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1.
Medicine (Baltimore) ; 98(41): e17535, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593129

RESUMO

Scedosporium genus as a significant emerging opportunist causes a broad spectrum of disease in not only immunosuppressed but also immunocompetent patients. The lung is one of the most commonly encountered sites of Scedosporium infection. Due to its very high levels of antifungal resistance, surgery has been recommended as an important part in the treatment of pulmonary Scedosporium spp infection, even in immunocompetent cases. However, whether lung surgery could help to reduce the risk of death in immunocompetent patients is not clear.We retrospectively retrieved the records of pulmonary infections with Scedosporium species in immunocompetent patients through a comprehensive literature search. The association of surgery on all-cause mortality was explored using binary logistic regression (BLR). Receiver operating characteristic (ROC) curve analysis was carried out to evaluate the capability of the model.The comprehensive searching strategy yielded 33 case reports and 3 case series in total, with 40 individual patients being included. The overall mortality was 12.50%. The fatality rate was 9.09% (2/22) in cases with surgery and 16.67% (3/18) in cases without surgery (odds ratio, 0.50; 95% confidence interval, 0.07-3.38; P = .48). Consistently, BLR analysis identified no statistical association between surgery and reduced mortality (odds ratio, 1.19; 95% confidence interval, 0.09-15.64; P = .89), after adjusting for age, gender, and antifungal chemotherapy. The area under the ROC curve was 0.88.For immunocompetent patients with pulmonary Scedosporium spp infection, surgical therapy may not be associated with reduced mortality. Surgical excision could be considered but is not imperative in this group of patients.


Assuntos
Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/cirurgia , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/cirurgia , Scedosporium/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/uso terapêutico , Farmacorresistência Fúngica/fisiologia , Feminino , Humanos , Hospedeiro Imunocomprometido/efeitos dos fármacos , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/mortalidade , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Micoses/tratamento farmacológico , Micoses/epidemiologia , Micoses/microbiologia , Micoses/mortalidade , Estudos Observacionais como Assunto , Cuidados Pós-Operatórios , Infecções Respiratórias/microbiologia , Infecções Respiratórias/mortalidade , Estudos Retrospectivos , Scedosporium/isolamento & purificação , Voriconazol/administração & dosagem , Voriconazol/uso terapêutico
2.
Int J Clin Oncol ; 24(11): 1449-1458, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31300904

RESUMO

BACKGROUND: The prevention of invasive fungal infections is important in patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) receiving cytoreductive chemotherapy. However, the role of oral voriconazole (VRCZ) in such patients has not been established. This study aimed to investigate the effectiveness of oral VRCZ compared to that of first-generation azoles prescribed within 7 days after the onset of chemotherapy in adult patients with AML/MDS using the Japanese administrative database. METHODS: This nationwide retrospective cohort study was conducted using the Diagnosis Procedure Combination/Per-Diem Payment System. The primary outcome was the proportion of patients who switched to intravenous antifungal agents. Analyses using the instrumental variable method were performed to address unmeasured confounding. RESULTS: In total, data on 5517 inpatients from 142 hospitals were analyzed. An oral VRCZ prescription was significantly associated with a reduction in the proportion of patients switching to intravenous antifungal agents compared to first-generation azole prescription (21.0% (95% confidence interval [CI] - 33.4 to - 8.6)). The impact of oral VRCZ in reducing the proportion of patients switching to intravenous antifungal agents was stronger in patients aged < 65 years than in those aged ≥ 65 years (- 40.6%, 95% CI - 63.2 to - 17.9; - 21.9%, 95% CI - 35.8 to - 8.1, respectively) and in patients prescribed oral azole within 3 days from the onset of chemotherapy than in those prescribed the same later (- 32.9%, 95% CI - 46.7 to - 19.2; - 9.0%, 95% CI - 33.7 to 15.7, respectively). CONCLUSION: Oral VRCZ administration may benefit adult patients with AML/MDS undergoing chemotherapy.


Assuntos
Antifúngicos/administração & dosagem , Infecções Fúngicas Invasivas/prevenção & controle , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Voriconazol/administração & dosagem , Administração Intravenosa , Administração Oral , Idoso , Feminino , Mortalidade Hospitalar , Humanos , Infecções Fúngicas Invasivas/mortalidade , Japão/epidemiologia , Tempo de Internação/estatística & dados numéricos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/mortalidade , Estudos Retrospectivos
3.
Int J Antimicrob Agents ; 54(4): 463-470, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31279853

RESUMO

Individualisation of the therapeutic strategy for the oral antifungal agent voriconazole (VCZ) is extremely important for treatment optimisation. To date, regulatory agencies include CYP2C19 as the only major pharmacogenetic (PGx) biomarker in their dosing guidelines; however, the effect of other genes might be important for VCZ dosing prediction. We developed an exploratory PGx study to identify new biomarkers related to VCZ pharmacokinetics. We first designed a 'clinical practice VCZ-AUC prediction model' based on CYP2C19 to be used as a reference model in this study. We then designed a multifactorial polygenic prediction model and found that genetic variability in FMO3, NR1I2, POR, CYP2C9 and CYP3A4 partially contributes to VCZ total area under the concentration-time curve (AUC0-∞) interindividual variability, and its inclusion in VCZ AUC0-∞ prediction algorithms improves model precision. To our knowledge, there are no PGx studies specifically relating POR, FMO3 and NR1I2 polymorphisms to VCZ pharmacokinetic variability. Further research is needed in order to test the model proposed here.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Estudos de Associação Genética , Voriconazol/administração & dosagem , Voriconazol/farmacocinética , Administração Oral , Adulto , Feminino , Humanos , Masculino , Farmacogenética/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Espanha , Adulto Jovem
5.
J Chemother ; 31(5): 267-273, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31140369

RESUMO

The aim of this study was to evaluate the effects of topical voriconazole with histopathological and immunohistochemical analysis of the conjunctiva in rats. Twenty-eight Sprague Dawley rats were divided into four groups as two study (S1, S2) and two control (C1, C2). Voriconazole was instilled four times daily to S1, S2 rats. Physiologic saline (0.9%) was instilled four times daily in C1 and C2 rats. S1 and C1 were followed in a dark room; S2 and C2 were held in a room with sunlight. Impression cytology was performed at 0, 15, 30, 45 and 60th d after instillations. After 2 months of treatment conjunctival tissue was removed for histological and immunohistochemical analysis. In impression cytology evaluation, there was no difference between S1 and S2. At 60 d the difference between S1 and C1 was significant. In other comparisons, there was no difference between S1 and C1, C2. The scores of S2 was higher than C1 and C2 for all comparisons except 15th day scores of S2 and C2. In study groups, epithelial and gland degeneration were higher in S2, but inflammation scores were similar. The comparison of immunreactivity of ERK, TGFß and E-cadherin were different in the study groups than the control groups for all comparisons. In conclusion, voriconazole has side effects due to phototoxicity including squamous cell carcinoma. Clinicians should particularly be careful with the long-term use of topical voriconazole and should follow-up patients strictly in terms of ocular surface alterations.


Assuntos
Antifúngicos/administração & dosagem , Túnica Conjuntiva/patologia , Imuno-Histoquímica/métodos , Inflamação/patologia , Voriconazol/administração & dosagem , Administração Tópica , Animais , Antifúngicos/toxicidade , Túnica Conjuntiva/efeitos dos fármacos , Inflamação/induzido quimicamente , Masculino , Ratos , Ratos Sprague-Dawley , Voriconazol/toxicidade
6.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096684

RESUMO

Single nucleotide polymorphisms in drug-metabolizing genes may affect tacrolimus pharmacokinetics. Here, we investigated the influence of genotypes of CYP3A5, CYP2C19, and POR on the concentration/dose (C/D) ratio of tacrolimus and episodes of acute graft-versus-host disease (GVHD) in Japanese recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty-six patients receiving the first HSCT using tacrolimus-based GVHD prophylaxis were enrolled with written informed consent. During continuous intravenous infusion, HSCT recipients carrying the CYP3A5*1 allele, particularly those with at least one POR*28 allele, had a significantly lower tacrolimus C/D ratio throughout all three post-HSCT weeks compared to that in recipients with POR*1/*1 (p < 0.05). The CYP3A5*3/*3 genotype and the concomitant use of voriconazole were independent predictors of an increased tacrolimus C/D ratio during the switch from continuous intravenous infusion to oral administration (p < 0.05). In recipients receiving concomitant administration of voriconazole, our results suggest an impact of not only CYP3A5 and CYP2C19 genotypes, but also plasma voriconazole concentration. Although switching from intravenous to oral administration at a ratio of 1:5 was seemingly appropriate in recipients with CYP3A5*1, a lower conversion ratio (1:2-3) was appropriate in recipients with CYP3A5*3/*3. Our results suggest that CYP3A5, POR, and CYP2C19 polymorphisms are useful biomarkers for individualized dosage adjustment of tacrolimus in HSCT recipients.


Assuntos
Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP3A/genética , Sistema Enzimático do Citocromo P-450/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Polimorfismo de Nucleotídeo Único , Tacrolimo/administração & dosagem , Adolescente , Adulto , Idoso , Alelos , Antifúngicos/farmacologia , Grupo com Ancestrais do Continente Asiático , Quimioterapia Combinada , Feminino , Genótipo , Doença Enxerto-Hospedeiro/genética , Humanos , Imunossupressores/administração & dosagem , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Tacrolimo/farmacologia , Fatores de Tempo , Voriconazol/administração & dosagem , Adulto Jovem
7.
Rinsho Shinkeigaku ; 59(4): 190-194, 2019 Apr 25.
Artigo em Japonês | MEDLINE | ID: mdl-30930365

RESUMO

The case was a 29-year-old male with no previous history of serious disease. He developed headache and fever, which then worsened and he was admitted to our hospital. His temperature was 38.3°C and he had a stiff neck. In cerebrospinal fluid (CSF) tests, the opening pressure was high, the cell count was increased, and the CSF/serum glucose ratio was decreased. In addition, he was positive for cryptococcal antigen. According to these findings, he was diagnosed with cryptococcal meningoencephalitis and antifungal treatment was initiated. His symptoms then improved, but on day 18 after admission, he developed convulsions, and on day 28, right visual field defects appeared. Brain MRI showed disseminated lesions in the bilateral cerebral cortex. Despite a decrease of the cryptococcal antigenic value in the CSF, the IgG index was elevated. IL-6, 8 and 10 in CSF were high levels on Day 1, then gradually reduced as the symptoms improved. But on Day 28, worsening of symptoms, IL-10 was significantly increased dispite IL-6 and 8 reducing. Therefore, the exacerbation of his symptoms and expansion of the lesions were not caused by the Cryptococcus itself, and it was considered that they were due to the late deterioration of cryptococcosis, which responded to steroid treatment.


Assuntos
Criptococose , Imunocompetência/imunologia , Meningoencefalite/imunologia , Meningoencefalite/microbiologia , Adulto , Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Antígenos de Fungos/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Cryptococcus neoformans/imunologia , Progressão da Doença , Humanos , Imunoglobulina G/líquido cefalorraquidiano , Imagem por Ressonância Magnética , Masculino , Meningoencefalite/diagnóstico , Meningoencefalite/tratamento farmacológico , Metilprednisolona/administração & dosagem , Neuroimagem , Pulsoterapia , Resultado do Tratamento , Voriconazol/administração & dosagem
8.
Regul Toxicol Pharmacol ; 104: 8-13, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30817970

RESUMO

It has been reported that voriconazole is used to treat infections caused by invasive aspergillosis, fluconazole-resistant Candida, Actinoplanes and Fusarium. This study was performed to investigate the safety of prodrug of voriconazole (POV) and explore the distribution and metabolism of POV in vivo. The POV for injection was formulated into POV injection. In this study, POV injection was given intravenously at the doses of 0, 30, 60, and 120 mg/kg/d to SD rats for 4 weeks consecutively. Toxicokinetic study was also performed to explore its distribution and metabolism. POV injection was found to be safe and well tolerated. Some statistically significant differences in relative liver weight were observed and several cases of hepatocyte hypertrophy occurred after the 4-week POV injection treatment. Liver-related toxic response could be reversed after recovery period. The results of toxicokinetics showed that POV can rapidly converts to voriconazole in SD rats after administration. The exposure of voriconazole in each group was significantly different between male and female rats. The results showed that the target organ for the toxic effect of POV is liver and the no-toxic-reaction-dose for long-term administration of POV injection was 60 mg/kg/d.


Assuntos
Fígado/efeitos dos fármacos , Pró-Fármacos/toxicidade , Voriconazol/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Fígado/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Pró-Fármacos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Voriconazol/administração & dosagem
9.
Mater Sci Eng C Mater Biol Appl ; 99: 1350-1361, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30889669

RESUMO

Local administration of antimicrobial agents is the first therapeutic approach for the treatment of Candida albicans infections. The duration of contact of formulations with the vaginal mucosa is critical for therapeutic efficacy. This study describes the development of organogels employing an oil phase composed of oleic acid (OA) and an aqueous phase consisting of the poloxamer PL407, alone or in association with PL188, together with 0.25-1% sodium alginate (SA), in order to obtain an intravaginal drug delivery system capable of modulating the release of voriconazole (VRC). VRC was solubilized in oleic acid homogenized with the PL-SA aqueous phase, at a final concentration of 5 mg/mL. Physicochemical characterization was performed for evaluation of the influence of SA on organogel structural organization, biopharmaceutical properties, pharmacological efficacy, and cytotoxicity, envisaging use of the formulation for the treatment of vaginal candidiasis. The enthalpy variation values showed greater changes in the presence of PL188 and after the incorporation of SA or VRC in the organogels. Rheological analysis showed Tsol-gel values in the ranges 11-39 °C and 27-30 °C for the OA-PL407 and OA-PL407-188 formulations, respectively. Oscillatory analysis of OA-PL407-188 showed that G' was ~20-fold higher than G″, even after submitting the formulation to temperature variation. VRC-OA-PL407 showed fast drug release from 0.5 to 4 h, maintaining total release (~100%) up to 24 h. The incorporation of SA in the organogels enabled modulation of VRC release, with different release percentages for 0.25% SA (~75%), 0.5% SA (~55%), and 1% SA (~35%). The formulation was non-cytotoxic towards HeLa and Vero cell lines. In diffusion tests, it was able to prevent the growth of Candida albicans and Candida krusei. In conclusion, the results suggested that OA-PL407-188-SA organogels could be possible new systems for VRC delivery, with potential for use in future vaginal applications.


Assuntos
Alginatos/química , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Géis/química , Óleos/química , Poloxâmero/química , Administração Intravaginal , Animais , Antifúngicos/química , Varredura Diferencial de Calorimetria , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Cinética , Testes de Sensibilidade Microbiana , Transição de Fase , Reologia , Temperatura Ambiente , Células Vero , Voriconazol/administração & dosagem , Voriconazol/química , Voriconazol/farmacologia , Difração de Raios X
10.
Eur J Pharm Sci ; 131: 218-229, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30731238

RESUMO

Voriconazole, a broad-spectrum antifungal drug used to prevent and treat invasive fungal infections, shows complex pharmacokinetics and is primarily metabolised by various CYP enzymes. An adequate unbound antibiotic concentration-time profile at the target-site of an infection is crucial for effective prophylaxis or therapy success. Therefore, the aim was to evaluate the pharmacokinetics of voriconazole after the approved sequence dosing in healthy volunteers in interstitial space fluid, assessed by microdialysis, and in plasma. Moreover, potential pharmacogenetic influences of CYP2C19 polymorphisms on pharmacokinetics were investigated. The prospective, open-labelled, uncontrolled long-term microdialysis study included 9 healthy male individuals receiving the approved sequence dosing regimen for voriconazole. Unbound voriconazole concentrations were sampled over 84 h in interstitial space fluid of subcutaneous adipose tissue and in plasma and subsequently quantified via high-performance liquid chromatography. For pharmacokinetic data analysis, non-compartmental analysis was used. High interindividual variability in voriconazole concentration-time profiles was detected although dosing was adapted to body weight for the first intravenous administrations. Due to nonlinear pharmacokinetics, target-site exposure of voriconazole in healthy volunteers was found to be highly comparable to plasma exposure, particularly after multiple dosing. Regarding the CYP2C19 genotype-predicted phenotype, the individuals revealed a broad spectrum, ranging from poor to rapid metaboliser status. A strong relation between CYP2C19 genotype-predicted phenotype and voriconazole clearance was identified.


Assuntos
Antifúngicos/administração & dosagem , Microdiálise , Voriconazol/administração & dosagem , Tecido Adiposo/metabolismo , Adulto , Antifúngicos/sangue , Antifúngicos/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Relação Dose-Resposta a Droga , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Voriconazol/sangue , Voriconazol/farmacocinética , Adulto Jovem
11.
Int J Pharm ; 560: 144-154, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30731259

RESUMO

Systemic administration of antifungal agents for the treatment of pulmonary aspergillosis is limited by the poor lung deposition and severe adverse effects. In contrast, pulmonary delivery allows a higher amount of drug to be delivered directly to the infection site and therefore a lower dose is required. This study aimed to develop porous and inhalable voriconazole dry powder with good lung deposition by spray freeze drying (SFD), using tert-butyl alcohol (TBA) as a co-solvent. A three-factor two-level full factorial design approach was used to investigate the effect of total solute concentration, drug content and co-solvent composition on the aerosol performance of the SFD powder. In general, the SFD voriconazole powder exhibited porous and spherical structure, and displayed crystalline characteristics. The analysis of factorial design indicated that voriconazole content was the most significant variable that could influence the aerosol performance of the SFD powders. The formulations that contained a high voriconazole content (40% w/w) and high TBA concentration in the feed solution (70% v/v) displayed the highest fine particle fraction of over 40% in the Next Generation Impactor study in which the powder was dispersed with a Breezhaler® at 100 L/min. In addition, the fine particle dose of the SFD powder showed a faster dissolution rate when compared to the unformulated voriconazole. Intratracheal administration of SFD voriconazole powder to mice resulted in a substantially higher drug concentration in the lungs when comparing to the group that received an equivalent dose of liquid voriconazole formulation intravenously, while a clinically relevant plasma drug concentration was maintained for at least two hours. Overall, an inhalable voriconazole dry powder formulation exhibiting good aerosol property and lung deposition was developed with clinical translation potential.


Assuntos
Antifúngicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Pulmão/metabolismo , Voriconazol/administração & dosagem , Administração por Inalação , Aerossóis , Animais , Antifúngicos/farmacocinética , Química Farmacêutica/métodos , Liberação Controlada de Fármacos , Inaladores de Pó Seco , Feminino , Liofilização , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Porosidade , Solventes/química , Distribuição Tecidual , Voriconazol/farmacocinética
12.
Med Mycol ; 57(8): 937-943, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30759261

RESUMO

Voriconazole is the mainstay of treatment for invasive aspergillosis in immunocompromised pediatric patients. Although Therapeutic Drug Monitoring (TDM) of voriconazole is recommended, it remains unknown if TDM-based dose adaptations result in target attainment. Patients <19 years from two pediatric hematologic-oncology wards were retrospectively identified based on unexplained high voriconazole trough concentrations (Cmin > 6 mg/l). Patient demographics, clinical characteristics, treatment, voriconazole dosing information, voriconazole Cmin before and after adjustment based on TDM were obtained. Twenty-one patients, median (range) age 7.0 (1.2-18.5) years, were identified in two centers. First Cmin (3.1 mg/l [0.1-13.5]) was obtained after 3 days (1-27) of treatment. The median of all Cmin (n = 485, median 11 per patient) was 2.16 mg/l (0.0 (undetectable)-28.0), with 24.1% of Cmin < 1 mg/l, 48.9% 1-4 mg/l, 9.3% 4-6 mg/l, and 17.7% > 6 mg/l. Intrapatient variability was large (94.1% for IV, 88.5% for PO). Dose increases at Cmin < 1 mg/l resulted in an increased Cmin in 76.4%, with 60% between 1 and 4 mg/l. Dose decreases at Cmin > 6 mg/l resulted in a decreased Cmin in 80%, with 51% between 1 and 4 mg/l. Overall, in 45% of the cases (33 out of 55 and 12 out of 45) therapeutic targets were attained after dose adjustment. Fifty-five percent of initial Cmin was outside the therapeutic target of 1-4 mg/l, with multiple dose adaptations required to achieve therapeutic concentrations. Only 60% and 51% of dose adaptations following sub- and supra-therapeutic Cmin, respectively, did result in target attainment. Intensive and continuous TDM of voriconazole is a prerequisite for ensuring adequate exposure in pediatric patients.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Monitoramento de Medicamentos , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Voriconazol/administração & dosagem , Voriconazol/farmacocinética , Adolescente , Criança , Pré-Escolar , Feminino , Neoplasias Hematológicas/complicações , Humanos , Hospedeiro Imunocomprometido , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Soro/química
14.
Basic Clin Pharmacol Toxicol ; 125(1): 34-43, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30715804

RESUMO

Voriconazole is a broad-spectrum antifungal agent commonly used to treat invasive fungal infections. Voriconazole has significant intraindividual and interindividual pharmacokinetics variability in different patient populations. Pharmacokinetic data of voriconazole in patients with liver dysfunction were limited. The aims of this study were to evaluate the population pharmacokinetics of voriconazole in patients with liver dysfunction and to identify the factors that affect voriconazole pharmacokinetics. A total of 166 samples taken from 57 patients with liver dysfunction were included in the study. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. Voriconazole clearance (CL) was 0.58 L/h, the volume of distribution (Vd ) was 134 L, and oral bioavailability (F) was 80.8%. This study showed that platelet count was significantly associated with voriconazole pharmacokinetic parameters. CYP2C19 polymorphisms had no effect on voriconazole pharmacokinetic parameters. Voriconazole CL was significantly decreased in patients with liver dysfunction. This study provides useful pharmacokinetics information for patients with liver dysfunction while highlighting the value of therapeutic drug monitoring in adjusting doses.


Assuntos
Antifúngicos/farmacocinética , Infecções Fúngicas Invasivas/tratamento farmacológico , Hepatopatias/fisiopatologia , Fígado/fisiopatologia , Voriconazol/farmacocinética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/administração & dosagem , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Humanos , Infecções Fúngicas Invasivas/sangue , Infecções Fúngicas Invasivas/complicações , Hepatopatias/sangue , Hepatopatias/complicações , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Estudos Retrospectivos , Voriconazol/administração & dosagem
15.
Mycoses ; 62(4): 399-404, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30687957

RESUMO

BACKGROUND: The wide pharmacokinetic variability of voriconazole leads to uncertainty regarding adequate exposure. OBJECTIVES: To create a pharmacokinetic model that could help to explain the variability. METHODS: Retrospective review of paediatric patients with cancer. Models were built using Pmetrics. RESULTS: We analysed 158 trough measurements in 55 patients; in 41.8%, the serum levels were between 1 and 6 mg/L on initial measurement. After the measurements, dosage adjustments were made in 42 (76.3%) patients, and the percentage of adequate levels rose to 54.5%. Fourteen deaths (25.4%) were attributed to invasive fungal diseases. The mean serum levels were higher in deceased patients (mean ± SD: 3.1 ± 3.2 mg/L vs 2.5 ± 3.6 mg/L in survivors; P = 0.018), but the median doses per kg were higher in survivors. Drug exposure was also higher in deceased patients (mean ± SD of AUC: 19.2 ± 8.1 vs 9.5 ± 19.1 in survivors; P = 0.005). No correlation was found between serum concentrations <1 mg/L and death attributable to fungal disease. Bioavailability was estimated in 50%. The maximum velocity of clearance was reduced in deceased patients. CONCLUSIONS: Extremely ill patients can be poor metabolizers of voriconazole. Therapeutic monitoring promotes only a limited improvement in drug management.


Assuntos
Antifúngicos/farmacocinética , Micoses/tratamento farmacológico , Neoplasias/complicações , Voriconazol/farmacocinética , Adolescente , Antifúngicos/administração & dosagem , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos , Voriconazol/administração & dosagem
16.
J Pak Med Assoc ; 69(1): 103-107, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30623922

RESUMO

Fungal infections of the central nervous system (CNS) are uncommon. Despite several advancements in diagnosis and treatment of these infections, the mortality rates remain high. The current retrospective study was planned to define the demographic and clinical features of patients with CNS fungal infections. Conducted at Aga Khan University Hospital, Karachi, and comprising CNS fungal infections operated between January 2000 and December 2015. The study analysed whether a short course of pre-operative anti-fungal therapy may improve outcomes in these patients. There were 47 cases confirmed on histopathology and/or microbiology. Outcome measures used were Glasgow coma score (GCS), Glasgow outcome score (GOS) and Karnofsky performance score (KPS). The overall 30-day mortality was 20(42.5%). Fungal infections of the CNS can occur in both immune-compromised and immune-competent patients. Early diagnosis, radical surgery, pre-operative anti-fungal therapy for at least 2 weeks, pre- and postoperative Voriconazole therapy results in more favourable outcomes.


Assuntos
Infecções Fúngicas do Sistema Nervoso Central , Craniotomia , Cuidados Pré-Operatórios/métodos , Voriconazol/administração & dosagem , Antifúngicos/administração & dosagem , Infecções Fúngicas do Sistema Nervoso Central/tratamento farmacológico , Infecções Fúngicas do Sistema Nervoso Central/microbiologia , Infecções Fúngicas do Sistema Nervoso Central/mortalidade , Infecções Fúngicas do Sistema Nervoso Central/cirurgia , Craniotomia/efeitos adversos , Craniotomia/métodos , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/efeitos adversos , Procedimentos Neurocirúrgicos/métodos , Paquistão/epidemiologia , Fatores de Risco , Fatores de Tempo
17.
Medicine (Baltimore) ; 98(3): e14137, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30653146

RESUMO

The aim of this study was to investigate the correlation between CYP2C19 genotype and dose-adjusted voriconazole (VCZ) trough concentrations (C0/dose).We analyzed the correlation between CYP2C192(681G>A), CYP2C193(636G>A), and CYP2C1917(-806C>T) genetic polymorphisms and the dose-corrected pre-dose concentration (C0/dose) in 106 South-western Chinese Han patients.The frequencies of variant alleles of CYP2C192, 3, and 17 were 29.7%, 4.25%, and 0.92%. For 49.3% of the VCZ samples, the therapeutic window between 1.5 and 5.5 µg/ml was reached. Following the first dose VCZ measurement, in subsequent samples the proportion of VCZ C0 within the therapeutic window increased, suggesting effective therapeutic drug monitoring (TDM) (P = .001). The VCZ C0 was significantly different (P = .010) between patients with normal metabolism (NMs), intermediate metabolism (IMs), and poor metabolism (PMs). The VZC C0/dose was 12.2 (interquartile range (IQR), 8.33-18.2 µg·ml/kg·day), and 7.68 (IQR, 4.07-16.3 µg·ml/kg·day) in PMs and IMs patients, respectively, which was significantly higher than in NMs phenotype patients (4.68; IQR, 2.51-8.87 µg·ml/kg·day, P = .008 and P = .014).This study demonstrated that the VCZ C0/dose was significantly influenced by the CYP2C19 genotype in South-western Chinese Han patients. In this patient population, more over-exposure was observed in patients with a CYP2C19 genotype associated with poor or intermediate metabolism. CYP2C19 genotype-based dosing combined with TDM will support individualization of VCZ dosing, and potentially will minimize toxicity and maximize therapeutic efficacy.


Assuntos
Antifúngicos/administração & dosagem , Citocromo P-450 CYP2C19/genética , Monitoramento de Medicamentos/métodos , Infecções Fúngicas Invasivas/tratamento farmacológico , Voriconazol/administração & dosagem , Adulto , Alelos , Antifúngicos/sangue , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Coortes , Feminino , Genótipo , Humanos , Infecções Fúngicas Invasivas/genética , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Fenótipo , Polimorfismo Genético , Estudos Retrospectivos , Voriconazol/sangue
18.
Fundam Clin Pharmacol ; 33(2): 232-238, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30306637

RESUMO

Voriconazole (VRC) overdoses are frequent and expose patients at high risk of adverse effects. This case-control study performed in hematological patients who benefited from VRC therapeutic drug monitoring from January 2012 to December 2015 aimed to identify risk factors of VRC overdose. Pharmacogenetic, biological, and demographic parameters at the time of VRC trough concentration (Cmin ) were retrospectively collected from medical records. Cases (VRC overdose: defined by a VRC Cmin ≥ 4 mg/L; n = 31) were compared to controls (no VRC overdose: defined by VRC Cmin < 4 mg/L; n = 31) using nonparametric or chi-square tests followed by multivariable analysis. VRC overdoses were significantly associated with high CRP and bilirubin levels, intravenous administration, and age in univariable analysis. In contrast, the proportion of CYP genotypes (CYP2C19, CYP3A4, or CYP3A5, considered alone or combined in a combined genetic score) were not significantly different between patients who experienced a VRC overdose and those who did not. In multivariable analysis, the class of CRP level (defined by median CRP levels of 96 mg/L) was the sole independent risk factor of VRC overdose (P < 0.01). Patients with CRP levels > 96 mg/L) had a 27-fold (IC 95%: [6-106]) higher risk of VRC overdose than patients with CRP levels ≤ 96 mg/L. This study demonstrates that inflammatory status, assessed by CRP levels, is the main risk factor of VRC overdose in French hematological patients, whereas pharmacogenetic determinants do not appear to be involved.


Assuntos
Antifúngicos/efeitos adversos , Neoplasias Hematológicas/terapia , Inflamação/induzido quimicamente , Micoses/tratamento farmacológico , Voriconazol/efeitos adversos , Adulto , Idoso , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Bilirrubina/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Monitoramento de Medicamentos/métodos , Overdose de Drogas , Feminino , França , Neoplasias Hematológicas/imunologia , Humanos , Hospedeiro Imunocomprometido , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Micoses/sangue , Micoses/imunologia , Micoses/microbiologia , Estudos Retrospectivos , Fatores de Risco , Voriconazol/administração & dosagem , Voriconazol/farmacocinética
19.
Cornea ; 38(2): 141-145, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30334872

RESUMO

PURPOSE: To evaluate the efficacy of the topical, systemic and targeted therapy (TST) protocol in management of fungal keratitis. METHOD: All cases of treatment-naive smear- or culture-proven fungal keratitis presenting between June 2013 and May 2017 were recruited. The TST protocol included initial treatment with topical natamycin 5% with addition of oral ketoconazole or voriconazole in ulcers with size >5 mm, depth >50%, or impending perforation. Topical voriconazole 1% was included in case of poor response at 7 to 10 days. Intrastromal or intracameral antifungal injections were administered in case of poor response to combination therapy. Penetrating keratoplasty was performed in case of poor response to any of the regimen. RESULTS: The study included 223 cases of fungal keratitis with a mean age of 43.6 ± 15.3 years and a male-to-female ratio of 1.8:1. The mean area of the ulcer and infiltrate at presentation was 25.52 ± 19 and 25.7 ± 14.4 mm, respectively. Corrected distance visual acuity at presentation was 2.05 ± 0.43 logMAR that improved to 1.6 ± 0.4 logMAR at 3 months. Fusarium (42.2%) was the most common microorganism isolated, followed by Aspergillus (32.8%). The mean healing time was 41.5 ± 22.2 days, with a final scar size of 14.6 ± 8.2 mm. The treatment success rate with the TST protocol was 79.8%. Corneal perforation developed in 7% of cases (n = 15), and keratoplasty was performed for 20.2% of cases (n = 45). CONCLUSIONS: The TST protocol provides a stepwise treatment algorithm for management of cases of fungal keratitis with varying severity.


Assuntos
Antifúngicos/administração & dosagem , Infecções Oculares Fúngicas/tratamento farmacológico , Ceratite/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Injeções Intraoculares , Ceratite/microbiologia , Cetoconazol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Natamicina/administração & dosagem , Soluções Oftálmicas/uso terapêutico , Estudos Prospectivos , Acuidade Visual , Voriconazol/administração & dosagem , Adulto Jovem
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