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Haemonchus contortus, a blood-feeding parasite in grazing sheep, causes economic losses. Drug resistance necessitates exploring plant-based anthelmintics like Artemisia cina (Asteraceae). The plant, particularly its ethyl acetate extract, shows anthelmintic activity against H. contortus. However, there is limited information on pharmacodynamic interactions in ethyl acetate compounds. The study aims to identify pharmacodynamic interactions in the ethyl acetate extract of A. cina with anthelmintic effects on H. contortus eggs and L3 larvae using binary mixtures. Bioactive compounds were isolated via chromatography and identified using spectroscopic techniques. Pharmacodynamic interactions were assessed through binary mixtures with a main compound. Four bioactive compounds were identified: 1-nonacosanol, hentriacontane, peruvin, and cinic acid. Binary mixtures, with peruvin as the main compound, were performed. Peruvin/1-nonacosanol-hentriacontane and peruvin/cinic acid mixtures demonstrated 1.42-fold and 4.87-fold increased lethal effects in H. contortus L3 infective larvae, respectively, at a 0.50LC25/0.50LC25 concentration. In this work, we determined the synergism between bioactive compounds isolated from the ethyl acetate extract of A. cina and identified unreported compounds for the specie.
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La homeopatía emplea el denominado 'principio de similares' como método terapéutico el cual consiste en administrar medicamentos que provocan ciertos síntomas en individuos sanos para tratar síntomas similares en individuos enfermos (similia similibus curantur) - para inducir una reacción curativa secundaria del cuerpo en contra de sus propios trastornos. Esta reacción secundaria (vital, homeostática o paradójica) del cuerpo se basa en el 'efecto de rebote' de los fármacos modernos, un tipo de evento adverso que se produce después de interrumpir varias clases de fármacos prescritos según el 'principio de los contrarios' (contraria contrariis curantur). Objetivo: La presente revisión ha buscado justificar científicamente el principio de curación homeopática frente a la farmacología clínica y experimental a través de un estudio sistemático del efecto de rebote de los fármacos modernos o reacción paradójica del cuerpo. Métodos: Empleando como referencia estudios y revisiones sobre el tema publicados a partir de 1998, actualizamos los datos añadiendo estudios recientes incluidos en la base de datos PubMed. Resultados: El efecto de rebote se produce después de interrumpir varias clases de fármacos con acción contraria a los síntomas de las enfermedades, exacerbándolos a niveles superiores a aquellos previos al tratamiento. Independientemente de la enfermedad, fármaco, dosis y duración del tratamiento, el fenómeno del rebote se manifiesta en una pequeña proporción de los individuos susceptibles. Siguiendo las premisas homeopáticas, los fármacos modernos también podrían usarse según el principio de la similitud terapéutica, empleando entonces el efecto de rebote (reacción paradójica) con propósito curativo. Conclusiones: Evidenciado por cientos de estudios que constatan la similitud de conceptos y manifestaciones, el efecto de rebote de los fármacos modernos justifica científicamente el principio de la cura homeopática. Aunque el fenómeno de rebote es un evento adverso estudiado por la farmacología moderna, no es conocido por los profesionales de la atención médica, lo cual priva a los médicos de un conocimiento indispensable para el manejo seguro de los fármacos.
Homeopathy employs the so-called 'principle of similars' as therapeutic method - which consists in administering medicines that cause certain symptoms in healthy individuals to treat similar symptoms in sick individuals (similia similibus curantur) - to induce a secondary and healing reaction by the body against its own disorders. This secondary (vital, homeostatic or paradoxical) reaction of the body is based on the 'rebound effect' of modern drugs, a type of adverse event that occurs following discontinuation of several classes of drugs prescribed according to the 'principle of contraries' (contraria contrariis curantur). Aim: The present review sought to scientifically substantiate the homeopathic healing principle vis-à-vis experimental and clinical pharmacology through a systematic study of the rebound effect of modern drugs or paradoxical reaction of the body. Methods: Employing as reference studies and revisions on the subject published since 1998, we updated the data adding recent studies included in database PubMed. Results: The rebound effect occurs after discontinuation of several classes of drugs with action contrary to the symptoms of diseases, exacerbating them to levels above the ones before treatment. Regardless of disease, drug, dose and duration of treatment, the rebound phenomenon manifests in a small proportion of susceptible individuals. Following the homeopathic premises, modern drugs might also be used according to the principle of therapeutic similitude, thus employing the rebound effect (paradoxical reaction) with curative intent. Conclusions: Evidenced by hundreds of studies that attest to the similarity of concepts and manifestations, the rebound effect of modern drugs scientifically substantiates the principle of homeopathic cure. Although the rebound phenomenon is an adverse event studied by modern pharmacology, it is not known by health care professionals, thus depriving doctors of knowledge indispensable for safe management of drugs.
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Farmacodinâmica do Medicamento Homeopático , /estatística & dados numéricos , Efeito Rebote , Efeito ReboteRESUMO
A patient with acute myeloid leukemia presented various episodes of febrile neutropenia, for which there was no positive response to antibiotic treatments. Following an episode of bacteremia by extensively drug-resistant Klebsiella pneumoniae, amikacin was prescribed, pharmacokinetic analyses of its plasma concentrations were performed and the dosage interval was narrowed to 12 and 8 h in order to counteract the reduced postantibiotic effect due to the patient being immunocompromised. The patient responded positively, with procalcitonin decreasing and body temperature normalizing. Recovery was finally achieved, without renal or auditory damage. This case proposes tightening dosage intervals for aminoglycosides as an effective strategy in immunocompromised patients. Aminoglycosides are given over extended intervals (24 h), considering concentration-dependent effectiveness, nephrotoxicity and postantibiotic effect. Leukocytes appear to play a determining role in the postantibiotic effect, with no proposed dosing strategy for strongly immunocompromised patients.
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Neutropenia Febril , Neoplasias Hematológicas , Humanos , Aminoglicosídeos/uso terapêutico , Antibacterianos/uso terapêutico , Amicacina , Neoplasias Hematológicas/tratamento farmacológico , Neutropenia Febril/tratamento farmacológicoRESUMO
Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. There is an urgent need for safe, effective, and accessible new treatments since the currently approved drugs have serious limitations. Drug development for Chagas disease has historically been hampered by the complexity of the disease, critical knowledge gaps, and lack of coordinated R&D efforts. This review covers some of the translational challenges associated with the progression of new chemical entities from preclinical to clinical phases of development, and discusses how recent technological advances might allow the research community to answer key questions relevant to the disease and to overcome hurdles in R&D for Chagas disease.
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Coagulase-negative staphylococci are main pathogens that produce goat mastitis. Marbofloxacin is a third-generation fluoroquinolone approved for treat mastitis in animals. The objectives of this study were: (i) to determine the pharmacokinetics of marbofloxacin (10 mg/kg/24 h) in serum and milk administered intramuscularly for five days in goats with mastitis induced by coagulase-negative staphylococci; (ii) to characterize the concentration-effect relationship of marbofloxacin against coagulase-negative staphylococci in Mueller Hinton broth and goat milk; (iii) to determine AUC/MIC cutoff values of marbofloxacin, and (iv) to perform a PK/PD analysis to evaluate the efficacy of the dose regimen for the treatment of goat mastitis produced by coagulase-negative staphylococci. Marbofloxacin presented context-sensitive pharmacokinetics, influenced by the evolution of the disease, which decreased marbofloxacin disposition in serum and milk. Marbofloxacin showed a median (95% CI) fAUC/MIC values for MIC of 0.4 and 0.8 µg/mL of 26.66 (22.26-36.64) and 32.28 (26.57-48.35) related with -2 log10CFU/mL reduction; and 32.26 (24.81-81.50) and 41.39 (29.38-128.01) for -3 log10CFU/mL reduction in Mueller Hinton broth. For milk, -2 log10CFU/mL reduction was achieved with 41.48 (35.29-58.73) and 51.91 (39.09-131.63), and -3 log10CFU/mL reduction with 51.04 (41.6-82.1) and 65.65 (46.68-210.16). The proposed dose regimen was adequate for the treatment of goat mastitis produced by coagulase-negative staphylococci, resulting in microbiological and clinical cure of all animals. The animal model used in this study provided important pharmacokinetic information about the effect of the infection on the pharmacokinetics of marbofloxacin. Pharmacodynamic modeling showed that fAUC/MIC cutoff values were higher in goat milk compared with Mueller Hinton broth.
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Tuberculosis has been described as a global health crisis since the 1990s, with an estimated 1.4 million deaths in the last year. Herein, a series of 20 1H-indoles were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Furthermore, the top hit compounds were active against multidrug-resistant strains, without cross-resistance with first-line drugs. Exposing HepG2 and Vero cells to the molecules for 72 h showed that one of the evaluated structures was devoid of apparent toxicity. In addition, this 3-phenyl-1H-indole showed no genotoxicity signals. Finally, time-kill and pharmacodynamic model analyses demonstrated that this compound has bactericidal activity at concentrations close to the Minimum Inhibitory Concentration, coupled with a strong time-dependent behavior. To the best of our knowledge, this study describes the activity of 3-phenyl-1H-indole against Mtb for the first time.
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Antituberculosos/síntese química , Antituberculosos/farmacologia , Indóis/síntese química , Indóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Chlorocebus aethiops , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana/métodos , Relação Estrutura-Atividade , Células VeroRESUMO
Objective: Describe primary pharmacokinetic/pharmacodynamic (PK/PD) parameters of vancomycin and meropenem in pediatric patients undergoing ECMO and analyze utilized dosing to reach PK/PD target. Design: Prospective, multicentric, population PK analysis. Setting: Two hospitals with pediatric intensive care unit. Patients: Pediatric patients (1 month - 15 years old) receiving vancomycin and meropenem for empiric or definitive infection treatment while ECMO support. Measurements and Main Results: Four serum concentration were obtained for patients receiving vancomycin (n = 9) and three for meropenem (n = 9). The PK/PD target for vancomycin was a ratio of the area under the curve to the minimal inhibitory concentration (AUC/MIC) of >400, and for meropenem was 4 times above MIC for 50% of the dosing interval (fT50% > 4xMIC). Pharmacokinetic modeling was performed using PMetrics 1.5.0. We included nine patients, with 11 PK profiles for each antimicrobial. The median age of patients was 4 years old (2 months - 13 years) and 45% were male. Creatinine clearance (CL) was 183 (30-550) ml/min/1.73 m2. The median dose was 13.6 (range 10-15) mg/kg every 6-12 h and 40 mg/kg every 8-12 h for vancomycin and meropenem, respectively. Two compartment models were fitted. Weight was included as a covariate on volume of the central compartment (Vc) for meropenem. Weight was included as a covariate on both Vc and clearance (CL) and serum creatinine was also included as a covariate on CL for vancomycin. The pharmacokinetic parameters CL and Vc were 0.139 ± 0.102 L/h/kg and 0.289 ± 0.295 L/kg for meropenem and 0.060 ± 0.055 L/h/kg and 0.419 ± 0.280 L/kg for vancomycin, respectively. Across each dosing interval 91% of patients achieved the PK/PD targets for adequate exposure for meropenem and 63.6% for vancomycin. Conclusion: Pharmacokinetic/pharmacodynamic objectives for vancomycin were achieved partially with conventional doses and higher dosing with extended infusion were needed in the case of meropenem.
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Medications are an important part of the management of patients with kidney disease. When used appropriately, pharmacotherapy can slow disease progression and reduce morbidity and mortality. Unfortunately, reduced kidney function can significantly alter the pharmacokinetics and pharmacodynamics of many medications, putting patients at risk for drug toxicity if modifications to therapy are not appropriately managed. Adding complexity to the appropriateness of medication and dosage selection is the difficulty in estimating kidney function and the discordance between the Cockcroft-Gault-derived dosing cut points in most medication package inserts and the estimations of glomerular filtration rate by newer and generally more accurate guideline-recommended equations. This installment of the AJKD Core Curriculum in Nephrology provides recent updates and practical considerations for designing optimal medication regimens. Given the prevalence of abnormal kidney function and its importance in medication selection and dose adjustment, additional focus and specific recommendations are provided for anticoagulant, anti-infective, analgesic, antidiabetic, and antihypertensive agents.
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Currículo , Taxa de Filtração Glomerular/fisiologia , Nefropatias/tratamento farmacológico , Rim/fisiopatologia , Nefrologistas/normas , Humanos , Nefropatias/fisiopatologiaRESUMO
Pharmacodynamic interactions between plant isolated compounds are important to understand the mode of action of an herbal extract to formulate or create better standardized extracts, phytomedicines, or phytopharmaceuticals. In this work, we propose binary mixtures using a leader compound to found pharmacodynamic interactions in inhibition of the NF-κB/AP-1 pathway using RAW-Blue™ cells. Eight compounds were isolated from Castilleja tenuiflora, four were new furofuran-type lignans for the species magnolin, eudesmin, sesamin, and kobusin. Magnolin (60.97%) was the most effective lignan inhibiting the NF-κB/AP-1 pathway, followed by eudesmin (56.82%), tenuifloroside (52.91%), sesamin (52.63%), and kobusin (45.45%). Verbascoside, a major compound contained in wild C. tenuiflora showed an inhibitory effect on NF-κB/AP-1. This polyphenol was chosen as a leader compound for binary mixtures. Verbacoside-aucubin and verbascoside-kobusin produced synergism, while verbascoside-tenuifloroside had subadditivity in all concentrations. Verbascoside-kobusin is a promising mixture to use on NF-κB/AP-1 related diseases and anti-inflammatory C. tenuiflora-based phytomedicines.
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Anti-Inflamatórios , Glucosídeos , Iridoides , Lignanas , NF-kappa B/antagonistas & inibidores , Orobanchaceae/química , Fenóis , Fator de Transcrição AP-1/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Linhagem Celular , Glucosídeos/química , Glucosídeos/farmacologia , Iridoides/química , Iridoides/farmacologia , Lignanas/química , Lignanas/farmacologia , Camundongos , NF-kappa B/metabolismo , Fenóis/química , Fenóis/farmacologia , Fator de Transcrição AP-1/metabolismoRESUMO
AIMS: The objective of the current study was to evaluate paediatric dosing regimens for meropenem plus fosfomycin that generate sufficient coverage against multidrug-resistant bacteria. METHODS: The physiologically based pharmacokinetic (PBPK) models of meropenem and fosfomycin were developed from previously published pharmacokinetic studies in five populations: healthy subjects of Japanese origin, and healthy adults, geriatric, paediatric and renally impaired of primarily Caucasian origins. Pharmacodynamic (PD) analyses were carried out by evaluating dosing regimens that achieved a ≥90% joint probability of target attainment (PTA), which was defined as the minimum of the marginal probabilities to achieve the target PD index of each antibiotic. For meropenem, the percentage of time over a 24-hour period wherein the free drug concentration was above the minimum inhibitory concentration (fT > MIC) of at least 40% was its PD target. The fosfomycin PD index was described by fAUC/MIC of at least 40.8. RESULTS: For coadministration consisting of 20 mg/kg meropenem q8h as a 3-hour infusion and 35 mg/kg fosfomycin q8h also as a 3-hour infusion in a virtual paediatric population between 1 month and 12 years of age with normal renal function and a corresponding body weight between 3 and 50 kg, a joint PTA ≥ 90% is achieved at MICs of 16 and 64 mg/L for meropenem and fosfomycin coadministration, respectively, against Klebsiella pneumoniae and Pseudomonas aeruginosa. CONCLUSION: The current study identified potentially effective paediatric dosing regimens for meropenem plus fosfomycin coadministration against multidrug-resistant bacteria.
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Fosfomicina , Pediatria , Adulto , Idoso , Antibacterianos/farmacologia , Criança , Fosfomicina/farmacologia , Humanos , Meropeném , Testes de Sensibilidade Microbiana , Método de Monte CarloRESUMO
This review aims to analyze and contrast the neurological effects associated with the use of caffeine on neurobehavior and neuroprotection in animal models. Caffeine belongs to the group of methylxanthines that exert a direct effect on adenosine receptors associated with inhibitory or excitatory G proteins, generating modification of cyclic AMP activity and intracellular calcium flow which produces alterations in the modulation system of the neurotransmitters dopamine and glutamate. The regulation of the neurotransmission systems generates protection against the inflammation of the central nervous system, by activation of the microglia and reinforcement of the blood-brain barrier. This drug will also restore cognition or prevent memory loss in Parkinson's or Alzheimer's diseases. It is important to establish new study models in other species to assess whether the behavior of the molecule is similar and to obtain other clinical applications in its behavioral and neuroprotective effects.(AU)
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Animais , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiopatologia , Estimulantes do Sistema Nervoso Central/análise , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Cafeína , Doenças NeurodegenerativasRESUMO
This review aims to analyze and contrast the neurological effects associated with the use of caffeine on neurobehavior and neuroprotection in animal models. Caffeine belongs to the group of methylxanthines that exert a direct effect on adenosine receptors associated with inhibitory or excitatory G proteins, generating modification of cyclic AMP activity and intracellular calcium flow which produces alterations in the modulation system of the neurotransmitters dopamine and glutamate. The regulation of the neurotransmission systems generates protection against the inflammation of the central nervous system, by activation of the microglia and reinforcement of the blood-brain barrier. This drug will also restore cognition or prevent memory loss in Parkinson's or Alzheimer's diseases. It is important to establish new study models in other species to assess whether the behavior of the molecule is similar and to obtain other clinical applications in its behavioral and neuroprotective effects.
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Animais , Estimulantes do Sistema Nervoso Central/análise , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiopatologia , Cafeína , Doenças NeurodegenerativasRESUMO
This study aimed to evaluate the reduction in vancomycin through intermittent haemodialysis (IHD) and prolonged haemodialysis (PHD) in acute kidney injury (AKI) patients with sepsis and to identify the variables associated with subtherapeutic concentrations. A prospective study was performed in patients admitted at an intensive care unit (ICU) of a Brazilian hospital. Blood samples were collected at the start of dialytic therapy, after 2 and 4 h of treatment and at the end of therapy to determine the serum concentration of vancomycin and thus perform pharmacokinetic evaluation and PK/PD modelling. Twenty-seven patients treated with IHD, 17 treated with PHD for 6 h and 11 treated with PHD for 10 h were included. The reduction in serum concentrations of vancomycin after 2 h of therapy was 26.65 ± 12.64% and at the end of dialysis was 45.78 ± 12.79%, higher in the 10-h PHD group, 57.70% (40, 48-64, 30%) (p = 0.037). The ratio of the area under the curve to minimal inhibitory concentration (AUC/MIC) at 24 h in the PHD group was significantly smaller than at 10 h (p = 0.047). In the logistic regression, PHD was a risk factor for an AUC/MIC ratio less than 400 (OR = 11.59, p = 0.033), while a higher serum concentration of vancomycin at T0 was a protective factor (OR = 0.791, p = 0.009). In conclusion, subtherapeutic concentrations of vancomycin in acute kidney injury (AKI) patients in dialysis were elevated and may be related to a higher risk of bacterial resistance and mortality, besides pointing out the necessity of additional doses of vancomycin during dialytic therapy, mainly in PHD.
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Antibacterianos , Estado Terminal , Diálise Renal , Vancomicina , Idoso , Antibacterianos/uso terapêutico , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vancomicina/uso terapêuticoRESUMO
BACKGROUND: Central Nervous System (CNS) depressants like antipsychotics, opioids, benzodiazepines and zolpidem are frequently used by patients of a wide range of ages. Uncertainty remains about their effect in very old adults (>80 years old) and their potential for pharmacodynamic and pharmacokinetic drug-drug interactions in this population. OBJECTIVE: To assess if the use of CNS depressants is associated with a higher risk of hospitalization due to community-acquired pneumonia (CAP) in very old patients. METHODS: In this prospective study, 362 patients over 80 years of age who had been consequently admitted to the general ward of a teaching hospital were examined. Each patient was assessed, by our pharmacovigilance team within 24 hours of admission, to identify outpatient medication use and potential drug-drug interactions. RESULTS: The overall use of CNS depressants as a group was not associated with a higher risk of admission due to CAP in very old patients (55% vs. 49%; OR=1.28 [0.76-2.16], p=0.34). However, the use of antipsychotics was associated with a higher rate of admissions due to CAP in this population (OR=1.98 [1.10-3.57], p=0.02). No association was seen between opioids (p=0.27), zolpidem (p=0.83), or benzodiazepines (p=0.15) and the rate of admissions due to CAP in these patients. Moreover, pharmacodynamic or pharmacokinetic interactions leading to CNS depression were equally found in patients admitted for CAP and those admitted for other reasons. CONCLUSION: The use of antipsychotics in very old adults was associated with an increased risk of hospital admission due to CAP. This suggests that the use of these medications in this population should be done with caution. No association was observed with opioids, benzodiazepines and zolpidem with the latter outcome.
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Depressores do Sistema Nervoso Central/efeitos adversos , Infecções Comunitárias Adquiridas/epidemiologia , Pneumonia/epidemiologia , Idoso de 80 Anos ou mais , Analgésicos Opioides , Antipsicóticos , Benzodiazepinas , Feminino , Hospitalização , Humanos , Masculino , Estudos Prospectivos , ZolpidemRESUMO
BACKGROUND: Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. In silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC. METHODS: Steady-state drug area under the curve ratio to MIC (AUC/MIC) or the percent time above MIC (fT > MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI. RESULTS: Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg q12 h followed by 400 mg q24 h and for teicoplanin 400 mg q12 h, respectively; 61% and 76% for vancomycin 1000 mg q12 h and q8 h, respectively. CONCLUSIONS: Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.
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Antibacterianos/farmacologia , Bacteriemia/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Vancomicina/farmacologia , Antibacterianos/farmacocinética , Bacteriemia/microbiologia , Brasil , Cefalosporinas/farmacocinética , Cefalosporinas/farmacologia , Daptomicina/farmacocinética , Daptomicina/farmacologia , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Estudos Retrospectivos , Infecções Estafilocócicas/microbiologia , Vancomicina/farmacocinética , CeftarolinaRESUMO
Aim: The aims of the study are to evaluate the activity of sulbactam, meropenem, and polymyxin B alone and in combination against six isolates of extremely drug resistant Acinetobacter baumannii and to determine dosing regimens that achieve a sufficient joint probability of target attainment (PTA) based on combination antimicrobial pharmacodynamics. Materials and Methods: The combinations were evaluated by the checkerboard method and were considered synergistic when the fractional inhibitory concentration index (FICI) ≤0.5. Pharmacodynamic analyses were carried out by evaluating dosing regimens that achieve ≥90% joint PTA at the percentage of time over a 24-h period wherein the free drug concentration is above the minimum inhibitory concentration (%fT> MIC) of 40% and 60% for meropenem and sulbactam, respectively, and 20 for the ratio of the area under the free drug concentration-time curve over MIC (fAUC/MIC) for polymyxin B. Results: For both polymyxin B-resistant and susceptible isolates, the addition of sulbactam in combination with meropenem and subinhibitory concentration of polymyxin B showed important synergistic activity (five isolates; FICI ≤0.281); the recommended dosing regimens were 2/4 g meropenem/sulbactam q8 hours and 0.5 mg/kg polymyxin B q12 hours. Conclusion: This in vitro study showed that sulbactam can significantly improve the action of meropenem and polymyxin B in OXA-producing A. baumannii isolates, especially when there are no new treatment options available for infections caused by these microorganisms.
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Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Meropeném/farmacologia , Polimixina B/farmacologia , Sulbactam/farmacologia , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/isolamento & purificação , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Humanos , Meropeném/administração & dosagem , Meropeném/farmacocinética , Testes de Sensibilidade Microbiana , Polimixina B/administração & dosagem , Polimixina B/farmacocinética , Sulbactam/administração & dosagem , Sulbactam/farmacocinéticaRESUMO
It is commonly assumed that loss of responsiveness and recovery of responsiveness occur at similar concentrations of propofol. However, the 'conscious' and 'anaesthetised' conditions produced by general anaesthetics may behave as two bistable states. We hypothesised that loss of responsiveness and recovery of responsiveness occur at different propofol concentrations. Propofol was administered to 19 healthy volunteers by effect-site target-controlled infusion using increasing and decreasing stable concentration steps of 7 min. Propofol serum concentrations were measured from venous blood samples at the end of each 7-min step. A long step of 14 min was performed at loss of responsiveness. At this step, propofol concentrations were measured at 7 and 14 min. Propofol concentrations measured at loss of responsiveness and recovery of responsiveness were 2.6 (1.2-4.7) µg.ml-1 and 1.6 (0.6-3.3) µg.ml-1 , respectively (p < 0.001). Propofol plasma concentration and the corresponding bispectral index values measured at minute 7 and minute 14 of the long step performed at loss of responsiveness were 2.6 (1.2-4.7) vs. 2.6 (1.3-4.3) at recovery of responsiveness, (p = 0.96) and 61.2 (49.0-77.0) vs. 58.4 (45.0-74.0), (p = 0.058), respectively. Loss of responsiveness and recovery of responsiveness appear to occur at different propofol concentrations. However, it is possible that, if equilibration was not achieved between plasma and effect-sites at the end of each 7-min step, the higher concentrations found at loss of responsiveness compared with those observed during recovery of responsiveness could be explained by a possible bias in estimations of the effect-site concentrations of propofol by the Schnider model, rather than neural inertia.
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Anestésicos Intravenosos/farmacologia , Estado de Consciência/efeitos dos fármacos , Propofol/farmacologia , Adulto , Anestésicos Intravenosos/sangue , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Feminino , Humanos , Masculino , Propofol/sangue , Valores de ReferênciaRESUMO
The aim of this in vivo study was to compare the efficacy of vancomycin at standard doses (VAN-SD) to that of VAN at adjusted doses (VAN-AD) in achieving a VAN area under the curve/MIC ratio (AUC/MIC) of ≥400 against three methicillin-resistant Staphylococcus aureus (MRSA) strains with different microdilution VAN MICs in an experimental endocarditis model. The valve vegetation bacterial counts after 48 h of VAN therapy were compared, and no differences were observed between the two treatment groups for any of the three strains tested. Overall, for VAN-SD and VAN-AD, the rates of sterile vegetations were 15/45 (33.3%) and 21/49 (42.8%) (P = 0.343), while the medians (interquartile ranges [IQRs]) for log10 CFU/g of vegetation were 2 (0 to 6.9) and 2 (0 to 4.5) (P = 0.384), respectively. In conclusion, this VAN AUC/MIC pharmacodynamic target was not a good predictor of vancomycin efficacy in MRSA experimental endocarditis.
Assuntos
Endocardite/tratamento farmacológico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Vancomicina/uso terapêutico , Animais , Antibacterianos/uso terapêutico , Farmacoeconomia , Endocardite Bacteriana/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , CoelhosRESUMO
ABSTRACT This study was carried out to understand the influence of a selected antiarrhythmic drug on the pharmacodynamics and pharmacokinetics of an antidiabetic drug in animal models. Pharmacodynamic and pharmacokinetic responses were determined by measurements of blood glucose and serum insulin and serum metformin to drug interactions between disopyramide and metformin. Single dose and multi dose studies showed that the maximum blood glucose reductions in normal and diabetic rats were at the 6th hour, and in rabbits at the 3rd hour. Glucose-insulin homeostasis was evaluated to assess the safety and effectiveness of the combination. There was a marginal increase in the pharmacokinetic parameters of metformin with multiple dose treatments of disopyramide but no significant changes in kinetic parameters between single and multiple dose studies, compared to metformine alone. There may be a possibility of disopyramide and metformin interaction at the excretion stage, or an additive pharmacodynamic action. This study validates the drug interaction in two dissimilar species, which indicates more probability of its occurrence in humans.