomic alterations and compound chemical and therapeutic properties were incorporated to determine the chemotherapeutic response in cancer patients. Using the Cancer Cell Line Encyclopedia (CCLE) study as the benchmark dataset, all pharmacogenomics data exhibited their roles in inferring the relationships between cancer cells and drugs. When integrating both genomic resources and compound information, the prediction coverage was significantly increased. The validity of PDRCC was also supported by its effective in uncovering the unknown cell-drug associations with database and literature evidences. It set the stage for clinical testing of novel therapeutic strategies, such as the sensitive association between cancer cell 'A549_LUNG' and compound 'Topotecan'. In conclusion, PDRCC offers the possibility for faster, safer, and cheaper the development of novel anti-cancer therapeutics in the early-stage clinical trails.

Mechanisms of Drug-Resistance in Kinases

PubMed Central

Barouch-Bentov, Rina; Sauer, Karsten

2010-01-01

Introduction Because of their important roles in disease and excellent “druggability”, kinases have become the second-largest drug target family. The great success of the BCR-ABL inhibitor imatinib in treating CML illustrates the high potential of kinase inhibitor (KI) therapeutics, but also unveiled a major limitation: the development of drug-resistance. This is a significant concern as KIs reach large patient populations for an expanding array of indications. Areas covered We provide an up-to-date understanding of the mechanisms through which KIs function, and through which cells can become KI-resistant. We review current and future approaches to overcome KI-resistance, focussing on currently approved KIs and KIs in clinical trials. We then discuss approaches to improve KI efficacy and overcome drug-resistance and novel approaches to develop less drug-resistance prone KI-therapeutics. Expert opinion Although drug-resistance is a concern for current KI-therapeutics, recent progress in our understanding of the underlying mechanisms and promising technological advances may overcome this limitation and provide powerful new therapeutics. PMID:21235428

Mathematical Modelling and Analysis of the Tumor Treatment Regimens with Pulsed Immunotherapy and Chemotherapy

PubMed Central

Pang, Liuyong; Shen, Lin; Zhao, Zhong

2016-01-01

To begin with, in this paper, single immunotherapy, single chemotherapy, and mixed treatment are discussed, and sufficient conditions under which tumor cells will be eliminated ultimately are obtained. We analyze the impacts of the least effective concentration and the half-life of the drug on therapeutic results and then find that increasing the least effective concentration or extending the half-life of the drug can achieve better therapeutic effects. In addition, since most types of tumors are resistant to common chemotherapy drugs, we consider the impact of drug resistance on therapeutic results and propose a new mathematical model to explain the cause of the chemotherapeutic failure using single drug. Based on this, in the end, we explore the therapeutic effects of two-drug combination chemotherapy, as well as mixed immunotherapy with combination chemotherapy. Numerical simulations indicate that combination chemotherapy is very effective in controlling tumor growth. In comparison, mixed immunotherapy with combination chemotherapy can achieve a better treatment effect. PMID:26997972

Mathematical Modelling and Analysis of the Tumor Treatment Regimens with Pulsed Immunotherapy and Chemotherapy.

PubMed

Pang, Liuyong; Shen, Lin; Zhao, Zhong

2016-01-01

To begin with, in this paper, single immunotherapy, single chemotherapy, and mixed treatment are discussed, and sufficient conditions under which tumor cells will be eliminated ultimately are obtained. We analyze the impacts of the least effective concentration and the half-life of the drug on therapeutic results and then find that increasing the least effective concentration or extending the half-life of the drug can achieve better therapeutic effects. In addition, since most types of tumors are resistant to common chemotherapy drugs, we consider the impact of drug resistance on therapeutic results and propose a new mathematical model to explain the cause of the chemotherapeutic failure using single drug. Based on this, in the end, we explore the therapeutic effects of two-drug combination chemotherapy, as well as mixed immunotherapy with combination chemotherapy. Numerical simulations indicate that combination chemotherapy is very effective in controlling tumor growth. In comparison, mixed immunotherapy with combination chemotherapy can achieve a better treatment effect.

The Implications and Future Perspectives of Nanomedicine for Cancer Stem Cell Targeted Therapies

PubMed Central

Singh, Vimal K.; Saini, Abhishek; Chandra, Ramesh

2017-01-01

Cancer stem cells (CSCs) are believed to exhibit distinctive self-renewal, proliferation, and differentiation capabilities, and thus play a significant role in various aspects of cancer. CSCs have significant impacts on the progression of tumors, drug resistance, recurrence and metastasis in different types of malignancies. Due to their primary role, most researchers have focused on developing anti-CSC therapeutic strategies, and tremendous efforts have been put to explore methods for selective eradication of these therapeutically resistant CSCs. In recent years, many reports have shown the use of CSCs-specific approaches such as ATP-binding cassette (ABC) transporters, blockade of self-renewal and survival of CSCs, CSCs surface markers targeted drugs delivery and eradication of the tumor microenvironment. Also, various therapeutic agents such as small molecule drugs, nucleic acids, and antibodies are said to destroy CSCs selectively. Targeted drug delivery holds the key to the success of most of the anti-CSCs based drugs/therapies. The convention CSCs-specific therapeutic agents, suffer from various problems. For instance, limited water solubility, small circulation time and inconsistent stability of conventional therapeutic agents have significantly limited their efficacy. Recent advancement in the drug delivery technology has demonstrated that specially designed nanocarrier-based drug delivery approaches (nanomedicine) can be useful in delivering sufficient amount of drug molecules even in the most interiors of CSCs niches and thus can overcome the limitations associated with the conventional free drug delivery methods. The nanomedicine has also been promising in designing effective therapeutic regime against pump-mediated drug resistance (ATP-driven) and reduces detrimental effects on normal stem cells. Here we focus on the biological processes regulating CSCs' drug resistance and various strategies developed so far to deal with them. We also review the various nanomedicine approaches developed so far to overcome these CSCs related issues and their future perspectives. PMID:28785557

Emerging Research and Clinical Development Trends of Liposome and Lipid Nanoparticle Drug Delivery Systems

PubMed Central

KRAFT, JOHN C.; FREELING, JENNIFER P.; WANG, ZIYAO; HO, RODNEY J. Y.

2014-01-01

Liposomes are spherical-enclosed membrane vesicles mainly constructed with lipids. Lipid nanoparticles are loaded with therapeutics and may not contain an enclosed bilayer. The majority of those clinically approved have diameters of 50–300 nm. The growing interest in nanomedicine has fueled lipid–drug and lipid–protein studies, which provide a foundation for developing lipid particles that improve drug potency and reduce off-target effects. Integrating advances in lipid membrane research has enabled therapeutic development. At present, about 600 clinical trials involve lipid particle drug delivery systems. Greater understanding of pharmacokinetics, biodistribution, and disposition of lipid–drug particles facilitated particle surface hydration technology (with polyethylene glycol) to reduce rapid clearance and provide sufficient blood circulation time for drug to reach target tissues and cells. Surface hydration enabled the liposome-encapsulated cancer drug doxorubicin (Doxil) to gain clinical approval in 1995. Fifteen lipidic therapeutics are now clinically approved. Although much research involves attaching lipid particles to ligands selective for occult cells and tissues, preparation procedures are often complex and pose scale-up challenges. With emerging knowledge in drug target and lipid–drug distribution in the body, a systems approach that integrates knowledge to design and scale lipid–drug particles may further advance translation of these systems to improve therapeutic safety and efficacy. PMID:24338748

Recent developments in anticancer drug delivery using cell penetrating and tumor targeting peptides.

PubMed

Dissanayake, Shama; Denny, William A; Gamage, Swarna; Sarojini, Vijayalekshmi

2017-03-28

Efficient intracellular trafficking and targeted delivery to the site of action are essential to overcome the current drawbacks of cancer therapeutics. Cell Penetrating Peptides (CPPs) offer the possibility of efficient intracellular trafficking, and, therefore the development of drug delivery systems using CPPs as cargo carriers is an attractive strategy to address the current drawbacks of cancer therapeutics. Additionally, the possibility of incorporating Tumor Targeting Peptides (TTPs) into the delivery system provides the necessary drug targeting effect. Therefore the conjugation of CPPs and/or TTPs with therapeutics provides a potentially efficient method of improving intracellular drug delivery mechanisms. Peptides used as cargo carriers in DDS have been shown to enhance the cellular uptake of drugs and thereby provide an efficient therapeutic benefit over the drug on its own. After providing a brief overview of various drug targeting approaches, this review focusses on peptides as carriers and targeting moieties in drug-peptide covalent conjugates and summarizes the most recent literature examples where CPPs on their own or CPPs together with TTPs have been conjugated to anticancer drugs such as Doxorubicin, Methotrexate, Paclitaxel, Chlorambucil etc. A short section on CPPs used in multicomponent drug delivery systems is also included. Copyright © 2017 Elsevier B.V. All rights reserved.

[Cladophilaphora bantiana brain abscess treated with voriconazole in an immunocompetent patient].

PubMed

Atalay, Mustafa Altay; Koç, Ayşe Nedret; Koyuncu, Sümeyra; Ulu Kiliç, Ayşegül; Kurtsoy, Ali; Alp Meşe, Emine

2014-07-01

Phaeohyphomycosis is a term used to define infections caused by darkly pigmented fungi with septate hyphae which contain melanin in their cell walls. Although fungi rarely cause central nervous system (CNS) infections, the incidence of CNS infections caused by melanin-containing fungi has been increasing in the recent years. Cladophialophora bantiana is the most frequently isolated species from cerebral phaeohyphomycosis. It mostly affects adult men in the second and third decade of life and about half of the cases occurs in immunocompetent patients. In this report, the isolation of C.bantiana from brain tissue of an immunocompetent patient who was operated with the initial diagnosis of a brain abscess, was presented. A 27 year-old male patient presenting without any chronic disease was admitted to the emergency department of our hospital with the complaints of persistent headache and diplopia. Magnetic resonance imaging (MRI) showed a space-occupying lesion in the right parietal lobe and left frontal lobe. Brain abscess was diagnosed in the patient who was referred to the neurosurgery department. Treatment was initiated with ceftriaxone and metronidazole. The abscess material sent for direct microscopic examination in the mycology laboratory was stained with Gram and Giemsa and cultured in the Sabouraud dextrose agar medium (SDA) with and without antibiotics (cycloheximide and chloramphenicol). Then, it was incubated at 37°C and 25°C. Direct examination and staining revealed a septate hyphae. The patient who received liposomal amphotericin B was referred to the infectious diseases department. Surface colors of all media including SDA with cycloheximide were olive-gray to black and contained velvety colonies. Lemon-like very long and integrated chains of conidium with poor branching in cornmeal Tween 80 agar, as well as growth at 42°C in passages, positive urease test result and cycloheximide resistance suggested C.bantiana. The isolate was confirmed as C. bantiana based on its DNA sequence analysis. Minimum inhibitor concentration (MIC) values for amphotericin B, voriconazole, caspofungin, and posaconazole were 2 µg/ml, 0.03 µg/ml, 0.03 µg/ml and 0.03 µg/ml, respectively. Liposomal amphotericin B was replaced with voriconazole due to the antifungal susceptibility profile. The patient who was symptom-free was discharged at 24 days after hospitalization with oral voriconazole treatment. In conclusion, cerebral phaeohyphomycosis should be considered in immunocompetent individuals. Given the fact that early diagnosis saves lives, such specimens should promptly be sent for mycological analysis.

Therapeutic Drug Monitoring and Clinical Outcomes in Immune Mediated Diseases: The Missing Link.

PubMed

Sorrentino, Dario; Nguyen, Vu; Henderson, Carl; Bankole, Adegabenga

2016-10-01

As the incidence of inflammatory bowel diseases and the number of patients treated with anti-TNF agents keep on increasing so are the phenomena of primary non response (PNR) and secondary loss of response (SLR) to these medications. Traditionally PNR and SLR have been managed empirically-that is, switching medications for PNR and increasing the anti-TNF dose for SNR. More recently an approach based on testing drug levels and antibodies to the drug (therapeutic drug monitoring) has gained increasing popularity in the management of inflammatory bowel diseases. However, while this strategy might offer an insight into the mechanisms leading to PNR/SLR it often falls short of providing a simple, reproducible method to manage these issues in clinical practice. Here, we will review the currently recommended therapeutic strategies when using therapeutic drug monitoring; the evidence for and against such approach and the current standard strategies in Rheumatology (the specialty with the largest and longest experience with anti-TNF agents). We will then discuss the possible reasons of the shortcomings of therapeutic drug monitoring and the rationale and need to move the therapeutic target to the disease burden in inflammatory bowel diseases-along with the supporting preliminary evidence. Finally, we will focus on future crucial studies that need to be done to make approaches to PNR/SLR more rigorous and at the same time user-friendly for the practicing gastroenterologist.

Use of Targeted Therapeutics in Epithelial Ovarian Cancer: A Review of Current Literature and Future Directions.

PubMed

Vetter, Monica Hagan; Hays, John L

2018-03-01

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the United States. Most patients will ultimately fail platinum-based chemotherapy and have the disease recur. Interest is increasing in the use of targeted therapies in the treatment of EOC. This review focuses on the current use of targeted therapeutics in EOC as well as future directions. A literature search of Medline and PubMed was conducted (January 2000-October 2017) to identify recent reports of targeted drugs in EOC. A wide range of targeted therapeutics is currently being used as both monotherapy and in combination in the treatment of EOC. Clinically, the most commonly used classes of drugs currently are antiangiogenics and poly (ADP-ribose) polymerase inhibitors. However, a number of drugs in varying stages in development target a wide range of biochemical pathways. Activity and response rates of these drugs vary greatly. Questions continue about combination drug therapy and appropriate patient selection. The use of targeted therapeutics in the treatment of EOC, both as monotherapy and in combination, will continue to expand as more mechanisms of tumorigenesis are identified. Multiple clinical trials of a wide range of targeted therapeutics are currently ongoing. Evidence-based selection of drug targets and appropriate patient populations will allow strategic application of targeted therapeutics. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

Propensity to Work Among Chronically Unemployed Adult Drug Users

PubMed Central

Sigurdsson, Sigurdur Oli; DeFulio, Anthony; Long, Lauren; Silverman, Kenneth

2014-01-01

Analyses were conducted to compare rates of employment before, during, and after employment at the therapeutic workplace, which is a novel employment-based treatment for drug misuse. Participants in two clinical trials attended the therapeutic workplace at higher rates than they worked before intake and six months after discharge. These data suggest that unemployed chronic drug misusers will attend work at higher rates at the therapeutic workplace than in the community when paid modest wages, and that the failure of chronic drug misusers to obtain employment in the community may not result from lack of interest in work. PMID:20964531

Analytical Pitfalls of Therapeutic Drug Monitoring of Thiopurines in Patients With Inflammatory Bowel Disease

PubMed Central

Meijer, Berrie; Mulder, Chris J. J.; van Bodegraven, Adriaan A.; de Boer, Nanne K. H.

2017-01-01

Abstract: The use of thiopurines in the treatment of inflammatory bowel disease (IBD) can be optimized by the application of therapeutic drug monitoring. In this procedure, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) metabolites are monitored and related to therapeutic response and adverse events, respectively. Therapeutic drug monitoring of thiopurines, however, is hampered by several analytical limitations resulting in an impaired translation of metabolite levels to clinical outcome in IBD. Thiopurine metabolism is cell specific and requires nucleated cells and particular enzymes for 6-TGN formation. In the current therapeutic drug monitoring, metabolite levels are assessed in erythrocytes, whereas leukocytes are considered the main target cells of these drugs. Furthermore, currently used methods do not distinguish between active nucleotides and their unwanted residual products. Last, there is a lack of a standardized laboratorial procedure for metabolite assessment regarding the substantial instability of erythrocyte 6-TGN. To improve thiopurine therapy in patients with IBD, it is necessary to understand these limitations and recognize the general misconceptions in this procedure. PMID:29040228

Drug-drug interactions involving lysosomes: mechanisms and potential clinical implications.

PubMed

Logan, Randall; Funk, Ryan S; Axcell, Erick; Krise, Jeffrey P

2012-08-01

Many commercially available, weakly basic drugs have been shown to be lysosomotropic, meaning they are subject to extensive sequestration in lysosomes through an ion trapping-type mechanism. The extent of lysosomal trapping of a drug is an important therapeutic consideration because it can influence both activity and pharmacokinetic disposition. The administration of certain drugs can alter lysosomes such that their accumulation capacity for co-administered and/or secondarily administered drugs is altered. In this review the authors explore what is known regarding the mechanistic basis for drug-drug interactions involving lysosomes. Specifically, the authors address the influence of drugs on lysosomal pH, volume and lipid processing. Many drugs are known to extensively accumulate in lysosomes and significantly alter their structure and function; however, the therapeutic and toxicological implications of this remain controversial. The authors propose that drug-drug interactions involving lysosomes represent an important potential source of variability in drug activity and pharmacokinetics. Most evaluations of drug-drug interactions involving lysosomes have been performed in cultured cells and isolated tissues. More comprehensive in vivo evaluations are needed to fully explore the impact of this drug-drug interaction pathway on therapeutic outcomes.

Discovery and Delivery of Synergistic Chemotherapy Drug Combinations to Tumors

NASA Astrophysics Data System (ADS)

Camacho, Kathryn Militar

Chemotherapy combinations for cancer treatments harbor immense therapeutic potentials which have largely been untapped. Of all diseases, clinical studies of drug combinations are the most prevalent in oncology, yet their effectiveness is disputable, as complete tumor regressions are rare. Our research has been devoted towards developing delivery vehicles for combinations of chemotherapy drugs which elicit significant tumor reduction yet limit toxicity in healthy tissue. Current administration methods assume that chemotherapy combinations at maximum tolerable doses will provide the greatest therapeutic effect -- a presumption which often leads to unprecedented side effects. Contrary to traditional administration, we have found that drug ratios rather than total cumulative doses govern combination therapeutic efficacy. In this thesis, we have developed nanoparticles to incorporate synergistic ratios of chemotherapy combinations which significantly inhibit cancer cell growth at lower doses than would be required for their single drug counterparts. The advantages of multi-drug incorporation in nano-vehicles are many: improved accumulation in tumor tissue via the enhanced permeation and retention effect, limited uptake in healthy tissue, and controlled exposure of tumor tissue to optimal synergistic drug ratios. To exploit these advantages for polychemotherapy delivery, two prominent nanoparticles were investigated: liposomes and polymer-drug conjugates. Liposomes represent the oldest class of nanoparticles, with high drug loading capacities and excellent biocompatibility. Polymer-drug conjugates offer controlled drug incorporations through reaction stoichiometry, and potentially allow for delivery of precise ratios. Here, we show that both vehicles, when armed with synergistic ratios of chemotherapy drugs, significantly inhibit tumor growth in an aggressive mouse breast carcinoma model. Furthermore, versatile drug incorporation methods investigated here can be broadly applied to various agents. Findings from our research can potentially widen the therapeutic window of chemotherapy combinations by emphasizing investigations of optimal drug ratios rather than maximum drug doses and by identifying appropriate nanoparticles for their delivery. Application of these concepts can ultimately help capture the full therapeutic potential of combination regimens.

Ultrasound-mediated drug delivery for cardiovascular disease

PubMed Central

Sutton, Jonathan T; Haworth, Kevin J; Pyne-Geithman, Gail; Holland, Christy K

2014-01-01

Introduction Ultrasound (US) has been developed as both a valuable diagnostic tool and a potent promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. These effects can be mediated by mechanical oscillations of circulating microbubbles, or US contrast agents, which may also encapsulate and shield a therapeutic agent in the bloodstream. Oscillating microbubbles can create stresses directly on nearby tissue or induce fluid effects that effect drug penetration into vascular tissue, lyse thrombi or direct drugs to optimal locations for delivery. Areas covered The present review summarizes investigations that have provided evidence for US-mediated drug delivery as a potent method to deliver therapeutics to diseased tissue for cardiovascular treatment. In particular, the focus will be on investigations of specific aspects relating to US-mediated drug delivery, such as delivery vehicles, drug transport routes, biochemical mechanisms and molecular targeting strategies. Expert opinion These investigations have spurred continued research into alternative therapeutic applications, such as bioactive gas delivery and new US technologies. Successful implementation of US-mediated drug delivery has the potential to change the way many drugs are administered systemically, resulting in more effective and economical therapeutics, and less-invasive treatments. PMID:23448121

Convergence of anatomy, technology, and therapeutics: a review of laser-assisted drug delivers.

PubMed

Brauer, Jeremy A; Krakowski, Andrew C; Bloom, Bradley S; Nguyen, Tuyet A; Geronemus, Roy G

2014-12-01

This is a very exciting time in cutaneous laser surgery with an ever-expanding therapeutic armamentarium and an increased sophistication of available technology. These recent trends have allowed for both a rapid development of interest and exploration of laser-assisted drug delivery and its potential applications. We review the current literature on anatomy, technology, and therapeutics as it relates to laser-assisted drug delivery. The focus of our review is on two areas of interest that have received much attention to date - photodynamic therapy in the treatment of actinic keratoses and nonmelanoma skin cancers as well as the treatment of scarring. We will also discuss potential complications of existing modalities used independently and in laser-assisted drug delivery and conclude with future indications for this burgeoning therapeutic methodology.

Cure of tuberculosis despite serum concentrations of antituberculosis drugs below published reference ranges.

PubMed

Meloni, Monica; Corti, Natascia; Müller, Daniel; Henning, Lars; Gutteck, Ursula; von Braun, Amrei; Weber, Rainer; Fehr, Jan

2015-01-01

Therapeutic target serum concentrations of first-line antituberculosis drugs have not been well defined in clinical studies in tuberculosis (TB) patients. We retrospectively investigated the estimated maximum serum concentrations (eC max) of antituberculosis drugs and clinical outcome of TB patients with therapeutic drug monitoring performed between 2010-2012 at our institution, and follow-up until March 2014. The eC max was defined as the highest serum concentration during a sampling period (2, 4 and 6 hours after drug ingestion). We compared the results with published eC max values, and categorised them as either "within reference range", "low eC max", or "very low eC max".Low/very low eC max-levels were defined as follows: isoniazid 2-3/<2 mg/l, rifampicin 4-8/<4 mg/l, rifabutin 0.2-0.3/<0.2 mg/l, ethambutol 1-2/<0.1 mg/l and pyrazinamide <20 mg/l. Concentrations of antituberculosis drugs in 175 serum samples of 17 patients with TB were analysed. In 12 (71%) patients, multiple therapeutic drug monitoring samples were collected over time, in 5 (29%) patients only one sample was available for therapeutic drug monitoring. Overall, 94% of all patients had at least one low antituberculosis drug concentration. Overall, 64% of all eC max levels were classified as "low" or "very low". The eC max was below the relevant reference range in 80% of isoniazid, 95% of rifampicin, 30% of pyrazinamide, and 30% of ethambutol measurements. All but one patient were cured of tuberculosis. Although many antituberculosis drug serum concentrations were below the widely used reference ranges, 16 of 17 patients were cured of tuberculosis. These results challenge the use of the published reference ranges for therapeutic drug monitoring.

77 FR 46444 - Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics (GREAT); Public Workshop

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-03

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0001] Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics (GREAT); Public Workshop AGENCY: Food and Drug Administration, HHS. ACTION: Notice of public workshop. SUMMARY: The Food and Drug Administration...

Personality Change in Drug Abusers: A Comparison of Therapeutic Community and Prison Groups.

ERIC Educational Resources Information Center

Skolnick, Neil J.; Zuckerman, Marvin

1979-01-01

Compared changes in male drug abusers treated in a therapeutic community (TC) with untreated drug abusers in prison. Results showed little change in subjects confined in prison relative to marked changes in those treated in a TC. TC treatment did not markedly affect psychopathic traits. (Author)

A case study in generic drug use: should there be risk adjustment in incentive payments for the use of generic medications?

PubMed

Walton, Surrey M; Rash, Christine; Lambert, Bruce L; Galanter, William L

2014-11-01

Encouraging generic drug use has reduced health care costs for payers and consumers, but the availability of therapeutically interchangeable medications or generic medications of choice is not equal across disease states. The extent to which systems of care are able to substitute with generics is not well understood.  To (a) define and measure the maximum generic rate (MGR) of currently prescribed drugs within an academic medical group in and (b) illustrate differences across drugs associated with selected underlying diseases.   Prescription claims data were examined from an academic medical group in Chicago, Illinois. Based on pharmacologic and therapeutic criteria, drugs were classified into 2 categories-potentially substitutable and not potentially substitutable-based on whether the drugs are branded forms of the same chemical entities that are available as generics or are therapeutically interchangeable with other medications that have different chemical compositions but the same mechanisms of action and potential efficacy. A medication was considered potentially substitutable if it (a) did not have a narrow therapeutic index as defined by the FDA; (b) did not belong to 1 of 6 protected classes of drugs in the Medicare D provisions; (c) was substitutable with a generic medication containing the same chemical entity; or (d) was therapeutically interchangeable with a therapeutically equivalent medication. MGR was defined as the percentage of prescriptions that could potentially be prescribed in generic form. This rate was examined overall and across drugs known to be associated with illustrative diseases including hypertension, diabetes mellitus, and obstructive lung diseases.   The MGR ranged from 100% for drugs used in hypertension to 26.7% for drugs used in obstructive lung diseases. The MGR was 83.6%.  Payers wishing to promote generic substitution should incorporate the potential for substitution of clinically appropriate generic medications as part of incentives for generic utilization to avoid unintended consequences of using a fixed target rate. A practical methodology for determining an MGR is offered.

Potential savings associated with drug substitution in Medicare Part D: the Translating Research into Action for Diabetes (TRIAD) study.

PubMed

Duru, O Kenrik; Ettner, Susan L; Turk, Norman; Mangione, Carol M; Brown, Arleen F; Fu, Jeffery; Simien, Leslie; Tseng, Chien-Wen

2014-01-01

Drug substitution is a promising approach to reducing medication costs. To calculate the potential savings in a Medicare Part D plan from generic or therapeutic substitution for commonly prescribed drugs. Cross-sectional, simulation analysis. Low-income subsidy (LIS) beneficiaries (n = 145,056) and non low-income subsidy (non-LIS) beneficiaries (n = 1,040,030) enrolled in a large, national Part D health insurer in 2007 and eligible for a possible substitution. Using administrative data from 2007, we identified claims filled for brand-name drugs for which a direct generic substitute was available. We also identified the 50 highest cost drugs separately for LIS and non-LIS beneficiaries, and reached consensus on which drugs had possible therapeutic substitutes (27 for LIS, 30 for non-LIS). For each possible substitution, we used average daily costs of the original and substitute drugs to calculate the potential out-of-pocket savings, health plan savings, and when applicable, savings for the government/LIS subsidy. Overall, 39 % of LIS beneficiaries and 51 % of non-LIS beneficiaries were eligible for a generic and/or therapeutic substitution. Generic substitutions resulted in an average annual savings of $160 in the case of LIS beneficiaries and $127 in the case of non-LIS beneficiaries. Therapeutic substitutions resulted in an average annual savings of $452 in the case of LIS beneficiaries and $389 in the case of non-LIS beneficiaries. Our findings indicate that drug substitution, particularly therapeutic substitution, could result in significant cost savings. There is a need for additional studies evaluating the acceptability of therapeutic substitution interventions within Medicare Part D.

1st Joint European Conference on Therapeutic Targets and Medicinal Chemistry (TTMC 2015)

PubMed Central

Le Borgne, Marc; Haidar, Samer; Duval, Olivier; Wünsch, Bernhard; Jose, Joachim

2015-01-01

The European Conference on Therapeutic Targets and Medicinal Chemistry is a new two-day meeting on drug discovery that is focused on therapeutic targets and the use of tools to explore all fields of drug discovery and drug design such as molecular modelling, bioorganic chemistry, NMR studies, fragment screening, in vitro assays, in vivo assays, structure activity relationships, autodisplay. Abstracts of keynote lectures, plenary lectures, junior lectures, flash presentations, and posters presented during the meeting are collected in this report. PMID:26712767

A Zebrafish Heart Failure Model for Assessing Therapeutic Agents.

PubMed

Zhu, Xiao-Yu; Wu, Si-Qi; Guo, Sheng-Ya; Yang, Hua; Xia, Bo; Li, Ping; Li, Chun-Qi

2018-03-20

Heart failure is a leading cause of death and the development of effective and safe therapeutic agents for heart failure has been proven challenging. In this study, taking advantage of larval zebrafish, we developed a zebrafish heart failure model for drug screening and efficacy assessment. Zebrafish at 2 dpf (days postfertilization) were treated with verapamil at a concentration of 200 μM for 30 min, which were determined as optimum conditions for model development. Tested drugs were administered into zebrafish either by direct soaking or circulation microinjection. After treatment, zebrafish were randomly selected and subjected to either visual observation and image acquisition or record videos under a Zebralab Blood Flow System. The therapeutic effects of drugs on zebrafish heart failure were quantified by calculating the efficiency of heart dilatation, venous congestion, cardiac output, and blood flow dynamics. All 8 human heart failure therapeutic drugs (LCZ696, digoxin, irbesartan, metoprolol, qiliqiangxin capsule, enalapril, shenmai injection, and hydrochlorothiazide) showed significant preventive and therapeutic effects on zebrafish heart failure (p < 0.05, p < 0.01, and p < 0.001) in the zebrafish model. The larval zebrafish heart failure model developed and validated in this study could be used for in vivo heart failure studies and for rapid screening and efficacy assessment of preventive and therapeutic drugs.

Do follow-on therapeutic substitutes induce price competition between hospital medicines? Evidence from the Danish hospital sector.

PubMed

Hostenkamp, Gisela

2013-06-01

The pricing of follow-on drugs, that offer only limited health benefits over existing therapeutic alternatives, is a recurring health policy debate. This study investigates whether follow-on therapeutic substitutes create price competition between branded hospital medicines. New follow-on drugs and their incumbent therapeutic competitors were identified from Danish sales and product registration data on hospital pharmaceuticals using medically relevant criteria. We examined whether follow-on drugs adopt lower prices than their incumbent competitors, and whether incumbent competitors react to entry of follow-ons through price adjustments using a random intercept panel model. We found no evidence that follow-on drugs adopt lower prices than their incumbent competitors. Furthermore, potentially due to low sample size, we found no evidence that prices for incumbent pioneer products were significantly reduced as a reaction to competition from follow-on drugs. Competition between patented therapeutic substitutes did not seem to increase price competition and containment of pharmaceutical expenditures in the Danish hospital market. Strengthening hospitals' incentives to consider the price of alternative treatment options paired with a more active formulary management may increase price competition between therapeutic substitutes in the Danish hospital sector in the future. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

MRI-Guided Focused Ultrasound as a New Method of Drug Delivery

PubMed Central

Thanou, M.; Gedroyc, W.

2013-01-01

Ultrasound-mediated drug delivery under the guidance of an imaging modality can improve drug disposition and achieve site-specific drug delivery. The term focal drug delivery has been introduced to describe the focal targeting of drugs in tissues with the help of imaging and focused ultrasound. Focal drug delivery aims to improve the therapeutic profile of drugs by improving their specificity and their permeation in defined areas. Focused-ultrasound- (FUS-) mediated drug delivery has been applied with various molecules to improve their local distribution in tissues. FUS is applied with the aid of microbubbles to enhance the permeability of bioactive molecules across BBB and improve drug distribution in the brain. Recently, FUS has been utilised in combination with MRI-labelled liposomes that respond to temperature increase. This strategy aims to “activate” nanoparticles to release their cargo locally when triggered by hyperthermia induced by FUS. MRI-guided FUS drug delivery provides the opportunity to improve drug bioavailability locally and therefore improve the therapeutic profiles of drugs. This drug delivery strategy can be directly translated to clinic as MRg FUS is a promising clinically therapeutic approach. However, more basic research is required to understand the physiological mechanism of FUS-enhanced drug delivery. PMID:23738076

New technologies for application to veterinary therapeutics.

PubMed

Riviere, Jim E

2010-01-01

The purpose of this contribution is to review new technologies and make an educated prediction as to how they will impact veterinary pharmacology over the coming decades. By examining past developments, it becomes evident that change is incremental and predictable unless either a transforming discovery or a change in societal behaviour occurs. In the last century, both discoveries and behaviours have dramatically changed medicine, pharmacology and therapeutics. In this chapter, the potential effects of six transforming technologies on veterinary therapeutics are examined: continued advances in computer technology, microfluidics, nanotechnology, high-throughput screening, control and targeted drug delivery and pharmacogenomics. These should lead to the more efficacious and safer use of existing medicants, and the development of novel drugs across most therapeutic classes through increases in our knowledge base, as well as more efficient drug development. Although this growth in technology portends major advances over the next few decades, economic and regulatory constraints must still be overcome for these new drugs or therapeutic approaches to become common practise.

Nasal-nanotechnology: revolution for efficient therapeutics delivery.

PubMed

Kumar, Amrish; Pandey, Aditya Nath; Jain, Sunil Kumar

2016-01-01

In recent years, nanotechnology-based delivery systems have gained interest to overcome the problems of restricted absorption of therapeutic agents from the nasal cavity, depending upon the physicochemical properties of the drug and physiological properties of the human nose. The well-tolerated and non-invasive nasal drug delivery when combined with the nanotechnology-based novel formulations and carriers, opens the way for the effective systemic and brain targeting delivery of various therapeutic agents. To accomplish competent drug delivery, it is imperative to recognize the interactions among the nanomaterials and the nasal biological environment, targeting cell-surface receptors, drug release, multiple drug administration, stability of therapeutic agents and molecular mechanisms of cell signaling involved in patho-biology of the disease under consideration. Quite a few systems have been successfully formulated using nanomaterials for intranasal (IN) delivery. Carbon nanotubes (CNTs), chitosan, polylactic-co-glycolic acid (PLGA) and PLGA-based nanosystems have also been studied in vitro and in vivo for the delivery of several therapeutic agents which shown promising concentrations in the brain after nasal administration. The use of nanomaterials including peptide-based nanotubes and nanogels (NGs) for vaccine delivery via nasal route is a new approach to control the disease progression. In this review, the recent developments in nanotechnology utilized for nasal drug delivery have been discussed.

Effectiveness of surface enhanced Raman spectroscopy of tear fluid with soft substrate for point-of-care therapeutic drug monitoring

NASA Astrophysics Data System (ADS)

Yamada, K.; Endo, T.; Imai, H.; Kido, M.; Jeong, H.; Ohno, Y.

2016-03-01

We have developed the point-of-care therapeutic drug monitoring kit based on Raman Spectroscopy of tear fluid. In this study, we were examined a soft substrate for an optimal lattice based on nanoimprint lithography using cyclo-olefin polymer to improve the sensitivity for measuring drug concentration in tear fluid. This is photonics crystal which is one of the nano-photonics based device was fabricated. Target is Sodium Phenobarbital which is an anticonvulsant agent. We show the effectiveness of Surface Enhanced Raman Spectroscopy of tear fluid with soft substrate for point-of-care therapeutic drug monitoring.

Acid-activatable oxidative stress-inducing polysaccharide nanoparticles for anticancer therapy.

PubMed

Yoo, Wooyoung; Yoo, Donghyuck; Hong, Eunmi; Jung, Eunkyeong; Go, Yebin; Singh, S V Berwin; Khang, Gilson; Lee, Dongwon

2018-01-10

Drug delivery systems have been extensively developed to enhance the therapeutic efficacy of drugs by altering their pharmacokinetics and biodistribution. However, the use of high quantities of drug delivery systems can cause toxicity due to their poor metabolism and elimination. In this study, we developed polysaccharide-based drug delivery systems which exert potent therapeutic effects and could display synergistic therapeutic effects with drug payloads, leading to dose reduction. Cinnamaldehyde, a major component of cinnamon is known to induce anticancer activity by generating ROS (reactive oxygen species). We developed cinnamaldehyde-conjugated maltodextrin (CMD) as a polymeric prodrug of cinnamaldehyde and a drug carrier. Cinnamaldehyde was conjugated to the hydroxyl groups of maltodextrin via acid-cleavable acetal linkages, allowing facile formulation of nanoparticles and drug encapsulation. CMD nanoparticles induced acid-triggered ROS generation to induce apoptotic cell death. Camptothecin (CPT) was used as a model drug to investigate the potential of CMD nanoparticles as a drug carrier and also evaluate the synergistic anticancer effects with CMD nanoparticles. CPT-loaded CMD nanoparticles exhibited significantly higher anticancer activity than empty CMD nanoparticles and CPT alone in the study of mouse xenograft models, demonstrating the synergistic therapeutic effects of CMD with CPT. Taken together, we believe that CMD nanoparticles hold tremendous potential as a polymeric prodrug of cinnamaldehyde and a drug carrier in anticancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

21 CFR 884.5960 - Genital vibrator for therapeutic use.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Genital vibrator for therapeutic use. 884.5960 Section 884.5960 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... of sexual dysfunction or as an adjunct to Kegel's exercise (tightening of the muscles of the pelvic...

21 CFR 884.5960 - Genital vibrator for therapeutic use.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Genital vibrator for therapeutic use. 884.5960 Section 884.5960 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... of sexual dysfunction or as an adjunct to Kegel's exercise (tightening of the muscles of the pelvic...

21 CFR 884.5960 - Genital vibrator for therapeutic use.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Genital vibrator for therapeutic use. 884.5960 Section 884.5960 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... of sexual dysfunction or as an adjunct to Kegel's exercise (tightening of the muscles of the pelvic...

21 CFR 884.5960 - Genital vibrator for therapeutic use.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Genital vibrator for therapeutic use. 884.5960 Section 884.5960 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... of sexual dysfunction or as an adjunct to Kegel's exercise (tightening of the muscles of the pelvic...

21 CFR 884.5960 - Genital vibrator for therapeutic use.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Genital vibrator for therapeutic use. 884.5960 Section 884.5960 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... of sexual dysfunction or as an adjunct to Kegel's exercise (tightening of the muscles of the pelvic...

75 FR 32482 - Investigational New Drug Applications; Co-development of Investigational Drugs

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-08

...- infectives, seizure disorders, cardiovascular diseases, and any other therapeutic category in which such co..., cardiovascular diseases, and any other therapeutic category in which such co-development is likely to occur. III... distinct investigational drugs intended to be used in combination to treat a disease or condition. FDA is...

The Therapeutic Effects of Group Process on the Behavioral Patterns of a Drug-Addicted Group.

ERIC Educational Resources Information Center

Campbell, Linda; Page, Richard

1993-01-01

Examined role of group therapy, specifically marathon group work, as treatment of choice for drug-addicted individuals. Explored specific behavioral characteristics of drug-addicted population in interaction with specific therapeutic factors. Findings from 12 inmates who participated in group therapy supported the treatment value of the marathon…

Latest advances in novel cannabinoid CB2 ligands for drug abuse and their therapeutic potential

PubMed Central

Yang, Peng; Wang, Lirong; Xie, Xiang-Qun

2012-01-01

The field of cannabinoid (CB) drug research is experiencing a challenge as the CB1 antagonist Rimonabant, launched in 2006 as an anorectic/anti-obesity drug, was withdrawn from the European market due to the complications of suicide and depression as side effects. There is interest in developing CB2 drugs without CB1 psychotropic side effects for drug-abuse treatment and therapeutic medication. The CB1 receptor was discovered predominantly in the brain, whereas the CB2 is mainly expressed in peripheral cells and tissues, and is involved in immune signal transduction. Conversely, the CB2 receptor was recently detected in the CNS, for example, in the microglial cells and the neurons. While the CB2 neurons activity remains controversial, the CB2 receptor is an attractive therapeutic target for neuropathic pain, immune system, cancer and osteoporosis without psychoactivity. This review addresses CB drug abuse and therapeutic potential with a focus on the most recent advances on new CB2 ligands from the literature as well as patents. PMID:22300098

Delivery of therapeutics for deep-seated ocular conditions - status quo.

PubMed

Nguyen, Hubert; Eng, Shawn; Ngo, Thanh; Dass, Crispin R

2018-04-19

There is a need for research into designing effective pharmaceutical systems for delivering therapeutic drugs to the posterior of the eye for glaucoma-related pathology, macular degeneration, diabetic retinopathy, macular oedema, retinitis and choroiditis. Conventionally, eye drops have been extensively utilised for topical drug delivery to the anterior segment of the eye, but are less effective for delivery of therapeutics to the back of the eye due to significant barriers hampering drug penetration into the target intraocular tissue. This review explores some of the current and novel delivery systems employed to deliver therapeutics to the back of the eye such as those using liposomes, ocular implants, in situ gels, and nanoparticles, and how they can overcome some of these limitations. Issues such as blinking, precorneal fluid drainage, tear dilution and turnover, conjunctiva and nasal drug absorption, the corneal epithelium, vitreous drug clearance, and the blood-ocular barriers are reviewed and discussed. Further studies are needed to address their shortcomings such as drug compatibility and stability, economic viability and patient compliance. © 2018 Royal Pharmaceutical Society.

The biopharmaceutics risk assessment roadmap for optimizing clinical drug product performance.

PubMed

Selen, Arzu; Dickinson, Paul A; Müllertz, Anette; Crison, John R; Mistry, Hitesh B; Cruañes, Maria T; Martinez, Marilyn N; Lennernäs, Hans; Wigal, Tim L; Swinney, David C; Polli, James E; Serajuddin, Abu T M; Cook, Jack A; Dressman, Jennifer B

2014-11-01

The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate "learning and confirming" studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Drug delivery system and breast cancer cells

NASA Astrophysics Data System (ADS)

Colone, Marisa; Kaliappan, Subramanian; Calcabrini, Annarica; Tortora, Mariarosaria; Cavalieri, Francesca; Stringaro, Annarita

2016-06-01

Recently, nanomedicine has received increasing attention for its ability to improve the efficacy of cancer therapeutics. Nanosized polymer therapeutic agents offer the advantage of prolonged circulation in the blood stream, targeting to specific sites, improved efficacy and reduced side effects. In this way, local, controlled delivery of the drug will be achieved with the advantage of a high concentration of drug release at the target site while keeping the systemic concentration of the drug low, thus reducing side effects due to bioaccumulation. Various drug delivery systems such as nanoparticles, liposomes, microparticles and implants have been demonstrated to significantly enhance the preventive/therapeutic efficacy of many drugs by increasing their bioavailability and targetability. As these carriers significantly increase the therapeutic effect of drugs, their administration would become less cost effective in the near future. The purpose of our research work is to develop a delivery system for breast cancer cells using a microvector of drugs. These results highlight the potential uses of these responsive platforms suited for biomedical and pharmaceutical applications. At the request of all authors of the paper an updated version was published on 12 July 2016. The manuscript was prepared and submitted without Dr. Francesca Cavalieri's contribution and her name was added without her consent. Her name has been removed in the updated and re-published article.

Gender differences in drug use and expenditures in a privately insured population of older adults.

PubMed

Correa-de-Araujo, Rosaly; Miller, G Edward; Banthin, Jessica S; Trinh, Yen

2005-01-01

We examine gender differences in use and expenditures for prescription drugs among Medicare and privately insured older adults aged 65 and over, using data on a nationally representative sample of prescription drug purchases collected for the Medical Expenditure Panel Survey Household Component. Overall, women spent about $1,178 for drugs, about 17% more than the $1,009 in average expenditures by men. Older women constituted 50.7% of the population and had average annual aggregate expenditures for prescribed medicines of $6.93 billion compared to $5.77 billion for men. Women were more likely than men to use drugs from a number of therapeutic classes-analgesics, hormones and psychotherapeutic agents-and therapeutic subclasses-thyroid drugs, COX-2 inhibitors and anti-depressants. Women also had higher average prescriptions per user for a number of therapeutic classes-hormones, psychotherapeutic agents and analgesics-and therapeutic subclasses-anti-diabetic drugs and beta blockers. Prescribed medications are, arguably, the most important healthcare technology in preventing illness, disability, and death in older adults. It is critical that older women and men have proper access to prescribed medicines. Given the financial vulnerability of this priority population, particularly women, the expanded drug coverage available under the Medicare Modernization Act is of particular relevance in meeting this goal.

Therapeutic drug monitoring of psychotropic medications

PubMed Central

Mitchell, Philip B

2000-01-01

Therapeutic drug monitoring (TDM) of a number of psychotropic medications has proven to be of value, enabling minimization of the limitations of considerable genetic variability in their metabolism and the high rates of poor compliance with many psychiatric disorders. Therapeutic ranges have been established for lithium, some of the tricyclic antidepressants, and clozapine. TDM has also been shown to be useful in avoiding toxicity (as many psychotropics have narrow therapeutic indices), particularly that due to interactions with other compounds. PMID:10759685

Failure of Chemotherapy in Hepatocellular Carcinoma Due to Impaired and Dysregulated Primary Liver Drug Metabolizing Enzymes and Drug Transport Proteins: What to Do?

PubMed

Ul Islam, Salman; Ahmed, Muhammad Bilal; Shehzad, Adeeb; Ul-Islam, Mazhar; Lee, Young Sup

2018-05-28

Most of the drugs are metabolized in the liver by the action of drug metabolizing enzymes. In hepatocellular carcinoma (HCC), primary drug metabolizing enzymes are severely dysregulated, leading to failure of chemotherapy. Sorafenib is the only standard systemic drug available, but it still presents certain limitations, and much effort is required to understand who is responsive and who is refractory to the drug. Preventive and therapeutic approaches other than systemic chemotherapy include vaccination, chemoprevention, liver transplantation, surgical resection, and locoregional therapies. This review details the dysregulation of primary drug metabolizing enzymes and drug transport proteins of the liver in HCC and their influence on chemotherapeutic drugs. Furthermore, it emphasizes the adoption of safe alternative therapeutic strategies to chemotherapy. The future of HCC treatment should emphasize the understanding of resistance mechanisms and the finding of novel, safe, and efficacious therapeutic strategies, which will surely benefit patients affected by advanced HCC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Recommendations of the Oligonucleotide Safety Working Group's Formulated Oligonucleotide Subcommittee for the Safety Assessment of Formulated Oligonucleotide-Based Therapeutics.

PubMed

Marlowe, Jennifer L; Akopian, Violetta; Karmali, Priya; Kornbrust, Douglas; Lockridge, Jennifer; Semple, Sean

2017-08-01

The use of lipid formulations has greatly improved the ability to effectively deliver oligonucleotides and has been instrumental in the rapid expansion of therapeutic development programs using oligonucleotide drugs. However, the development of such complex multicomponent therapeutics requires the implementation of unique, scientifically sound approaches to the nonclinical development of these drugs, based upon a hybrid of knowledge and experiences drawn from small molecule, protein, and oligonucleotide therapeutic drug development. The relative paucity of directly applicable regulatory guidance documents for oligonucleotide therapeutics in general has resulted in the generation of multiple white papers from oligonucleotide drug development experts and members of the Oligonucleotide Safety Working Group (OSWG). The members of the Formulated Oligonucleotide Subcommittee of the OSWG have utilized their collective experience working with a variety of formulations and their associated oligonucleotide payloads, as well as their insights into regulatory considerations and expectations, to generate a series of consensus recommendations for the pharmacokinetic characterization and nonclinical safety assessment of this unique class of therapeutics. It should be noted that the focus of Subcommittee discussions was on lipid nanoparticle and other types of particulate formulations of therapeutic oligonucleotides and not on conjugates or other types of modifications of oligonucleotide structure intended to facilitate delivery.

[Minocycline as a therapeutic drug for methamphetamine use disorders].

PubMed

Hashimoto, Kenji

2008-02-01

Use of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) is an extremely serious and growing problem throughout the world, including Japan. Antipsychotic drugs have been used for psychotic symptoms associated with these abused drugs. However, there are currently no particular pharmacological treatments for the wide range of symptoms associated with these abused drugs. Recently, we reported that the second generation antibiotic drug minocycline can attenuate behavioral abnormalities and neurotoxicity in the brain after administration of methamphetamine or MDMA. In this review, we discuss minocycline as a new potential therapeutic drug for schizophrenia as well as psychosis associated with these abused drugs.

Prediction of polypharmacological profiles of drugs by the integration of chemical, side effect, and therapeutic space.

PubMed

Cheng, Feixiong; Li, Weihua; Wu, Zengrui; Wang, Xichuan; Zhang, Chen; Li, Jie; Liu, Guixia; Tang, Yun

2013-04-22

Prediction of polypharmacological profiles of drugs enables us to investigate drug side effects and further find their new indications, i.e. drug repositioning, which could reduce the costs while increase the productivity of drug discovery. Here we describe a new computational framework to predict polypharmacological profiles of drugs by the integration of chemical, side effect, and therapeutic space. On the basis of our previous developed drug side effects database, named MetaADEDB, a drug side effect similarity inference (DSESI) method was developed for drug-target interaction (DTI) prediction on a known DTI network connecting 621 approved drugs and 893 target proteins. The area under the receiver operating characteristic curve was 0.882 ± 0.011 averaged from 100 simulated tests of 10-fold cross-validation for the DSESI method, which is comparative with drug structural similarity inference and drug therapeutic similarity inference methods. Seven new predicted candidate target proteins for seven approved drugs were confirmed by published experiments, with the successful hit rate more than 15.9%. Moreover, network visualization of drug-target interactions and off-target side effect associations provide new mechanism-of-action of three approved antipsychotic drugs in a case study. The results indicated that the proposed methods could be helpful for prediction of polypharmacological profiles of drugs.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-12-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: 131I-chTNT; Abatacept, adalimumab, alemtuzumab, APC-8015, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, azimilide hydrochloride; Bevacizumab, bortezomib, bosentan, buserelin; Caspofungin acetate, CC-4047, ChAGCD3, ciclesonide, clopidogrel, curcumin, Cypher; Dabigatran etexilate, dapoxetine hydrochloride, darbepoetin alfa, darusentan, denosumab, DMXB-Anabaseine, drospirenone, drospirenone/estradiol, duloxetine hydrochloride, dutasteride; Edodekin alfa, efaproxiral sodium, elaidic acid-cytarabine, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, eszopiclone, etonogestrel/testosterone decanoate, exenatide; Fulvestrant; Gefitinib, glycine, GVS-111; Homoharringtonine; ICC-1132, imatinib mesylate, iodine (I131) tositumomab, i.v. gamma-globulin; Levetiracetam, levocetirizine, lintuzumab, liposomal nystatin, lumiracoxib, lurtotecan; Manitimus, mapatumumab, melatonin, micafungin sodium, mycophenolic acid sodium salt; Oblimersen sodium, OGX-011, olmesartan medoxomil, omalizumab, omapatrilat, oral insulin; Parathyroid hormone (human recombinant), pasireotide, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, phVEGF-A165, pimecrolimus, pitavastatin calcium, plerixafor hydrochloride, posaconazole, pramlintide acetate, prasterone, pregabalin, PT-141; Quercetin; Ranolazine, rosuvastatin calcium, rubitecan, rupatadine fumarate; Sardomozide, sunitinib malate; Tadalafil, talactoferrin alfa, tegaserod maleate, telithromycin, testosterone transdermal patch, TH-9507, tigecycline, tiotropium bromide, tipifarnib, tocilizumab, treprostinil sodium; Valdecoxib, vandetanib, vardenafil hydrochloride hydrate, voriconazole. Copyright 2005 Prous Science. All rights reserved.

Therapeutic drug monitoring of isoniazid and rifampicin during anti-tuberculosis treatment in Auckland, New Zealand.

PubMed

Maze, M J; Paynter, J; Chiu, W; Hu, R; Nisbet, M; Lewis, C

2016-07-01

There is uncertainty as to the optimal therapeutic concentrations of anti-tuberculosis drugs to achieve cure. To characterise the use of therapeutic drug monitoring (TDM), and identify risk factors and outcomes for those with concentrations below the drug interval. Patients treated for tuberculosis (TB) who had rifampicin (RMP) or isoniazid (INH) concentrations measured between 1 January 2005 and 31 December 2012 were studied retrospectively. Matched concentrations and drug dosing time were assessed according to contemporary regional drug intervals (RMP > 6 μmol/l, INH > 7.5 μmol/l) and current international recommendations (RMP > 10 μmol/l, INH > 22 μmol/l). Outcomes were assessed using World Health Organization criteria. Of 865 patients, 121 had concentrations of either or both medications. RMP concentrations were within the regional drug intervals in 106/114 (93%) and INH in 91/100 (91%). Concentrations were within international drug intervals for RMP in 76/114 (67%) and INH in 53/100 (53%). Low weight-based dose was the only statistically significant risk factor for concentrations below the drug interval. Of the 35 patients with low concentrations, 21 were cured, 9 completed treatment and 5 transferred out. There were no relapses during follow-up (mean 66.5 months). There were no clinically useful characteristics to guide use of TDM. Many patients had concentrations below international therapeutic intervals, but were successfully treated.

Novel therapeutic approaches for pulmonary arterial hypertension: Unique molecular targets to site-specific drug delivery.

PubMed

Vaidya, Bhuvaneshwar; Gupta, Vivek

2015-08-10

Pulmonary arterial hypertension (PAH) is a cardiopulmonary disorder characterized by increased blood pressure in the small arterioles supplying blood to lungs for oxygenation. Advances in understanding of molecular and cellular biology techniques have led to the findings that PAH is indeed a cascade of diseases exploiting multi-faceted complex pathophysiology, with cellular proliferation and vascular remodeling being the key pathogenic events along with several cellular pathways involved. While current therapies for PAH do provide for amelioration of disease symptoms and acute survival benefits, their full therapeutic potential is hindered by patient incompliance and off-target side effects. To overcome the issues related with current therapy and to devise a more selective therapy, various novel pathways are being investigated for PAH treatment. In addition, inability to deliver anti-PAH drugs to the disease site i.e., distal pulmonary arterioles has been one of the major challenges in achieving improved patient outcomes and improved therapeutic efficacy. Several novel carriers have been explored to increase the selectivity of currently approved anti-PAH drugs and to act as suitable carriers for the delivery of investigational drugs. In the present review, we have discussed potential of various novel molecular pathways/targets including RhoA/Rho kinase, tyrosine kinase, endothelial progenitor cells, vasoactive intestinal peptide, and miRNA in PAH therapeutics. We have also discussed various techniques for site-specific drug delivery of anti-PAH therapeutics so as to improve the efficacy of approved and investigational drugs. This review will provide gainful insights into current advances in PAH therapeutics with an emphasis on site-specific drug payload delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

Recovery Journeys of Counselors and Clients: A Case Study of the Therapeutic Alliance in a Drug Treatment and Rehabilitation Center in Malaysia

ERIC Educational Resources Information Center

Amat, Mohamad Isa

2013-01-01

The therapeutic alliance is a significant research area in counseling. The understanding of the therapeutic alliance, particularly in drug treatment settings helps counselors and clients to increase the treatment outcomes and its treatment process. The present study investigated the journeys of recovering counselors and clients in a private…

Therapeutic applications of hydrogels in oral drug delivery

PubMed Central

Sharpe, Lindsey A; Daily, Adam M; Horava, Sarena D; Peppas, Nicholas A

2015-01-01

Introduction Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications. Areas covered This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed. Expert opinion Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest. PMID:24848309

Cubosomes and other potential ocular drug delivery vehicles for macromolecular therapeutics.

PubMed

Hartnett, Terence E; O'Connor, Andrea J; Ladewig, Katharina

2015-01-01

Many macromolecular therapeutics designed to treat posterior segment eye diseases (PSEDs) are administered through frequent ocular injection, which can further deteriorate eye health. Due to the high frequency of injection and the high cost of the therapeutics, there is a need to develop new ways in which to deliver these therapeutics: ways which are both safer and more cost effective. Using the most common PSED, age-related macular degeneration, as an example of a debilitating ocular disease, this review examines the key barriers limiting the delivery of macromolecular therapeutics to the posterior segment of the eye and defines the key requirements placed on particulate drug delivery vehicles (DDVs) to be suitable for this application. Recent developments in macromolecular drug delivery to treat this disease as well as the remaining shortcomings in its treatment are surveyed. Lastly, an emerging class of DDVs potentially suited to this application, called cubosomes, is introduced. Based on their excellent colloidal stability and high internal surface area, cubosomes hold great potential for the sustained release of therapeutics. Novel production methods and a better understanding of the mechanisms through which drug release from these particles can be controlled are two major recent developments toward successful application.

Multifunctional mesoporous bioactive glasses for effective delivery of therapeutic ions and drug/growth factors.

PubMed

Wu, Chengtie; Chang, Jiang

2014-11-10

Regeneration of large-size bone defects represents a significant challenge clinically, which requires the use of scaffolds with multifunction, such as anti-bacterial activity, and stimulation of osteogenesis and angiogenesis. It is known that functional ions or drug/growth factors play an important role to stimulate tissue regeneration. Mesoporous bioactive glasses (MBG) possess excellent bioactivity and drug-delivery ability as well as effective ionic release in the body fluids microenvironment due to its specific mesoporous structure and large surface area. For these reasons, functional ions (e.g. lithium (Li), strontium (Sr), Copper (Cu) and Boron (B)) and drug/growth factors (e.g. dexamethasone, vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)) have been incorporated into MBG, which shows high loading efficiency and effective release. The release of therapeutic ions and drug/growth factors from MBG offers it multifunctional properties, such as improved osteogenesis, angiogenesis, anti-bacterial/cancer activity. However, there is no a systematic review about delivery of therapeutic ions and drugs/growth factors from MBG for the functional effect on the tissue regeneration despite that significant progress has been achieved in the past five years. Therefore, in this review, we mainly focused on the new advances for the functional effect of delivering therapeutic ions and drugs/growth factors on the ostegeogenesis, angiogenesis and antibacterial activity. It is expected that the review will offer new concept to develop multifunctional biomaterials for bone regeneration by the synergistic effect of therapeutic ions and drug/growth factors. Copyright © 2014 Elsevier B.V. All rights reserved.

Drug delivery across length scales.

PubMed

Delcassian, Derfogail; Patel, Asha K; Cortinas, Abel B; Langer, Robert

2018-02-20

Over the last century, there has been a dramatic change in the nature of therapeutic, biologically active molecules available to treat disease. Therapies have evolved from extracted natural products towards rationally designed biomolecules, including small molecules, engineered proteins and nucleic acids. The use of potent drugs which target specific organs, cells or biochemical pathways, necessitates new tools which can enable controlled delivery and dosing of these therapeutics to their biological targets. Here, we review the miniaturisation of drug delivery systems from the macro to nano-scale, focussing on controlled dosing and controlled targeting as two key parameters in drug delivery device design. We describe how the miniaturisation of these devices enables the move from repeated, systemic dosing, to on-demand, targeted delivery of therapeutic drugs and highlight areas of focus for the future.

Albumin nanoparticle encapsulation of potent cytotoxic therapeutics shows sustained drug release and alleviates cancer drug toxicity.

PubMed

Wang, Hangxiang; Wu, Jiaping; Xu, Li; Xie, Ke; Chen, Chao; Dong, Yuehan

2017-02-23

We here provide the first report on the construction of nanoparticles formulating highly potent cytotoxic therapeutics using albumin. Maytansinoid DM1 can be efficiently integrated into albumin nanoparticles, resulting in remarkable alleviation of in vivo drug toxicity and expanding the repertoire of albumin technology available for cancer therapy.

Drug-disease association and drug-repositioning predictions in complex diseases using causal inference-probabilistic matrix factorization.

PubMed

Yang, Jihong; Li, Zheng; Fan, Xiaohui; Cheng, Yiyu

2014-09-22

The high incidence of complex diseases has become a worldwide threat to human health. Multiple targets and pathways are perturbed during the pathological process of complex diseases. Systematic investigation of complex relationship between drugs and diseases is necessary for new association discovery and drug repurposing. For this purpose, three causal networks were constructed herein for cardiovascular diseases, diabetes mellitus, and neoplasms, respectively. A causal inference-probabilistic matrix factorization (CI-PMF) approach was proposed to predict and classify drug-disease associations, and further used for drug-repositioning predictions. First, multilevel systematic relations between drugs and diseases were integrated from heterogeneous databases to construct causal networks connecting drug-target-pathway-gene-disease. Then, the association scores between drugs and diseases were assessed by evaluating a drug's effects on multiple targets and pathways. Furthermore, PMF models were learned based on known interactions, and associations were then classified into three types by trained models. Finally, therapeutic associations were predicted based upon the ranking of association scores and predicted association types. In terms of drug-disease association prediction, modified causal inference included in CI-PMF outperformed existing causal inference with a higher AUC (area under receiver operating characteristic curve) score and greater precision. Moreover, CI-PMF performed better than single modified causal inference in predicting therapeutic drug-disease associations. In the top 30% of predicted associations, 58.6% (136/232), 50.8% (31/61), and 39.8% (140/352) hit known therapeutic associations, while precisions obtained by the latter were only 10.2% (231/2264), 8.8% (36/411), and 9.7% (189/1948). Clinical verifications were further conducted for the top 100 newly predicted therapeutic associations. As a result, 21, 12, and 32 associations have been studied and many treatment effects of drugs on diseases were investigated for cardiovascular diseases, diabetes mellitus, and neoplasms, respectively. Related chains in causal networks were extracted for these 65 clinical-verified associations, and we further illustrated the therapeutic role of etodolac in breast cancer by inferred chains. Overall, CI-PMF is a useful approach for associating drugs with complex diseases and provides potential values for drug repositioning.

Mining FDA drug labels using an unsupervised learning technique--topic modeling.

PubMed

Bisgin, Halil; Liu, Zhichao; Fang, Hong; Xu, Xiaowei; Tong, Weida

2011-10-18

The Food and Drug Administration (FDA) approved drug labels contain a broad array of information, ranging from adverse drug reactions (ADRs) to drug efficacy, risk-benefit consideration, and more. However, the labeling language used to describe these information is free text often containing ambiguous semantic descriptions, which poses a great challenge in retrieving useful information from the labeling text in a consistent and accurate fashion for comparative analysis across drugs. Consequently, this task has largely relied on the manual reading of the full text by experts, which is time consuming and labor intensive. In this study, a novel text mining method with unsupervised learning in nature, called topic modeling, was applied to the drug labeling with a goal of discovering "topics" that group drugs with similar safety concerns and/or therapeutic uses together. A total of 794 FDA-approved drug labels were used in this study. First, the three labeling sections (i.e., Boxed Warning, Warnings and Precautions, Adverse Reactions) of each drug label were processed by the Medical Dictionary for Regulatory Activities (MedDRA) to convert the free text of each label to the standard ADR terms. Next, the topic modeling approach with latent Dirichlet allocation (LDA) was applied to generate 100 topics, each associated with a set of drugs grouped together based on the probability analysis. Lastly, the efficacy of the topic modeling was evaluated based on known information about the therapeutic uses and safety data of drugs. The results demonstrate that drugs grouped by topics are associated with the same safety concerns and/or therapeutic uses with statistical significance (P<0.05). The identified topics have distinct context that can be directly linked to specific adverse events (e.g., liver injury or kidney injury) or therapeutic application (e.g., antiinfectives for systemic use). We were also able to identify potential adverse events that might arise from specific medications via topics. The successful application of topic modeling on the FDA drug labeling demonstrates its potential utility as a hypothesis generation means to infer hidden relationships of concepts such as, in this study, drug safety and therapeutic use in the study of biomedical documents.

Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies.

PubMed

van den Broek, Marcel P H; Groenendaal, Floris; Egberts, Antoine C G; Rademaker, Carin M A

2010-05-01

Examples of clinical applications of therapeutic hypothermia in modern clinical medicine include traumatic cardiac arrest, ischaemic stroke and, more recently, acute perinatal asphyxia in neonates. The exact mechanism of (neuro)protection by hypothermia is unknown. Since most enzymatic processes exhibit temperature dependency, it can be expected that therapeutic hypothermia may cause alterations in both pharmacokinetic and pharmacodynamic parameters, which could result in an increased risk of drug toxicity or therapy failure. Generalizable knowledge about the effect of therapeutic hypothermia on pharmacokinetics and pharmacodynamics could lead to more appropriate dosing and thereby prediction of clinical effects. This article reviews the evidence on the influence of therapeutic hypothermia on individual pharmacokinetic and pharmacodynamic parameters. A literature search was conducted within the PubMed, Embase and Cochrane databases from January 1965 to September 2008, comparing pharmacokinetic and/or pharmacodynamic parameters in hypothermia and normothermia regarding preclinical (animal) and clinical (human) studies. During hypothermia, pharmacokinetic parameters alter, resulting in drug and metabolite accumulation in the plasma for the majority of drugs. Impaired clearance is the most striking effect. Based on impaired clearance, dosages should be decreased considerably, especially for drugs with a low therapeutic index. Hypothetically, high-clearance compounds are affected more than low-clearance compounds because of the additional effect of impaired hepatic blood flow. The volume of distribution also changes, which may lead to therapy failure when it increases and could lead to toxicity when it decreases. The pH-partitioning hypothesis could contribute to the changes in the volumes of distribution for weak bases and acids, depending on their acid dissociation constants and acid-base status. Pharmacodynamic parameters may also alter, depending on the hypothermic regimen, drug target location, pharmacological mechanism and metabolic pathway of inactivation. The pharmacological response changes when target sensitivity alters. Rewarming patients to normothermia can also result in toxicity or therapy failure. The integrated effect of hypothermia on pharmacokinetic and pharmacodynamic properties of individual drugs is unclear. Therefore, therapeutic drug monitoring is currently considered essential for drugs with a low therapeutic index, drugs with active metabolites, high-clearance compounds and drugs that are inactivated by enzymes at the site of effect. Because most of the studies (74%) included in this review contain preclinical data, clinical pharmacokinetic/pharmacodynamic studies are essential for the development of substantiated dose regimens to avoid toxicity and therapy failure in patients treated with hypothermia.

Recent Trends in Nanotechnology-Based Drugs and Formulations for Targeted Therapeutic Delivery.

PubMed

Iqbal, Hafiz M N; Rodriguez, Angel M V; Khandia, Rekha; Munjal, Ashok; Dhama, Kuldeep

2017-01-01

In the recent past, a wider spectrum of nanotechnologybased drugs or drug-loaded devices and systems has been engineered and investigated with high interests. The key objective is to help for an enhanced/better quality of patient life in a secure way by avoiding/limiting drug abuse, or severe adverse effects of some in practice traditional therapies. Various methodological approaches including in vitro, in vivo, and ex vivo techniques have been exploited, so far. Among them, nanoparticles-based therapeutic agents are of supreme interests for an enhanced and efficient delivery in the current biomedical sector of the modern world. The development of new types of novel, effective and highly reliable therapeutic drug delivery system (DDS) for multipurpose applications is essential and a core demand to tackle many human health related diseases. In this context, nanotechnology-based several advanced DDS have been engineered with novel characteristics for biomedical, pharmaceutical and cosmeceutical applications that include but not limited to the enhanced/improved bioactivity, bioavailability, drug efficacy, targeted delivery, and therapeutically safer with an extra advantage of overcoming demerits of traditional drug formulations/designs. This review work is focused on recent trends/advances in nanotechnology-based drugs and formulations designed for targeted therapeutic delivery. Moreover, information is also reviewed and given from recent patents and summarized or illustrated diagrammatically to depict a better understanding. Recent patents covering various nanotechnology-based approaches for several applications have also been reviewed. The drug-loaded nanoparticles are among versatile candidates with multifunctional characteristics for potential applications in biomedical, and tissue engineering sector. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A pragmatic definition of therapeutic synergy suitable for clinically relevant in vitro multicompound analyses.

PubMed

Kashif, Muhammad; Andersson, Claes; Åberg, Magnus; Nygren, Peter; Sjöblom, Tobias; Hammerling, Ulf; Larsson, Rolf; Gustafsson, Mats G

2014-07-01

For decades, the standard procedure when screening for candidate anticancer drug combinations has been to search for synergy, defined as any positive deviation from trivial cases like when the drugs are regarded as diluted versions of each other (Loewe additivity), independent actions (Bliss independence), or no interaction terms in a response surface model (no interaction). Here, we show that this kind of conventional synergy analysis may be completely misleading when the goal is to detect if there is a promising in vitro therapeutic window. Motivated by this result, and the fact that a drug combination offering a promising therapeutic window seldom is interesting if one of its constituent drugs can provide the same window alone, the largely overlooked concept of therapeutic synergy (TS) is reintroduced. In vitro TS is said to occur when the largest therapeutic window obtained by the best drug combination cannot be achieved by any single drug within the concentration range studied. Using this definition of TS, we introduce a procedure that enables its use in modern massively parallel experiments supported by a statistical omnibus test for TS designed to avoid the multiple testing problem. Finally, we suggest how one may perform TS analysis, via computational predictions of the reference cell responses, when only the target cell responses are available. In conclusion, the conventional error-prone search for promising drug combinations may be improved by replacing conventional (toxicology-rooted) synergy analysis with an analysis focused on (clinically motivated) TS. ©2014 American Association for Cancer Research.

[Pulmonary non invasive infection by Scedosporium apiospermum].

PubMed

Cruz, Rodrigo; Barros, Manuel; Reyes, Mirtha

2015-08-01

We reported a case of non-invasive pulmonary infection by Scedosporium apiospermum in 67 years old female with bronchiectasis and caverns secondary to tuberculosis. Diagnosis was made with lung CT and bronchial lavage cultures. The patient was initially treated with itraconazole for six weeks without success and then voriconazole for 16 weeks, with good clinical response.

Long-term efficacy of wood dip-treated with multicomponent biocides

Treesearch

Carol A. Clausen; Vina W. Yang

2005-01-01

Biocides designed for prevention of indoor mold growth on wood-based materials need to provide long-term protection under conditions of high humidity. Specimens of kiln-dried southern pine and unseasoned southern pine, aspen, and Douglas-fir were dip-treated with borate-dimethylcocoamine (DMCA) supplemented with voriconazole, thiabendazole, or thujaplicin and evaluated...

Experimental treatment of Curvularia infection.

PubMed

Paredes, Katihuska; Capilla, Javier; Sutton, Deanna A; Mayayo, Emilio; Fothergill, Annette W; Guarro, Josep

2014-08-01

We have evaluated the efficacy of amphotericin B, posaconazole, and voriconazole in immunosuppressed murine models of disseminated infection by Curvularia spicifera and Curvularia hawaiiensis. The 3 antifungals improved survival of mice in comparison to controls; however, only the 2 azoles were able to reduce significantly the fungal load. Copyright © 2014 Elsevier Inc. All rights reserved.

Management of an Outbreak of Exophiala dermatitidis Bloodstream Infections at an Outpatient Oncology Clinic.

PubMed

Vasquez, Amber; Zavasky, D; Chow, N A; Gade, L; Zlatanic, E; Elkind, S; Litvintseva, A P; Pappas, P G; Perfect, J R; Revankar, S; Lockhart, S R; Chiller, T; Ackelsberg, J; Vallabhaneni, S

2018-03-05

We report the presentation and management of 17 cases of Exophiala dermatitidis and Rhodotorula mucilaginosa bloodstream infections caused by a compounded parenteral medication at an oncology clinic. Twelve patients were asymptomatic. All central venous catheters were removed and antifungal therapy, primarily voriconazole, was administered to patients. Three patients died.

ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others.

PubMed

Tortorano, A M; Richardson, M; Roilides, E; van Diepeningen, A; Caira, M; Munoz, P; Johnson, E; Meletiadis, J; Pana, Z-D; Lackner, M; Verweij, P; Freiberger, T; Cornely, O A; Arikan-Akdagli, S; Dannaoui, E; Groll, A H; Lagrou, K; Chakrabarti, A; Lanternier, F; Pagano, L; Skiada, A; Akova, M; Arendrup, M C; Boekhout, T; Chowdhary, A; Cuenca-Estrella, M; Guinea, J; Guarro, J; de Hoog, S; Hope, W; Kathuria, S; Lortholary, O; Meis, J F; Ullmann, A J; Petrikkos, G; Lass-Flörl, C

2014-04-01

Mycoses summarized in the hyalohyphomycosis group are heterogeneous, defined by the presence of hyaline (non-dematiaceous) hyphae. The number of organisms implicated in hyalohyphomycosis is increasing and the most clinically important species belong to the genera Fusarium, Scedosporium, Acremonium, Scopulariopsis, Purpureocillium and Paecilomyces. Severely immunocompromised patients are particularly vulnerable to infection, and clinical manifestations range from colonization to chronic localized lesions to acute invasive and/or disseminated diseases. Diagnosis usually requires isolation and identification of the infecting pathogen. A poor prognosis is associated with fusariosis and early therapy of localized disease is important to prevent progression to a more aggressive or disseminated infection. Therapy should include voriconazole and surgical debridement where possible or posaconazole as salvage treatment. Voriconazole represents the first-line treatment of infections due to members of the genus Scedosporium. For Acremonium spp., Scopulariopsis spp., Purpureocillium spp. and Paecilomyces spp. the optimal antifungal treatment has not been established. Management usually consists of surgery and antifungal treatment, depending on the clinical presentation. © 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.

Scleral and intraocular amoebic dissemination in Acanthamoeba keratitis.

PubMed

Arnalich-Montiel, Francisco; Jaumandreu, Laia; Leal, Marina; Valladares, Basilio; Lorenzo-Morales, Jacob

2013-12-01

To review an Acanthamoeba keratitis case series for the documented extracorneal spread of the amoeba. A retrospective review of an observational case series from a single institution. Three patients with 4 instances of microbiologically confirmed extracorneal amoebic spread were identified. Patient 1 had nodular scleritis after undergoing penetrating keratoplasty and was treated successfully with double freeze-thaw cryotherapy; patient 2 had intraocular dissemination of the amoeba detected in a retrocorneal membrane; and patient 3 had, after undergoing tectonic keratoplasty, intraocular dissemination of the amoeba that was treated successfully with intraocular and systemic voriconazole and, afterwards, a nodular scleritis treated with double freeze-thaw cryotherapy and a large-diameter corneal graft to treat corneal recurrence. Acanthamoeba can migrate to the sclera or to the intraocular tissues in some instances, such as in long-standing disease or in penetrating keratoplasty. A prompt biopsy for microbiological analysis and early treatment are required, if this is suspected. Voriconazole can be effective for intraocular invasion when used orally and intraocularly. Scleral involvement might require a surgical approach with double freeze-thaw cryotherapy to treat the localized disease.

A concise review on advances in development of small molecule anti-inflammatory therapeutics emphasising AMPK: An emerging target.

PubMed

Gejjalagere Honnappa, Chethan; Mazhuvancherry Kesavan, Unnikrishnan

2016-12-01

Inflammatory diseases are complex, multi-factorial outcomes of evolutionarily conserved tissue repair processes. For decades, non-steroidal anti-inflammatory drugs and cyclooxygenase inhibitors, the primary drugs of choice for the management of inflammatory diseases, addressed individual targets in the arachidonic acid pathway. Unsatisfactory safety and efficacy profiles of the above have necessitated the development of multi-target agents to treat complex inflammatory diseases. Current anti-inflammatory therapies still fall short of clinical needs and the clinical trial results of multi-target therapeutics are anticipated. Additionally, new drug targets are emerging with improved understanding of molecular mechanisms controlling the pathophysiology of inflammation. This review presents an outline of small molecules and drug targets in anti-inflammatory therapeutics with a summary of a newly identified target AMP-activated protein kinase, which constitutes a novel therapeutic pathway in inflammatory pathology. © The Author(s) 2016.

[How I treat: from specialized pharmacology to drug therapy: a plea for an optimal educational program for rational therapeutics, from decision making to drug prescription].

PubMed

Scheen, A J

2000-09-01

Clinical pharmacology and therapeutics are two complementary disciplines which should lead the medical student, through an optimized training, to a rational prescription of drugs, ultimate and important step of the medical approach. Such a learning should occur progressively throughout the medical education, focusing, first, on the therapeutic reasoning ("why?") and, second, on the practical application leading to the prescription ("how?"). The medical student should learn the difficult task of integrating disease, drug and patient, in order to optimize the benefit/risk ratio, while being informed about new concepts such as "Evidence-Based Medicine" and pharmacoeconomics.

Engineered magnetic core shell nanoprobes: Synthesis and applications to cancer imaging and therapeutics.

PubMed

Mandal, Samir; Chaudhuri, Keya

2016-02-26

Magnetic core shell nanoparticles are composed of a highly magnetic core material surrounded by a thin shell of desired drug, polymer or metal oxide. These magnetic core shell nanoparticles have a wide range of applications in biomedical research, more specifically in tissue imaging, drug delivery and therapeutics. The present review discusses the up-to-date knowledge on the various procedures for synthesis of magnetic core shell nanoparticles along with their applications in cancer imaging, drug delivery and hyperthermia or cancer therapeutics. Literature in this area shows that magnetic core shell nanoparticle-based imaging, drug targeting and therapy through hyperthermia can potentially be a powerful tool for the advanced diagnosis and treatment of various cancers.

Increased prescribing of Valium, Librium, and other drugs--an example of the influence of economic and social factors on the practice of medicine.

PubMed

Waldron, I

1977-01-01

Drug prescriptions per capita in the United States have more than doubled since 1950 without a commensurate improvement in health. Drugs are often prescribed for clinical conditions in which therapeutic benefits do not outweigh the risk of adverse drug reactions. Deaths due to adverse drug reactions are roughly as frequent as deaths due to automobile accidents. Valium and Librium are the first and fourth most commonly prescribed drugs in the U.S., used by one ten adults each year. The rapid rise in use of these drugs has occurred during a period of rising social stress, as indicated by increases in alcohol consumption, suicide, and homicide, Valium and Librium are frequently prescribe for patients who go to doctors with social or other nonmedical problems, often in lieu of attempts to resolve these underlying problems. Overprescribing occurs because the decision to prescribe is influenced not only by consideration of therapeutic benefit, but also by nonmedical factors, for example the widespread expectation by both patient and doctor that the doctor will provide a drug or some other technological treatment. Prescribing decisions are also influenced by the profit-motivated activities of drug companies, including the expenditure of almost one-quarter of every sales dollar on drug promotion. The most widely used source of drug information for doctors is the industry-sponsored Physicians' Desk Reference, which overrates the therapeutic value of Valium and Librium as compared to disinterested medical sources. Drug companies also contribute to overprescribing by introducing numerous minor variants of existing drugs. The therapeutic benefits of such new drugs are often overestimated in the early years of use when adverse side effects are not well known and apparent efficacy is enhanced by placebo effects in uncontrolled observations.

The prefrontal cortex: a target for antipsychotic drugs.

PubMed

Artigas, F

2010-01-01

At therapeutic doses, classical antipsychotic drugs occupy a large proportion of subcortical dopamine D2 receptors, whereas atypical antipsychotics preferentially occupy cortical 5-HT(2) receptors. However, the exact cellular and network basis of their therapeutic action is not fully understood. To review the mechanism of action of antipsychotic drugs with a particular emphasis on their action in the prefrontal cortex (PFC). The PFC controls a large number of higher brain functions altered in schizophrenia. Histological studies indicate the presence of a large proportion of PFC neurons expressing monoaminergic receptors sensitive to the action of atypical- and to a lesser extentclassical antipsychotic drugs. Functional studies also indicate that both drug families act at PFC level. Atypical antipsychotic drugs likely exert their therapeutic activity by a preferential action on PFC neurons, thus modulating the PFC output to basal ganglia circuits. Classical antipsychotics also interact with these PFC targets in addition to blocking massively striatal D2 receptors.

Evaluation of methylene blue, pyrimethamine and its combination on an in vitro Neospora caninum model.

PubMed

Pereira, Luiz Miguel; Vigato-Ferreira, Isabel Cristina; DE Luca, Gabriela; Bronzon DA Costa, Cássia Mariana; Yatsuda, Ana Patrícia

2017-05-01

Neospora caninum is an apicomplexan parasite strongly related to reproductive problems in cattle. The neosporosis control is not well established and several fronts are under development, predominantly based on immune protection, immunomodulation and chemotherapy. The use of anti-malarial drugs as therapeutic sources has, in theory, considerable potential for any apicomplexan. Drugs such as methylene blue (MB) and pyrimethamine (Pyr) represent therapeutic options for malaria; thus, their use for neosporosis should be assessed. In this work, we tested the effects of MB and Pyr on N. caninum proliferation and clearance, using LacZ-tagged tachyzoites. The drugs inhibited at nanomolar dosages and its combination demonstrated an antagonistic interaction in proliferation assays, according to the Chou and Talalay method for drug combination index. However, the drug combination significantly improved the parasite in vitro clearance. The repositioning of well-established drugs opens a short-term strategy to obtain low-cost therapeutics approaches against neosporosis.

Gas chromatography-mass spectrometry assay method for the therapeutic drug monitoring of the antiepileptic drug tiagabine.

PubMed

Chollet, D F; Castella, E; Goumaz, L; Anderegg, G

1999-11-01

A gas chromatography-mass spectrometry assay method suitable for the therapeutic drug monitoring of the antiepileptic drug tiagabine is described. Tiagabine and its desmethylated analogue used as internal standard were first extracted from serum by liquid-liquid extraction using an ethyl ether-isobutanol 98:2 mixture. Tiagabine and the internal standard were then methylated in the organic phase in presence of methanol by means of a safe and stable diazomethane derivative. After evaporation, the reconstituted extracts were chromatographed on a crosslinked phenyl methyl siloxane capillary column and detected by mass fragmentometry at m/z = 156. No other antiepileptic drug possibly administrated in polytherapy and no metabolite were found to interfere in the assay. The limit of quantification was 5 ng/ml. The precision and the accuracy were found to be suitable for the therapeutic drug monitoring of tiagabine.

The new frontiers of the targeted interventions in the pulmonary vasculature: precision and safety (2017 Grover Conference Series).

PubMed

Brenner, Jacob S; Kiseleva, Raisa Yu; Glassman, Patrick M; Parhiz, Hamideh; Greineder, Colin F; Hood, Elizabeth D; Shuvaev, Vladimir V; Muzykantov, Vladimir R

2018-01-01

The pulmonary vasculature plays an important role in many lung pathologies, such as pulmonary arterial hypertension, primary graft dysfunction of lung transplant, and acute respiratory distress syndrome. Therapy for these diseases is quite limited, largely due to dose-limiting side effects of numerous drugs that have been trialed or approved. High doses of drugs targeting the pulmonary vasculature are needed due to the lack of specific affinity of therapeutic compounds to the vasculature. To overcome this problem, the field of targeted drug delivery aims to target drugs to the pulmonary endothelial cells, especially those in pathological regions. The field uses a variety of drug delivery systems (DDSs), ranging from nano-scale drug carriers, such as liposomes, to methods of conjugating drugs to affinity moieites, such as antibodies. These DDSs can deliver small molecule drugs, protein therapeutics, and imaging agents. Here we review targeted drug delivery to the pulmonary endothelium for the treatment of pulmonary diseases. Cautionary notes are made of the risk-benefit ratio and safety-parameters one should keep in mind when developing a translational therapeutic.

Gold-mediated drug delivery for improved outcome in chemotherapy

NASA Astrophysics Data System (ADS)

Yang, C.; Chithrani, B. D.

2017-02-01

Nanoparticles can be used to overcome the side effects due to poor distribution of anticancer drugs. Among other NPs, colloidal gold nanoparticles (GNPs) offer the possibility of transporting major quantities of drugs due to their large surface-to volume ratio while confining anticancer drugs as closely as possible to their biological targets through passive and active targeting ensuring limited harmful systemic distribution. In this study, we chose bleomycin (BLM) as the anticancer drug since its therapeutic efficiency is severely limited because of its side effects. Bleomycin was conjugated to GNPs through a thiol bond. The effectiveness of the chemotherapeutic drug, bleomycin, is observed by visualizing DNA double strand breaks and calculating the survival fraction. The action of the drug is known to be in the nucleus and our experiments have shown GNPs in the nucleus along with bleomycin. Use of GNPs to deliver bleomycin increased the therapeutic efficacy of the drug. Having a better understanding of the interaction of GNPs and drugs will establish a more successful NP-based platform for combined therapeutic approach in cancer research since GNPs can be used as radiation dose enhancers.

Osteomyelitis caused by Aspergillus species: a review of 310 reported cases.

PubMed

Gabrielli, E; Fothergill, A W; Brescini, L; Sutton, D A; Marchionni, E; Orsetti, E; Staffolani, S; Castelli, P; Gesuita, R; Barchiesi, F

2014-06-01

Aspergillus osteomyelitis is a rare infection. We reviewed 310 individual cases reported in the literature from 1936 to 2013. The median age of patients was 43 years (range, 0-86 years), and 59% were males. Comorbidities associated with this infection included chronic granulomatous disease (19%), haematological malignancies (11%), transplantation (11%), diabetes (6%), pulmonary disease (4%), steroid therapy (4%), and human immunodeficiency virus infection (4%). Sites of infection included the spine (49%), base of the skull, paranasal sinuses and jaw (18%), ribs (9%), long bones (9%), sternum (5%), and chest wall (4%). The most common infecting species were Aspergillus fumigatus (55%), Aspergillus flavus (12%), and Aspergillus nidulans (7%). Sixty-two per cent of the individual cases were treated with a combination of an antifungal regimen and surgery. Amphotericin B was the antifungal drug most commonly used, followed by itraconazole and voriconazole. Several combination or sequential therapies were also used experimentally. The overall crude mortality rate was 25%. © 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.

[Drug advertising as communication between the pharmaceutical industry and the physician: advertisements for psychotropic drugs in the Dutch medical journal, Nederlands Tijdschrift voor Geneeskunde, 1900-1940].

PubMed

van der Hoogte, Arjo Roersch; Pieters, Toine

2010-01-01

In this article we explore the historical development of drug advertisements for psychotropic drugs in the leading Dutch medical journal from 1900 to 1940. The advertisements for hypnotics and sedatives, in The Nederlands Tijdschrift voor Geneeskunde (Dutch medical journal) reflected the changes in the vocabulary and image promoted by the pharmaceutical companies. In the first two decades, the advertisements were sober and to the point, and included the trademark, company name, molecular formula and therapeutic properties of the medication. The emphasis was on creating a scientific image of reliable symptom control for the therapeutic drug. In doing so, the ethical drug companies tried (successfully) to distinguish themselves from the producers of patent medicines. Once scientific credibility was established, the form and content of the advertisements changed significantly. In the late 1920s and 1930s drug companies embraced modern advertising techniques, developing a figurative language to address the changing beliefs and practices of Dutch physicians. Instead of promoting therapeutic drugs as safe and scientific, the emphasis was on their effectiveness in comparison to similar drugs. In the process, scientific information was reduced to an indispensable standardized minimum, whereby therapeutic drugs were advertised according to the latest pharmacological taxonomy rather than molecular formulas. The image-making of 'ethical marketing' began during the interwar years when marketers applied modern advertising techniques and infotainment strategies. The scanty black and white informational bulletins transitioned into colourful advertisements. The pharmaceutical companies employed the same medical language as used by physicians, so that one word or image in an advertisement would suffice for the physician to recognize a drug and its therapeutic properties. These developments show the changing relationship between the modern ethical pharmaceutical industry and Dutch doctors during the interwar years--from rapprochement towards concerted action.

Fusarium Infection in Lung Transplant Patients

PubMed Central

Carneiro, Herman A.; Coleman, Jeffrey J.; Restrepo, Alejandro; Mylonakis, Eleftherios

2013-01-01

Fusarium is a fungal pathogen of immunosuppressed lung transplant patients associated with a high mortality in those with severe and persistent neutropenia. The principle portal of entry for Fusarium species is the airways, and lung involvement almost always occurs among lung transplant patients with disseminated infection. In these patients, the immunoprotective mechanisms of the transplanted lungs are impaired, and they are, therefore, more vulnerable to Fusarium infection. As a result, fusariosis occurs in up to 32% of lung transplant patients. We studied fusariosis in 6 patients following lung transplantation who were treated at Massachusetts General Hospital during an 8-year period and reviewed 3 published cases in the literature. Cases were identified by the microbiology laboratory and through discharge summaries. Patients presented with dyspnea, fever, nonproductive cough, hemoptysis, and headache. Blood tests showed elevated white blood cell counts with granulocytosis and elevated inflammatory markers. Cultures of Fusarium were isolated from bronchoalveolar lavage, blood, and sputum specimens. Treatments included amphotericin B, liposomal amphotericin B, caspofungin, voriconazole, and posaconazole, either alone or in combination. Lung involvement occurred in all patients with disseminated disease and it was associated with a poor outcome. The mortality rate in this group of patients was high (67%), and of those who survived, 1 patient was treated with a combination of amphotericin B and voriconazole, 1 patient with amphotericin B, and 1 patient with posaconazole. Recommended empirical treatment includes voriconazole, amphotericin B or liposomal amphotericin B first-line, and posaconazole for refractory disease. High-dose amphotericin B is recommended for treatment of most cases of fusariosis. The echinocandins (for example, caspofungin, micafungin, anidulafungin) are generally avoided because Fusarium species have intrinsic resistance to them. Treatment should ideally be based on the Fusarium isolate, susceptibility testing, and host-specific factors. Prognosis of fusariosis in the immunocompromised is directly related to a patient’s immune status. Prevention of Fusarium infection is recommended with aerosolized amphotericin B deoxycholate, which also has activity against other important fungi. PMID:21200188

Therapeutic Potential of Phytochemicals in Combination with Drugs for Cardiovascular Disorders.

PubMed

Shen, James Z; Ng, Ting L J; Ho, Wing S

2017-01-01

The incidence of cardiovascular disorders is increasing worldwide. Heart disease is the leading cause of death for both men and women. High blood pressure, high low-density lipoprotein cholesterol level, and smoking are key risk factors for heart disease. Other medical conditions such as diabetes, overweight, obesity and lifestyle can put people at a higher risk for coronary heart disease. The preventive measures based on the common drugs may help reduce the risk of cardiovascular diseases. The present review highlights the contributions of therapeutic potential of phytochemicals in management of cardiovascular diseases. However, the delivery efficiency of therapeutic agents can be enhanced in order to improve the efficacy of phytochemicals as a therapeutic agent. The oral administration of phytochemicals as therapeutic agents is a common approach. The review highlights the recent development of natural products for the complementary treatment of cardiovascular diseases. These findings indicate that the combination of therapeutic drugs and natural products may improve the treatment efficacy of therapeutic agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Implantable and transdermal polymeric drug delivery technologies for the treatment of central nervous system disorders.

PubMed

Govender, Thiresen; Choonara, Yahya E; Kumar, Pradeep; Bijukumar, Divya; du Toit, Lisa C; Modi, Girish; Naidoo, Dinesh; Pillay, Viness

2017-06-01

The complexity of the brain and the membranous blood-brain barrier (BBB) has proved to be a significant limitation to the systemic delivery of pharmaceuticals to the brain rendering them sub-therapeutic and ineffective in the treatment of neurological diseases. Apart from this, lack of innovation in product development to counteract the problem is also a major contributing factor to a poor therapeutic outcome. Various innovative strategies show potential in treating some of the neurological disorders; however, drug delivery remains the most popular. To attain therapeutic drug levels in the central nervous system, large, intolerable systemic doses are generally administered. The major factors responsible for the success maintenance therapy of neurological diseases included controlled and sustained release of neurotherapeutics, reduced frequency of administration, higher bioavailability, and patient compliances. Conventional oral or injectable formulations cannot satisfy all the requirements in many circumstances. This article reviews the therapeutic implantable polymeric and transdermal devices employed in an attempt to effectively achieve therapeutic quantities of drug across the BBB over a prolonged period, to improve patient disease prognosis.

Maintenance of reinforcement to address the chronic nature of drug addiction

PubMed Central

Silverman, Kenneth; DeFulio, Anthony; Sigurdsson, Sigurdur O.

2012-01-01

Background Drug addiction can be a chronic problem. Abstinence reinforcement can initiate drug abstinence, but as with other treatments many patients relapse after the intervention ends. Abstinence reinforcement can be maintained to promote long-term drug abstinence, but practical means of implementing long-term abstinence reinforcement are needed. Methods We reviewed 8 clinical trials conducted in Baltimore, MD from 1996 through 2010 that evaluated the therapeutic workplace as a vehicle for maintaining reinforcement for the treatment of drug addiction. The therapeutic workplace uses employment-based reinforcement in which employees must provide objective evidence of drug abstinence or medication adherence to work and earn wages. Results Employment-based reinforcement can initiate (3 of 4 studies) and maintain (2 studies) cocaine abstinence in methadone patients, although relapse can occur even after long-term exposure to abstinence reinforcement (1 study). Employment-based reinforcement can also promote abstinence from alcohol in homeless alcohol dependent adults (1 study), and maintain adherence to extended-release naltrexone in opioid dependent adults (2 studies). Conclusion Treatments should seek to promote life-long effects in patients. Therapeutic reinforcement may need to be maintained indefinitely to prevent relapse. Workplaces could be effective vehicles for the maintenance of therapeutic reinforcement contingencies for drug abstinence and adherence to addiction medications. PMID:22668883

TDM in psychiatry and neurology: A comprehensive summary of the consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology, update 2017; a tool for clinicians^.

PubMed

Schoretsanitis, Georgios; Paulzen, Michael; Unterecker, Stefan; Schwarz, Markus; Conca, Andreas; Zernig, Gerald; Gründer, Gerhard; Haen, Ekkerhard; Baumann, Pierre; Bergemann, Niels; Clement, Hans Willi; Domschke, Katharina; Eckermann, Gabriel; Egberts, Karin; Gerlach, Manfred; Greiner, Christine; Havemann-Reinecke, Ursula; Hefner, Gudrun; Helmer, Renate; Janssen, Ger; Jaquenoud-Sirot, Eveline; Laux, Gerd; Messer, Thomas; Mössner, Rainald; Müller, Matthias J; Pfuhlmann, Bruno; Riederer, Peter; Saria, Alois; Schoppek, Bernd; Silva Gracia, Margarete; Stegmann, Benedikt; Steimer, Werner; Stingl, Julia C; Uhr, Manfred; Ulrich, Sven; Waschgler, Roland; Zurek, Gabriela; Hiemke, Christoph

2018-04-01

Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug-drug interactions. Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated. This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine. The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment.

Teachers' Drug Reference: A Guide to Medical Conditions and Drugs Commonly Used in School-Aged Children.

ERIC Educational Resources Information Center

Agins, Alan P.

This book provides a guide to approximately 175 drugs used with children. An introduction precedes the three major sections of the guide. Section 1 provides an overview of pharmacology and therapeutics in chapters on the basics of pharmacology, the language of pharmacology and therapeutics, compliance, side effects, and medications in school.…

Parent & Educators' Drug Reference: A Guide to Common Medical Conditions & Drugs Used in School-Aged Children.

ERIC Educational Resources Information Center

Agins, Alan P.

This book provides a guide to more than 180 drugs used for children. An introduction precedes the four major sections of the guide. Section 1 provides an overview of pharmacology and therapeutics in chapters on the basics of pharmacology, the language of pharmacology and therapeutics, compliance, side effects, medications in school, and drug…

Update of Ablative Fractionated Lasers to Enhance Cutaneous Topical Drug Delivery.

PubMed

Waibel, Jill S; Rudnick, Ashley; Shagalov, Deborah R; Nicolazzo, Danielle M

2017-08-01

Ablative fractional lasers (AFXL) enhance uptake of therapeutics and this newly emerging field is called laser-assisted drug delivery (LAD). This new science has emerged over the past decade and is finding its way into clinical practice. LAD is poised to change how medicine delivers drugs. Topical and systemic application of pharmaceutical agents for therapeutic effect is an integral part of medicine. With topical therapy, the stratum corneum barrier of the skin impairs the ability of drugs to enter the body. The purpose of LAD is to alter the stratum corneum, epidermis, and dermis to facilitate increased penetration of a drug, device, or cell to its respected target. AFXL represents an innovative, non-invasive strategy to overcome the epidermal barrier. LAD employs three steps: (1) breakdown of the skin barrier with a laser, (2) optional use a laser for a therapeutic effect, (3) delivery of the medicine through laser channels to further enhance the therapeutic effect. The advantages of using lasers for drug delivery include the ease of accessibility, the non-invasive aspect, and its effectiveness. By changing the laser settings, one may use LAD to have a drug remain locally within the skin or to have systemic delivery. Many drugs are not intended for use in the dermis and so it has yet to be determined which drugs are appropriate for this technique. It appears this developing technology has the ability to be a new delivery system for both localized and systemic delivery of drugs, cells, and other molecules. With responsible development AFXL-assisted drug delivery may become a new important part of medicine.

Silica-based mesoporous nanoparticles for controlled drug delivery

PubMed Central

Kwon, Sooyeon; Singh, Rajendra K; Perez, Roman A; Abou Neel, Ensanya A

2013-01-01

Drug molecules with lack of specificity and solubility lead patients to take high doses of the drug to achieve sufficient therapeutic effects. This is a leading cause of adverse drug reactions, particularly for drugs with narrow therapeutic window or cytotoxic chemotherapeutics. To address these problems, there are various functional biocompatible drug carriers available in the market, which can deliver therapeutic agents to the target site in a controlled manner. Among the carriers developed thus far, mesoporous materials emerged as a promising candidate that can deliver a variety of drug molecules in a controllable and sustainable manner. In particular, mesoporous silica nanoparticles are widely used as a delivery reagent because silica possesses favourable chemical properties, thermal stability and biocompatibility. Currently, sol-gel-derived mesoporous silica nanoparticles in soft conditions are of main interest due to simplicity in production and modification and the capacity to maintain function of bioactive agents. The unique mesoporous structure of silica facilitates effective loading of drugs and their subsequent controlled release. The properties of mesopores, including pore size and porosity as well as the surface properties, can be altered depending on additives used to fabricate mesoporous silica nanoparticles. Active surface enables functionalisation to modify surface properties and link therapeutic molecules. The tuneable mesopore structure and modifiable surface of mesoporous silica nanoparticle allow incorporation of various classes of drug molecules and controlled delivery to the target sites. This review aims to present the state of knowledge of currently available drug delivery system and identify properties of an ideal drug carrier for specific application, focusing on mesoporous silica nanoparticles. PMID:24020012

Economic Cost of the Therapeutic Workplace Intervention Added to Methadone Maintenance

PubMed Central

Knealing, Todd W.; Roebuck, M. Christopher; Wong, Conrad J.; Silverman, Kenneth

2008-01-01

The therapeutic workplace is a novel intervention that uses access to paid training and employment to reinforce drug abstinence within the context of standard methadone maintenance. We used the Drug Abuse Treatment Cost Analysis Program as a standard method of estimating the economic costs of this intervention. Over a one-year period, the therapeutic workplace served 122 methadone maintenance clients who had a median length of stay of 22 weeks. The workplace maintained a mean daily census of 48 clients. The combined cost of methadone maintenance and the therapeutic workplace was estimated at $362 per week. This cost is less than other treatments that might be used to promote abstinence in individuals who continue to use drugs during methadone treatment. Given prior evidence of effectiveness, these cost data may be useful to policymakers, social service agencies, and researchers interested in using or further developing the therapeutic workplace intervention. PMID:17614239

Modeling Tumor Clonal Evolution for Drug Combinations Design.

PubMed

Zhao, Boyang; Hemann, Michael T; Lauffenburger, Douglas A

2016-03-01

Cancer is a clonal evolutionary process. This presents challenges for effective therapeutic intervention, given the constant selective pressure towards drug resistance. Mathematical modeling from population genetics, evolutionary dynamics, and engineering perspectives are being increasingly employed to study tumor progression, intratumoral heterogeneity, drug resistance, and rational drug scheduling and combinations design. In this review, we discuss promising opportunities these inter-disciplinary approaches hold for advances in cancer biology and treatment. We propose that quantitative modeling perspectives can complement emerging experimental technologies to facilitate enhanced understanding of disease progression and improved capabilities for therapeutic drug regimen designs.

Caffeine citrate - Is it a silver bullet in neonatology?

PubMed

Shrestha, Bikash; Jawa, Gaurav

2017-10-01

Caffeine citrate is one of the most prescribed drug in the present day NICU for apnea. Its efficacy, tolerability, wide therapeutic index and safety margin has made it the drug of choice among the methylxanthines. Its therapeutic uses in apnea of prematurity, mechanical ventilation, bronchopulmonary dysplasia has made it a "silver bullet" in neonatology. However, there are still controversies surrounding this drug. This review is aimed to update the reader about the basic pharmacology, current therapeutic uses, adverse effects, controversies as well as present and future research of caffeine. Copyright © 2017. Published by Elsevier B.V.

Antibody Therapeutics in Oncology.

PubMed

Wold, Erik D; Smider, Vaughn V; Felding, Brunhilde H

2016-03-01

One of the newer classes of targeted cancer therapeutics is monoclonal antibodies. Monoclonal antibody therapeutics are a successful and rapidly expanding drug class due to their high specificity, activity, favourable pharmacokinetics, and standardized manufacturing processes. Antibodies are capable of recruiting the immune system to attack cancer cells through complement-dependent cytotoxicity or antibody dependent cellular cytotoxicity. In an ideal scenario the initial tumor cell destruction induced by administration of a therapeutic antibody can result in uptake of tumor associated antigens by antigen-presenting cells, establishing a prolonged memory effect. Mechanisms of direct tumor cell killing by antibodies include antibody recognition of cell surface bound enzymes to neutralize enzyme activity and signaling, or induction of receptor agonist or antagonist activity. Both approaches result in cellular apoptosis. In another and very direct approach, antibodies are used to deliver drugs to target cells and cause cell death. Such antibody drug conjugates (ADCs) direct cytotoxic compounds to tumor cells, after selective binding to cell surface antigens, internalization, and intracellular drug release. Efficacy and safety of ADCs for cancer therapy has recently been greatly advanced based on innovative approaches for site-specific drug conjugation to the antibody structure. This technology enabled rational optimization of function and pharmacokinetics of the resulting conjugates, and is now beginning to yield therapeutics with defined, uniform molecular characteristics, and unprecedented promise to advance cancer treatment.

Functional differentiation of cytotoxic cancer drugs and targeted cancer therapeutics.

PubMed

Winkler, Gian C; Barle, Ester Lovsin; Galati, Giuseppe; Kluwe, William M

2014-10-01

There is no nationally or internationally binding definition of the term "cytotoxic drug" although this term is used in a variety of regulations for pharmaceutical development and manufacturing of drugs as well as in regulations for protecting medical personnel from occupational exposure in pharmacy, hospital, and other healthcare settings. The term "cytotoxic drug" is frequently used as a synonym for any and all oncology or antineoplastic drugs. Pharmaceutical companies generate and receive requests for assessments of the potential hazards of drugs regularly - including cytotoxicity. This publication is intended to provide functional definitions that help to differentiate between generically-cytotoxic cancer drugs of significant risk to normal human tissues, and targeted cancer therapeutics that pose much lesser risks. Together with specific assessments, it provides comprehensible guidance on how to assess the relevant properties of cancer drugs, and how targeted therapeutics discriminate between cancer and normal cells. The position of several regulatory agencies in the long-term is clearly to regulate all drugs regardless of classification, according to scientific risk based data. Despite ongoing discussions on how to replace the term "cytotoxic drugs" in current regulations, it is expected that its use will continue for the near future. Copyright © 2014 Elsevier Inc. All rights reserved.

Recent advances in mechanism-based chemotherapy drug-siRNA pairs in co-delivery systems for cancer: A review.

PubMed

Wang, Mingfang; Wang, Jinyu; Li, Bingcheng; Meng, Lingxin; Tian, Zhaoxing

2017-09-01

Co-delivery of chemotherapy drugs and siRNA for cancer therapy has achieved remarkable results according to synergistic/combined antitumor effects, and is recognized as a promising therapeutic modality. However, little attention has been paid to the extremely complex mechanisms of chemotherapy drug-siRNA pairs during co-delivery process. Proper selection of chemotherapy drug-siRNA pairs is beneficial for achieving desirable cancer therapeutic effects. Exploring the inherent principles during chemotherapy drug-siRNA pair selection for co-delivery would greatly enhanced therapeutic efficiency. To achieve ideal results, this article will systematically review current different mechanism-based chemotherapy drug-siRNA pairs for co-delivery in cancer treatment. Large-scale library screening of recent different chemotherapy drug-siRNA pairs for co-delivery would help to establish the chemotherapy drug-siRNA pair selection principle, which could pave the way for co-delivery of chemotherapy drugs and siRNA for cancer treatment in clinic. Following the inherent principle of chemotherapy drug-siRNA pair, more effective co-delivery vectors can be designed in the future. Copyright © 2017 Elsevier B.V. All rights reserved.

Protease-mediated drug delivery

NASA Astrophysics Data System (ADS)

Dickson, Eva F.; Goyan, Rebecca L.; Kennedy, James C.; Mackay, M.; Mendes, M. A. K.; Pottier, Roy H.

2003-12-01

Drugs used in disease treatment can cause damage to both malignant and normal tissue. This toxicity limits the maximum therapeutic dose. Drug targeting is of high interest to increase the therapeutic efficacy of the drug without increasing systemic toxicity. Certain tissue abnormalities, disease processes, cancers, and infections are characterized by high levels of activity of specific extracellular and/or intracellular proteases. Abnormally high activity levels of specific proteases are present at sites of physical or chemical trauma, blood clots, malignant tumors, rheumatoid arthritis, inflammatory bowel disease, gingival disease, glomerulonerphritis, and acute pancreatitis. Abnormal protease activity is suspected in development of liver thrombosis, pulmonary emphysema, atherosclerosis, and muscular dystrophy. Inactiviating disease-associated proteases by the administration of appropriate protease inhibitors has had limited success. Instead, one could use such proteases to target drugs to treat the condition. Protease mediated drug delivery offers such a possibility. Solubilizing groups are attached to insoluble drugs via a polypeptide chain which is specifically cleavable by certian proteases. When the solubilized drug enounters the protease, the solubilizing moieties are cleaved, and the drug precipitates at the disease location. Thus, a smaller systemic dosage could result in a therapeutic drug concentration at the treatment site with less systemic toxicity.

Establishing a compulsory drug treatment prison: Therapeutic policy, principles, and practices in addressing offender rights and rehabilitation.

PubMed

Birgden, Astrid; Grant, Luke

2010-01-01

A Compulsory Drug Treatment Correctional Center (CDTCC) was established in Australia in 2006 for repeat drug-related male offenders. Compulsory treatment law is inconsistent with a therapeutic jurisprudence approach. Despite the compulsory law, a normative offender rehabilitation framework has been established based on offender moral rights. Within moral rights, the offender rehabilitation framework addresses the core values of freedom (supporting autonomous decision-making) and well-being (supporting support physical, social, and psychological needs). Moral rights are underpinned by a theory or principle which, in this instance, is a humane approach to offender rehabilitation. While a law that permits offenders to choose drug treatment and rehabilitation is preferable, the article discusses the establishment of a prison based on therapeutic policy, principles, and practices that respond to participants as both rights-violators and rights-holders. The opportunity for accelerated community access and a therapeutic alliance with staff has resulted in offenders actively seeking to be ordered into compulsory drug treatment and rehabilitation. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.

High phenobarbital clearance during continuous renal replacement therapy: a case report and pharmacokinetic analysis.

PubMed

Rosenborg, Staffan; Saraste, Lars; Wide, Katarina

2014-08-01

Phenobarbital is an old antiepileptic drug used in severe epilepsy. Despite this, little is written about the need for dose adjustments in renal replacement therapy. Most sources recommend a moderately increased dose guided by therapeutic drug monitoring.A 14 year old boy with nonketotic hyperglycinemia, a rare inborn error of metabolism, characterized by high levels of glycine, epilepsy, spasticity, and cognitive impairment, was admitted to the emergency department with respiratory failure after a few days of fever and cough. The boy was unconscious at admittance and had acute renal and hepatic failure.Due to the acute respiratory infection, hypoxic hepatic and renal failure occurred and the patient had a status epilepticus.The patient was intubated and mechanically ventilated. Continuous renal replacement therapy was initiated. Despite increased phenobarbital doses, therapeutic levels were not reached until the dose was increased to 500 mg twice daily. Therapeutic drug monitoring was performed in plasma and dialysate. Calculations revealed that phenobarbital was almost freely dialyzed.Correct dosing of drugs in patients on renal replacement therapy may need a multidisciplinary approach and guidance by therapeutic drug monitoring.

High Phenobarbital Clearance During Continuous Renal Replacement Therapy

PubMed Central

Rosenborg, Staffan; Saraste, Lars; Wide, Katarina

2014-01-01

Abstract Phenobarbital is an old antiepileptic drug used in severe epilepsy. Despite this, little is written about the need for dose adjustments in renal replacement therapy. Most sources recommend a moderately increased dose guided by therapeutic drug monitoring. A 14 year old boy with nonketotic hyperglycinemia, a rare inborn error of metabolism, characterized by high levels of glycine, epilepsy, spasticity, and cognitive impairment, was admitted to the emergency department with respiratory failure after a few days of fever and cough. The boy was unconscious at admittance and had acute renal and hepatic failure. Due to the acute respiratory infection, hypoxic hepatic and renal failure occurred and the patient had a status epilepticus. The patient was intubated and mechanically ventilated. Continuous renal replacement therapy was initiated. Despite increased phenobarbital doses, therapeutic levels were not reached until the dose was increased to 500 mg twice daily. Therapeutic drug monitoring was performed in plasma and dialysate. Calculations revealed that phenobarbital was almost freely dialyzed. Correct dosing of drugs in patients on renal replacement therapy may need a multidisciplinary approach and guidance by therapeutic drug monitoring. PMID:25101986

[Special considerations in generic substitution of immunosuppressive drugs in transplantation].

PubMed

Remport, Adám; Dankó, Dávid; Gerlei, Zsuzsa; Czebe, Krisztina; Kiss, István

2012-08-26

Long-term success in solid organ transplantation strongly depends on the optimal use of maintenance immunosuppressive treatment. Cyclosporin and tacrolimus are the most frequently administered immunosuppressants and they are designed to narrow therapeutic index drugs. The substitution of the branded formulation by their generic counterparts may lead to economic benefit only if equivalent clinical outcomes can be achieved. There is no published evidence to date on the guarantee of their long-term therapeutic equivalence and cases of therapeutic failures have been reported due to inadvertent drug conversion. The disadvantageous clinical consequences of a non medical, mechanistic forced switch from the original to generic formulation of tacrolimus and the estimated loss of the payer's presumed savings are presented in a kidney transplant recipient population. Special problems related to pediatric patients, drug interactions with concurrent medications and the burden of additional therapeutic drug monitoring and follow up visits are also discussed. The authors are convinced that the implementation of the European Society of Organ Transplantation guidelines on generic substitution may provide a safe way for patients and healthcare payers.

Forecasting drug utilization and expenditure in a metropolitan health region.

PubMed

Wettermark, Björn; Persson, Marie E; Wilking, Nils; Kalin, Mats; Korkmaz, Seher; Hjemdahl, Paul; Godman, Brian; Petzold, Max; Gustafsson, Lars L

2010-05-17

New pharmacological therapies are challenging the healthcare systems, and there is an increasing need to assess their therapeutic value in relation to existing alternatives as well as their potential budget impact. Consequently, new models to introduce drugs in healthcare are urgently needed. In the metropolitan health region of Stockholm, Sweden, a model has been developed including early warning (horizon scanning), forecasting of drug utilization and expenditure, critical drug evaluation as well as structured programs for the introduction and follow-up of new drugs. The aim of this paper is to present the forecasting model and the predicted growth in all therapeutic areas in 2010 and 2011. Linear regression analysis was applied to aggregate sales data on hospital sales and dispensed drugs in ambulatory care, including both reimbursed expenditure and patient co-payment. The linear regression was applied on each pharmacological group based on four observations 2006-2009, and the crude predictions estimated for the coming two years 2010-2011. The crude predictions were then adjusted for factors likely to increase or decrease future utilization and expenditure, such as patent expiries, new drugs to be launched or new guidelines from national bodies or the regional Drug and Therapeutics Committee. The assessment included a close collaboration with clinical, clinical pharmacological and pharmaceutical experts from the regional Drug and Therapeutics Committee. The annual increase in total expenditure for prescription and hospital drugs was predicted to be 2.0% in 2010 and 4.0% in 2011. Expenditures will increase in most therapeutic areas, but most predominantly for antineoplastic and immune modulating agents as well as drugs for the nervous system, infectious diseases, and blood and blood-forming organs. The utilisation and expenditure of drugs is difficult to forecast due to uncertainties about the rate of adoption of new medicines and various ongoing healthcare reforms and activities to improve the quality and efficiency of prescribing. Nevertheless, we believe our model will be valuable as an early warning system to start developing guidance for new drugs including systems to monitor their effectiveness, safety and cost-effectiveness in clinical practice.

Forecasting drug utilization and expenditure in a metropolitan health region

PubMed Central

2010-01-01

Background New pharmacological therapies are challenging the healthcare systems, and there is an increasing need to assess their therapeutic value in relation to existing alternatives as well as their potential budget impact. Consequently, new models to introduce drugs in healthcare are urgently needed. In the metropolitan health region of Stockholm, Sweden, a model has been developed including early warning (horizon scanning), forecasting of drug utilization and expenditure, critical drug evaluation as well as structured programs for the introduction and follow-up of new drugs. The aim of this paper is to present the forecasting model and the predicted growth in all therapeutic areas in 2010 and 2011. Methods Linear regression analysis was applied to aggregate sales data on hospital sales and dispensed drugs in ambulatory care, including both reimbursed expenditure and patient co-payment. The linear regression was applied on each pharmacological group based on four observations 2006-2009, and the crude predictions estimated for the coming two years 2010-2011. The crude predictions were then adjusted for factors likely to increase or decrease future utilization and expenditure, such as patent expiries, new drugs to be launched or new guidelines from national bodies or the regional Drug and Therapeutics Committee. The assessment included a close collaboration with clinical, clinical pharmacological and pharmaceutical experts from the regional Drug and Therapeutics Committee. Results The annual increase in total expenditure for prescription and hospital drugs was predicted to be 2.0% in 2010 and 4.0% in 2011. Expenditures will increase in most therapeutic areas, but most predominantly for antineoplastic and immune modulating agents as well as drugs for the nervous system, infectious diseases, and blood and blood-forming organs. Conclusions The utilisation and expenditure of drugs is difficult to forecast due to uncertainties about the rate of adoption of new medicines and various ongoing healthcare reforms and activities to improve the quality and efficiency of prescribing. Nevertheless, we believe our model will be valuable as an early warning system to start developing guidance for new drugs including systems to monitor their effectiveness, safety and cost-effectiveness in clinical practice. PMID:20478043

What criteria for pharmaceuticals reimbursement? An empirical analysis of the evaluation of "medical service rendered" by reimbursable drugs in France.

PubMed

Le Pen, C; Priol, G; Lilliu, H

2003-01-01

The criteria for the registration of new drugs may differ from the criteria for drug reimbursement. In 2000 the French government entrusted the French Medicines Agency with determining the "medical service rendered" (MSR) for each reimbursable drug. The goal was to determine which drugs could be classified with an "insufficient" MSR and therefore should be taken out of the scope of health insurance. We analyze the concepts and methods used for this evaluation and the kind of results that are obtained. We collected data on the result of MSR classification and the criteria used to perform this classification (efficacy-security, severity of the disease,place in the therapeutic strategy, existence of therapeutic alternative, public health value) for a sample of 1453 drugs belonging to five therapeutic areas. We used statistical analysis to determine what were the most influential criteria. Only two criteria - efficacy and disease severity - suffice to very largely explain the MSR classification. The other criteria contribute little added value. Some of these criteria clearly suffer from a lack of clarification, leading to different interpretations according to therapeutic class or even according to drug or drug family. The evaluation procedure differs between therapeutic classes, at least at intermediate MSR levels. Analysis of the French experience with MSR shows that the evaluation procedure has not succeeded in completely breaking away from the traditional logic of the marketing authorization and registration, as witnessed by the importance of the "efficacy/safety" criterion, the absence of an economic criterion, and the vagueness of the "public health value" criterion, which one would have thought would instead be decisive.

[Anticancer drugs: Which prices for therapeutic innovations?].

PubMed

Gonçalves, Anthony; Maraninchi, Dominique; Marino, Patricia

2016-04-01

The expanding knowledge of the biological mechanisms underlying tumor development made it possible the recent emergence of new therapeutic approaches that are considered as undoubtedly innovative. Yet, to define and to evaluate the magnitude of a drug innovation require an examination of its intrinsic drug properties, medical utility as well as its mode of emergence. Recently, international academic societies, such as ESMO and ASCO, have proposed practical tools that may help quantifying the medical value of a given innovation. Currently, the sustained flux of therapeutic innovations in oncology is associated with an unprecedented growth of costs, the actual determinants of which remain under debate, but raising the critical issue of drugs pricing, and their potential individual or societal "financial toxicity". Copyright © 2016. Published by Elsevier Masson SAS.

Potential of Surface Enhanced Raman Spectroscopy (SERS) in Therapeutic Drug Monitoring (TDM). A Critical Review

PubMed Central

Jaworska, Aleksandra; Fornasaro, Stefano; Sergo, Valter; Bonifacio, Alois

2016-01-01

Surface-Enhanced Raman Spectroscopy (SERS) is a label-free technique that enables quick monitoring of substances at low concentrations in biological matrices. These advantages make it an attractive tool for the development of point-of-care tests suitable for Therapeutic Drug Monitoring (TDM) of drugs with a narrow therapeutic window, such as chemotherapeutic drugs, immunosuppressants, and various anticonvulsants. In this article, the current applications of SERS in the field of TDM for cancer therapy are discussed in detail and illustrated according to the different strategies and substrates. In particular, future perspectives are provided and special concerns regarding the standardization of self-assembly methods and nanofabrication procedures, quality assurance, and technology readiness are critically evaluated. PMID:27657146

Thermally targeted delivery of chemotherapeutics and anti-cancer peptides by elastin-like polypeptide.

PubMed

Raucher, Drazen; Massodi, Iqbal; Bidwell, Gene L

2008-03-01

Current chemotherapy treatment of solid tumors is limited due to a lack of specific delivery of the drugs to the tumor, leading to systemic toxicity. Therefore, it is necessary to develop targeted cancer therapies and tumor-targeted drug carriers. The authors review the development of elastin-like polypeptide (ELP) as a potential carrier for thermally targeted delivery of therapeutics. The authors searched Medline for articles concerning the application of ELP as a drug delivery vector for small molecule drugs and therapeutic peptides. ELP has been demonstrated to be a promising thermally targeted carrier. Further examination of the in vivo biodistribution and efficacy will provide the necessary data to advance ELP technology toward the ultimate goal of human therapeutics.

[Microdose clinical trial--impact of PET molecular imaging].

PubMed

Yano, Tsuneo; Watanabe, Yasuyoshi

2010-10-01

Microdose (MD) clinical trial and exploratory IND study including sub-therapeutic dose and therapeutic dose which are higher than microdoses are expected to bring about innovations in drug development. The outlines of guidances for microdose clinical trial and ICH-M3 (R2) issued by the MHLW in June, 2008, and February, 2010, are first explained, respectively, and some examples of their application to clinical developments of therapeutic drugs in the infection and cancer fields are introduced. Especially, thanks to the progress of molecular imaging research, a new field of drug development is explored by using imaging biomarkers for efficacy or safety evaluation which visualize biomarkers by PET imaging agents. Finally, the roadmap for drug development in infection and cancer fields utilizing PET molecular imaging is discussed.

Emerging therapeutic targets for treatment of leishmaniasis.

PubMed

Sundar, Shyam; Singh, Bhawana

2018-06-01

Parasitic diseases that pose a threat to human life include leishmaniasis - caused by protozoan parasite Leishmania species. Existing drugs have limitations due to deleterious side effects like teratogenicity, high cost and drug resistance. This calls for the need to have an insight into therapeutic aspects of disease. Areas covered: We have identified different drug targets via. molecular, imuunological, metabolic as well as by system biology approaches. We bring these promising drug targets into light so that they can be explored to their maximum. In an effort to bridge the gaps between existing knowledge and prospects of drug discovery, we have compiled interesting studies on drug targets, thereby paving the way for establishment of better therapeutic aspects. Expert opinion: Advancements in technology shed light on many unexplored pathways. Further probing of well established pathways led to the discovery of new drug targets. This review is a comprehensive report on current and emerging drug targets, with emphasis on several metabolic targets, organellar biochemistry, salvage pathways, epigenetics, kinome and more. Identification of new targets can contribute significantly towards strengthening the pipeline for disease elimination.

Therapeutic drug monitoring in pregnancy.

PubMed

Matsui, Doreen M

2012-10-01

Therapeutic drug monitoring (TDM) is commonly recommended to optimize drug dosing regimens of various medications. It has been proposed to guide therapy in pregnant women, in whom physiological changes may lead to altered pharmacokinetics resulting in difficulty in predicting the appropriate drug dosage. Ideally, TDM may play a role in enhancing the effectiveness of treatment while minimizing toxicity of both the mother and fetus. Monitoring of drug levels may also be helpful in assessing adherence to prescribed therapy in selected cases. Limitations exist as therapeutic ranges have only been defined for a limited number of drugs and are based on data obtained in nonpregnant patients. TDM has been suggested for anticonvulsants, antidepressants, and antiretroviral drugs, based on pharmacokinetic studies that have shown reduced drug concentrations. However, there is only relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Further studies are required to determine whether implementation of TDM during pregnancy improves outcome and is associated with any benefit beyond that achieved by clinical judgment alone. The cost effectiveness of TDM programs during pregnancy also remains to be examined.

A hybrid method for prediction and repositioning of drug Anatomical Therapeutic Chemical classes.

PubMed

Chen, Lei; Lu, Jing; Zhang, Ning; Huang, Tao; Cai, Yu-Dong

2014-04-01

In the Anatomical Therapeutic Chemical (ATC) classification system, therapeutic drugs are divided into 14 main classes according to the organ or system on which they act and their chemical, pharmacological and therapeutic properties. This system, recommended by the World Health Organization (WHO), provides a global standard for classifying medical substances and serves as a tool for international drug utilization research to improve quality of drug use. In view of this, it is necessary to develop effective computational prediction methods to identify the ATC-class of a given drug, which thereby could facilitate further analysis of this system. In this study, we initiated an attempt to develop a prediction method and to gain insights from it by utilizing ontology information of drug compounds. Since only about one-fourth of drugs in the ATC classification system have ontology information, a hybrid prediction method combining the ontology information, chemical interaction information and chemical structure information of drug compounds was proposed for the prediction of drug ATC-classes. As a result, by using the Jackknife test, the 1st prediction accuracies for identifying the 14 main ATC-classes in the training dataset, the internal validation dataset and the external validation dataset were 75.90%, 75.70% and 66.36%, respectively. Analysis of some samples with false-positive predictions in the internal and external validation datasets indicated that some of them may even have a relationship with the false-positive predicted ATC-class, suggesting novel uses of these drugs. It was conceivable that the proposed method could be used as an efficient tool to identify ATC-classes of novel drugs or to discover novel uses of known drugs.

Characterization of the surface properties of MgO using paper spray mass spectrometry.

PubMed

Zheng, Yajun; Zhang, Xiaoling; Bai, Zongquan; Zhang, Zhiping

2016-08-01

Significant advances have been made in the preparation of different morphologies of magnesium oxide (MgO), but the relationship between MgO morphology and its interactions with therapeutic drugs is rarely studied. Herein, we investigated the interactions between different morphologies of MgO and therapeutic drugs using paper spray mass spectrometry. Different morphologies of MgO including trapezoidal, needle-like, flower-like and nest-like structures were prepared through a facile precipitation method. The as-obtained MgO particles were then coated onto the surface of filter paper via vacuum filtration strategy. The coated papers with different morphologies of MgO were used as the substrates for paper spray mass spectrometry to explore the interactions between different MgO and therapeutic drugs. Through investigating the interactions between different morphologies of MgO coated papers and therapeutic drugs, it demonstrated that, in contrast to the trapezoidal, needle-like and nest-like MgO coated papers, different drugs in dried blood spots (DBS) were more favourably eluted off from the paper coated with flower-like MgO due to its weaker surface basicity. Also, the signal intensities of different drugs during paper spray were highly dependent on their elution behaviours. Paper spray mass spectrometry (MS) provides an avenue to elaborate the surface properties of MgO with different structures. The surface basicity of MgO played a crucial role in determining the elution behaviours of therapeutic drugs in DBS, and a more favourable elution behaviour tended to result in a higher MS signal. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

The Therapeutic Utility of Employment in Treating Drug Addiction: Science to Application.

PubMed

Silverman, Kenneth; Holtyn, August F; Morrison, Reed

2016-06-01

Research on a model Therapeutic Workplace has allowed for evaluation of the use of employment in the treatment of drug addiction. Under the Therapeutic Workplace intervention, adults with histories of drug addiction are hired and paid to work. To promote drug abstinence or adherence to addiction medications, participants are required to provide drug-free urine samples or take prescribed addiction medications, respectively, to gain access to the workplace and/or to maintain their maximum rate of pay. Research has shown that the Therapeutic Workplace intervention is effective in promoting and maintaining abstinence from heroin, cocaine and alcohol and in promoting adherence to naltrexone. Three models could be used to implement and maintain employment-based reinforcement in the treatment of drug addiction: A Social Business model, a Cooperative Employer model, and a Wage Supplement model. Under all models, participants initiate abstinence in a training and abstinence initiation phase (Phase 1). Under the Social Business model, Phase 1 graduates are hired as employees in a social business and required to maintain abstinence to maintain employment and/or maximum pay. Under the Cooperative Employer model, cooperating community employers hire graduates of Phase 1 and require them to maintain abstinence to maintain employment and/or maximum pay. Under the Wage Supplement Model, graduates of Phase 1 are offered abstinence-contingent wage supplements if they maintain competitive employment in a community job. Given the severity and persistence of the problem of drug addiction and the lack of treatments that can produce lasting effects, continued development of the Therapeutic Workplace is warranted.

A reinforcement-based therapeutic workplace for the treatment of drug abuse: three-year abstinence outcomes.

PubMed

Silverman, Kenneth; Svikis, Dace; Wong, Conrad J; Hampton, Jacqueline; Stitzer, Maxine L; Bigelow, George E

2002-08-01

Long-term Therapeutic Workplace effects were evaluated in heroin- and cocaine-dependent, unemployed, treatment-resistant young mothers. Participants were paid to work or to train in the Therapeutic Workplace but had to provide drug-free urine samples to gain daily access. Participants (N = 40) were randomly assigned to a Therapeutic Workplace or usual care control group. Therapeutic Workplace participants could work for 3 years. Relative to controls, Therapeutic Workplace participants increased cocaine (28% vs. 54% negative; p = .04) and opiate (37% vs. 60% negative; p = .05) abstinence on the basis of monthly urine samples collected until 3 years after intake. The Therapeutic Workplace can be an effective long-term treatment of cocaine and heroin addiction in poor and chronically unemployed young mothers.

The evolving landscape of therapeutic drug development for hepatocellular carcinoma.

PubMed

Chong, Dawn Qingqing; Tan, Iain Beehuat; Choo, Su-Pin; Toh, Han Chong

2013-11-01

Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates while still conferring an overall survival benefit. Unlike other solid tumors, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered. Our group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient derived xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumors. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward. Copyright © 2013 Elsevier Inc. All rights reserved.

Therapeutic inertia and intensified treatment in diabetes mellitus prescription patterns: A nationwide population-based study in Taiwan.

PubMed

Huang, Li-Ying; Yeh, Hseng-Long; Yang, Ming-Chin; Shau, Wen-Yi; Su, Syi; Lai, Mei-Shu

2016-12-01

Objective To measure therapeutic inertia by characterizing prescription patterns using secondary data obtained from the nationwide diabetes mellitus pay-for-performance (DM-P4P) programme in Taiwan. Methods Using reimbursement claims from Taiwan's National Health Insurance Research Database, a nationwide retrospective cohort study was undertaken of patients with diabetes mellitus who participated in the DM-P4P programme from 2006-2008. Glycosylated haemoglobin results were used to evaluate modifications in therapy in response to poor diabetes control. Prescription patterns were used to assign patients to either a therapeutic inertia group or an intensified treatment group. Therapeutic inertia was defined as the failure to act on a known problem. Results The research sample comprised of 168 876 patients with diabetes mellitus who had undergone 899 135 tests. Of these, 37.4% (336 615 visits) of prescriptions were for a combination of two types of drug and 27.7% (248 788 visits) were for a combination of three types of drug. The proportion of patients in the intensified therapy group who were prescribed more than two types of drug was considerably higher than that in the therapeutic inertia group. Conclusion In many cases in the therapeutic inertia group only a single type of hypoglycaemic drug was prescribed or the dosage remained unchanged.

Comparing drug classification systems.

PubMed

Mahoney, Anne; Evans, Jonathan

2008-11-06

An essential quality of drug classification systems is the ability to assign medications to a structured hierarchy for categories such as mechanism of action, physiological effects, and therapeutic indications. No single classification system can meet all of these needs; however, there should be consistency among those that group by the same underlying principals. We discovered discrepancies in how drugs with multiple therapeutic indications are classified among four widely used schemas.

Engineering DNA scaffolds for delivery of anticancer therapeutics.

PubMed

Sun, Wujin; Gu, Zhen

2015-07-01

Engineering DNA nanostructures with programmability in size, shape and surface chemistry holds tremendous promise in biomedical applications. As an emerging platform for drug delivery, DNA nanostructures have been extensively studied for delivering anticancer therapeutics, including small-molecule drug, nucleic acids and proteins. In this mini-review, current advances in utilizing DNA scaffolds as drug carriers for cancer treatment were summarized and future challenges were also discussed.

Fatal Mycotic Aneurysms Due to Scedosporium and Pseudallescheria Infection▿

PubMed Central

Ong, Adrian; Blyth, Christopher C.; Bency, Rosamma; Vicaretti, Mauro; Harun, Azian; Meyer, Wieland; Shingde, Meena; Gilroy, Nicky; Chapman, Jeremy; Chen, Sharon C.-A.

2011-01-01

Angioinvasive complications of Scedosporium infections are rare. We report two cases of mycotic aneurysm, following apparent localized infection, due to Scedosporium apiospermum and Pseudallescheria boydii. The thoracoabdominal aorta was affected in one patient, and cerebral vessels were affected in the other. Despite voriconazole therapy and surgical resection, the patients died. Previously reported cases are reviewed. PMID:21430108

Nanotechnology inspired advanced engineering fundamentals for optimizing drug delivery.

PubMed

Kassem, Ahmed Alaa

2018-02-06

Drug toxicity and inefficacy are commonly experienced problems with drug therapy failure. To face these problems, extensive research work took place aiming to design new dosage forms for drug delivery especially nanoparticulate systems. These systems are designed to increase the quantity of the therapeutic molecule delivered to the desired site concurrently with reduced side effects. In order to achieve this objective, nanocarriers must principally display suitable drug vehiculization abilities and a controlled biological destiny of drug molecules. Only the intelligent design of the nanomedicine will accomplish these fundamentals. The present review article is dedicated to the discussion of the important fundamentals to be considered in the fabrication of nanomedicines. These include the therapeutic agent, the nanocarrier and the functionalization moieties. Special consideration is devoted to the explanation and compilation of highly potential fabrication approaches assisting how to control the in vivo destiny of the nanomedicine. Finally, some nanotechnology-based drug delivery systems, for the development of nanomedicine, are also discussed. The nanotechnology-based drug delivery systems showed remarkable outcomes based on passive and active targeting as well as improvement of the drug pharmacodynamic and pharmacokinetic profiles. Multifunctional nanocarrier concept affords a revolutionary drug delivery approach for maximizing the efficacy, safety and monitoring the biological fate of the therapeutic molecule. Nanomedicines may enhance the efficacy of therapeutic molecules and reduce their toxic effects. Meanwhile, further research works are required to rightly optimize (and define) the effectiveness, nanotoxicity, in vivo destiny and feasibility of these nanomedicines which, from a preclinical standpoint, are actually promising. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Silk Fibroin-Based Nanoparticles for Drug Delivery

PubMed Central

Zhao, Zheng; Li, Yi; Xie, Mao-Bin

2015-01-01

Silk fibroin (SF) is a protein-based biomacromolecule with excellent biocompatibility, biodegradability and low immunogenicity. The development of SF-based nanoparticles for drug delivery have received considerable attention due to high binding capacity for various drugs, controlled drug release properties and mild preparation conditions. By adjusting the particle size, the chemical structure and properties, the modified or recombinant SF-based nanoparticles can be designed to improve the therapeutic efficiency of drugs encapsulated into these nanoparticles. Therefore, they can be used to deliver small molecule drugs (e.g., anti-cancer drugs), protein and growth factor drugs, gene drugs, etc. This paper reviews recent progress on SF-based nanoparticles, including chemical structure, properties, and preparation methods. In addition, the applications of SF-based nanoparticles as carriers for therapeutic drugs are also reviewed. PMID:25749470

Development of drug-loaded polymer microcapsules for treatment of epilepsy.

PubMed

Chen, Yu; Gu, Qi; Yue, Zhilian; Crook, Jeremy M; Moulton, Simon E; Cook, Mark J; Wallace, Gordon G

2017-09-26

Despite significant progress in developing new drugs for seizure control, epilepsy still affects 1% of the global population and is drug-resistant in more than 30% of cases. To improve the therapeutic efficacy of epilepsy medication, a promising approach is to deliver anti-epilepsy drugs directly to affected brain areas using local drug delivery systems. The drug delivery systems must meet a number of criteria, including high drug loading efficiency, biodegradability, neuro-cytocompatibility and predictable drug release profiles. Here we report the development of fibre- and sphere-based microcapsules that exhibit controllable uniform morphologies and drug release profiles as predicted by mathematical modelling. Importantly, both forms of fabricated microcapsules are compatible with human brain derived neural stem cells and differentiated neurons and neuroglia, indicating clinical compliance for neural implantation and therapeutic drug delivery.

Structurally Based Therapeutic Evaluation: A Therapeutic and Practical Approach to Teaching Medicinal Chemistry.

ERIC Educational Resources Information Center

Alsharif, Naser Z.; And Others

1997-01-01

Explains structurally based therapeutic evaluation of drugs, which uses seven therapeutic criteria in translating chemical and structural knowledge into therapeutic decision making in pharmaceutical care. In a Creighton University (Nebraska) medicinal chemistry course, students apply the approach to solve patient-related therapeutic problems in…

Drug-Free Macromolecular Therapeutics – A New Paradigm in Polymeric Nanomedicines

PubMed Central

Chu, Te-Wei; Kopeček, Jindřich

2015-01-01

This review highlights a unique research area in polymer-based nanomedicine designs. Drug-free macromolecular therapeutics induce apoptosis of malignant cells by the crosslinking of surface non-internalizing receptors. The receptor crosslinking is mediated by the biorecognition of high-fidelity natural binding motifs (such as antiparallel coiled-coil peptides or complementary oligonucleotides) that are grafted to the side chains of polymers or attached to targeting moieties against cell receptors. This approach features the absence of low-molecular-weight cytotoxic compounds. Here, we summarize the rationales, different designs, and advantages of drug-free macromolecular therapeutics. Recent developments of novel therapeutic systems for B-cell lymphomas are discussed, as well as relevant approaches for other diseases. We conclude by pointing out various potential future directions in this exciting new field. PMID:26191406

Observational therapeutics: Scope, challenges, and organization.

PubMed

Vaidya, Rama

2011-10-01

The importance of Observational Therapeutics in the progress of medicine has been neglected in the current era of the hierarchal position imparted to Randomized Controlled Trials (RCTs) for new drug discovery and practice of evidence-based medicine. There is a need to reflect on the reason for many new drugs being withdrawn during post marketing surveillance. There are several examples in literature where drug-discovery has originated initially from keen clinical and / or laboratory observations. The roots of these discoveries have often been from observations made by practitioners of traditional medicine including Ayurveda. The present article draws attention to the scope and challenges for observational therapeutics. There is an urgent need for the meticulous planning for a systematic organization of developing observational therapeutics, with a full understanding of its strengths and limitations.

Evaluation of the Triage TOX Drug Screen Assay for Detection of 11 Drugs of Abuse and Therapeutic Drugs.

PubMed

Bang, Hae In; Jang, Mi Ae; Lee, Yong Wha

2017-11-01

The demand for rapid and broad clinical toxicology screens is on the rise. Recently, a new rapid toxicology screening test, the Triage TOX Drug Screen (Alere Inc., USA), which can simultaneously detect 11 drugs of abuse and therapeutic drugs with an instrument-read cartridge, was developed. In the present study, we evaluated the efficacy of this new on-site immunoassay using 105 urine specimens; the results were compared with those obtained by using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-TMS). Precision was evaluated according to the CLSI EP12-A2 for analyte concentrations near the cutoff, including C₅₀ and±30% of C₅₀, for each drug using standard materials. The C₅₀ specimens yielded 35-65% positive results and the±30% concentration range of all evaluated drugs encompassed the C₅-C₉₅ interval. The overall percent agreement of the Triage TOX Drug Screen was 92.4-100% compared with UPLC-TMS; however, the Triage TOX Drug Screen results showed some discordant cases including acetaminophen, amphetamine, benzodiazepine, opiates, and tricyclic antidepressants. The overall performance of the Triage TOX Drug Screen assay was comparable to that of UPLC-TMS for screening of drug intoxication in hospitals. This assay could constitute a useful screening method for drugs of abuse and therapeutic drugs in urine. © The Korean Society for Laboratory Medicine.

21 CFR 884.5900 - Therapeutic vaginal douche apparatus.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Therapeutic vaginal douche apparatus. 884.5900... (CONTINUED) MEDICAL DEVICES OBSTETRICAL AND GYNECOLOGICAL DEVICES Obstetrical and Gynecological Therapeutic Devices § 884.5900 Therapeutic vaginal douche apparatus. (a) Identification. A therapeutic vaginal douche...

21 CFR 884.5900 - Therapeutic vaginal douche apparatus.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Therapeutic vaginal douche apparatus. 884.5900... (CONTINUED) MEDICAL DEVICES OBSTETRICAL AND GYNECOLOGICAL DEVICES Obstetrical and Gynecological Therapeutic Devices § 884.5900 Therapeutic vaginal douche apparatus. (a) Identification. A therapeutic vaginal douche...

21 CFR 884.5900 - Therapeutic vaginal douche apparatus.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Therapeutic vaginal douche apparatus. 884.5900... (CONTINUED) MEDICAL DEVICES OBSTETRICAL AND GYNECOLOGICAL DEVICES Obstetrical and Gynecological Therapeutic Devices § 884.5900 Therapeutic vaginal douche apparatus. (a) Identification. A therapeutic vaginal douche...

THERAPEUTIC HYPOTHERMIA DECREASES PHENYTOIN ELIMINATION IN CHILDREN WITH TRAUMATIC BRAIN INJURY

PubMed Central

Empey, Philip E.; Velez de Mendizabal, Nieves; Bell, Michael J.; Bies, Robert R.; Anderson, Kacey B.; Kochanek, Patrick M.; Adelson, P. David; Poloyac, Samuel M.

2013-01-01

Objective Preclinical and clinical studies have suggested that therapeutic hypothermia, while decreasing neurological injury, may also lead to drug toxicity that may limit its benefit. Cooling decreases cytochrome p450(CYP)-mediated drug metabolism and limited clinical data suggest that drug levels are elevated. Fosphenytoin is metabolized by CYP2C, has a narrow therapeutic range, and is a commonly used antiepileptic medication. The objective of the study was to evaluate the impact of therapeutic hypothermia on phenytoin levels and pharmacokinetics in children with severe TBI. Design Pharmacokinetic analysis of subjects participating in a multicenter randomized Phase III study of therapeutic hypothermia for severe TBI. Setting Intensive care unit at the Children’s Hospital of Pittsburgh Patients Nineteen children with severe TBI. Interventions None Measurements and Main Results A total of 121 total and 114 free phenytoin levels were evaluated retrospectively in 10 hypothermia- and 9 normothermia-treated children who were randomized to 48h of cooling to 32–33°C followed by slow rewarming or controlled normothermia. Drug dosing, body temperatures, and demographics were collected during cooling, rewarming, and post-treatment periods(8 days). A trend towards elevated free phenytoin levels in the hypothermia group(p=0.051) to a median of 2.2 mg/L during rewarming was observed and was not explained by dosing differences. Nonlinear mixed effects modeling incorporating both free and total levels demonstrated that therapeutic hypothermia specifically decreased the time-variant component of the maximum velocity of phenytoin metabolism(Vmax) 4.6-fold(11.6 to 2.53 mg/h) and reduced the overall Vmax by ~50%. Simulations showed that the increased risk for drug toxicity extends many days beyond the end of the cooling period. Conclusions Therapeutic hypothermia significantly reduces phenytoin elimination in children with severe TBI leading to increased drug levels for an extended period of time after cooling. Pharmacokinetic interactions between hypothermia and medications should be considered when caring for children receiving this therapy. PMID:23896831

The potential of magneto-electric nanocarriers for drug delivery

PubMed Central

Kaushik, Ajeet; Jayant, Rahul Dev; Sagar, Vidya; Nair, Madhavan

2015-01-01

Introduction The development and design of personalized nanomedicine for better health quality is receiving great attention. In order to deliver and release a therapeutic concentration at the target site, novel nanocarriers (NCs) were designed, for example, magneto-electric (ME) which possess ideal properties of high drug loading, site-specificity and precise on-demand controlled drug delivery. Areas covered This review explores the potential of ME-NCs for on-demand and site-specific drug delivery and release for personalized therapeutics. The main features including effect of magnetism, improvement in drug loading, drug transport across blood-brain barriers and on-demand controlled release are also discussed. The future directions and possible impacts on upcoming nanomedicine are highlighted. Expert opinion Numerous reports suggest that there is an urgent need to explore novel NC formulations for safe and targeted drug delivery and release at specific disease sites. The challenges of formulation lie in the development of NCs that improve biocompatibility and surface modifications for optimum drug loading/preservation/transmigration and tailoring of electrical–magnetic properties for on-demand drug release. Thus, the development of novel NCs is anticipated to overcome the problems of targeted delivery of therapeutic agents with desired precision that may lead to better patient compliance. PMID:24986772

The potential of magneto-electric nanocarriers for drug delivery.

PubMed

Kaushik, Ajeet; Jayant, Rahul Dev; Sagar, Vidya; Nair, Madhavan

2014-10-01

The development and design of personalized nanomedicine for better health quality is receiving great attention. In order to deliver and release a therapeutic concentration at the target site, novel nanocarriers (NCs) were designed, for example, magneto-electric (ME) which possess ideal properties of high drug loading, site-specificity and precise on-demand controlled drug delivery. This review explores the potential of ME-NCs for on-demand and site-specific drug delivery and release for personalized therapeutics. The main features including effect of magnetism, improvement in drug loading, drug transport across blood-brain barriers and on-demand controlled release are also discussed. The future directions and possible impacts on upcoming nanomedicine are highlighted. Numerous reports suggest that there is an urgent need to explore novel NC formulations for safe and targeted drug delivery and release at specific disease sites. The challenges of formulation lie in the development of NCs that improve biocompatibility and surface modifications for optimum drug loading/preservation/transmigration and tailoring of electrical-magnetic properties for on-demand drug release. Thus, the development of novel NCs is anticipated to overcome the problems of targeted delivery of therapeutic agents with desired precision that may lead to better patient compliance.

Liposomal Formulations in Clinical Use: An Updated Review

PubMed Central

Bulbake, Upendra; Doppalapudi, Sindhu; Kommineni, Nagavendra; Khan, Wahid

2017-01-01

Liposomes are the first nano drug delivery systems that have been successfully translated into real-time clinical applications. These closed bilayer phospholipid vesicles have witnessed many technical advances in recent years since their first development in 1965. Delivery of therapeutics by liposomes alters their biodistribution profile, which further enhances the therapeutic index of various drugs. Extensive research is being carried out using these nano drug delivery systems in diverse areas including the delivery of anti-cancer, anti-fungal, anti-inflammatory drugs and therapeutic genes. The significant contribution of liposomes as drug delivery systems in the healthcare sector is known by many clinical products, e.g., Doxil®, Ambisome®, DepoDur™, etc. This review provides a detailed update on liposomal technologies e.g., DepoFoam™ Technology, Stealth technology, etc., the formulation aspects of clinically used products and ongoing clinical trials on liposomes. PMID:28346375

Therapeutic Potential of Foldamers: From Chemical Biology Tools To Drug Candidates?

PubMed

Gopalakrishnan, Ranganath; Frolov, Andrey I; Knerr, Laurent; Drury, William J; Valeur, Eric

2016-11-10

Over the past decade, foldamers have progressively emerged as useful architectures to mimic secondary structures of proteins. Peptidic foldamers, consisting of various amino acid based backbones, have been the most studied from a therapeutic perspective, while polyaromatic foldamers have barely evolved from their nascency and remain perplexing for medicinal chemists due to their poor drug-like nature. Despite these limitations, this compound class may still offer opportunities to study challenging targets or provide chemical biology tools. The potential of foldamer drug candidates reaching the clinic is still a stretch. Nevertheless, advances in the field have demonstrated their potential for the discovery of next generation therapeutics. In this perspective, the current knowledge of foldamers is reviewed in a drug discovery context. Recent advances in the early phases of drug discovery including hit finding, target validation, and optimization and molecular modeling are discussed. In addition, challenges and focus areas are debated and gaps highlighted.

A natural history of botanical therapeutics

PubMed Central

Schmidt, Barbara; Ribnicky, David M.; Poulev, Alexander; Logendra, Sithes; Cefalu, William T.; Raskin, Ilya

2010-01-01

Plants have been used as a source of medicine throughout history and continue to serve as the basis for many pharmaceuticals used today. Although the modern pharmaceutical industry was born from botanical medicine, synthetic approaches to drug discovery have become standard. However, this modern approach has led to a decline in new drug development in recent years and a growing market for botanical therapeutics that are currently available as dietary supplements, drugs, or botanical drugs. Most botanical therapeutics are derived from medicinal plants that have been cultivated for increased yields of bioactive components. The phytochemical composition of many plants has changed over time, with domestication of agricultural crops resulting in the enhanced content of some bioactive compounds and diminished content of others. Plants continue to serve as a valuable source of therapeutic compounds because of their vast biosynthetic capacity. A primary advantage of botanicals is their complex composition consisting of collections of related compounds having multiple activities that interact for a greater total activity. PMID:18555851

Analytical interference in the therapeutic drug monitoring of methotrexate.

PubMed

Oudart, Jean-Baptiste; Marquet, Benjamin; Feliu, Catherine; Gozalo, Claire; Djerada, Zoubir; Millart, Hervé

2016-06-01

High-dose of methotrexate chemotherapy is used in the treatment of some tumors. It presents several side effects that required therapeutic drug monitoring, which is commonly performed on 24, 48 and 72h after the beginning of the methotrexate infusion. Treatment of overexposure to methotrexate is based on injection of carboxypeptidase G2, which specifically degrades methotrexate into inactive metabolite: DAMPA. FPIA immunoassay on TDx automated analyzer (Abbott™) was used for therapeutic drug monitoring of methotrexate. This immunoassay presented a significant cross-reactivity between methotrexate and DAMPA, which widely overestimate the residual concentration compared to the gold standard HPLC/MS. TDx automated analyzer was substituted by a new immunoassay on Architect automated analyzer (Abbott™). However, this immunoassay has the same cross-reactivity, which needs to be careful when monitoring methotrexate after an injection of carboxypeptidase G2. In order to determine the most suitable assay for the therapeutic drug monitoring of methotrexate, the knowledge of injection of carboxypeptidase G2 remains essential.

Colloidal drug delivery systems: current status and future directions.

PubMed

Garg, Tarun; Rath, Goutam; Goyal, Amit Kumar

2015-01-01

In this paper, we provide an overview an extensive range of colloidal drug delivery systems with special focus on vesicular and particulates systems that are being used in research or might be potentially useful as carriers systems for drug or active biomolecules or as cell carriers with application in the therapeutic field. We present some important examples of commercially available drug delivery systems with applications in research or in clinical fields. This class of systems is widely used due to excellent drug targeting, sustained and controlled release behavior, higher entrapment efficiency of drug molecules, prevention of drug hydrolysis or enzymatic degradation, and improvement of therapeutic efficacy. These characteristics help in the selection of suitable carrier systems for drug, cell, and gene delivery in different fields.

Untethered magnetic millirobot for targeted drug delivery.

PubMed

Iacovacci, Veronica; Lucarini, Gioia; Ricotti, Leonardo; Dario, Paolo; Dupont, Pierre E; Menciassi, Arianna

2015-01-01

This paper reports the design and development of a novel millimeter-sized robotic system for targeted therapy. The proposed medical robot is conceived to perform therapy in relatively small diameter body canals (spine, urinary system, ovary, etc.), and to release several kinds of therapeutics, depending on the pathology to be treated. The robot is a nearly-buoyant bi-component system consisting of a carrier, in which the therapeutic agent is embedded, and a piston. The piston, by exploiting magnetic effects, docks with the carrier and compresses a drug-loaded hydrogel, thus activating the release mechanism. External magnetic fields are exploited to propel the robot towards the target region, while intermagnetic forces are exploited to trigger drug release. After designing and fabricating the robot, the system has been tested in vitro with an anticancer drug (doxorubicin) embedded in the carrier. The efficiency of the drug release mechanism has been demonstrated by both quantifying the amount of drug released and by assessing the efficacy of this therapeutic procedure on human bladder cancer cells.

Current treatment options for vulvovaginal candidiasis caused by azole-resistant Candida species.

PubMed

Sobel, J D; Sobel, R

2018-06-22

Clinicians are increasingly challenged by patients with refractory vulvovaginal candidiasis (VVC) caused by azole-resistant Candida species. Fluconazole resistant C.albicans is a growing and perplexing problem following years of indiscriminate drug prescription and unnecessary drug exposure and for which there are few therapeutic alternatives. Regrettably, although the azole class of drugs has expanded, new classes of antifungal drugs have not been forthcoming, limiting effective treatment options in patients with azole resistant Candida vaginitis. Areas covered: This review covers published data on epidemiology, pathophysiology and treatment options for women with azole-resistant refractory VVC. Expert opinion: Fluconazole resistant C.albicans adds to the challenge of azole resistant non-albicans Candida spp. Both issues follow years of indiscriminate drug prescription and unnecessary fluconazole exposure. Although an understanding of azole resistance in yeast has been established, this knowledge has not translated into useful therapeutic advantage. Treatment options for such women with refractory symptoms are extremely limited. New therapeutic options and strategies are urgently needed to meet this challenge of azole drug resistance.

Delivery of Cancer Therapeutics Using Nanotechnology

PubMed Central

Lim, Eun-Kyung; Jang, Eunji; Lee, Kwangyeol; Haam, Seungjoo; Huh, Yong-Min

2013-01-01

Nanoparticles have been investigated as drug carriers, because they provide a great opportunity due to their advantageous features: (i) various formulations using organic/inorganic materials, (ii) easy modification of targeting molecules, drugs or other molecules on them, (iii) effective delivery to target sites, resulting in high therapeutic efficacy and (iv) controlling drug release by external/internal stimuli. Because of these features, therapeutic efficacy can be improved and unwanted side effects can be reduced. Theranostic nanoparticles have been developed by incorporating imaging agents in drug carriers as all-in-one system, which makes it possible to diagnose and treat cancer by monitoring drug delivery behavior simultaneously. Recently, stimuli-responsive, activatable nanomaterials are being applied that are capable of producing chemical or physical changes by external stimuli. By using these nanoparticles, multiple tasks can be carried out simultaneously, e.g., early and accurate diagnosis, efficient cataloguing of patient groups of personalized therapy and real-time monitoring of disease progress. In this paper, we describe various types of nanoparticles for drug delivery systems, as well as theranostic systems. PMID:24300452

Pharmacogenomics in the assessment of therapeutic risks versus benefits: inside the United States Food and Drug Administration.

PubMed

Zineh, Issam; Pacanowski, Michael A

2011-08-01

Pharmacogenomics is the study of how genetic variations influence responses to drugs, diagnostics, or biologic agents. The field of pharmacogenomics has significant potential to enhance drug development and aid in making regulatory decisions. The United States Food and Drug Administration (FDA) has supported pharmacogenomics for nearly a decade by providing regulatory advice and reviewing applications, with the intent of discovering and applying genetic determinants of treatment effects. The FDA will continue to develop policies and processes centered on genomics and individualized therapeutics to guide rational drug development. It will also continue to inform the public of clinically relevant pharmacogenomic issues through various mechanisms of communication, such as drug labeling. In this review, we provide a perspective on several pharmacogenomic activities at the FDA. In addition, we attempt to clarify what we believe are several misperceptions regarding the FDA's pharmacogenomic initiatives. We hope this perspective provides a window into some ways in which the FDA is enabling individualized therapeutics through its mission-critical activities.

Modeling Tumor Clonal Evolution for Drug Combinations Design

PubMed Central

Zhao, Boyang; Hemann, Michael T.; Lauffenburger, Douglas A.

2016-01-01

Cancer is a clonal evolutionary process. This presents challenges for effective therapeutic intervention, given the constant selective pressure towards drug resistance. Mathematical modeling from population genetics, evolutionary dynamics, and engineering perspectives are being increasingly employed to study tumor progression, intratumoral heterogeneity, drug resistance, and rational drug scheduling and combinations design. In this review, we discuss promising opportunities these inter-disciplinary approaches hold for advances in cancer biology and treatment. We propose that quantitative modeling perspectives can complement emerging experimental technologies to facilitate enhanced understanding of disease progression and improved capabilities for therapeutic drug regimen designs. PMID:28435907

Detection of the antiepileptic drug phenytoin using a single free-standing piezoresistive microcantilever for therapeutic drug monitoring.

PubMed

Huang, Long-Sun; Pheanpanitporn, Yotsapoom; Yen, Yi-Kuang; Chang, Kai-Fung; Lin, Lung-Yi; Lai, Dar-Ming

2014-09-15

Phenytoin, one of the most widely used antiepileptic drugs, suppresses the abnormal brain activity often seen in seizures. In this study, we report the electrical detection of phenytoin as an antiepileptic medication with a narrow therapeutic dosage range to which therapeutic drug monitoring (TDM) is applied. The measurement technique used an electrical detection of a piezoresistive microcantilever biosensor. This label-free, electrically measured microcantilever can be miniaturized in order to be portable for point-of-care, personal diagnosis or for personalized therapeutic drug monitoring. The miniaturized piezoresistive microcantilever was fabricated by micro-electro-mechanical system processes, and was integrated into a microfluidic channel with a system for label-free detection. The microcantilever biosensor was approved for the detection of phenytoin in solutions of deionized water and 100% fetal bovine serum. A linear profile in a drug-concentration range of 10-80 μg/mL was detected, with the signal resolution being about 0.005 Ω. The concentration sensitivity was 2.94×10(-6) (μg/mL)(-1). The binding affinity (KD) was calculated to be 58 μg/mL. The results of the present piezoresistive microcantilever biosensors showed a solid correlation of phenytoin drug detection with that in the clinically used fluorescence polarization immunoassay (FPIA). Copyright © 2014 Elsevier B.V. All rights reserved.

Trends in Non-prescription Drug Recalls in Japan.

PubMed

Yamamoto, Chikoto; Ishida, Takuya; Osawa, Takashi; Naito, Takafumi; Kawakami, Junichi

2016-01-01

Recalls of non-prescription drugs can contribute to preventing harm to human health, however, they also interrupt the supply of medicines to the market. The aim of the present study was to investigate the trends in non-prescription drug recalls in Japan. Class I, II, and III recalls reported from April 2009 to March 2014 were obtained from the websites of the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency. Each drug recall was classified according to year, dosage form, therapeutic category, and reasons for the recall. The trends over the 5 year period were assessed for each class. A total of 220 recalls were reported in the 5-year study period. The numbers of drug recalls were 21, 16, 80, 58, and 45 in 2009, 2010, 2011, 2012, and 2013, respectively. The drugs recalled consisted of 177 internal medications, 35 topical agents, and 8 others. Drug recalls were observed in 12 therapeutic categories of drug effects. The largest number of recalls was for Chinese herbal medicines and crude drugs. Of all the drug recalls in 2011, Chinese herbal medicines and crude drugs produced by one manufacturer accounted for 84%. Slightly more than half (54%) of drug recalls were due to a violation of the regulations. One manufacturer recalled many drugs because of non-compliance with the standard regulations for manufacturing drugs after 2011. In conclusion, non-prescription drug recalls can occur for any drug regardless of the dosage form and therapeutic category.

Strategies for improving the intratumoral distribution of liposomal drugs in cancer therapy

PubMed Central

Goins, Beth; Phillips, William T.; Bao, Ande

2016-01-01

Introduction A major limitation of current liposomal cancer therapies is the inability of liposome therapeutics to penetrate throughout the entire tumor mass. This inhomogeneous distribution of liposome therapeutics within the tumor has been linked to treatment failure and drug resistance. Both liposome particle transport properties and tumor microenvironment characteristics contribute to this challenge in cancer therapy. This limitation is relevant to both intravenously and intratumorally administered liposome therapeutics. Areas covered Strategies to improve the intratumoral distribution of liposome therapeutics are described. Combination therapies of intravenous liposome therapeutics with pharmacologic agents modulating abnormal tumor vasculature, interstitial fluid pressure, extracellular matrix components, and tumor associated macrophages are discussed. Combination therapies using external stimuli (hyperthermia, radiofrequency ablation, magnetic field, radiation, and ultrasound) with intravenous liposome therapeutics are discussed. Intratumoral convection-enhanced delivery (CED) of liposomal therapeutics is reviewed. Expert opinion Optimization of the combination therapies and drug delivery protocols are necessary. Further research should be conducted in appropriate cancer types with consideration of physiochemical features of liposomes and their timing sequence. More investigation of the role of tumor associated macrophages in intratumoral distribution is warranted. Intratumoral infusion of liposomes using CED is a promising approach to improve their distribution within the tumor mass. PMID:26981891

Delivery of RNAi Therapeutics to the Airways-From Bench to Bedside.

PubMed

Qiu, Yingshan; Lam, Jenny K W; Leung, Susan W S; Liang, Wanling

2016-09-20

RNA interference (RNAi) is a potent and specific post-transcriptional gene silencing process. Since its discovery, tremendous efforts have been made to translate RNAi technology into therapeutic applications for the treatment of different human diseases including respiratory diseases, by manipulating the expression of disease-associated gene(s). Similar to other nucleic acid-based therapeutics, the major hurdle of RNAi therapy is delivery. Pulmonary delivery is a promising approach of delivering RNAi therapeutics directly to the airways for treating local conditions and minimizing systemic side effects. It is a non-invasive route of administration that is generally well accepted by patients. However, pulmonary drug delivery is a challenge as the lungs pose a series of anatomical, physiological and immunological barriers to drug delivery. Understanding these barriers is essential for the development an effective RNA delivery system. In this review, the different barriers to pulmonary drug delivery are introduced. The potential of RNAi molecules as new class of therapeutics, and the latest preclinical and clinical studies of using RNAi therapeutics in different respiratory conditions are discussed in details. We hope this review can provide some useful insights for moving inhaled RNAi therapeutics from bench to bedside.

Therapeutics for Equine Endocrine Disorders.

PubMed

Durham, Andy E

2017-04-01

Equine endocrine disease is commonly encountered by equine practitioners. Pituitary pars intermedia dysfunction (PPID) and equine metabolic syndrome (EMS) predominate. The most logical therapeutic approach in PPID uses dopamine agonists; pergolide mesylate is the most common. Bromocryptine and cabergoline are alternative drugs with similar actions. Drugs from other classes have a poor evidence basis, although cyproheptadine and trilostane might be considered. EMS requires management changes as the primary approach; reasonable justification for use of drugs such as levothyroxine and metformin may apply. Therapeutic options exist in rare cases of diabetes mellitus, diabetes insipidus, hyperthyroidism, and critical illness-related corticosteroid insufficiency. Copyright © 2016 Elsevier Inc. All rights reserved.

The renaissance of complement therapeutics

PubMed Central

Ricklin, Daniel; Mastellos, Dimitrios C.; Reis, Edimara S.; Lambris, John D.

2018-01-01

The increasing number of clinical conditions that involve a pathological contribution from the complement system — many of which affect the kidneys — has spurred a regained interest in therapeutic options to modulate this host defence pathway. Molecular insight, technological advances, and the first decade of clinical experience with the complement-specific drug eculizumab, have contributed to a growing confidence in therapeutic complement inhibition. More than 20 candidate drugs that target various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. Such diversity is clearly needed in view of the complex and distinct involvement of complement in a wide range of clinical conditions, including rare kidney disorders, transplant rejection and haemodialysis-induced inflammation. The existing drugs cannot be applied to all complement-driven diseases, and each indication has to be assessed individually. Alongside considerations concerning optimal points of intervention and economic factors, patient stratification will become essential to identify the best complement-specific therapy for each individual patient. This Review provides an overview of the therapeutic concepts, targets and candidate drugs, summarizes insights from clinical trials, and reflects on existing challenges for the development of complement therapeutics for kidney diseases and beyond. PMID:29199277

New drugs or alternative therapy to blurring the symptoms of fibromyalgia-a patent review.

PubMed

Oliveira, Marlange A; Guimarães, Adriana G; Araújo, Adriano A S; Quintans-Júnior, Lucindo J; Quintans, Jullyana S S

2017-10-01

Fibromyalgia (FM) is a musculoskeletal condition characterized by chronic widespread pain, tenderness and often accompanied by other comorbid conditions such as depression, anxiety, chronic fatigue, among others. Now, we aimed to survey the recent patents describing new drugs or alternative therapy for FM. Areas covered: This review covers the therapeutic patents published between 2010 and 2017 from specialized search databases (WIPO, DERWENT, INPI, ESPANET and USPTO) that report the discovery of new drugs or pharmacologic alternative for the treatment of FM. Expert opinion: New therapeutic substances have been proposed in the last seven years. At least as it has been found in our survey, most are still in the pre-clinical phase of the study, and its clinical applicability is unclear. However, other therapeutic approaches were found in patents such as well-established drugs in the market in combination or drug repositioning that combines the 'new analgesic' effects with the old side effects. Hence, it is a safe approach for pharmaceutical market, but poorer to patients who need a radical innovation. So, there is the emerging need for further studies on the safety and efficacy of such therapeutic measures and the search for improvement of side effects, as well as the development of new drugs that are unorthodox for different FM symptoms.

Therapeutics Insight with Inclusive Immunopharmacology Explication of Human Rotavirus A for the Treatment of Diarrhea.

PubMed

Hossain, Mohammad Uzzal; Hashem, Abu; Keya, Chaman Ara; Salimullah, Md

2016-01-01

Rotavirus is the most common cause of severe infant and childhood diarrhea worldwide, and the morbidity and mortality rate is going to be outnumbered in developing countries like Bangladesh. To mitigate this substantial burden of disease, new therapeutics such as vaccine and drug are swiftly required against rotavirus. The present therapeutics insight study was performed with comprehensive immunoinformatics and pharmacoinformatics approach. T and B-cell epitopes were assessed in the conserved region of outer capsid protein VP4 among the highly reviewed strains from different countries including Bangladesh. The results suggest that epitope SU1 (TLKNLNDNY) could be an ideal candidate among the predicted five epitopes for both T and B-cell epitopes for the development of universal vaccine against rotavirus. This research also suggests five novel drug compounds from medicinal plant Rhizophora mucronata Lamk. for better therapeutics strategies against rotavirus diarrhea based on 3D structure building, pharmacophore, ADMET, and QSAR properties. The exact mode of action between drug compounds and target protein VP4 were revealed by molecular docking analysis. Drug likeness and oral bioavailability further confirmed the effectiveness of the proposed drugs against rotavirus diarrhea. This study might be implemented for experimental validation to facilitate the novel vaccine and drug design.

Introduction to current and future protein therapeutics: a protein engineering perspective.

PubMed

Carter, Paul J

2011-05-15

Protein therapeutics and its enabling sister discipline, protein engineering, have emerged since the early 1980s. The first protein therapeutics were recombinant versions of natural proteins. Proteins purposefully modified to increase their clinical potential soon followed with enhancements derived from protein or glycoengineering, Fc fusion or conjugation to polyethylene glycol. Antibody-based drugs subsequently arose as the largest and fastest growing class of protein therapeutics. The rationale for developing better protein therapeutics with enhanced efficacy, greater safety, reduced immunogenicity or improved delivery comes from the convergence of clinical, scientific, technological and commercial drivers that have identified unmet needs and provided strategies to address them. Future protein drugs seem likely to be more extensively engineered to improve their performance, e.g., antibodies and Fc fusion proteins with enhanced effector functions or extended half-life. Two old concepts for improving antibodies, namely antibody-drug conjugates and bispecific antibodies, have advanced to the cusp of clinical success. As for newer protein therapeutic platform technologies, several engineered protein scaffolds are in early clinical development and offer differences and some potential advantages over antibodies. Copyright © 2011 Elsevier Inc. All rights reserved.

Introduction to current and future protein therapeutics: A protein engineering perspective

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carter, Paul J., E-mail: pjc@gene.com

2011-05-15

Protein therapeutics and its enabling sister discipline, protein engineering, have emerged since the early 1980s. The first protein therapeutics were recombinant versions of natural proteins. Proteins purposefully modified to increase their clinical potential soon followed with enhancements derived from protein or glycoengineering, Fc fusion or conjugation to polyethylene glycol. Antibody-based drugs subsequently arose as the largest and fastest growing class of protein therapeutics. The rationale for developing better protein therapeutics with enhanced efficacy, greater safety, reduced immunogenicity or improved delivery comes from the convergence of clinical, scientific, technological and commercial drivers that have identified unmet needs and provided strategies tomore » address them. Future protein drugs seem likely to be more extensively engineered to improve their performance, e.g., antibodies and Fc fusion proteins with enhanced effector functions or extended half-life. Two old concepts for improving antibodies, namely antibody-drug conjugates and bispecific antibodies, have advanced to the cusp of clinical success. As for newer protein therapeutic platform technologies, several engineered protein scaffolds are in early clinical development and offer differences and some potential advantages over antibodies.« less

Drug Abuse & the Criminal Justice System. Chapter 7.

ERIC Educational Resources Information Center

Acampora, Alfonso P., Ed.; Nebelkopf, Ethan, Ed.

This document contains seven papers from the ninth World Conference of Therapeutic Communities (TCs) that deal with drug abuse and the criminal justice system. Papers include: (1) "Some Characteristics of the Social Structure & Social Organization of the TCs" (Lewis Yablonsky); (2) "Therapeutics & Incarceration: They Said It…

[Bioequivalence and generics of index drugs with narrow therapeutic margins].

PubMed

Le Corre, Pascal

2010-02-01

The market share of generic drugs in France is quite low compared to that in other European countries. Because the scientific aspects of bioequivalence that govern the use of generics are sometimes described ambiguously in the literature, they are not always perceived clearly by health professionals. This lack of clarity may be an obstacle to their use. Two drugs are considered bioequivalent if the upper and lower limits of the 90% confidence interval (90% CI) of the generic-to-brand ratio for the area under the curve (AUC) and for the maximum plasma concentration (Cmax) are included in the [-20%, +25%] interval. This interval applies to the 90% CI of the ratios of the AUC (or Cmax) and not directly to the ratio of their values. Hence, it is wrong to consider that there is a -20% to + 25% variation in the AUC (and thus in the bioavailability) between a generic and a brand-name drug. This mistake can sometimes be seen in the medical literature, however, with incorrect extrapolations. The bioequivalence is defined for a generic in relation to a brand-name drug. Consequently, two different generics of the same proprietary drug do not automatically meet the criteria for bioequivalence. Their interchangeability can present problems, especially for drugs with a narrow therapeutic index, that is, those that have a<2-fold difference between the minimum toxic concentration and minimum effective concentration in blood. More restrictive criteria have been proposed for narrow therapeutic index drugs, but there is currently no international consensus on the subject. Determining individual bioequivalence would require modified study protocols to guaranty the interchangeability of the brand-name and generic drugs so that a patient taking one formulation could change to another that would provide the same efficacy and safety. Some antiepileptic drugs have biopharmaceutical and pharmacokinetic properties inducing high levels of intraindividual variability, which can cause problems. According to the French drug agency (AFSSAPS), however, a link between epileptic attacks and treatment with generic drugs has not been established. The economic evaluation of generics should go beyond the simple comparison of the sales price, especially for drugs with a narrow therapeutic range for which therapeutic drug monitoring (plasma assays) can be used. Copyright 2009 Elsevier Masson SAS. All rights reserved.

Drug repurposing for the treatment of glioblastoma multiforme.

PubMed

Abbruzzese, Claudia; Matteoni, Silvia; Signore, Michele; Cardone, Luca; Nath, Kavindra; Glickson, Jerry D; Paggi, Marco G

2017-11-28

Glioblastoma Multiforme is the deadliest type of brain tumor and is characterized by very poor prognosis with a limited overall survival. Current optimal therapeutic approach has essentially remained unchanged for more than a decade, consisting in maximal surgical resection followed by radiotherapy plus temozolomide. Such a dismal patient outcome represents a compelling need for innovative and effective therapeutic approaches. Given the development of new drugs is a process presently characterized by an immense increase in costs and development time, drug repositioning, finding new uses for existing approved drugs or drug repurposing, re-use of old drugs when novel molecular findings make them attractive again, are gaining significance in clinical pharmacology, since it allows faster and less expensive delivery of potentially useful drugs from the bench to the bedside. This is quite evident in glioblastoma, where a number of old drugs is now considered for clinical use, often in association with the first-line therapeutic intervention. Interestingly, most of these medications are, or have been, widely employed for decades in non-neoplastic pathologies without relevant side effects. Now, the refinement of their molecular mechanism(s) of action through up-to-date technologies is paving the way for their use in the therapeutic approach of glioblastoma as well as other cancer types. The spiraling costs of new antineoplastic drugs and the long time required for them to reach the market demands a profoundly different approach to keep lifesaving therapies affordable for cancer patients. In this context, repurposing can represent a relatively inexpensive, safe and fast approach to glioblastoma treatment. To this end, pros and cons must be accurately considered.

21 CFR 880.5160 - Therapeutic medical binder.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Therapeutic medical binder. 880.5160 Section 880...) MEDICAL DEVICES GENERAL HOSPITAL AND PERSONAL USE DEVICES General Hospital and Personal Use Therapeutic Devices § 880.5160 Therapeutic medical binder. (a) Identification. A therapeutic medical binder is a...

21 CFR 880.5160 - Therapeutic medical binder.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Therapeutic medical binder. 880.5160 Section 880...) MEDICAL DEVICES GENERAL HOSPITAL AND PERSONAL USE DEVICES General Hospital and Personal Use Therapeutic Devices § 880.5160 Therapeutic medical binder. (a) Identification. A therapeutic medical binder is a...

Drug policy in Nicaragua, between need-oriented activities and aggression.

PubMed

Laporte, J R; Tognoni, G

1985-01-01

In this case study from Nicaragua, an account is given of how the Essential Drugs Program developed in a context which relectss exceptional political, economic and military pressures. The overall picture could provide a useful guide to the issues behind such an apparently simple concept as the essential drugs list. The criteria for including drugs in the National Formulary were those of the WHO report on essential drugs: proven efficacy, acceptable risks associated with their use, favorable cost, and need. A proposal of the basic list of drugs, classified in therapeutic groups and according to their priority and level of use, was prepared by a central Committee for the National Drug Formulary. An annotated Formulary was prepared to ensure consistency with rigorous scientific standards and to meet the needs of daily practice. The annotated therapeutic formulary has been distributed to all physicians, other health workers responsible for peripheral health centers, pharmacists, and medical students. It has been adopted as the main reference textbook for teaching clinical pharmacology and therapeutics to medical students. A training program in clinical pharmacology has been started at the University Autonoma de Barcelona. It pays particular attention to drug evaluation, drug epidemiology methods, and retrieval and preparation of drug information for health workers.

Patient centric drug product design in modern drug delivery as an opportunity to increase safety and effectiveness.

PubMed

Stegemann, Sven

2018-06-01

The advances in drug delivery technologies have enabled pharmaceutical scientists to deliver a drug through various administration routes and optimize the drug release and absorption. The wide range of drug delivery systems and dosage forms represent a toolbox of technology for the development of pharmaceutical drug products but might also be a source of medication errors and nonadherence. Patient centric drug product development is being suggested as an important factor to increase therapeutic outcomes. Areas covered: Patients have impaired health and potentially disabilities and they are not medical or pharmaceutical experts but are requested to manage complex therapeutic regimens. As such the application of technology should also serve to reduce complexity, build on patients' intuition and ease of use. Patients form distinct populations based on the targeted disease, disease cluster or age group with specific characteristics or therapeutic contexts. Expert opinion: Establishing a target product and patient profile is essential to guide drug product design development. Including the targeted patient populations in the process is a prerequisite to achieve patient-centric pharmaceutical drug product design. Addressing the needs early on in the product design process, will create more universal design, avoiding the necessity for multiple product presentations to cover the different patient populations.

Nanoparticle-Hydrogel: A Hybrid Biomaterial System for Localized Drug Delivery

PubMed Central

Gao, Weiwei; Zhang, Yue; Zhang, Qiangzhe; Zhang, Liangfang

2016-01-01

Nanoparticles have offered a unique set of properties for drug delivery including high drug loading capacity, combinatorial delivery, controlled and sustained drug release, prolonged stability and lifetime, and targeted delivery. To further enhance therapeutic index, especially for localized application, nanoparticles have been increasingly combined with hydrogels to form a hybrid biomaterial system for controlled drug delivery. Herein, we review recent progresses in engineering such nanoparticle-hydrogel hybrid system (namely ‘NP-gel’) with a particular focus on its application for localized drug delivery. Specifically, we highlight four research areas where NP-gel has shown great promises, including (1) passively controlled drug release, (2) stimuli-responsive drug delivery, (3) site-specific drug delivery, and (4) detoxification. Overall, integrating therapeutic nanoparticles with hydrogel technologies creates a unique and robust hybrid biomaterial system that enables effective localized drug delivery. PMID:26951462

A fabric phase sorptive extraction-High performance liquid chromatography-Photo diode array detection method for the determination of twelve azole antimicrobial drug residues in human plasma and urine.

PubMed

Locatelli, Marcello; Kabir, Abuzar; Innosa, Denise; Lopatriello, Teresa; Furton, Kenneth G

2017-01-01

This paper reports a novel fabric phase sorptive extraction-high performance liquid chromatography-photodiode array detection (FPSE-HPLC-PDA) method for the simultaneous extraction and analysis of twelve azole antimicrobial drug residues that include ketoconazole, terconazole, voriconazole, bifonazole, clotrimazole, tioconazole, econazole, butoconazole, miconazole, posaconazole, ravuconazole, and itraconazole in human plasma and urine samples. The selected azole antimicrobial drugs were well resolved by using a Luna C 18 column (250mm×4.6mm; 5μm particle size) in gradient elution mode within 36min. The analytical method was calibrated and validated in the range from 0.1 to 8μg/mL for all the drug compounds. Blank human plasma and urine were used as the sample matrix for the analysis; while benzyl-4-hydroxybenzoate was used as the internal standard (IS). The limit of quantification of the FPSE-HPLC-PDA method was found as 0.1μg/mL and the weighted-matrix matched standard calibration curves of the drugs showed a good linearity upto a concentration of 8μg/mL. The parallelism tests were also performed to evaluate whether overrange sample can be analyzed after dilution, without compromising the analytical performances of the validated method. The intra- and inter-day precision (RSD%) values were found ≤13.1% and ≤13.9%, respectively. The intra- and inter-day trueness (bias%) values were found in the range from -12.1% to 10.5%. The performances of the validated FPSE-HPLC-PDA were further tested on real samples collected from healthy volunteers after a single dose administration of itraconazole and miconazole. To the best of our knowledge, this is the first FPSE extraction procedure applied on plasma and urine samples for the simultaneous determination of twelve azole drugs possessing a wide range of logK ow values (extending from 0.4 for fluconazole to 6.70 of butoconazole) and could be adopted as a rapid and robust green analytical tool for clinical and pharmaceutical applications. Copyright © 2016 Elsevier B.V. All rights reserved.

Self-Assembly of pH-Responsive Microspheres for Intestinal Delivery of Diverse Lipophilic Therapeutics.

PubMed

Zhou, Xing; Zhao, Yang; Chen, Siyu; Han, Songling; Xu, Xiaoqiu; Guo, Jiawei; Liu, Mengyu; Che, Ling; Li, Xiaohui; Zhang, Jianxiang

2016-08-08

Targeted delivery of therapeutics to the intestine is preferred for the management of many diseases due to its diverse advantages. Currently, there are still challenges in creating cost-effective and translational pH-responsive microspheres for intestinal delivery of various hydrophobic drugs. Herein we report a multiple noncovalent interactions-mediated assembly strategy in which carboxyl-bearing compounds (CBCs) are guest molecules, while poly(N-isopropylacrylamide) (PNIPAm) serves as a host polymer. Formation of microparticles and therapeutic packaging can be achieved simultaneously by this assembly approach, leading to well-shaped microspheres with extremely higher drug loading capacity as compared to microspheres based on two FDA-approved materials of poly(d,l-lactide-co-glycolide) (PLGA) and an enteric coating polymer EudragitS 100 (S100). Also, carboxyl-deficient hydrophobic drugs can be effectively entrapped. These assembled microspheres, with excellent reconstitution capability as well as desirable scalability, could selectively release drug molecules under intestinal conditions. By significantly enhancing drug dissolution/release in the intestine, these pH-responsive assemblies may notably improve the oral bioavailability of loaded therapeutics. Moreover, the assembled microspheres possessed superior therapeutic performance in rodent models of inflammation and tumor over the control microspheres derived from PLGA and S100. Therapy with newly developed microspheres did not cause undesirable side effects. Furthermore, in vivo evaluation in mice revealed the carrier material PNIPAm was safe for oral delivery at doses as high as 10 g/kg. Collectively, our findings demonstrated that this type of pH-responsive microsphere may function as superior and translational intestine-directed delivery systems for a diverse array of therapeutics.

The role of public-sector research in the discovery of drugs and vaccines.

PubMed

Stevens, Ashley J; Jensen, Jonathan J; Wyller, Katrine; Kilgore, Patrick C; Chatterjee, Sabarni; Rohrbaugh, Mark L

2011-02-10

Historically, public-sector researchers have performed the upstream, basic research that elucidated the underlying mechanisms of disease and identified promising points of intervention, whereas corporate researchers have performed the downstream, applied research resulting in the discovery of drugs for the treatment of diseases and have carried out development activities to bring them to market. However, the boundaries between the roles of the public and private sectors have shifted substantially since the dawn of the biotechnology era, and the public sector now has a much more direct role in the applied-research phase of drug discovery. We identified new drugs and vaccines approved by the Food and Drug Administration (FDA) that were discovered by public-sector research institutions (PSRIs) and classified them according to their therapeutic category and potential therapeutic effect. We found that during the past 40 years, 153 new FDA-approved drugs, vaccines, or new indications for existing drugs were discovered through research carried out in PSRIs. These drugs included 93 small-molecule drugs, 36 biologic agents, 15 vaccines, 8 in vivo diagnostic materials, and 1 over-the-counter drug. More than half of these drugs have been used in the treatment or prevention of cancer or infectious diseases. PSRI-discovered drugs are expected to have a disproportionately large therapeutic effect. Public-sector research has had a more immediate effect on improving public health than was previously realized.

New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics.

PubMed

Pan, Si-Yuan; Zhou, Shu-Feng; Gao, Si-Hua; Yu, Zhi-Ling; Zhang, Shuo-Feng; Tang, Min-Ke; Sun, Jian-Ning; Ma, Dik-Lung; Han, Yi-Fan; Fong, Wang-Fun; Ko, Kam-Ming

2013-01-01

With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM) therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is "experience driven," the search for a therapeutically useful synthetic drug, like "looking for a needle in a haystack," is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development.

Improving pharmacy and therapeutics committee operations.

PubMed

Cohen, M R; Klapp, D; Miller, K B; Shaffer, V L; Slotfeldt, M; Miller, D E

1984-09-01

A panel discussion of various aspects of the operations of pharmacy and therapeutics (P & T) committees is presented. Pharmacy and therapeutics committee operations in various types and sizes of hospitals are described. Ways of stimulating physicians' interest in P & T committee activities, difficult problems faced, scope of issues dealt with by P & T committees, functions of P & T subcommittees, the value of drug information from pharmaceutical representatives, and the influence of research funds from the pharmaceutical industry on committee decisions are discussed. Panel members also present their views on therapeutic alternates, FDA-nonapproved use of drugs, and counter-detailing. Finally, suggestions for improving P & T drug evaluations, cost-containment issues, and the authority of P & T committees are discussed. A well-prepared agenda, good educational material, active members, and strong leadership are important for successful P & T committee operations.