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Introduction Breast cancer is the most common cancer and the leading cause of cancer death in women. Recent research indicates that human endogenous retroviruses (HERVs) may be linked to carcinogenesis, but the data remain controversial. Methods HERVs´ expression was evaluated to show the differences between breast cancer and control samples, and their associations with clinicopathological parameters. Gene expression of 12 HERVs, i.e. ERVE-4, ERVW-1, ERVFRD-1, ERVV-1, ERV3-1, ERVH48-1, ERVMER34-1, ERVK7, ERVK13-1, ERVK11-1, ERVK3-1 and HCP5 was analyzed by qPCR and/or TCGA datasets for breast cancer. Results ERV3-1, ERVFRD-1, ERVH48-1 and ERVW-1 provided data to support their tumor suppressor roles in breast cancer. ERV3-1 evinced the best performing diagnostic data based on qPCR, i.e. AUC: 0.819 (p <0.0001), sensitivity of 72.41%, and specificity of 89.66%. Lower levels of ERV3-1 were noted in advanced stage and higher grades, and significant negative association was found in relation to Ki-67 levels. Oncogenic roles may be inferred for ERVK13-1, ERVV-1, and ERVMER34-1. Data for ERVK-7, ERVE-4, ERVK11-1 and HCP5 remain inconclusive. Conclusion Differential HERVs expression may be applicable to evaluate novel biomarkers for breast cancer. However, more research is needed to reveal their real clinical impact, the biological roles and regulatory mechanisms in breast carcinogenesis.
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Introduction Breast cancer comprises the leading cause of cancer-related death in women. MicroRNAs (miRNAs) have emerged as important factors with concern to carcinogenesis and have potential for use as biomarkers. Methods This study provides a comprehensive evaluation of the microRNA expression in invasive breast carcinoma of no special type tissues compared with benign tissues via large-scale screening and the candidate-specific validation of 15 miRNAs and U6 snRNA applying qPCR and the examination of clinicopathological data. Results Of the six downregulated miRNAs, let-7c was identified as the most promising miRNA biomarker and its lower expression was linked with Ki-67 positivity, luminal B versus luminal A samples, multifocality, lymph-node metastasis and inferior PFS. Of the 9 upregulated sncRNAs, the data on U6 snRNA, miR-493 and miR-454 highlighted their potential oncogenic functions. An elevated U6 snRNA expression was associated with the tumor grade, Ki-67 positivity, luminal B versus A samples, lymph-node metastasis and worsened PFS (and OS) outcomes. An elevated miR-454 expression was detected in higher grades, Ki-67 positive and luminal B versus A samples. Higher miR-493 levels were noted for the tumor stage (and grade) and worse patient outcomes (PFS, OS). The data also suggested that miR-451a and miR-328 may have tumor suppressor roles, and miR-182 and miR-200c pro-oncogenic functions, while the remaining sncRNAs did not evince any significant associations. Conclusion We showed particular microRNAs and U6 snRNA as differentially expressed between tumors and benign tissues and associated with clinicopathological parameters thus potentially corresponding with important roles in breast carcinogenesis. Their importance should be further investigated and evaluated in follow-up studies to reveal their potential in clinical practice.
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AIMS: Abiraterone treatment requires regular drug intake under fasting conditions due to pronounced food effect, which may impact patient adherence. The aim of this prospective study was to evaluate adherence to abiraterone treatment in patients with prostate cancer. To achieve this aim, an abiraterone population pharmacokinetic model was developed and patients' adherence has been estimated by comparison of measured levels of abiraterone with population model-based simulations. METHODS: A total of 1469 abiraterone plasma levels from 83 healthy volunteers collected in a bioequivalence study were analysed using a nonlinear mixed-effects model. Monte Carlo simulation was used to describe the theoretical distribution of abiraterone pharmacokinetic profiles at a dose of 1000 mg once daily. Adherence of 36 prostate cancer patients treated with abiraterone was then evaluated by comparing the real abiraterone concentration measured in each patient during follow-up visit with the theoretical distribution of profiles based on simulations. Patients whose abiraterone levels were Ë5th or Ë95th percentile of the distribution of simulated profiles were considered to be non-adherent. RESULTS: Based on this evaluation, 13 patients (36%) have been classified as non-adherent. We observed significant association (P = .0361) between richness of the breakfast and rate of non-adherence. Adherent patients reported significantly better overall condition in self-assessments (P = .0384). A trend towards a higher occurrence of adverse effects in non-adherent patients was observed. CONCLUSIONS: We developed an abiraterone population pharmacokinetic model and proposed an advanced approach to medical adherence evaluation. Due to the need for administration under fasting conditions, abiraterone therapy is associated with a relatively high rate of non-adherence.
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Visual loss in acute optic neuritis is typically attributed to axonal conduction block due to inflammatory demyelination, but the mechanisms remain unclear. Recent research has highlighted tissue hypoxia as an important cause of neurological deficits and tissue damage in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) and, here, we examine whether the optic nerves are hypoxic in experimental optic neuritis induced in Dark Agouti rats. At both the first and second peaks of disease expression, inflamed optic nerves labelled significantly for tissue hypoxia (namely, positive for hypoxia inducible factor-1α (HIF1α) and intravenously administered pimonidazole). Acutely inflamed nerves were also labelled significantly for innate markers of oxidative and nitrative stress and damage, including superoxide, nitric oxide and 3-nitrotyrosine. The density and diameter of capillaries were also increased. We conclude that in acute optic neuritis, the optic nerves are hypoxic and come under oxidative and nitrative stress and damage. Tissue hypoxia can cause mitochondrial failure and thus explains visual loss due to axonal conduction block. Tissue hypoxia can also induce a damaging oxidative and nitrative environment. The findings indicate that treatment to prevent tissue hypoxia in acute optic neuritis may help to restore vision and protect from damaging reactive oxygen and nitrogen species.
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Encefalomielitis Autoinmune Experimental , Neuritis Óptica , Ratas , Animales , Ratones , Neuritis Óptica/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Nervio Óptico/metabolismo , Hipoxia/metabolismo , Factores Inmunológicos/metabolismo , Ratones Endogámicos C57BLRESUMEN
Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic drugs used to treat schizophrenia, bipolar disorder, and related psychiatric conditions. The plasma concentration of antipsychotic drugs is a valid measure of the drug at its primary target structure in the brain, and therefore determines the efficacy and safety of these drugs. However, despite the well-known high variability in pharmacokinetics of these substances, psychiatric medication is usually administered in uniform dosage schedules. Therapeutic drug monitoring (TDM), as the specific method that can help personalised medicine in dose adjustment according to the characteristics of the individual patient, minimizing the risk of toxicity, monitoring adherence, and increasing cost-effectiveness in the treatment, thus seems to be an elegant tool to solve this problem. Non-response to therapeutic doses, uncertain adherence to medication, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM of SGAs. This review aims to summarize an overview of the current knowledge and evidence of the possibilities to tailor the dosage of selected SGAs using TDM, including the necessary pharmacokinetic parameters for personalised pharmacotherapy.
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Antipsicóticos , Monitoreo de Drogas , Humanos , Monitoreo de Drogas/métodos , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapéutico , Esquizofrenia/tratamiento farmacológicoRESUMEN
Mycophenolate mofetil (MMF) is an immunosuppressant drug approved for prophylaxis of transplant rejection in patients undergoing solid organ transplantation and is further employed in management of various autoimmune disorders. MMF exhibits notable pharmacokinetic inter- and intraindividual variability necessitating tailored therapeutic approaches to achieve optimal therapeutic outcomes while mitigating risks of adverse effects. The objective of this review was to summarize factors that influence the pharmacokinetics of MMF and its active metabolite mycophenolic acid in order to deduce recommendations for personalized treatment strategies. Presumed predictors were analysed in relation to each of the four pharmacokinetic phases, providing tools and targets for MMF dosing optimization amenable to clinical implementation.
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Inmunosupresores , Ácido Micofenólico , Trasplante de Órganos , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/administración & dosificación , Humanos , Inmunosupresores/farmacocinética , Inmunosupresores/administración & dosificación , Rechazo de Injerto/prevención & control , Medicina de PrecisiónRESUMEN
AIM: The objective of this study was to evaluate off-label high-dose ceftazidime population pharmacokinetics in cancer patients with suspected or proven extensively drug-resistant (XDR) Pseudomonas aeruginosa infections and then to compare the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target after standard and off-label high-dose regimens using population model-based simulations. A further aim was to clinically observe the occurrence of adverse effects during the off-label high-dose ceftazidime treatment. METHODS: In patients treated with off-label high-dose ceftazidime (3 g every 6 h), blood samples were collected and ceftazidime serum levels measured using LC-MS/MS. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were then used to compare standard and high-dose regimens for PK/PD target attainment. RESULTS: A total of 14 cancer patients with serious infection suspected of XDR P. aeruginosa aetiology were eligible for PK analysis. XDR P. aeruginosa was confirmed in 10 patients as the causative pathogen. Population ceftazidime volume of distribution was 13.23 L, while clearance started at the baseline of 1.48 L/h and increased by 0.0076 L/h with each 1 mL/min/1.73 m2 of eGFR. High-dose regimen showed significantly higher probability of target attainment (i.e., 86% vs. 56% at MIC of 32 mg/L). This was translated into a very low mortality rate of 20%. Only one case of reversible neurological impairment was observed. CONCLUSION: We proved the superiority of the ceftazidime off-label high-dose regimen in PK/PD target attainment with very low occurrence of adverse effects. The off-label high-dose regimen should be used to optimize treatment of XDR P. aeruginosa infections.
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Neoplasias , Infecciones por Pseudomonas , Humanos , Ceftazidima/efectos adversos , Ceftazidima/farmacocinética , Infecciones por Pseudomonas/tratamiento farmacológico , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Cromatografía Liquida , Uso Fuera de lo Indicado , Pseudomonas aeruginosa , Espectrometría de Masas en Tándem , Método de Montecarlo , Pruebas de Sensibilidad Microbiana , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológicoRESUMEN
Collagen-induced arthritis is the most com-mon in vivo model of rheumatoid arthritis used for investigation of new potential therapies in preclinical research. Rheumatoid arthritis is a systemic inflammatory and autoimmune disease affecting joints, accompanied by significant extra-articular symptoms. The pathogenesis of rheumatoid arthritis and collagen-induced arthritis involves a so far properly unexplored network of immune cells, cytokines, antibodies and other factors. These agents trigger the autoimmune response leading to polyarthritis with cell infiltration, bone and cartilage degeneration and synovial cell proliferation. Our review covers the knowledge about cytokines present in the rat collagen-induced arthritis model and the factors affecting them. In addition, we provide a comparison with rheumatoid arthritis and a description of their important effects on the development of both diseases. We discuss the crucial roles of various immune cells (subtypes of T and B lymphocytes, dendritic cells, monocytes, macrophages), fibroblast-like synoviocy-tes, and their related cytokines (TNF-α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, IL-23, GM-CSF, TGF-ß). Finally, we also focus on key antibodies (rheu-matoid factor, anti-citrullinated protein antibodies, anti-collagen II antibodies) and tissue-degrading enzymes (matrix metalloproteinases).
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Artritis Experimental , Artritis Reumatoide , Ratas , Animales , Citocinas/metabolismo , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/terapia , Anticuerpos , Factor de Necrosis Tumoral alfa , Colágeno/efectos adversosRESUMEN
Cannabidiol (CBD) is the second most abundant component of the plant Cannabis sativa. Currently, CBD is approved for Lennox-Gastaut and Dravet syndrome and newly for tuberous sclerosis complex. However, based on the available data, CBD migth have a broad spectrum of potential therapeutic uses. Therefore, the aim of this review was to summarize the evidence on the effects of CBD on pain and inflammation of various causes. PubMed and Web of Science databases were searched until January 2023. The medical keyword term "cannabidiol" was combined with "pain", "arthritis", and "inflammation". Based on the initial search for these terms, 9, 5, and 5 relevant publications have been selected. Based on the available data, it is not possible to draw a clear conclusion about the effect of CBD to releave pain, because each study used a different route of administration or treatment regimen. The studies also differed in etiopathogenesis of pain (chronic, neuropathic, and possibly inflammatory pain), and in general included only small number of subjects. In case of anti-inflammatory qualities of CBD, its effect on the intestinal system is negligible. On the other hand, positive treatment results were observed in all publications dealing with the effect of CBD on arthritis.
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Artritis , Cannabidiol , Epilepsias Mioclónicas , Humanos , Cannabidiol/uso terapéutico , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Dolor/etiología , Epilepsias Mioclónicas/tratamiento farmacológicoRESUMEN
Targeted therapy with protein kinase inhibitors (PKIs) represents one of the important treatment options for non-small cell lung cancer (NSCLC). It has contributed to improve patients' survival and quality of life significantly. These anticancer drugs are administrated orally in flat-fixed doses despite the well-known large interpatient pharmacokinetic variability and the possible need for dose individualization. To optimize and individualize dosing of PKIs, and thereby increasing the effectiveness and safety of the treatment, therapeutic drug monitoring (TDM) is the most frequently mentioned method. Unlike other areas of medicine, TDM has been rather exceptional in oncological practise since there is a little evidence or no data for concentration-effect relationships of PKIs. Therefore, the aim of this review is to summarize the pharmacokinetic characteristics of PKIs and provide the evidence supporting the use of TDM for personalised treatment of patients with NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Monitoreo de Drogas , Calidad de Vida , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
Mucormycosis is a rare invasive fungal disease diagnosed in immunocompromised patients, including those with diabetes or iron overload, and in patients treated for hematological malignancies or after transplantation. Isavuconazole is a triazole antifungal effective against Mucorales with good tolerability, but with potential for relatively high interindividual variability in pharmacokinetics. This report demonstrates the case of a lung transplant recipient treated with isavuconasole that exhibits a very long elimination half-life of 159 hours, and discusses the practical implications of this finding for dosage adjustment and need for therapeutic drug monitoring.
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Aspergilosis , Mucormicosis , Humanos , Receptores de Trasplantes , Monitoreo de Drogas , Aspergilosis/tratamiento farmacológico , Triazoles/uso terapéutico , Triazoles/farmacocinética , Mucormicosis/diagnóstico , Mucormicosis/tratamiento farmacológico , PulmónRESUMEN
OBJECTIVES: Ciprofloxacin induces rare neuro-psychiatric adverse drug reactions (ADRs) that are, as yet, not possible to predict due to unknown predisposition factors. BACKGROUND: The aim of the analysis was to assess the frequency of neuro-psychiatric ADRs and to identify potential risk factors that predisposed patients to ciprofloxacin neurotoxicity. METHODS: This observational retrospective study involved the evaluation of the medical records of patients in the Nephrology department and 3rd Internal Clinic of the General University Hospital in Prague. RESULTS: The overall incidence of neurological ADRs was 3.6 %. No neurological ADRs developed in patients aged less than 70 years. The covariates that were significantly more prevalent in the patients who developed neuropsychiatric ADRs were as follows: higher age, a history of neuropsychiatric disorders and the use of anticonvulsants. The administration of drugs from other ATC groups, gender, weight, body mass index, body surface area, renal functions, level of C-reactive protein at the beginning of treatment and the total daily dose/kg did not differ significantly between the two groups. CONCLUSION: Ciprofloxacin neuropsychiatric ADRs are more frequent in older patients with a history of neurologic or psychiatric disorders. No other tested covariates were proven to predispose patients to neuropsychiatric ADRs during treatment with ciprofloxacin (Tab. 2, Ref. 20).
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Ciprofloxacina , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Anciano , Ciprofloxacina/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Susceptibilidad a EnfermedadesRESUMEN
BACKGROUND: Breast cancer is a leading cause of cancer-related death in women. Most cases are invasive ductal carcinomas of no special type (NST breast carcinomas). METHODS AND RESULTS: In this prospective, multicentric biomarker discovery study, we analyzed the expression of small non-coding RNAs (mainly microRNAs) in plasma by qPCR and evaluated their association with NST breast cancer. Large-scale expression profiling and subsequent validations have been performed in patient and control groups and compared with clinicopathological data. Small nuclear U6 snRNA, miR-548b-5p and miR-451a have been identified as candidate biomarkers. U6 snRNA was remarkably overexpressed in all the validations, miR-548b-5p levels were generally elevated and miR-451a expression was mostly downregulated in breast cancer groups. Combined U6 snRNA/miR-548b-5p signature demonstrated the best diagnostic performance based on the ROC curve analysis with AUC of 0.813, sensitivity 73.1% and specificity 82.6%. There was a trend towards increased expression of both miR-548b-5p and U6 snRNA in more advanced stages. Further, increased miR-548b-5p levels have been partially associated with higher grades, multifocality, Ki-67 positivity, and luminal B rather than luminal A samples. On the other hand, an association has been observed between high miR-451a expression and progesterone receptor positivity, lower grade, unifocal samples, Ki-67-negativity, luminal A rather than luminal B samples as well as improved progression-free survival and overall survival. CONCLUSIONS: Our results indicated that U6 snRNA and miR-548b-5p may have pro-oncogenic functions, while miR-451a may act as tumor suppressor in breast cancer.
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Neoplasias de la Mama , MicroARNs , Biomarcadores , Biomarcadores de Tumor/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , MicroARNs/metabolismo , Pronóstico , Estudios Prospectivos , ARN Nuclear PequeñoRESUMEN
PURPOSE: Data on the anti-Xa efficacy of fondaparinux in dialysis-dependent chronic kidney disease (DD-CKD) patients are scarce. This study characterizes the pharmacokinetics (PK) and pharmacodynamics (PD) of fondaparinux in DD-CKD patients undergoing renal replacement therapy (RRT), to assess dosing strategies. METHODS: A retrospective, observational study was conducted using data on anti-Xa activity (112 samples) from 12 (3 male and 9 female) DD-CKD patients (median (IQR) age 71 years (63-88), weight 73 kg (59-98.5)). Eleven patients underwent high-flux or low-flux hemodialysis (HD) and one patient underwent peritoneal dialysis. Three patients were also treated with therapeutic plasma exchange (TPE). A non-linear mixed effects analysis was performed using NONMEM 7.3.0. RESULTS: The lab-specific slope of the relationship between fondaparinux concentration and anti-Xa levels was 1.18 IU/µg. In a one-compartment model, clearance (CL) and volume of distribution (Vd) were 0.05289 L/h and 5.55 L, respectively. High-flux HD was found to increase the CL of fondaparinux 2.26 times. TPE also considerably increased CL, but the fold-change could not be accurately estimated. Low-flux HD and peritoneal dialysis did not impact PK parameters. CONCLUSIONS: Model-based simulations showed that standard dosing (2.5 mg three times weekly before HD) results in a median anti-Xa activity of 0.55 IU/mL and 0.98 IU/mL, pre- and post-low-flux HD, respectively. In patients undergoing high-flux HD, these values are approximately 27% lower. Additional caution is warranted with TPE, as this treatment can reduce anti-Xa activity even further.
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Inhibidores del Factor Xa/farmacocinética , Fondaparinux/farmacocinética , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/terapia , Terapia de Reemplazo Renal , Factores de Edad , Anciano , Anciano de 80 o más Años , Peso Corporal , Inhibidores del Factor Xa/farmacología , Femenino , Fondaparinux/farmacología , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: The dosing of aminoglycosides (AGs) in patients with kidney disease is challenging due to their markedly prolonged half-life, which renders pulse dosing schedules unsuitable. We performed a review of the literature that describes the pharmacokinetics of, and dosing recommendations for, AG for patients with abnormal renal functions and various renal replacement therapy modalities, focusing on patients treated with intermittent hemodialysis (iHD). SUMMARY: During one iHD session, dialysis removes a remarkable amount of the drug regardless of the dialyzer type. In patients with severely reduced kidney functions, the distribution phase is prolonged, which needs to be taken into account when drawing samples shortly after drug administration or following an iHD session. KEY MESSAGES: The doses recommended for the pulse dosing of patients without kidney disease leads to unacceptably high overall systemic exposure for patients with severely reduced kidney functions even with dosing intervals extended up to 48 h. Therefore, lower doses accompanied by extended dosing intervals must be applied for this patient group. The clinical evidence and current recommendations support the dosing of AG following, rather than before, HD sessions. In patients with end-stage kidney disease, the samples for TDM of AGs should not be drawn earlier than 2 h after end of the infusion and 4 h after the end of iHD session to allow full (re)distribution of the drug.
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Fallo Renal Crónico , Insuficiencia Renal Crónica , Insuficiencia Renal , Aminoglicósidos/farmacocinética , Aminoglicósidos/uso terapéutico , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Humanos , Fallo Renal Crónico/complicaciones , Diálisis Renal , Insuficiencia Renal/complicaciones , Insuficiencia Renal Crónica/complicaciones , Terapia de Reemplazo RenalRESUMEN
WHAT IS KNOWN AND OBJECTIVES: mTOR inhibitors possess narrow therapeutic range and substantial pharmacokinetic variability and the consequences from suboptimal dosing are serious. The aim of this review is to summarize the current knowledge about the factors influencing mTOR inhibitors pharmacokinetics and the possibility of using these relationships in order to improve its therapy individualization in solid organ transplanted patients. METHODS: Literature search from Pubmed and Web of Science databases were performed using Boolean search operators in order to identify relevant studies. RESULTS AND DISCUSSION: A total of 701 reports were identified from the initial literature search. Out of which 40 studies dealt with relationships between various factors and pharmacokinetics of mTOR inhibitors and with relevance of these associations for dosage optimization. WHAT IS NEW AND CONCLUSION: The overview of the current covariates for pharmacokinetic variability of mTOR inhibitors has been provided on the level of absorption, distribution and elimination, and consequences of these relationships for dosing optimization has been summarized.
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Trasplante de Órganos , Sirolimus , Humanos , Inmunosupresores , Inhibidores mTOR , Sirolimus/farmacocinética , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TORRESUMEN
Administration of drugs by inhalation is mainly used to treat lung diseases and is being investigated as a possible route for systemic drug delivery. It offers several benefits, but it is also fraught with many difficulties. The lung is a complex organ with complicated physiology and specific pharmacokinetic processes. Therefore, the exposure and subsequently efficacy of a drug after inhalation is affected by a number of factors. In this review, we summarize the main variables that may affect drug fate after inhalation delivery, such as physicochemical properties of the drug, pulmonary clearance and metabolism, pathophysiological factors and inhalation device. Factors that have impact on pharmacokinetic processes need to be considered during development as their correct setting can lead to new effective inhaled drugs.
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Sistemas de Liberación de Medicamentos , Pulmón , Administración por Inhalación , Humanos , Pulmón/metabolismo , Preparaciones Farmacéuticas/metabolismoRESUMEN
PURPOSE: Statin therapy should be considered in children with familial hypercholesterolemia and sustained high LDL-C levels. There are no data on rosuvastatin exposure in patients <6 years and efficacy/safety can only be derived from case reports. Our aim was to examine developmental changes in pharmacokinetics of rosuvastatin in rats in vivo as a basis for clinical development of formulations for patients < 6 years. METHODS: Rosuvastatin pharmacokinetics was examined in rats aged 1, 4, 7, 10, 14, 21, 28, 35 and 42 days (from birth to sexual maturity). After intraperitoneal dose of 5 mg/kg, blood samples to determine serum rosuvastatin levels were taken at 0.5, 3 and 5 hours. Pharmacokinetic parameters (Vd, CL, AUClast, AUC0-∞) were calculated using pharmacokinecic simulations. RESULTS: Both rosuvastatin CL and Vd started to increase systematically between 2 - 3 weeks of age, which was reflected by decreased total drug exposure. The AUC was up to 13 times higher in the age groups ≤14 days compared with the value at 42 days. CONCLUSIONS: Based on interspecies scaling, a dose reduction could be a feasible way, how to develop appropriate dosing schedule and formulations for children aged 2 - 6 years. However, confirmation in clinical development studies will be needed.
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Rosuvastatina Cálcica/farmacocinética , Animales , Animales Recién Nacidos , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Tasa de Depuración Metabólica , Ratas , Maduración SexualRESUMEN
BACKGROUND: Although biologic agents (BAs) are very effective, solid data proving they are safer than other therapies in psoriasis are still lacking. METHODS: A total of 289 psoriatic patients were followed for 30 months; of which number 118 were treated with topical agents alone, 112 received BAs, and the remaining 59 patients were on non-biologic systemic agents (NBSAs). The rates of adverse events in these groups were recorded and statistically analysed. RESULTS: Patients treated with BAs had higher rates of adverse events (P = .017), including overall infections (P = .003), respiratory infections (P < .001), renal, urinary (P < .001), musculoskeletal, connective tissue (P < .001, and P = .021) and oral cavity-related (P = .046) disorders. Except for the incidence of infections, all the above adverse events occurred more often in our study than in clinical trials. The occurrence of serious adverse events was P = .066, with the incidence of serious infections being P = .164. Unlike patients on topical therapy and NBSAs, patients treated with BAs were forced to discontinue their therapies (P = .001). The Psoriasis Area Severity Index (PASI) and body surface area (BSA) scores were the lowest among patients on BAs. CONCLUSION: While BAs were the most effective therapies, they were associated with higher rates of treatment discontinuation and adverse events in comparison with other forms of therapy.
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Fármacos Dermatológicos , Psoriasis , Factores Biológicos , Fármacos Dermatológicos/efectos adversos , Humanos , Estudios Prospectivos , Psoriasis/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
INTRODUCTION: Sufentanil is a potent synthetic opioid used for analgesia in neonates; however, data concerning drug disposition of sufentanil and dosage regimen are sparse in this population. Therefore, the aim of the study was to explore sufentanil disposition and to propose optimal loading and maintenance doses of sufentanil in ventilated full-term neonates. METHODS: Individual sufentanil pharmacokinetic parameters were calculated based on therapeutic drug monitoring data using a 2-compartmental model. Linear regression models were used to explore the covariates. RESULTS: The median (IQR) central volume of distribution (Vdc) and clearance (CL) for sufentanil were 4.7 (4.1-5.4) L/kg and 0.651 (0.433-0.751) L/h/kg, respectively. Linear regression models showed relationship between Vdc (L) and GA (r2 = 0.3436; p = 0.0452) as well as BW (r2 = 0.4019; p = 0.0268). Median optimal sufentanil LD and MD were 2.13 (95% CI: 1.78-2.48) µg/kg and 0.29 (95% CI: 0.22-0.37) µg/kg/h, respectively. Median daily COMFORT-B (IQR) scores ranged from 6 to 23 while no significant relationship between pharmacokinetic parameters and COMFORT-B scores was found. DISCUSSION/CONCLUSION: Body weight and gestational age were found as weak covariates for sufentanil distribution, and the dosage regimen was developed for a prospective trial.