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INTRODUCTION: Multiple myeloma (MM) is the second most common hematologic malignancy. MM is associated with significant morbidity due to its end-organ destruction and is a disease of the older population. Although survival rates for MM have improved over the last decade, due to an increase in treatment options, the disease remains incurable. Expensive (oral) agents are widely used in MM patients; however, tools for supporting patients in complex treatment regimens are scarce. To investigate if a tool will support MM patients and healthcare professionals, the MM e-coach was developed and tested. The aim of this study is to study the impact of telemonitoring on adherence, complications and quality of life in patients with MM (ITUMM study). METHODS: A two-arm open-label parallel-group randomized controlled trial will be conducted between March 2021 and June 2024 to compare the telemonitoring (MM e-coach) with standard MM care. This study aimed to recruit 150 patients with recently diagnosed multiple myeloma (RDMM), starting first or second line of treatment. Blinded primary outcome is adherence by pill count after start of treatment at 1-3 months. Secondary outcomes are patient reported outcomes: GFI, EQ-5D-5L, EORTC-QLQ-C30, SDM-Q-9, MARS-5, single item questions, PREMs, adverse events, OS and PFS. Patient reported outcomes were developed and integrated in the e-coach MM to regularly measure digitized outcomes of MM patients from time of RDMM until 12 months post-diagnosis. Online measurements will be performed at baseline (0), 3, 6, 9 and 12 months. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Ethics Committee of the Isala klinieken in The Netherlands (No. 201111) at 25 February 2021. Study results will be disseminated to the relevant healthcare communities by publication in peer-reviewed journals, and at scientific and clinical conferences. STUDY REGISTRATION NUMBER: ClinicalTrials.gov number: NCT05964270 and ABR number: NL75771.075.20.
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Mieloma Múltiplo , Qualidade de Vida , Telemedicina , Feminino , Humanos , Masculino , Adesão à Medicação , Mieloma Múltiplo/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVE: In this retrospective cohort study, we compared neonatal and maternal outcomes after exposure of different psychopharmacological classes of drugs. Both psychiatric diseases and pharmacological treatment of these are associated with lower birth weights, lower APGAR scores, and NICU admission. Therefore, we tried to rule out the role of psychotropics as if no differences were found between pharmacological classes, the lower birthweights might not be attributable to these. METHOD: We divided our groups in exposed to atypical antipsychotic drugs, Selective Serotonin Reuptake Inhibitors (SSRI), Tricyclic Antidepressants (TCA), benzodiazepines, and different combinations of psychotropic drugs. The last group included SSRIs combined with benzodiazepines, methylphenidate, lithium, and classic antipsychotic drugs. RESULTS: We used univariate regression analysis to see which factors from our rich dataset including pharmacological class, are associated with birth weight, APGAR scores, gestational age, and NICU admission. The significant associations from univariate analyses were further analyzed using ancova analysis or logistic regression where applicable. CONCLUSION: We found no clinically relevant differences in neonatal and maternal outcomes between the different exposed pharmacological classes. However, our dataset may have been too small to draw firm conclusions.
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Objectives: This study aimed to investigate the plasma and breastmilk concentrations for sertraline, citalopram and paroxetine for assessment of the Milk/Plasma (M/P) ratio and Absolute Infant Dose (AID), and to determine actual infant drug exposure through breastfeeding. Subsequently, informed recommendations will be formulated regarding the advisability of breastfeeding in women undergoing treatment with the three most widely used antidepressants. Methods: A pharmacokinetic study in lactating women and their infants using sertraline, citalopram or paroxetine was performed. Paired breastmilk and plasma samples and single point infant plasma samples were collected to determine antidepressant concentrations. An Area Under the Curve (AUC) based approach with the trapezoidal rule was used to calculate M/P ratios and AID for all three antidepressants by combining all measured concentrations for the same dose. Results: Thirty-seven lactating women and their infants participated in this study. 111 paired breastmilk and plasma samples and 37 single point infant plasma samples were collected. Detectable concentrations of sertraline, citalopram and paroxetine were present in all breastmilk samples. For sertraline and citalopram M/P ratio is above one, indicating higher breastmilk than plasma concentrations, however, drug exposure by breastmilk did not lead to detectable plasma drug levels in any of the 15 infants for sertraline, for nine (out of 13) infants for citalopram and for eight (out of nine) infants for paroxetine. Conclusion: Given the well-known benefits of breastfeeding, our findings support breastfeeding of infants by mothers who are taking sertraline, citalopram or paroxetine is safe. Sertraline and paroxetine are the preferred antidepressants during breastfeeding, reaching mostly undetectable infant drug levels.
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PURPOSE: In a cohort of pregnant women using antihypertensive drugs, we compared exposure to antidepressants versus no exposure and the possible association with birth weight, APGAR scores, NICU admission, and maternal admission to an obstetrical intensive care unit (OHC). It was hypothesized that pregnant women with hypertensive disorders using antidepressants are at greater risk of complications. METHODS: A retrospective cohort study in a general teaching hospital in Zwolle, in the Middle-Northern part of The Netherlands. Finally, 58 pregnancies in the exposed group and 273 pregnancies in the reference group met all inclusion and exclusion criteria. We compared the neonate's birthweight between the exposed to antidepressants group and the reference group as the primary outcome. Secondary outcomes were the APGAR score at 1 and 5 min and obstetric high care (OHC) admission of the mother and neonatal intensive care unit (NICU) admission of the child. RESULTS: We found no differences in birth weight in neonates of mothers with hypertensive disorders and whether or not to use antidepressants. Besides a possible higher risk of admission to an OHC in women with hypertension-complicated pregnancies using antidepressants, we found no other maternal or neonatal risks in this population. CONCLUSION: We found no additional maternal or neonatal risks of using antidepressants prescribed to women with hypertension disorders during pregnancy.
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Antidepressivos , Peso ao Nascer , Hipertensão Induzida pela Gravidez , Humanos , Feminino , Gravidez , Estudos Retrospectivos , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Adulto , Recém-Nascido , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Peso ao Nascer/efeitos dos fármacos , Índice de Apgar , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Países Baixos/epidemiologia , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Resultado da Gravidez/epidemiologiaRESUMO
AIMS: To compare the gestational age of neonates in utero exposed to benzodiazepines (BDZs) with nonexposed controls. Secondary objectives were birth weight, presence of congenital malformations, APGAR score and the need for >3 months (prolonged) maternal psychiatric care. METHODS: A retrospective cohort study of women and neonates from 2013 to 2021 with univariate and multivariable analysis to study the associations between BDZ exposure and gestational age compared to nonexposed women with mental health problems. RESULTS: We found that BDZ exposure was not associated with a lower gestational age. We found that women in the exposed group had an increased risk of psychiatric care (adjusted odds ratio 2.58 [95% confidence interval 1.71-3.91], P < .001). CONCLUSION: We found that in utero BDZ exposure was not associated with a significantly lower gestational age of the neonates and was associated with prolonged psychiatric care of their mothers.
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Benzodiazepinas , Transtornos Mentais , Gravidez , Recém-Nascido , Humanos , Feminino , Benzodiazepinas/efeitos adversos , Estudos Retrospectivos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/epidemiologia , Idade GestacionalRESUMO
OBJECTIVES: Therapeutic drug monitoring is performed routinely in patients on anti-epileptic drugs (AEDs) for optimisation and individualisation of therapy. The dried blood spot (DBS) sampling technique is a suitable, more patient-friendly alternative for conventional venous sampling methods. However, before DBS can be used in routine care, data are needed to establish the correlation between standard plasma concentrations obtained from venous puncture and concentrations measured through DBS obtained by finger prick. This study aims to investigate the correlation between carbamazepine, lamotrigine and levetiracetam drug concentrations in venous blood and DBS samples in the same patients at the same time. METHODS: Clinical validation was conducted by direct comparison of paired DBS and venous plasma samples. Method agreement was evaluated using Passing-Bablok regression analysis and Bland-Altman plots to provide insight into the relationship between the two analytically validated methods. For Bland-Altman analysis the acceptance limit required by both FDA and EMA guidelines is at least two-thirds (67%) of the paired samples within 80-120% of the mean of both methods. RESULTS: Paired samples from 79 patients were studied. For all three AEDs, plasma and DBS concentrations correlated highly (r=0.90 for carbamazepine, r=0.93 for lamotrigine and r=0.93 for levetiracetam), indicating a linear relationship. For carbamazepine and lamotrigine, no proportional or constant bias was revealed. For levetiracetam, concentrations were higher in plasma samples than in DBS (slope 1.21), implying a conversion factor is needed. The acceptance limit was met for carbamazepine and levetiracetam with a value of 72% and 81%, respectively. For lamotrigine, this acceptance limit was not met with a value of 60%. CONCLUSIONS: The method was successfully validated and will be used for therapeutic drug monitoring in patients using carbamazepine, lamotrigine and/or levetiracetam.
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OBJECTIVES: Limited data exist about the antimicrobial target attainment and pharmacokinetics of cefotaxime in critically ill patients in the ICU undergoing continuous kidney replacement therapy (CKRT). We conducted a prospective observational study in two large teaching hospitals [Isala Hospital (IH) and Zwolle and Maasstad Hospital (MH)] to investigate target attainment and pharmacokinetics of cefotaxime in patients undergoing CKRT. PATIENTS AND METHODS: Patients aged ≥18â years admitted to the ICU treated with IV cefotaxime 1000â mg three times daily (IH) or 4 times daily (MH) were included. Fifteen patients were enrolled in total. Per patient eight cefotaxime plasma and eight ultrafiltrate samples were drawn in IH and four plasma samples in MH on Day 2 of treatment. In ICU patients the recommended antimicrobial target of cefotaxime is a plasma concentration 100% of the time above the MIC. RESULTS: In IH 10/11 patients had higher plasma trough concentrations than the MIC breakpoint of Enterobacterales of 1â mg/L (clinical breakpoint for susceptible strains) and 9/11 patients had concentrations above 2â mg/L (clinical breakpoint for resistant strains). All patients (4/4) in MH had higher plasma trough concentrations than 2â mg/L. A sieving coefficient of 0.74 was identified, with a median amount of 40% of cefotaxime eliminated by CKRT. CONCLUSIONS: We conclude that cefotaxime 1000â mg 3-4 times daily gives adequate plasma concentrations in patients with anuria or oliguria undergoing CKRT. The 1000â mg four times daily dosage is recommended in patients undergoing CKRT with partially preserved renal function to achieve the target.
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Cefotaxima , Terapia de Substituição Renal Contínua , Humanos , Adolescente , Adulto , Cefotaxima/farmacocinética , Estado Terminal/terapia , Antibacterianos , Combinação Piperacilina e TazobactamRESUMO
AIMS: Platelet inhibition induced by P2Y12 receptor antagonists in patients with ST-elevation myocardial infarction (STEMI) can be affected by concomitant use of opioids. The aim of this trial was to examine the effect of intravenous (iv) acetaminophen compared with iv fentanyl on P2Y12 receptor inhibition in patients with STEMI. METHODS AND RESULTS: The Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial randomized 195 STEMI patients who were scheduled to undergo primary percutaneous coronary intervention (PCI) and were pre-treated with crushed ticagrelor to iv acetaminophen (N = 98) or iv fentanyl (N = 97) in the ambulance. The primary endpoint, consisting of the level of platelet reactivity units (PRU) measured immediately after primary PCI, was not significantly different between the study arms [median PRU 104 (IQR 37-215) vs. 175 (63-228), P = 0.18]. However, systemic levels of ticagrelor were significantly higher in the acetaminophen arm at the start of primary PCI [151 ng/mL (32-509) vs. 60 ng/mL (13-206), P = 0.007], immediately after primary PCI [326 ng/mL (94-791) vs. 115 ng/mL (38-326), P = 0.002], and at 1 h after primary PCI [488 ng/mL (281-974) vs. 372 ng/mL (95-635), P = 0.002]. Acetaminophen resulted in the same extent of pain relief when compared with fentanyl [reduction of 3 points on 10-step-pain scale before primary PCI (IQR 1-5)] in both study arms (P = 0.67) and immediately after PCI [reduction of 5 points (3-7); P = 0.96]. CONCLUSION: The iv acetaminophen in comparison with iv fentanyl was not associated with significantly lower platelet reactivity in STEMI patients but resulted in significantly higher ticagrelor plasma levels and was effective in pain relief.
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Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Analgésicos Opioides/efeitos adversos , Humanos , Inibidores da Agregação Plaquetária , Antagonistas do Receptor Purinérgico P2Y , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Ticagrelor/uso terapêuticoRESUMO
BACKGROUND: The prevalence of diagnosed chronic hepatitis C virus (HCV) infection among pregnant women in the Netherlands is 0.26%, yet many cases remain undiagnosed. HCV screening and treatment of pregnant HCV carriers could reduce the burden of disease and limit vertical transmission from mother to child. We assessed the impact of HCV screening and subsequent treatment with new direct-acting antivirals (DAAs) among pregnant women in the Netherlands. METHODS: An HCV natural history Markov transition state model was developed, to evaluate the public-health and economic impact of HCV screening and treatment. Besides all 179,000 pregnant women in the Netherlands (cohort 1), we modelled 3 further cohorts: all 79,000 first-time pregnant women (cohort 2), 33,000 pregnant migrant women (cohort 3) and 16,000 first-time pregnant migrant women (cohort 4). Each cohort was analyzed in various scenarios: i no intervention, i.e., the current practice, ii screen-and-treat, i.e., the most extensive approach involving treatment of all individuals found HCV-positive, and iii screen-and-treat/monitor, i.e., a strategy involving treatment of symptomatic (F1-F4) patients and follow-up of asymptomatic (F0) HCV carriers with subsequent treatment only at progression. RESULTS: For all cohorts, comparison between scenarios (ii) and (i) resulted in ICERs between 9,306 and 10,173 per QALY gained and 5 year budget impacts varying between 6,283,830 and 19,220,405. For all cohorts, comparison between scenarios (iii) and (i) resulted in ICERs between 1,739 and 2,749 per QALY gained and budget impacts varying between 1,468,670 and 5,607,556. For all cohorts, the ICERs (scenario iii versus ii) involved in delayed treatment of asymptomatic (F0) HCV carriers varied between 56,607 and 56,892, well above the willingness-to-pay (WTP) threshold of 20,000 per QALY gained and even above a threshold of 50,000 per QALY gained. CONCLUSION: Universal screening for HCV among all pregnant women in the Netherlands is cost-effective. However, it would be reasonable to consider smaller risk groups in view of the budget impact of the intervention.
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Hepatite C Crônica , Antivirais/uso terapêutico , Análise Custo-Benefício , Feminino , Hepacivirus , Hepatite C Crônica/tratamento farmacológico , Humanos , Transmissão Vertical de Doenças Infecciosas , Programas de Rastreamento , Países Baixos , Gravidez , Gestantes , Anos de Vida Ajustados por Qualidade de VidaRESUMO
WHAT IS KNOWN AND OBJECTIVE: Nephrotoxicity is a frequently occurring side effect of cisplatin, which may be reduced by applying ample hydration. The aim of this study was to determine whether there is a difference in decline in renal function due to cisplatin between a short hydration (SH) and long hydration scheme (LH). METHODS: A retrospective, observational, cohort study was conducted in two hospitals. Patients in one hospital received an SH scheme (SH group), whereas patients in the other hospital received an LH scheme (LH group). Other aspects of treatment and hydration were comparable between both patient groups. Consecutive patients (≥18 years) treated for non-small-cell lung cancer with cisplatin-pemetrexed with ≥1 cisplatin dose were included. Patients were excluded when serum creatinine at baseline was <40 µmol/L. Primary outcome was the difference in estimated glomerular filtration rate (eGFR) between baseline and after the last cisplatin cycle for the SH and LH patients, regardless of the number of administered cisplatin courses. RESULTS: Fifty patients were included in the SH and LH group. There were no significant differences in baseline characteristics between the two groups. None of the patients had renal failure at baseline. After two cisplatin cycles, the median differences between the baseline eGFR and the eGFR after the last cisplatin dose were 1 (-6 to 5) and -9 (-22 to -2) mL/min/1.73 m2 (interquartile range) for the SH and LH group, respectively (P = .000). Less patients completed the four cycles in the LH group (16%) compared to the SH group (64%), mainly because more LH patients were switched to another treatment and due to nephrotoxicity. However, the difference in eGFR remained statistically significant (P = .027). WHAT IS NEW AND CONCLUSION: In this retrospective study, the SH scheme resulted in less decrease in renal function compared with the LH scheme, with a significant and clinically relevant difference. Additionally, more LH patients had to stop this effective treatment prematurely due to nephrotoxicity. Therefore, a short hydration scheme provides adequate and safe hydration, with a lower risk of nephrotoxic side effects and therefore better outcomes for patients and a reduction of healthcare costs.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/efeitos adversos , Nefropatias/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Estudos de Coortes , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Nefropatias/epidemiologia , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de TempoRESUMO
During pregnancy, the pharmacokinetics of an antiepileptic drug is altered because of changes in the clearance capacity and volume of distribution. These changes may have consequences for the frequency of seizures during pregnancy and fetal exposure to antiepileptic drugs. In 2009, a review was published providing guidance for the dosing and therapeutic drug monitoring of antiepileptic drugs during pregnancy. Since that review, new drugs have been licensed and new information about existing drugs has been published. With this review, we aim to provide an updated narrative overview of changes in the pharmacokinetics of antiepileptic drugs in women during pregnancy. In addition, we aim to formulate advice for dose modification and therapeutic drug monitoring of antiepileptic drugs. We searched PubMed and the available literature on the pharmacokinetic changes of antiepileptic drugs and seizure frequency during pregnancy published between January 2007 and September 2018. During pregnancy, an increase in clearance and a decrease in the concentrations of lamotrigine, levetiracetam, oxcarbazepine's active metabolite licarbazepine, topiramate, and zonisamide were observed. Carbamazepine clearance remains unchanged during pregnancy. There is inadequate or no evidence for changes in the clearance or concentrations of clobazam and its active metabolite N-desmethylclobazam, gabapentin, lacosamide, perampanel, and valproate. Postpartum elimination rates of lamotrigine, levetiracetam, and licarbazepine resumed to pre-pregnancy values within the first few weeks after pregnancy. We advise monitoring of antiepileptic drug trough concentrations twice before pregnancy. This is the reference concentration. We also advise to consider dose adjustments guided by therapeutic drug monitoring during pregnancy if the antiepileptic drug concentration decreases 15-25% from the pre-pregnancy reference concentration, in the presence of risk factors for convulsions. If the antiepileptic drug concentration changes more than 25% compared with the reference concentration, dose adjustment is advised. Monitoring of levetiracetam, licarbazepine, lamotrigine, and topiramate is recommended during and after pregnancy. Monitoring of clobazam, N-desmethylclobazam, gabapentin, lacosamide, perampanel, and zonisamide during and after pregnancy should be considered. Because of the risk of teratogenic effects, valproate should be avoided during pregnancy. If that is impossible, monitoring of both total and unbound valproate is recommended. More research is needed on the large number of unclear pregnancy-related effects on the pharmacokinetics of antiepileptic drugs.
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Anticonvulsivantes/farmacocinética , Monitoramento de Medicamentos/métodos , Epilepsia/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Trimestres da Gravidez/sangue , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Monitoramento de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Período Pós-Parto/metabolismo , Gravidez , Complicações na Gravidez/epidemiologia , Trimestres da Gravidez/efeitos dos fármacos , Fatores de Risco , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Teratogênicos/química , Ácido Valproico/efeitos adversos , Ácido Valproico/farmacocinéticaRESUMO
It is important for healthcare professionals and pregnant women to have knowledge of the risks of using medicines during pregnancy and lactation. This not only concerns the influence of the medicinal product on the pregnant woman and the pregnancy, but also its impact on the growth and development of the (unborn) child, neonatal adaptation, possible precautions regarding child-birth, drug excretion in breast milk, and the short-term and long-term consequences for the newborn child. At present, information and advices are often fragmentary, sometimes contradictory, not easily accessible, or even not available at all. It is high time for one independent source to provide unambiguous, scientifically substantiated information and advice, accessible to both healthcare professionals and pregnant women - preferably in a digital format.
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Aleitamento Materno/estatística & dados numéricos , Letramento em Saúde/estatística & dados numéricos , Preparações Farmacêuticas/administração & dosagem , Cuidado Pré-Natal/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Bem-Estar do Lactente , Recém-Nascido , Lactação , Bem-Estar Materno , GravidezRESUMO
It has been estimated by the World Health Organization (WHO) that over 71 million people were infected with the hepatitis C virus (HCV) in 2015. Since then, a number of highly effective direct-acting antiviral (DAA) regimens have been licensed for the treatment of chronic HCV infection: sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir. With these treatment regimens, almost all chronic HCV-infected patients, even including prior DAA failures, can be treated effectively and safely. It is therefore likely that further development of DAAs will be limited. In this descriptive review we provide an overview of the clinical pharmacokinetic characteristics of currently available DAAs by describing their absorption, distribution, metabolism, and excretion. Potential drug-drug interactions with the DAAs are briefly discussed. Furthermore, we summarize what is known about the pharmacodynamics of the DAAs in terms of efficacy and safety. We briefly discuss the relationship between the pharmacokinetics of the DAAs and efficacy or toxicity in special populations, such as hard to cure patients and patients with liver cirrhosis, liver transplantation, renal impairment, hepatitis B virus or HIV co-infection, bleeding disorders, and children. The aim of this overview is to educate/update prescribers and pharmacists so that they are able to safely and effectively treat HCV-infected patients even in the presence of underlying co-infections or co-morbidities.
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Antivirais/farmacocinética , Hepatite C/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , Interações Medicamentosas , Hepatite C/tratamento farmacológico , HumanosRESUMO
Breastfeeding is important for the development of the child. Many antibiotics are considered safe during breastfeeding. The aim of the study was to assess the quality of lactation studies with antibiotics using the FDA and International Lactation Consultant Association quality guidelines for lactation studies. The secondary goal was to determine the exposure of the breastfed infant to antibiotics in relation to bacterial resistance and the developing microbiome. A literature search was performed and the included studies were scored on methodology, parameters concerning maternal exposure to antibiotics, maternal plasma and milk sampling. The infant exposure has been calculated and expressed as a percentage of a normal infant therapeutic dose. Sixty-six studies were included in five antibiotic groups (broad-spectrum penicillin, cephalosporins, macrolides and lincosamides, quinolones and sulphonamides). Cephalosporins were the most studied group of antibiotics (n = 21). Fifteen studies met all the criteria of "mother exposure to antibiotic". Six studies met every criterion related to "plasma sampling". Only one case report met all listed criteria for lactation studies. The correct calculation of infant exposure to antibiotics via the milk:plasma ratio (AUC) varies between 13% for macrolides and 38% for broad-spectrum penicillin. The highest assessed exposure as a percentage of infant therapeutic dose was for metronidazole (11%). The studies meet to a limited extent with the quality standards for lactation research. The breastfed infants are exposed to a subtherapeutic concentration of antibiotics.
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Antibacterianos/efeitos adversos , Aleitamento Materno , Farmacorresistência Bacteriana/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Exposição Materna/efeitos adversos , Feminino , Humanos , Lactente , Leite Humano/químicaRESUMO
BACKGOUND: Patients are at risk for severe postoperative infections after coronary artery bypass graft (CABG) surgery. Clinical laboratory data showed that unbound plasma concentrations of cefuroxime were not always adequate, therefore we developed a new dosing regimen. OBJECTIVE: The aim of this prospective study is to evaluate the new dosing strategy by monitoring patients for unbound cefuroxime plasma concentrations during CABG surgery with cardiopulmonary bypass (CPB). SETTING: A Dutch teaching hospital. METHODS: In this prospective trial, patients scheduled for CABG surgery with CPB were included. A starting dose of 1500 mg cefuroxime was given with anesthesia induction, followed by 750 mg cefuroxime every hour until wound closure. In case of renal failure the dosing regimen was adapted. Serial blood samples were collected before, during and after the CPB process. Pharmacokinetic modelling was performed by using an 'iterative two-stage Bayesian population procedure'. MAIN OUTCOME MEASURE: Unbound plasma concentrations of cefuroxime. RESULTS: 22 patients were included, data could be evaluated of 21 patients. In 24 % of the patients the unbound cefuroxime plasma concentration was below the target range during surgery before CPB started. Patients with a bodyweight above 100 kg or age <60 years were more likely to have unbound plasma concentrations below the target range (P = 0.030 and P = 0.008). During CPB, the half-life of unbound cefuroxime increased by 17 % and the clearance decreased by 11 % compared to before CPB (P = 0.033 and P = 0.014). The mean pharmacokinetic parameters before, during and after CPB were as follows: elimination half-life 72, 84 and 76 min; clearance of unbound cefuroxime (Clu) 14.2, 12.7, 13.8 l/h and volume of distribution (Vu) 0.280, 0.284 and 0.290 l/kg respectively. Variations in unbound fractions before, during and after CPB were below 2 %, implicating the unbound fraction of cefuroxime is not influenced by CPB. CONCLUSION: Our results show that CPB during CABG surgery does not lead to inadequate unbound cefuroxime concentrations. Age, renal function and possibly also weight are more important factors that can result in unbound plasma cefuroxime concentrations below the target value.
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Antibacterianos/sangue , Ponte Cardiopulmonar/métodos , Cefuroxima/sangue , Ponte de Artéria Coronária/métodos , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Antibioticoprofilaxia/métodos , Ponte Cardiopulmonar/efeitos adversos , Cefuroxima/administração & dosagem , Cefuroxima/farmacocinética , Cefuroxima/uso terapêutico , Ponte de Artéria Coronária/efeitos adversos , Esquema de Medicação , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Infecção da Ferida Cirúrgica/prevenção & controleRESUMO
AIM: The aim of this review was to investigate the quality of the current literature on the transfer of anticonvulsants to breast milk to provide an overview of which anticonvulsants are in need of further research. METHODS: We reviewed the quality of the available lactation studies for 19 anticonvulsants against the guidelines of the Food and Drug Administration (FDA) and the International Lactation Consultant Association (ILCA). RESULTS: Except for one study on lamotrigine and one case report on gabapentin, no study on anticonvulsants had both the absolute infant dose (AID) and milk to plasma ratio (M : P) correctly assessed. Only one study on carbamazepine, phenytoin and vigabatrin was found that correctly assessed the AID. The main cause for this low number is the lack of essential details in published studies, since 25 of 62 studies were case reports, letters or abstracts. Other major shortcomings were the lack of information on sampling methods, the number of samples in a particular dose interval as well as the low number of study participants. CONCLUSION: The quality of the current literature on the transfer of anticonvulsants to breast milk is low, except for lamotrigine, which makes it hard to draw conclusions about the safety of the use of anticonvulsants during the lactation period. Therefore, further research is needed.
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Anticonvulsivantes/análise , Recém-Nascido/sangue , Lactação/metabolismo , Leite Humano/química , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/sangue , Europa (Continente) , Feminino , Humanos , Agências Internacionais , Guias de Prática Clínica como Assunto , Estados Unidos , United States Food and Drug AdministrationRESUMO
In the present study we developed and validated a liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay for the determination of flucloxacillin in human plasma and microdialysis samples and cloxacillin in microdialysis samples, using oxacillin as the internal standard for the assay. The samples were separated on a UPLC BEH C18,1.7 µm column (2.1x50mm) and analyzed by a tandem-quadrupole mass spectrometer in multiple reaction monitoring mode using an electronspray ionization interface. For flucloxacillin the method was demonstrated to be accurate and precise in the linearity range of 1-30 mg/L in plasma and 0.05-5.0 mg/L for microdialysate with a regression coefficient (r) of 0.9986 and 0.9989 in plasma and microdialysate respectively. For cloxacillin it was accurate and precise in the range of 0.1-5.0 mg/L for microdialysate with a regression coefficient of 0.9972. The method presents a high sensitivity for flucloxacillin (lower limit of quantification of 1 mg/L for plasma and 0.05 mg/L for microdialysis samples) combined with a low within- and between-day variation (<5.0% for flucloxacillin and cloxacillin in microdialysis samples and <6.5% for plasma samples of flucloxacillin). The validation experiments for the microdialysis probes showed a relative recovery of 85.5% for flucloxacillin at a flow rate of 1.0 µL/min. The results justify the use of this assay for clinical studies for measuring free unbound tissue concentrations of flucloxacillin in patients with a Staphylococcus aureus bacteremia.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cloxacilina/análise , Floxacilina/análise , Microdiálise/métodos , Espectrometria de Massas em Tandem/métodos , Cloxacilina/química , Estabilidade de Medicamentos , Floxacilina/química , Humanos , Análise dos Mínimos Quadrados , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
BACKGROUND: Data about adherence of antidepressants during pregnancy are lacking. However, it is important to gain insight into adherence in this population to reduce perinatal risks for relapse of depression. OBJECTIVE: The objective of this study was to search for an inexpensive and easy method to implement daily for assessing medication adherence during pregnancy. METHODS: An observational study was conducted to measure adherence by comparing pill count, Beliefs about Medicine questionnaire (BMQ) and blood level monitoring against the standard, the Medication Event Monitoring System (MEMS). We used a logistic regression model to determine potential predictors for poor adherence (age, marital class, highest level of education, monthly net income, employment, smoking, alcohol use and type of antidepressant). RESULTS: From January 2010 until January 2012, 41 women were included within the first trimester of pregnancy; data could be evaluated in 29 women. Using MEMS, 86% of the women took in more than 80% of all prescribed doses on time and could be classified as adherent. Pill counts showed good agreement with MEMS. We did not find predictors for poor adherence in our study population. CONCLUSION: Adherence of antidepressants during pregnancy using MEMS is 86%. There was a good agreement between MEMS and pill counts. This method may serve as a good alternative that can be easily implemented into daily practice.
RESUMO
BACKGROUND: Weight-loss products, which are freely available in some other countries and on the Internet, may be contaminated with ingredients not mentioned on the label. CASE DESCRIPTION: We describe a 43-year-old woman who presented to the emergency ward of our hospital after stabbing herself in the stomach with a knife, because of severe psychosis. A few days after admission her symptoms were completely gone and there were no longer signs of psychosis. The most likely explanation for the psychosis was the use of sibutramine-contaminated weight-loss coffee (Brazil Potent Slimming Coffee). CONCLUSION: Brazil Potent Slimming Coffee and possibly also other weight-loss products may be contaminated with sibutramine and as a result cause severe adverse reactions. It is always important to consider intoxication due to the use of herbal supplements and other OTC products in the differential diagnosis.
Assuntos
Depressores do Apetite/efeitos adversos , Café/química , Ciclobutanos/efeitos adversos , Transtornos Psicóticos/etiologia , Adulto , Brasil , Café/efeitos adversos , Ciclobutanos/administração & dosagem , Feminino , Contaminação de Alimentos , Humanos , Internet , Redução de PesoRESUMO
OBJECTIVES: Patients with coronary artery bypass graft (CABG) surgery are at risk for severe postoperative infections. Prophylactic cefuroxime may help to reduce this risk, however sufficient concentrations, i.e. above the breakpoint (32 mg/L), are mandatory. The aim of this study is to evaluate the blood concentrations of cefuroxime during and after CABG surgery with cardiopulmonary bypass (CPB) and hypothermia, to determine the concentration of cefuroxime in sternum fluid and to evaluate possible factors of influence. METHODS: Seventeen patients were enrolled in this study, given 1.5 g cefuroxime at anaesthesia induction and an additional 1.5 g at start CPB. Blood samples were collected at skin incision, start CPB, every 30 min on CPB, end CPB, at wound closure and 1 h after surgery. Cefuroxime concentrations were determined by high performance liquid chromatography. RESULTS: In 47 % of the patients the cefuroxime concentration was below the breakpoint at some point during the operation and in 59 % of the patients 1 h after surgery. A statistically significant inverse correlation between estimated glomerular filtration rate and plasma cefuroxime concentrations was found (P = 0.034). Cefuroxime levels in the sternum are not significantly different from blood levels from the radial artery catheter, taken at approximately the same time (P = 0.30). CONCLUSIONS: The current antibiotic regimen used did not maintain cefuroxime concentrations above the breakpoint throughout the operation, suggesting insufficient antibiotic prophylaxis. Further research to other antibiotic regimes is therefore necessary.