ABSTRACT
Background: Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved in Europe for the treatment of platinum-sensitive patients with newly diagnosed or recurrent platinum-sensitive ovarian cancer with a confirmed BRCA mutation or homologous recombination deficiency (HRD). Epidemiological studies have shown an incompatible association between ovarian cancer and obesity, but there have also been scientific reports indicating that obesity, especially severe obesity, increases the risk of ovarian cancer. Olaparib has a wide range of side effects, especially anaemia and neutropenia, which may lead to dose reduction or therapy discontinuation. Therefore, therapeutic drug monitoring (TDM) is recommended. The aim of the study was a retrospective analysis of threshold value of the trough concentration of olaparib (Ctrough) and haematological adverse reactions after olaparib treatment (300 mg/12 h) in excess-weight and normal body mass index (BMI) patients with ovarian cancer. Materials and methods: The pilot study was conducted on 38 ovarian cancer patients who were divided into two groups: I - normal BMI patients (BMI = 18.5-24.9 kg/m2; n = 14), II - excess-weight patients, i.e. overweight and obese patients (BMI ≥ 25 kg/m2; n = 24). The severity of neutropenia and anaemia was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The values of the mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), and red blood cell distribution width (RDW) parameters were also taken into account. HPLC-UV method (λ = 254 nm) was applied to measure olaparib plasma concentrations. Results: There were no statistically significant differences in olaparib Ctrough between the groups - 1602.86 vs. 1567.40 ng/mL (p = 0.9156). However, the overweight and obese patients had slightly higher dose/kg-adjusted olaparib Ctrough - 204.17 vs. 159.32 ng/mL/mg/kg. The incidence of grade 1 anaemia in the groups was as follows: I - 42.86%, II - 41.67%. Grade 2 and 3 anaemia was observed only in group II - 4.17% and 8.33%, respectively. The incidence of neutropenia in the groups of patients was as follows: grade 1: group I - 21.43%, group II - 20.83%; grade 2: group I - 7.14%, group II - 4.17%. Conclusions: The incidence of haematological adverse reactions to olaparib, such as neutropenia and grade 1 anaemia in the group of overweight and obese patients was the same as in the normal BMI group. The overweight and obese patients were characterised by higher severity of haematological adverse reactions to olaparib and slightly higher dose/kg-adjusted olaparib Ctrough. After one month of treatment with olaparib the overweight and obese patients had significantly lower red blood cells (RBC) and haemoglobin (Hgb) levels than the patients with normal BMI, which may indicate that anaemia develops faster in this group of patients.
ABSTRACT
Background Lapatinib is a small-molecule tyrosine kinase inhibitor of human epidermal receptor 2 (HER2) and EGFR that has currently been approved for the treatment of HER2-positive advanced and metastatic breast cancer (BC). The ATP-binding cassette (ABC) family of transporters includes P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2), which substantially restrict the penetration of drugs, including chemotherapeutics, through the blood-brain barrier and blood-cerebrospinal fluid barrier. The aim of this study was to investigate the effects of elacridar, an ABCB1 and ABCG2 inhibitor, on the brain and cerebrospinal fluid uptake of lapatinib. Methods Rats were divided into two groups: one group received 5 mg/kg elacridar and 100 mg/kg lapatinib (an experimental group), and the other group received 100 mg/kg lapatinib (a control group). Lapatinib concentrations in the blood plasma (BP), cerebrospinal fluid (CSF) and brain tissue (BT) were measured by liquid chromatography coupled with tandem mass spectrometry. Results Elacridar significantly increased lapatinib penetration into the CSF and BT (Cmax increase of 136.4% and 54.7% and AUC0-∞ increase of 53.7% and 86.5%, respectively). The Cmax of lapatinib in BP was similar in both experimental groups (3057.5 vs. 3257.5 ng/mL, respectively). Conclusion This study showed that elacridar influenced the pharmacokinetics of lapatinib. The inhibition of ABCB1 and ABCG2 transporters by elacridar substantially enhanced the penetration of lapatinib into the CSF and BT. The blocking of protein transporters could become indispensable in the treatment of patients with breast cancer and brain metastases.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Acridines/pharmacology , Brain/metabolism , Cerebrospinal Fluid/metabolism , Lapatinib/pharmacokinetics , Tetrahydroisoquinolines/pharmacology , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Animals , Biological Transport/physiology , Blood-Brain Barrier/metabolism , Male , Protein Transport/physiology , Rats , Rats, WistarABSTRACT
Cardiac output (CO) is expected to affect elimination and distribution of highly extracted and perfusion rate-limited drugs. This work was undertaken to quantify the effect of CO measured by the pulse pressure method on pharmacokinetics and pharmacodynamics of propofol and fentanyl administrated during total intravenous anesthesia (TIVA). The data were obtained from 22 ASA III patients undergoing abdominal aortic surgery. Propofol was administered via target-controlled infusion system (Diprifusor) and fentanyl was administered at a dose of 2-3 µg/kg each time analgesia appeared to be inadequate. Hemodynamic measurements as well as bispectral index were monitored and recorded throughout the surgery. Data analysis was performed by using a non-linear mixed-effect population modeling (NONMEM 7.4 software). Three compartment models that incorporated blood flows as parameters were used to describe propofol and fentanyl pharmacokinetics. The delay of the anesthetic effect, with respect to plasma concentrations, was described using a biophase (effect) compartment. The bispectral index was linked to the propofol and fentanyl effect site concentrations through a synergistic Emax model. An empirical linear model was used to describe CO changes observed during the surgery. Cardiac output was identified as an important predictor of propofol and fentanyl pharmacokinetics. Consequently, it affected the depth of anesthesia and the recovery time after propofol-fentanyl TIVA infusion cessation. The model predicted (not observed) CO values correlated best with measured responses. Patients' age was identified as a covariate affecting the rate of CO changes during the anesthesia leading to age-related difference in individual patient's responses to both drugs.
Subject(s)
Anesthesia, Intravenous/methods , Anesthetics, Intravenous/pharmacokinetics , Cardiac Output , Models, Biological , Vascular Surgical Procedures/adverse effects , Age Factors , Aged , Aged, 80 and over , Anesthetics, Intravenous/administration & dosage , Aorta, Abdominal/surgery , Biological Variation, Population , Blood Pressure , Drug Synergism , Female , Fentanyl/administration & dosage , Fentanyl/pharmacokinetics , Humans , Infusions, Intravenous , Male , Middle Aged , Monitoring, Intraoperative , Propofol/administration & dosage , Propofol/pharmacokineticsABSTRACT
The purpose of this work was i) to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model of dexmedetomidine (DEX) in New Zealand White rabbits, ii) to investigate the influence of the age and weight of the animals on the model parameters, and iii) to assess the linearity of DEX PKs in the examined dose range. This was a prospective, crossover study, using a total of 18 New Zealand White rabbits. DEX was administered as a single intravenous bolus injection in the doses from 25 to 300 µg kg-1 . Each New Zealand White rabbit was given the same dose of drug in its three developmental stages. To determine the DEX PK, seven blood samples were taken from each animal. The pedal withdrawal reflex was the PD response used to assess the degree of sedation. Nonlinear mixed effects modelling was used for the population PK/PD analysis. The typical value of elimination clearance was 0.061 L min-1 and was 35% higher in younger New Zealand White rabbits compared with older animals. The PK of DEX was linear in the examined concentration range. Age-related changes in sensitivity to DEX were not detected. The results suggest that due to the pharmacokinetics, younger animals will have lower DEX concentrations and a shorter duration of sedation than older animals given the same doses of DEX per kg of body weight.
Subject(s)
Dexmedetomidine/administration & dosage , Hypnotics and Sedatives/administration & dosage , Models, Biological , Age Factors , Animals , Body Weight , Cross-Over Studies , Dexmedetomidine/pharmacokinetics , Dexmedetomidine/pharmacology , Dose-Response Relationship, Drug , Hypnotics and Sedatives/pharmacokinetics , Hypnotics and Sedatives/pharmacology , Injections, Intravenous , Nonlinear Dynamics , Prospective Studies , RabbitsABSTRACT
Lapatinib is a tyrosine kinase inhibitor used for the treatment of breast cancer. Paracetamol is an analgesic commonly applied to patients with mild or moderate pain and fever. Cancer patients are polymedicated, which involves high risk of drug interactions during therapy. The aim of the study was to assess the interaction between lapatinib and paracetamol in rats. The rats were divided into three groups of eight animals in each. One group received lapatinib + paracetamol (IL + PA), another group received lapatinib (IIL), whereas the last group received paracetamol (IIIPA). A single dose of lapatinib (100 mg/kg b.w.) and paracetamol (100 mg/kg b.w.) was administered orally. Plasma concentrations of lapatinib, paracetamol and its metabolites - glucuronide and sulphate, were measured with the validated HPLC-MS/MS method and HPLC-UV method, respectively. The pharmacokinetic parameters of both drugs were calculated using non-compartmental methods. The co-administration of lapatinib and paracetamol increased the area under the plasma concentration-time curve (AUC) and the maximum concentration (Cmax) of lapatinib by 239.6% (p = 0.0030) and 184% (p = 0.0011), respectively. Lapatinib decreased the paracetamol AUC0-∞ by 48.8% and Cmax by 55.7%. In the IL + PA group the Cmax of paracetamol glucuronide was reduced, whereas the Cmax of paracetamol sulphate was higher than in the IIIPA group. Paracetamol significantly affected the enhanced plasma exposure of lapatinib. Additionally, lapatinib reduced the concentrations of paracetamol. The co-administration of lapatinib decreased the paracetamol glucuronidation but increased the sulphation. The findings of this study may be of clinical relevance to patients requiring analgesic therapy.
Subject(s)
Acetaminophen/pharmacokinetics , Analgesics, Non-Narcotic/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Lapatinib/pharmacokinetics , Protein Kinase Inhibitors/pharmacokinetics , Acetaminophen/blood , Administration, Oral , Analgesics, Non-Narcotic/blood , Animals , Antineoplastic Agents/blood , Drug Interactions , Glucuronides/blood , Lapatinib/blood , Male , Protein Kinase Inhibitors/blood , Rats, Wistar , Sulfates/bloodABSTRACT
Dexmedetomidine (DEX) is a fairly new alfa2-agonist which has been increasingly used in recent years for analgosedation, mostly because it offers a unique ability of providing both moderate level of sedation and analgesia without respiratory depression. Despite of many papers published, there are still only a few concerning the PK of the drug given as long-term infusion in ICU patients. The aim of this work was to characterize the population pharmacokinetics of dexmedetomidine and to investigate the potential benefits of individualization of drug dosing based on patient characteristics in the heterogeneous group of medical and surgical patients staying in intensive care unit. This study was performed in the group of 17 males and 10 females patients with a median age of 59.5 years and median body weight of 75 kg. Blood samples for dexmedetomidine assay were collected from arterial catheter, during and after discontinuation of a standard infusion, that ranged from 24 to 102 h. The following covariates were examined to influence dexmedetomidine PK: age, sex, body weight, patients' health status described by Sequential Organ Failure Assessment Score (SOFA), inotropes usage, and infusion duration. The dexmedetomidine PK was best described by a two-compartment model. The typical values of PK parameters were estimated as 27 L for the volume of the central compartment, 87.6 L for the volume of the peripheral compartment, 38.5 L/h (9.2 mL/min/kg for a 70 kg patient) for systemic clearance and 46.4 L/h for the distribution clearance. Those values are consistent with literature findings. We were unable to show any significant relationship between collected covariates and dexmedetomidine PK. This study does not provide sufficient evidence to support the individualization of dexmedetomidine dosing based on age, sex, body weight, SOFA, and infusion duration.
Subject(s)
Dexmedetomidine/pharmacokinetics , Hypnotics and Sedatives/pharmacokinetics , Adult , Aged , Aged, 80 and over , Female , Humans , Infusions, Intravenous/methods , Intensive Care Units , Male , Metabolic Clearance Rate/physiology , Middle Aged , Models, Biological , Nonlinear Dynamics , Young AdultABSTRACT
OBJECTIVE: Systemic inflammation may change the bioavailability and pharmacokinetics of opioids. However, there are insufficient data on morphine pharmacokinetics in mild inflammatory conditions. This study aimed to determine the pharmacokinetics of morphine during low-dose endotoxemia in rabbits. DESIGN: In two experiments (separated by a 14-day washout period), 10 rabbits received intravenous morphine at a dose of 3 mg/kg. In the second set of experiments, morphine infusion was preceded by low-dose endotoxemia induced with lipopolysaccharide (Escherichia coli 0111: B4) at a dose of 5 µg/kg. The kinetics of systemic morphine concentrations and chosen physiological parameters were measured at specific time intervals up to 6 hours after morphine administration. RESULTS: In endotoxemia, decreased elimination half-life (P = 0.017), mean residence time (P = 0.022), and volume of distribution (P = 0.037) as well as an increased elimination rate constant (P = 0.013) and total body clearance (P = 0.023) were noted. The inverse linear correlation between morphine clearance versus the percentage (%) change in body temperature and pulse rate observed under control conditions was abolished under endotoxemia. CONCLUSIONS: Low-dose endotoxemia is correlated with significant alterations in morphine pharmacokinetics in rabbits, leading to the faster elimination of the drug. CLINICAL IMPLICATIONS: These findings may have important implications in patients with low-grade inflammation and imply the need to modify morphine dosing regimens to ensure optimal analgesia. The issue warrants further experimental and clinical investigation.
Subject(s)
Analgesics, Opioid/pharmacology , Endotoxemia/metabolism , Morphine/pharmacokinetics , Animals , Disease Models, Animal , Endotoxemia/chemically induced , Escherichia coli , Female , Half-Life , Lipopolysaccharides/toxicity , Male , RabbitsABSTRACT
The purpose of this study was to assess the pharmacokinetics of dexmedetomidine in the ICU settings during the prolonged infusion and to compare it with the existing literature data using the Bayesian population modeling with literature-based informative priors. Thirty-eight patients were included in the analysis with concentration measurements obtained at two occasions: first from 0 to 24 h after infusion initiation and second from 0 to 8 h after infusion end. Data analysis was conducted using WinBUGS software. The prior information on dexmedetomidine pharmacokinetics was elicited from the literature study pooling results from a relatively large group of 95 children. A two compartment PK model, with allometrically scaled parameters, maturation of clearance and t-student residual distribution on a log-scale was used to describe the data. The incorporation of time-dependent (different between two occasions) PK parameters improved the model. It was observed that volume of distribution is 1.5-fold higher during the second occasion. There was also an evidence of increased (1.3-fold) clearance for the second occasion with posterior probability equal to 62 %. This work demonstrated the usefulness of Bayesian modeling with informative priors in analyzing pharmacokinetic data and comparing it with existing literature knowledge.
Subject(s)
Bayes Theorem , Dexmedetomidine/administration & dosage , Dexmedetomidine/pharmacokinetics , Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/pharmacokinetics , Models, Biological , Algorithms , Child , Child, Preschool , Critical Illness , Dexmedetomidine/blood , Dexmedetomidine/therapeutic use , Dose-Response Relationship, Drug , Female , Humans , Hypnotics and Sedatives/blood , Hypnotics and Sedatives/therapeutic use , Infant , Infusions, Intravenous , Male , Software , Time FactorsABSTRACT
Propofol is routinely combined with opioid analgesics to ensure adequate anesthesia during surgery. The aim of the study was to assess the effect of fentanyl on the hypnotic effect of propofol and the possible clinical implications of this interaction. The pharmacokinetic/pharmacodynamic (PK/PD) data were obtained from 11 patients undergoing abdominal aortic surgery, classified as ASA III. Propofol was administered by a target-controlled infusion system. Fentanyl 2-3 µg/kg was given whenever insufficient analgesia occurred. The bispectral index (BIS) was used to monitor the depth of anesthesia. A population PK/PD analysis with a non-linear mixed-effect model (NONMEM 7.2 software) was conducted. Two-compartment models satisfactorily described the PK of propofol and fentanyl. The delay of the anesthetic effect in relation to PK was described by the effect compartment. The BIS was linked to propofol and fentanyl effect-site concentrations through an additive Emax model. Context-sensitive decrement times (CSDT) determined from the final model were used to assess the influence of fentanyl on the recovery after anesthesia. The population PK/PD model was successfully developed to describe simultaneously the time course and variability of propofol and fentanyl concentrations and BIS. Additive propofol-fentanyl interactions were observed and quantitated. The duration of the fentanyl infusion had minimal effect on CSDT when it was shorter than the duration of the propofol infusion. If the fentanyl infusion was longer than the propofol infusion, an almost two-fold increase in CSDT occurred. Additional doses of fentanyl administered after the cessation of the propofol infusion result in lower BIS values, and can prolong the time of recovery from anesthesia. Copyright © 2016 John Wiley & Sons, Ltd.
Subject(s)
Analgesics, Opioid , Anesthetics, Intravenous , Fentanyl , Hypnotics and Sedatives , Models, Biological , Propofol , Aged , Analgesics, Opioid/pharmacokinetics , Analgesics, Opioid/pharmacology , Anesthetics, Intravenous/pharmacokinetics , Anesthetics, Intravenous/pharmacology , Aorta, Abdominal/surgery , Drug Interactions , Fentanyl/pharmacokinetics , Fentanyl/pharmacology , Humans , Hypnotics and Sedatives/pharmacokinetics , Hypnotics and Sedatives/pharmacology , Middle Aged , Propofol/pharmacokinetics , Propofol/pharmacologyABSTRACT
The aim of this study was to characterize the pharmacokinetics (PK) of propofol in ICU patients undergoing long-term sedation and to assess the influence of routinely collected covariates on the PK parameters. Propofol concentration-time profiles were collected from 29 patients. Non-linear mixed-effects modelling in NONMEM 7.2 was used to analyse the observed data. The propofol pharmacokinetics was best described with a three-compartment disposition model. Non-parametric bootstrap and a visual predictive check were used to evaluate the adequacy of the developed model to describe the observations. The typical value of the propofol clearance (1.46 l/min) approximated the hepatic blood flow. The volume of distribution at steady state was high and was equal to 955.1 l, which is consistent with other studies involving propofol in ICU patients. There was no statistically significant covariate relationship between PK parameters and opioid type, SOFA score on the day of admission, APACHE II, predicted death rate, reason for ICU admission (sepsis, trauma or surgery), gender, body weight, age, infusion duration and C-reactive protein concentration. The population PK model was developed successfully to describe the time-course of propofol concentration in ICU patients undergoing prolonged sedation. Despite a very heterogeneous group of patients, consistent PK profiles were observed. Copyright © 2016 John Wiley & Sons, Ltd.
Subject(s)
Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/pharmacokinetics , Intensive Care Units , Propofol/administration & dosage , Propofol/pharmacokinetics , Adult , Aged , Aged, 80 and over , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Intensive Care Units/trends , Male , Middle Aged , Time FactorsABSTRACT
Despite the growing number of cancer cases and cancer surgeries around the world, the pharmacokinetics (PK) and pharmacodynamics (PD) of anesthetics used in this population are poorly understood. Patients operated due to cancer are usually in severe state and often require chemotherapy. It might affect the PK/PD of drugs used in this population. Therefore, in this study we explored the PK/PD of propofol in cancer patients having a major lung surgery. 23 patients that underwent a propofol-fentanyl total intravenous anesthesia were included in the analysis. A large set of demographic, biochemical and hemodynamic parameters was collected for the purpose of covariate analysis. Nonlinear mixed effect modeling in NONMEM was used to analyze the collected data. A three-compartment model was sufficient to describe PK of propofol. The anesthetic effect (AAI index) was linked to the propofol effect site concentrations through a sigmoidal E max model. A slightly higher value of clearance, a lower value of distribution clearance, and a decreased volume of peripheral compartment were observed in our patients, as compared with the literature values reported for healthy volunteers by Schnider et al. and by Eleveld et al. Despite these differences, both models led to a clinically insignificant bias of -8 and -1 % in concentration predictions, as reflected by the median performance error. The C e50 and propofol biophase concentration at the time of postoperative orientation were low and equaled 1.40 and 1.13 mg/L. The population PK/PD model was proposed for cancer patients undergoing a major lung surgery. The large body of studied covariates did not affect PK/PD of propofol significantly. The modification of propofol dosage in the group of patients under study is not necessary when TCI-guided administration of propofol by means of the Schnider model is used.
Subject(s)
Anesthetics, Intravenous/administration & dosage , Anesthetics, Intravenous/pharmacokinetics , Lung/surgery , Neoplasms/surgery , Propofol/administration & dosage , Propofol/pharmacokinetics , Aged , Dose-Response Relationship, Drug , Female , Fentanyl/administration & dosage , Humans , Infusions, Intravenous/methods , Kinetics , Male , Middle Aged , Nonlinear DynamicsABSTRACT
The study aimed to examine the effect of sunitinib on the plasma exposure of intravenous paracetamol and its major metabolite, paracetamol glucuronide. Both drugs share metabolic pathways in the liver, and the drug interactions between sunitinib and paracetamol administered in higher doses were reported. These interactions resulted in hepatotoxicity. The adult New Zealand male rabbits were divided into three groups (6 animals each): rabbits receiving sunitinib and paracetamol (SUN + PC), rabbits receiving sunitinib (SUN), and a control group receiving paracetamol (PC). Sunitinib was administered orally (25 mg) and paracetamol was administrated intravenously (35 mg/kg). Blood samples for sunitinib and SU12662 assays were collected up to 96 h after drug administration and for paracetamol and paracetamol glucuronide up to 300 min after drug administration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin were analysed before and after drug administration. A number of pharmacokinetic parameters were analysed. There were no differences in the levels of AST, ALT, and bilirubin among the groups at either time point. Significantly higher values of AUC0-t , AUC0-∞ , and C max and lower clearance and volume of distribution of paracetamol were observed in group PC vs. group SUN + PC (p < 0.01). The maximum plasma concentration of paracetamol glucuronide tended to be higher in group PC 213.27 µg/mL (90 % CI 1.06, 1.25; p = 0.0267). Statistically significant differences were revealed for paracetamol glucuronide mean residence time (MRT); MRT was higher in group SUN + PC than in group PC (p = 0.0375). The mean t max of paracetamol glucuronide was similar in both groups: SUN + PC and group PC (15 and 20 min, respectively). The mean t max of sunitinib was different in groups SUN + PC and SUN (10.0 and 7.0, respectively; p = 0.0134). At the studied doses, neither of the drugs, whether administered alone or together, had hepatotoxic effects. The present study was not able to confirm that sunitinib, administered at low doses in conjunction with paracetamol, displays a hepatoprotective effect. Significant differences were observed in some pharmacokinetic parameters of paracetamol.
Subject(s)
Acetaminophen/analogs & derivatives , Acetaminophen/pharmacokinetics , Indoles/pharmacology , Pyrroles/pharmacology , Acetaminophen/blood , Animals , Area Under Curve , Drug Interactions , Male , Rabbits , SunitinibABSTRACT
INTRODUCTION: Recently an increasing number of reports indicate the participation of genetic factors in the pathogenesis of preeclampsia (PE). The genes involved in the synthesis of nitric oxide that participates in the vasolidation, may play an important role in the development of this disorder. Hydrogen sulfide (H2S) which is produced by cystathionine gamma-lyase exhibits a similar effect to nitric oxide. It is suggested that certain polymorphisms of the CTH gene may participate in the development of chronic hypertension and preeclampsia. AIM OF THE STUDY: To evaluate the frequency of genotypes and alleles of rs1021737 and rs482843 polymorphisms of CTH gene in women with preeclampsia from Wielkopolska region. MATERIAL AND METHODS: The study group consisted of 60 patients with diagnosed preeclampsia, into the control group 120 healthy pregnant women were enrolled. The examined rs1021737 and rs482843 polymorphisms of CTH gene were determined using PCR-RFLP method. RESULTS: Analysis of rs482843 polymorphism in the CTH gene showed a statistically significant difference in the prevalence of mutated GG genotype (p<0.000001) and mutated G allele (p<0.000001) in the group of pregnant women with PE compared to the control group. There was no such correlation for the rs1021737 polymorphism. Furthermore, there are also no relationship between studied polymorphisms and selected clinical and biochemical parameters. CONCLUSIONS: The results of rs482843 polymorphism analysis suggest that mutated GG genotype predisposes to preeclampsia occurrence. There was no such relationship for the rs1021737 polymorphism of CTH gene. Hence, further studies based on the determination of CSE expression level in women with PE may confirm the observed relationship between the rs482843 polymorphism and the risk of preeclampsia.
Subject(s)
Cystathionine gamma-Lyase/genetics , Polymorphism, Genetic , Pre-Eclampsia/genetics , White People/genetics , Adult , Case-Control Studies , DNA Mutational Analysis/methods , Female , Humans , Maternal-Fetal Exchange/genetics , Point Mutation/genetics , Polymorphism, Single Nucleotide , Pregnancy , Prenatal Care/methods , Young AdultABSTRACT
Urinary tract infections (UTIs) in women are a growing clinical concern. The most frequent risk factors of UTIs with fungal aetiology in women are: antibiotic therapy (especially broad-spectrum antibiotics), immunosuppressive therapy, diabetes, malnutrition, pregnancy, and frequent intercourse. The aim of the study was to analyse urinary tract infections with Candida spp. aetiology in women hospitalised at the Clinical Hospital in Poznan, Poland, between 2009 and 2011. The investigations revealed that as many as 71% of positive urine cultures with Candida fungi came from women. The following fungi were most frequently isolated from the patients under analysis: C. albicans (47%), C. glabrata (31%), C. tropicalis (6%), C. krusei (3%). In order to diagnose a UTI the diagnosis cannot be based on a single result of a urine culture. Due to the small number of antifungal drugs and high costs of treatment, antifungal drugs should be applied with due consideration and care.
Subject(s)
Candidiasis/epidemiology , Hospitalization/statistics & numerical data , Urinary Tract Infections/epidemiology , Women's Health , Antifungal Agents/therapeutic use , Candidiasis/drug therapy , Candidiasis/microbiology , Causality , Female , Humans , Poland/epidemiology , Pregnancy , Pregnancy Complications, Infectious/epidemiology , Retrospective Studies , Risk Factors , Urinary Tract Infections/drug therapy , Urinary Tract Infections/microbiology , Urine/microbiologyABSTRACT
The aim of this study was an in vitro - in vivo evaluation of a new oral dosage form of tramadol hydrochloride (TH), controlled-release capsules filled with coated pellets, 100 mg (TC), compared to the sustained release tablets, Tramal Retard, 100 mg (TR). In vitro release study of both formulations showed a similar release profile of TH over 8 h (f2 was 52). In vivo study (single oral, 100 mg dose administration in 8 rabbits) showed that the amount of TH absorbed into the systemic circulation after TC and TR administration was also similar (90% CI for AUC(0-t) and AUC(0-infinity) were 90-124% and 97-109%, respectively). However, a comparison of AUC(0-t) of pharmacokinetics of TC and TR indicates significantly prolonged absorption and elimination processes of TH when the drug is given in controlled-release capsules filled with coated pellets. It was manifested by longer: mean absorption time (p = 0.0016), mean residence time (p = 0.0268), absorption half-life (p = 0.0016), elimination half-life (p = 0.0493) and lower: absorption rate constant (p = 0.0016), elimination rate constant (p = 0.0148) and total body clearance Cl/F (p = 0.0076). It may be concluded that the new TH formulation could be expected to have a more prolonged analgesic activity than commercial sustained release tablets.
Subject(s)
Analgesics, Opioid/administration & dosage , Tramadol/administration & dosage , Administration, Oral , Analgesics, Opioid/blood , Analgesics, Opioid/chemistry , Analgesics, Opioid/pharmacokinetics , Animals , Area Under Curve , Capsules , Chemistry, Pharmaceutical , Delayed-Action Preparations , Half-Life , Intestinal Absorption , Metabolic Clearance Rate , Rabbits , Solubility , Technology, Pharmaceutical/methods , Tramadol/blood , Tramadol/chemistry , Tramadol/pharmacokineticsABSTRACT
This study was aimed at a biopharmaceutical evaluation of a new oral dosage form of tramadol hydrochloride (TH)--slow release tablets obtained by hot tableting of coated pellets, 100 mg (TP), compared to the conventional slow release tablets, Tramal Retard, 100 mg (TR). Both TP and TR formulations showed a similar release profile of TH (f2 was 71) in in vitro release studies. The in vivo study was a two-treatment, two-period, two-sequence, single-oral dose 100 mg, crossover design using rabbit model with the phases separated by a washout period of 14 days. It was shown that the amount of TH absorbed into the systemic circulation is similar for TP and TR (the 90% confidence intervals for the AUC(0-1), AUC(0-infinity) and ratios were 85-122 and 92-107%, respectively). However, after administration of slow release tablets obtained by hot tableting of coated pellets, a prolonged absorption and elimination processes and a smoother and more extended plasma profile of TH were observed. It can be assumed that the use of a new oral dosage form of TH in patients affects the extension of analgesia after single administration of the drug, with its gradual absorption into the systemic circulation.
Subject(s)
Analgesics, Opioid/pharmacokinetics , Tramadol/pharmacokinetics , Administration, Oral , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/blood , Analgesics, Opioid/chemistry , Animals , Biological Availability , Chemistry, Pharmaceutical , Delayed-Action Preparations , Injections, Intravenous , Intestinal Absorption , Rabbits , Solubility , Tablets , Technology, Pharmaceutical/methods , Tramadol/administration & dosage , Tramadol/blood , Tramadol/chemistryABSTRACT
OBJECTIVES: Changes of kinase activity of non-genomic cellular signaling pathway may influence the effectiveness of pharmacotherapy in case of hormone-dependent tumors. Our study investigated a possible interaction at the molecular level between an aqueous herbal extract of Epilobium angustifolium as well as a lipid-sterolic fruit extract of Serenoa repens and synthetic drugs used in the treatment of hormone-dependent cancers. MATERIAL AND METHODS: E. angustifolium and Serenoa repens extracts were orally administered to testosterone-induced rats for 21 days. Changes of RafA/Mapk3/Mapk1 mRNA levels were analyzed by real-time quantitative PCR using target specific primers. RESULTS: The level of RafA mRNA slightly increased in rats receiving Epilobium angustifolium (p = 0.076) and Serenoa repens (p = 0.016) extracts. Administration of these extracts resulted in significantly elevated Mapk1 and Mapk3 transcripts in the investigated animals (p < 0.05 for each extract). The levels of Mapk1 and Mapk3 mRNA strongly increased (p < 0.05 for each extract) in animals receiving concomitantly testosterone and the extracts, while RafA transcription slightly decreased (p < 0.05), as compared to controls. CONCLUSIONS: The results of our study may indicate a potential effect of S. repens and E. angustifolium extracts on the functioning of non-genomic cellular signaling kinases pathway. We investigated safety of these extracts to detect possible drug interactions between synthetic drugs used in the treatment of proliferative changes in hormone-dependent reproductive organs and herbal preparations.
Subject(s)
MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinase Kinases/drug effects , Plant Extracts/pharmacology , Serenoa , Administration, Oral , Animals , Female , Neoplasms, Hormone-Dependent/prevention & control , Polymerase Chain Reaction/methods , Rats , Rats, Wistar , Signal Transduction/drug effectsABSTRACT
OBJECTIVE: Soybean phytoestrogens, such as genistein and daidzein, reduce climacteric symptoms and the risk of certain chronic diseases such as cancer and cardiovascular diseases. Despite their widespread use in functional foods and dietary supplements, there is very little data available on their safety and herb-drug interactions, especially with antineoplastic agents. Hence, the aim of our study was to assess the effects of soybean extracts on the expression level of CYP genes and their transcriptional factors. We also investigated the effect of soybean on the mRNA level of transporters, such as P-glycoprotein (MDRI) and multidrug resistance-associated proteins (MRP1, MRP2). MATERIALS AND METHODS: Wistar rats were fed a standardized soybean extract (100 mg/kg, p.o.). cDNA was synthesized from total RNA isolated from different tissues (liver and intestinal epithelium) using reverse transcription. Gene expression level was analyzed by RT-PCR method. RESULTS: We demonstrated a significant increase of CYP1A1 mRNA level (by 89%, p = 0.002 and 125%, p = 0.004) as compared with the control group. An increase of AHR and CAR expression after 10 days was also observed (by 60%, p < 0.001 and 52%, p > 0.05, respectively). Additionally an inductive effect for CYP2D1 by 22% (p = 0.008), Mdr1a by 267% (p < 0.0001), Mdr2b by 86% (p < 0.00001), Mrp1 by 9-fold (p < 0.0001), Mrp2 by 83% (p < 0.0001) in the liver and for Mrp2 by 35% (p < 0.001) in the intestinal epithelium, was evaluated. A significant decrease of mRNA level was observed for CYP3A1 (human CYP3A4) in the liver and Mdr1b in the intestinal epithelium. Moreove, we also showed a slight decrease in the amount of mRNA for CAR, PXR and ARNT after 3 days. CONCLUSIONS: Our results suggest that Glycine max may change the expression level of CYPs, especially CYP3A4 and CYP1A 7, involved in biotransformation of xenobiotics (drugs, procarcinogens) and may participate in clinically significant interactions with drugs metabolized by these enzymes. Moreover an increase of CYP1A1 (homologue to human CYPIA 1) mRNA level may not only reduce the carcinogenicity of foreign compounds, but may also activate some compounds to their carcinogenicity In case of transporters, it is considered that an increase of their expression in the body may lead to increased fetoprotection. Also, it may reduce both, the exposure of sensitive tissues (e.g. brain, placenta) to xenobiotics and treatment effectiveness of certain diseases. Hence, the search for a safe substance that could effectively modulate transporter activity especially in the treatment of certain hormone -dependent disorders, e.g. osteoporosis and breast cancer occurring mainly in postmenopausal period, continues.
Subject(s)
Alcohol Oxidoreductases/genetics , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP3A/genetics , Glycine max/chemistry , Isoflavones/pharmacology , Plant Extracts/pharmacology , RNA, Messenger/metabolism , Animals , Base Sequence , Biological Transport/genetics , Biotransformation/genetics , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP2E1/genetics , Cytochrome P-450 CYP2E1/metabolism , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P450 Family 2 , Female , Gene Expression/drug effects , Humans , Intestinal Mucosa/metabolism , Isoflavones/administration & dosage , Liver/metabolism , RNA, Messenger/drug effects , RNA, Messenger/genetics , Rats , Rats, WistarABSTRACT
INTRODUCTION: In the era of problems with resistant bacteria strains, pharmacokinetic (PK) modelling offers ways to optimise antibiotic therapy and minimise the risk of resistance development. This bibliometric study aimed to investigate trends in PK modelling stu-dies. The goal was to provide researchers with comprehensive insight and identify future needs. MATERIAL AND METHODS: We used Bibliometrix, VOSviewer, and CiteSpace to analyse Web of Science articles on antibiotic PK modelling from 1983 to March 2023. RESULTS: We analysed 968 papers following the inclusion criteria and built a keywords co-occurrence map and timeline. The average annual growth rate of subject-related publications was 35.56% between 1983 and 2022, maintaining a continuous upward trend. Roberts J.A., Lipman J., and Wallis S.C. are the three most productive and impactful authors (82, 57, 34 articles, and h-index of 30, 25, 15, respectively). The United States leads in this field of research (29.13% of papers). The most relevant affiliations are the University of Queensland, Royal Brisbane and Women's Hospital, and Monash University. The top three most productive and impactful journals are Antimicrobial Agents and Chemotherapy, Journal of Antimicrobial Chemotherapy, and International Journal of Antimicrobial Agents (181, 83, 47 articles and h-index of 42, 30, 18, respectively). Most articles by keyword clustered on meropenem, vancomycin, and amikacin. Moreover, therapeutic drug monitoring, resistance, antibiotic dosing, target attainment, the intensive care unit, and paediatrics are the most trending aspects. CONCLUSIONS: Given the results of this study, we expect to see a steady increase in interest in exploiting the potential of PK modelling for optimising antibiotic therapy.
Subject(s)
Anti-Bacterial Agents , Bibliometrics , Humans , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/administration & dosage , Drug Resistance, Bacterial , Models, BiologicalABSTRACT
The lack of data on drug-drug interactions in pediatrics represents a relevant problem in making appropriate therapeutic decisions. Our study aimed to investigate the incidence and risk factors for potential drug-drug interactions (pDDIs) in pediatric pneumonology units, including cystic fibrosis patients. We performed a 6-month prospective observational study during which clinical pharmacists, using the Lexicomp Drug Interactions checker, screened medical records to identify pDDIs. Spearman's rank coefficient, logistic regression, and the Mann-Whitney U test were used to identify correlations, analyze risk factors for pDDIs, and compare cystic fibrosis patients with the rest, respectively. Recommendations were provided for the D and X pDDIs categories. Within the 218 patients, 428 pDDIs were identified, out of which 237 were classified as clinically significant. Almost 60% of patients were exposed to at least one relevant interaction. The number of pDDIs correlated with the number of; drugs (rs = 0.53, P < .001), hospitalization length (rs = 0.20, P < .01), and off-label medicines (rs = 0.25, P < .001). According to the multivariate analysis, at least 6 administered medications (OR = 4.15; 95% CI = 2.21-7.78), 4 days of hospitalization (OR = 6.41; 95% CI = 2.29-17.97), and off-label therapy (OR = 3.37; 95% CI = 1.69-6.70) were the risk factor for pDDIs. Despite significant differences in the number of medications taken, comorbidities, and off-label drugs, cystic fibrosis patients were not more exposed to pDDI. Given the lack of data on pDDIs in the pediatric population, the need for close cooperation between clinicians and clinical pharmacists to improve the safety and efficacy of pharmacotherapy is highlighted.