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1.
Artigo em Inglês | MEDLINE | ID: mdl-32678694

RESUMO

Purpose: The therapeutic utility of Cannabis in cancer is a topic of intense interest. Dronabinol is synthetic Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of Cannabis sativa, and is approved for treating refractory chemotherapy-induced nausea and vomiting. Little is known about dronabinol prescribing in children and young adults, and no published concentration data are available. This study evaluated national level dronabinol use and assessed concentrations of THC and its primary metabolites in patients with cancer <27 years of age prescribed dronabinol. Methods: Observational review of records from the Pediatric Health Information System (PHIS) and a regional network of hospitals in the Intermountain West, including a tertiary care children's hospital, Primary Children's Hospital (PCH), for inpatients <27 years of age prescribed dronabinol. Prospective blood samples were collected from children with cancer at PCH. Results: Across PHIS institutions, overall dronabinol prescribing aligned with the pharmacy records for those with cancer (p < 0.0001), and of these, 10.4% received dronabinol as inpatients. Blood collected within 72 hours of dronabinol administration was available from 10 children with a median age of 12.5 (range 6-17) years. Quantifiable concentrations were found in 4 (13%), 6 (20%), and 1 (3%) samples assayed for THC, 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC), and 11-hydroxy-Δ9-tetrahydrocannabinol (OH-THC), respectively. THC concentrations ranged between 0.100 and 0.128 ng/mL and were not associated with dose. Conclusion: Dronabinol prescribing appears exclusive to patients diagnosed with cancer, and its use has increased steadily in the past decade. In a small sample of children administered dronabinol, THC and metabolite concentrations were consistently low or undetectable.

2.
Leuk Lymphoma ; : 1-12, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32264729

RESUMO

Pharmacokinetic (PK) conflicts can arise between supportive care medications (SCM) and chemotherapy in children with hematologic malignancy (HM). In this retrospective study, medical records for children (28 days-18 years) diagnosed with HM and receiving an SCM antimicrobial were collected from a hospital network between 1 May 2000 and 31 December 2014. PK drug-gene associations were obtained from a curated pharmacogenomics database. Among 730 patients (median age of 7.5 (IQR 3.7-13.9) years), primarily diagnosed with lymphoid leukemia (52%), lymphoma (28%), or acute myeloid leukemia (16%), chemotherapy was administered in 2846 hospitalizations. SCM accounted for 90.5% (n = 448) of distinct drugs with 93% (n = 679) of children, receiving ≥5 different SCM/hospitalization. Same-day SCM/chemotherapeutic PK gene overlap occurred in 48.3% of hospitalizations and was associated with age (p = 0.026), number of SCM, HM subtype, surgery, and hematopoietic stem cell transplant (p < 0.0001). A high and variable SCM burden among children with HM receiving chemotherapy poses a risk for unanticipated PK conflicts.

3.
Expert Opin Drug Metab Toxicol ; 13(7): 715-724, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28490206

RESUMO

INTRODUCTION: Advancing appropriate and adequate analgesic pharmacotherapy in pediatric patients with cancer is an area of clinical need. Few studies have been performed to evaluate the selection of an analgesic and appropriate dosing corresponding to analgesic effect among pediatric cancer patients. This review describes information related to pharmacokinetic, pharmacodynamic, and pharmacogenomic (when applicable) considerations for analgesics that are commonly used to manage pain experienced by pediatric patients with cancer. Areas covered: Analgesics commonly used to treat pediatric patients with malignancy patterned after the World Health Organization's 'analgesic ladder' for cancer pain management. Expert opinion: Addressing pain management safely and effectively in pediatric patients with cancer will require advances in both drug development, to increase the armament of analgesics available for children, and our pharmacologic understanding of those analgesics in current use. However, performing the necessary types of studies to develop new analgesics, or gain knowledge of existing therapy, within a population that is relatively small, diverse, and who experience pain originating from a variety of sources, is a tremendous challenge.


Assuntos
Analgésicos Opioides/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Dor/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Analgésicos/farmacologia , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacologia , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Criança , Desenho de Fármacos , Humanos , Neoplasias/complicações , Dor/etiologia , Farmacogenética
4.
Expert Rev Clin Pharmacol ; 9(12): 1597-1609, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27644147

RESUMO

INTRODUCTION: Similar to other nations North American people used herbs for thousands of years to treat diseases and purify their spirits. By the middle of the 1900s, evidence-based conventional medicine received wide acceptance in Canada and the United States (US). Nowadays, people are going back to their roots and actively using herbal medicines (HMs) and natural health products (NHPs). Areas covered: This article is focusing on use and regulation of the HMs and NHPs in Canada and the US, raises concerns regarding HM and NHP safety and efficacy, offers suggestions on how to overcome these problems. Materials available from legislative and governmental websites, PubMed and news media were used. Expert commentary: Use of HMs, especially dietary supplements is widespread among adults in Canada and US. HMs and NHPs are regulated in both countries, but minimum criteria for product approval and post-market surveillance have been set. Concerns of quality, contamination, adulteration, and efficacy in are of central importance in the discussion of HMs and NHPs. Detailed product description and research are of vital importance to ensure safety and efficacy of these products. Additionally, 'herbal' education of healthcare providers and patients is needed to guarantee further successful integration of HM and conventional medicines.


Assuntos
Legislação de Medicamentos , Fitoterapia , Preparações de Plantas/uso terapêutico , Plantas Medicinais , Canadá , Humanos , Estados Unidos
5.
Expert Rev Anti Infect Ther ; 14(8): 731-46, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27355512

RESUMO

INTRODUCTION: Voriconazole is a broad-spectrum antifungal agent commonly used to treat invasive fungal infections (IFI), including aspergillosis, candidiasis, Scedosporium infection, and Fusarium infection. IFI often occur in immunocompromised patients, leading to increased morbidity and mortality. AREAS COVERED: The objective of this review is to summarize the pharmacodynamic properties of voriconazole and to provide considerations for potential optimal dosing strategies. Studies have demonstrated superior clinical response when an AUC/MIC >25 or Cmin/MIC >1 is attained in adult patients, correlating to a trough concentration range as narrow as 2-4.5 mg/L; however, these targets are poorly established in the pediatric population. Topics in this discussion include voriconazole use in multiple age groups, predisposing patient factors for IFI, and considerations for clinicians managing IFI. Expert commentary: The relationship between voriconazole dosing and exposure is not well defined due to the large inter- and intra-subject variability. Development of comprehensive decision support tools for individualizing dosing, particularly in children who require higher dosing, will help to increase the probability of achieving therapeutic efficacy and decrease sub-therapeutic dosing and adverse events.


Assuntos
Antifúngicos/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Voriconazol/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Área Sob a Curva , Relação Dose-Resposta a Droga , Predisposição Genética para Doença , Humanos , Infecções Fúngicas Invasivas/genética , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/microbiologia , Testes de Sensibilidade Microbiana , Modelos Biológicos , Voriconazol/administração & dosagem , Voriconazol/farmacocinética , Voriconazol/farmacologia
7.
J Clin Pharmacol ; 56(5): 528-40, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26412385

RESUMO

Growth and maturational changes have been identified as significant covariates in describing variability in clearance of renally excreted drugs such as vancomycin. Because of immaturity of clearance mechanisms, quantification of renal function in neonates is of importance. Several serum creatinine (SCr)-based renal function descriptors have been developed in adults and children, but none are selectively derived for neonates. This review summarizes development of the neonatal kidney and discusses assessment of the renal function regarding estimation of glomerular filtration rate using renal function descriptors. Furthermore, identification of the renal function descriptors that best describe the variability of vancomycin clearance was performed in a sample study of a septic neonatal cohort. Population pharmacokinetic models were developed applying a combination of age-weight, renal function descriptors, or SCr alone. In addition to age and weight, SCr or renal function descriptors significantly reduced variability of vancomycin clearance. The population pharmacokinetic models with Léger and modified Schwartz formulas were selected as the optimal final models, although the other renal function descriptors and SCr provided reasonably good fit to the data, suggesting further evaluation of the final models using external data sets and cross validation. The present study supports incorporation of renal function descriptors in the estimation of vancomycin clearance in neonates.


Assuntos
Antibacterianos/farmacocinética , Creatinina/sangue , Rim/fisiologia , Vancomicina/farmacocinética , Taxa de Filtração Glomerular , Humanos , Recém-Nascido , Rim/metabolismo , Taxa de Depuração Metabólica
8.
Arch Dis Child Fetal Neonatal Ed ; 101(3): F236-43, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26400103

RESUMO

BACKGROUND: The incidence of nephrotoxicity among vancomycin-treated neonates has been reported to range from 2% to 20%. These widely varying estimates have led to confusion and controversy regarding the safety of vancomycin among neonates. OBJECTIVE: Evaluate the incidence of nephrotoxicity among neonates receiving vancomycin concomitantly with gentamicin. DESIGN: Retrospective observational cohort study using propensity score matching to provide covariate balance between neonates who did or did not receive vancomycin based on factors known to be related to the development of renal dysfunction. SETTING: Hospitals (n=22) throughout the Intermountain West, including a quaternary care children's hospital. PATIENTS: Neonates ≤44 postmenstrual weeks (median gestational age: 31 (IQR 28-36) weeks) receiving intravenous gentamicin with or without exposure to vancomycin from January 2006 to December 2012. MAIN OUTCOME MEASURES: Nephrotoxicity based on the modified Acute Kidney Injury Network criteria for acute kidney injury (AKI) or serum creatinine concentration ≥1.5 mg/dL persisting for ≥48 h. RESULTS: The final cohort was comprised of 1066 neonates (533 receiving vancomycin and gentamicin vs 533 receiving gentamicin). In a propensity score-matched cohort that was well balanced across 16 covariates, AKI was not associated with vancomycin use (16 neonates receiving vancomycin vs 7 controls experienced AKI; OR 1.5; 95% CI 0.6 to 4.0). However, the presence of a patent ductus arteriosus, concomitant non-steroidal anti-inflammatory drug use, ≥1 positive blood cultures, low birth weight and higher severity of illness and risk of mortality scores were associated with an increased risk of nephrotoxicity. CONCLUSIONS: These results corroborate several earlier reports and much anecdotal evidence describing the infrequent occurrence of nephrotoxicity in neonates receiving concomitant vancomycin and gentamicin.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antibacterianos/efeitos adversos , Vancomicina/efeitos adversos , Lesão Renal Aguda/epidemiologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Bacteriemia/epidemiologia , Estudos de Coortes , Creatinina/sangue , Quimioterapia Combinada , Permeabilidade do Canal Arterial/epidemiologia , Feminino , Gentamicinas/administração & dosagem , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Estados Unidos/epidemiologia
9.
Expert Opin Drug Metab Toxicol ; 11(12): 1861-78, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26535960

RESUMO

INTRODUCTION: Neonatal patients, because of the inability of their immune system to properly respond to microbial challenge, are highly susceptible to viral infections. Immunoglobulins, monoclonal antibody and antiviral drugs are used for prophylaxis and treatment of viral diseases in neonates. Neonates and, especially, preterm infants differ in drug absorption, distribution, metabolism and excretion from adults and older children. AREAS COVERED: This review will evaluate deficiencies of neonatal immune responses to microbial challenge that predispose newborns to viral infections, clinical manifestations and the treatment of viral diseases in neonates. We focus on published studies describing antiviral drug pharmacokinetics in neonates and make recommendations on the dosing of these drugs, allowing achievement of maximal clinical benefits in neonates. EXPERT OPINION: While some efforts were undertaken to study pharmacokinetics and pharmacodynamics of antiviral drugs, much more needs to be done. Current data indicate that the pharmacokinetics of antiviral drugs may vary significantly depending on gestational age, maturation processes of drug-metabolizing enzymes and renal clearance. Specifics of pharmacokinetics of antiviral drugs need to be taken into consideration when they are prescribed to neonates and infants.


Assuntos
Antivirais/farmacocinética , Sistema Imunitário/fisiologia , Viroses/tratamento farmacológico , Adulto , Fatores Etários , Animais , Antivirais/administração & dosagem , Criança , Suscetibilidade a Doenças/imunologia , Relação Dose-Resposta a Droga , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Viroses/epidemiologia , Viroses/imunologia
10.
Clin Res Regul Aff ; 32(2): 47-56, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26401094

RESUMO

Special populations, including women (non-pregnant and pregnant), pediatrics, and the elderly, require additional consideration with regard to clinical research. There are very specific regulatory laws, which protect these special populations, that need to be understood and adhered to in order to perform clinical research. This review provides a broad overview of some of the physiological differences in special populations and discusses how these differences may affect study design and regulatory considerations. These various special populations, with respect to regulatory affairs, are clearly defined within the Code of Federal Regulations. The definition of "special population" exists to provide enhanced awareness of their vulnerabilities, thereby allowing the creation of regulatory guidance aimed to decrease injury or outright harm. Currently, progress is being made to be more inclusive of special populations in clinical trials. This reflects changing attitudes towards drug information, with it being more representative of those patients that will ultimately be prescribed or exposed to the therapy. However, all research undertaken in these populations should be performed in a manner that ensures all protections of each participant are upheld.

11.
J Clin Pharmacol ; 55(2): 212-20, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25264036

RESUMO

Monitoring of vancomycin trough concentrations is recommended for pediatric patients in the product label and by several professional societies. However, among a network of freestanding children's hospitals vancomycin therapeutic drug monitoring (TDM) practices were reported to be highly variable. In this study, we sought to evaluate whether trends in vancomycin use and TDM changed across a large healthcare delivery system in Utah and Idaho from 2006 to 2012. Children ≤18 years who received ≥2 vancomycin doses were included. Overall, vancomycin TDM was performed during 5,035 (80%) of 6,259 hospital encounters, in which 85,442 doses were administered and 7,935 concentrations were obtained. Across this time period, the median trough concentration increased from 10.9 to 13.7 µg/mL (P < .001), which temporally coincided with recommendations published by the Infectious Disease Society of America that recommend targeting higher trough concentrations. Two or more abnormally low trough concentrations were accompanied by an increase in the dose 75% of the time. Similarly, ≥2 abnormally high trough concentrations were followed by a decrease in the dose 35% of the time. In aggregate, these data suggest that vancomycin TDM is commonly performed among children and the majority of abnormal trough concentrations were associated with an appropriate modification to the dosing regimen.


Assuntos
Antibacterianos/administração & dosagem , Monitoramento de Medicamentos/tendências , Uso de Medicamentos/tendências , Vancomicina/administração & dosagem , Antibacterianos/sangue , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Feminino , Hospitais/estatística & dados numéricos , Humanos , Idaho/epidemiologia , Incidência , Lactente , Masculino , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas/epidemiologia , Utah/epidemiologia , Vancomicina/sangue , Vancomicina/farmacocinética , Vancomicina/uso terapêutico
12.
Expert Opin Drug Metab Toxicol ; 11(1): 53-65, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25488904

RESUMO

INTRODUCTION: Acute myeloid leukemia (AML) is a clonal hematological malignancy characterized by accumulation of poorly differentiated and immature blast cells in bone marrow and blood circulation. The initiation of intensive chemotherapy is necessary to control further progression of the disease. Therapeutic success is less common in older patients (> 65 years) than it is in younger patients with AML. Cytarabine in combination with an anthracycline has been the mainstays of AML therapy for many years and continues to serve as the foundation for the current standard therapeutic regimen. AREAS COVERED: This review discusses the pharmacokinetic (PK), metabolic and toxicological issues associated with antileukemic agents used to treat elderly patients (> 60 years) with AML. EXPERT OPINION: Profound and predictable changes often occur with age and can have effects on drug metabolism, PK and toxicity with consequences bearing on overall efficacy. Few studies focus specifically on elderly patients with AML, but modifications to intensive induction therapy may be beneficial as the current number and rate of individuals achieving complete remission of the disease remains low. Therapeutic options, for the treatment of AML, have remained static for many years, but it has become clear that among elderly patients with AML, improved antileukemic therapy is greatly needed.


Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Leucemia Mieloide Aguda/metabolismo , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico
13.
Indian J Microbiol ; 54(4): 389-95, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25320436

RESUMO

The objective of this study was to assess the frequency of blood culture (BC) collection among neonates who received vancomycin. Demographic, clinical, microbiologic, and pharmacy data were collected for 1275 neonates (postnatal age 0-27 days) who received vancomycin at an Intermountain Healthcare facility between 1/2006 and 9/2011. Neonates treated with vancomycin had a BC collected 94 % (n = 1198) of the time, of which 37 % (n = 448) grew one or more bacterial organisms (BC positive). Of these, 1 % (n = 5) grew methicillin-resistant Staphylococcus aureus (MRSA), 71 % (n = 320) grew coagulase-negative Staphylococci (CoNS), 9 % (n = 40) grew methicillin-sensitive Staphylococcus aureus (MSSA), and 22 % (n = 97) grew other bacterial species (total exceeds 100 % due to co-detection). In patients with negative BC or no BC, vancomycin therapy was extended beyond 72 h 52 % of the time. The median duration of vancomycin therapy for patients with a negative BC was 4 (IQR: 2-10) days. BCs were frequently obtained among neonates who received vancomycin. Vancomycin therapy beyond the conventional 'empiric' treatment window of 48-72 h was common without isolation of resistant gram-positive bacteria.

14.
Expert Rev Anti Infect Ther ; 12(11): 1371-88, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25301231

RESUMO

This review aims to critically evaluate the pharmacokinetic literature describing the use of vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Guidelines recommend that trough concentrations be used to guide vancomycin dosing for the treatment of MRSA infections; however, numerous in vitro, animal model and clinical studies have demonstrated that the therapeutic effectiveness of vancomycin is best described by the area under the concentration versus time curve (AUC) divided by the minimum inhibitory concentration (MIC) of the infecting organism (AUC/MIC). Among patients with lower respiratory tract infections, an AUC/MIC ≥400 was associated with a superior clinical and bacteriological response. Similarly, patients with MRSA bacteremia who achieved an Etest AUC/MIC ≥320 within 48 h were 50% less likely to experience treatment failure. For other patient populations and different clinical syndromes (e.g., children, the elderly, patients with osteomyelitis, etc.), pharmacokinetic/pharmacodynamic studies and prospective clinical trials are needed to establish appropriate therapeutic targets.


Assuntos
Antibacterianos/farmacocinética , Infecções Bacterianas/tratamento farmacológico , Farmacorresistência Bacteriana , Resistência a Vancomicina , Vancomicina/farmacocinética , Antibacterianos/uso terapêutico , Infecções Bacterianas/microbiologia , Humanos , Vancomicina/uso terapêutico
15.
Clin Pharmacokinet ; 53(7): 581-610, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24871768

RESUMO

Antimicrobials and antivirals are widely used in young infants and neonates. These patients have historically been largely excluded from clinical trials and, as a consequence, the pharmacokinetics and pharmacodynamics of commonly used antibacterials, antifungals, and antivirals are incompletely understood in this population. This review summarizes the current literature specific to neonates and infants regarding pharmacokinetic parameters and changes in neonatal development that affect antimicrobial and antiviral pharmacodynamics. Specific drug classes addressed include aminoglycosides, aminopenicillins, cephalosporins, glycopeptides, azole antifungals, echinocandins, polyenes, and guanosine analogs. Within each drug class, the pharmacodynamics, pharmacokinetics, and clinical implications and future directions for prototypical agents are discussed. ß-Lactam antibacterial activity is maximized when the plasma concentration exceeds the minimum inhibitory concentration for a prolonged period, suggesting that more frequent dosing may optimize ß-lactam therapy. Aminoglycosides are typically administered at longer intervals with larger doses in order to maximize exposure (i.e., area under the plasma concentration-time curve) with gestational age and weight strongly influencing the pharmacokinetic profile. Nonetheless, safety concerns necessitate therapeutic drug monitoring across the entire neonatal and young infant spectrum. Vancomycin, representing the glycopeptide class of antibacterials, has a long history of clinical utility, yet there is still uncertainty about the optimal pharmacodynamic index in neonates and young infants. The high degree of pharmacokinetic variability in this population makes therapeutic drug monitoring essential to ensure adequate therapeutic exposure. Among neonates treated with the triazole agent fluconazole, it has been speculated that loading doses may improve pharmacodynamic target attainment rates. The use of voriconazole necessitates therapeutic drug monitoring and dose adjustments for patients with hepatic dysfunction. Neonates treated with lipid-based formulations of the polyene amphotericin B may be at an increased risk of death, such that alternative antifungal agents should be considered for neonates with invasive fungal infections. Alternative antifungal agents such as micafungin and caspofungin also exhibit unique pharmacokinetic considerations in this population. Neonates rapidly eliminate micafungin and require nearly three times the normal adult dose to achieve comparable levels of systemic exposure. Conversely, peak caspofungin concentrations have been reported to be similar among neonates and adults. However, both of these drugs feature favorable safety profiles. Recent studies with acyclovir have suggested that current dosing regimens may not result in therapeutic central nervous system concentrations and more frequent dosing may be required for neonates at later postmenstrual ages. Though ganciclovir and valganciclovir demonstrate excellent activity against cytomegalovirus, they are associated with significant neutropenia. In summary, many pharmacokinetic and pharmacodynamic studies have been conducted in this vulnerable population; however, there are also substantial gaps in our knowledge that require further investigation. These studies will be invaluable in determining optimal neonatal dosing regimens that have the potential to improve clinical outcomes and decrease adverse effects associated with antimicrobial and antiviral treatments.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Antifúngicos/farmacologia , Antifúngicos/farmacocinética , Antivirais/farmacologia , Antivirais/farmacocinética , Fatores Etários , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Monitoramento de Medicamentos , Humanos , Lactente , Recém-Nascido
16.
Clin Pharmacokinet ; 53(5): 429-54, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24595533

RESUMO

Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of the causative pathogen, appropriate antifungal selection, and optimisation of its pharmacokinetic and pharmacodynamic properties to maximise its antifungal activity and minimise toxicity and the emergence of resistance. This review highlights salient scientific advancements in paediatric antifungal pharmacotherapies and focuses on pharmacokinetic and pharmacodynamic studies that underpin current clinical decision making. Four classes of drugs are widely used in the treatment of invasive fungal infections in children, including the polyenes, triazoles, pyrimidine analogues and echinocandins. Several lipidic formulations of the polyene amphotericin B have substantially reduced the toxicity associated with the traditional amphotericin B formulation. Monotherapy with the pyrimidine analogue flucytosine rapidly promotes the emergence of resistance and cannot be recommended. However, when used in combination with other antifungal agents, therapeutic drug monitoring of flucytosine has been shown to reduce high peak flucytosine concentrations, which are strongly associated with toxicity. The triazoles feature large inter-individual pharmacokinetic variability, although this pattern is less pronounced with fluconazole. In clinical trials, posaconazole was associated with fewer adverse effects than other members of the triazole family, though both posaconazole and itraconazole display erratic absorption that is influenced by gastric pH and the gastric emptying rate. Limited data suggest that the clinical response to therapy may be improved with higher plasma posaconazole and itraconazole concentrations. For voriconazole, pharmacokinetic studies among children have revealed that children require twice the recommended adult dose to achieve comparable blood concentrations. Voriconazole clearance is also affected by the cytochrome P450 (CYP) 2C19 genotype and hepatic impairment. Therapeutic drug monitoring is recommended as voriconazole pharmacokinetics are highly variable and small dose increases can result in marked changes in plasma concentrations. For the echinocandins, the primary source of pharmacokinetic variability stems from an age-dependent decrease in clearance with increasing age. Consequently, young children require larger doses per kilogram of body weight than older children and adults. Routine therapeutic drug monitoring for the echinocandins is not recommended. The effectiveness of many systemic antifungal agents has been correlated with pharmacodynamic targets in in vitro and in murine models of invasive candidiasis and aspergillosis. Further study is needed to translate these findings into optimal dosing regimens for children and to understand how these agents interact when multiple antifungal agents are used in combination.


Assuntos
Antifúngicos/farmacologia , Antifúngicos/farmacocinética , Animais , Criança , Interações Medicamentosas , Equinocandinas/farmacocinética , Equinocandinas/farmacologia , Humanos , Polienos/farmacocinética , Polienos/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Triazóis/farmacocinética , Triazóis/farmacologia
17.
Paediatr Drugs ; 16(1): 67-81, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24218112

RESUMO

The management of neonatal sepsis is challenging owing to complex developmental and environmental factors that contribute to inter-individual variability in the pharmacokinetics and pharmacodynamics of many antimicrobial agents. In this review, we describe (i) the changing epidemiology of early- and late-onset neonatal sepsis; (ii) the pharmacologic considerations that influence the safety and efficacy of antibacterials, antifungals, and immunomodulatory adjuvants; and (iii) the recommended dosing regimens for pharmacologic agents commonly used in the treatment and prevention of neonatal sepsis. Neonatal sepsis is marked by high morbidity and mortality, such that prompt initiation of antimicrobial therapy is essential following culture collection. Before culture results are available, combination therapy with ampicillin and an aminoglycoside is recommended. When meningitis is suspected, ampicillin and cefotaxime may be considered. Following identification of the causative organism and in vitro susceptibility testing, antimicrobial therapy may be narrowed to provide targeted coverage. Therapeutic drug monitoring should be considered for neonates receiving vancomycin or aminoglycoside therapies. For neonates with invasive fungal infections, the development of new antifungal agents has significantly improved therapeutic outcomes in recent years. Liposomal amphotericin B has been found to be safe and efficacious in patients with renal impairment or toxicity caused by conventional amphotericin B. Antifungal prophylaxis with fluconazole has also been reported to dramatically reduce rates of neonatal invasive fungal infections and to improve long-term neurodevelopmental outcomes among treated children. Additionally, several large multicenter studies are currently investigating the safety and efficacy of oral lactoferrin as an immunoprophylactic agent for the prevention of neonatal sepsis.


Assuntos
Anfotericina B/uso terapêutico , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Infecções Bacterianas/tratamento farmacológico , Fungemia/tratamento farmacológico , Micoses/tratamento farmacológico , Antifúngicos/uso terapêutico , Bacteriemia/microbiologia , Infecções Bacterianas/microbiologia , Monitoramento de Medicamentos , Fungemia/microbiologia , Humanos , Lactente , Recém-Nascido , Micoses/microbiologia
18.
J Clin Pharmacol ; 54(4): 432-7, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24165853

RESUMO

Physiologic changes during pregnancy alter the pharmacokinetics, safety, and efficacy of many drugs. For clinicians, there is often uncertainty regarding the safety of these drugs due to a scarcity of published data. This study aimed to comprehensively evaluate the characteristics and publication patterns of obstetric studies registered in ClinicalTrials.gov from 2007 to 2012. Primary outcome measures, funding sources, inclusion criteria, and the reporting of study results were evaluated. A manual review of Medline/PubMed was performed to identify publications associated with studies registered in ClinicalTrials.gov. Of 93,709 total studies, there were 5,203 (6%) obstetric studies registered in ClinicalTrials.gov. Interventional studies accounted for 70% and 30% were observational. Clinical trials of drugs (49%), procedures (13%), and behavioral interventions (12%) were most common. Among interventional drug trials, 84% featured randomized allocation to study arms and 93% included measures of safety and/or efficacy as primary endpoints. Of 946 (18%) studies completed more than 2 years ago, only 11% had reported results and <7% had been published. In an area with a great need for evidence of safe and effective therapies, the low publication rate of completed studies incorporating elements of high-quality trial design is concerning. The sources of this trend should be closely investigated.


Assuntos
Bibliometria , Bases de Dados Factuais , Obstetrícia , Editoração/estatística & dados numéricos , Ensaios Clínicos como Assunto , Feminino , Humanos
19.
Mol Pharm ; 9(11): 3318-29, 2012 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-22957899

RESUMO

The oncoprotein Bcr-Abl stimulates prosurvival pathways and suppresses apoptosis from its exclusively cytoplasmic locale, but when targeted to the mitochondrial compartment of leukemia cells, Bcr-Abl was potently cytotoxic. Therefore, we designed a protein construct to act as a mitochondrial chaperone to move Bcr-Abl to the mitochondria. The chaperone (i.e., the 43.6 kDa intracellular cryptic escort (iCE)) contains an EGFP tag and two previously characterized motifs: (1) an optimized Bcr-Abl binding motif that interacts with the coiled-coil domain of Bcr (ccmut3; 72 residues), and (2) a cryptic mitochondrial targeting signal (cMTS; 51 residues) that selectively targets the mitochondria in oxidatively stressed cells (i.e., Bcr-Abl positive leukemic cells) via phosphorylation at a key residue (T193) by protein kinase C. While the iCE colocalized with Bcr-Abl, it did not relocalize to the mitochondria. However, the iCE was selectively toxic to Bcr-Abl positive K562 cells as compared to Bcr-Abl negative Cos-7 fibroblasts and 1471.1 murine breast cancer cells. The toxicity of the iCE to leukemic cells was equivalent to 10 µM imatinib at 48 h and the iCE combined with imatinib potentiated cell death beyond imatinib or the iCE alone. Substitution of either the ccmut3 or the cMTS with another Bcr-Abl binding domain (derived from Ras/Rab interaction protein 1 (RIN1; 295 residues)) or MTS (i.e., the canonical IMS derived from Smac/Diablo; 49 residues) did not match the cytotoxicity of the iCE. Additionally, a phosphorylation null mutant of the iCE also abolished the killing effect. The mitochondrial toxicity of Bcr-Abl and the iCE in Bcr-Abl positive K562 leukemia cells was confirmed by flow cytometric analysis of 7-AAD, TUNEL, and annexin-V staining. DNA segmentation and cell viability were assessed by microscopy. Subcellular localization of constructs was determined using confocal microscopy (including statistical colocalization analysis). Overall, the iCE was highly active against K562 leukemia cells and the killing effect was dependent upon both the ccmut3 and functional cMTS domains.


Assuntos
Apoptose/efeitos dos fármacos , Fibroblastos/patologia , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Neoplasias Mamárias Animais/patologia , Mitocôndrias/metabolismo , Piperazinas/farmacologia , Pirimidinas/farmacologia , Animais , Anexina A5/metabolismo , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Western Blotting , Células COS , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Chlorocebus aethiops , Sinergismo Farmacológico , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Citometria de Fluxo , Proteínas de Fusão bcr-abl/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos
20.
Ther Deliv ; 3(8): 961-79, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22946430

RESUMO

The current status of peptides that target the mitochondria in the context of cancer is the focus of this review. Chemotherapy and radiotherapy used to kill tumor cells are principally mediated by the process of apoptosis that is governed by the mitochondria. The failure of anticancer therapy often resides at the level of the mitochondria. Therefore, the mitochondrion is a key pharmacological target in cancer due to many of the differences that arise between malignant and healthy cells at the level of this ubiquitous organelle. Additionally, targeting the characteristics of malignant mitochondira often rely on disruption of protein--protein interactions that are not generally amenable to small molecules. We discuss anticancer peptides that intersect with pathological changes in the mitochondrion.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Peptídeos/administração & dosagem , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Modelos Biológicos , Peptídeos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
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