The detachment forces of various polymers are frequently measured to determine their mucoadhesion strength. As the process of mucoadhesion is a consequence of interactions between the mucus layer on ...mucosa and mucoadhesive polymers, it is greatly dependent on mucus and polymer structure including their charge. It is also known that the glycosaminoglycan layer, which covers the urinary bladder mucosa surface, is highly negatively charged. Therefore, by measuring the zeta potential of polymer dispersions and mucosal homogenates an insight into electrostatic interactions during mucoadhesion can be obtained. In our experiments we chose three polymers, two anionic (polycarbophil, PC; sodium carboxymethyl cellulose, CMCNa) and one cationic (chitosan hydrochloride, CH), for which we expected different zeta potential values and different mucoadhesion strengths. The correlation between the zeta potential and the detachment force was determined. In addition to that, the zeta potential of the scraped surface layer of pig urinary bladders was measured to confirm its negative value. The mucoadhesion strength decreased in the following order: CH>CMCNa=PC. The zeta potentials for all three polymers and for porcine vesical mucosal homogenates were measured in Tyrode solution and two NaCl solutions with different ionic strengths. The lower values of the detachment force correlated well with the more negative zeta potential of the polymer, which might be a consequence of the greater repulsion between negative charges of polymers and glycosaminoglycans.
In this paper, to improve the oral bioavailability of erythromycin in rainbow trout, new formulations of medicated feed (based on two double microemulsions and a self-emulsifying system) were ...developed and tested
in vivo, and their pharmacokinetic was studied.
The aim of this work was to enhance the bioavailability of erythromycin base when administered orally in rainbow trout (
Oncorhynchus mykiss). Since erythromycin is normally given in the form of medicated feed, in this study three new types of feed formulation were developed. A self-emulsifying system and two types of double microemulsions (O/W/O) were prepared, characterized and adsorbed on a commercial extruded diet for fish. The emulsified systems were based on saturated polyglycolized glycerides and mono- and diglycerides of medium-chain fatty acids (as oily phase), Tween® 80 (as surfactant) and, in the case of double microemulsions, distilled water. The systems differed in percentage composition and for the amount and position of erythromycin in different phases. The three medicated feed were then administered orally by means of a gastric probe to rainbow trout and their relative bioavailability was estimated in comparison with that obtained after oral administration of feed with erythromycin powder. For each medicated feed, 80 fish were tested. Finally, plasma profiles of erythromycin after single administration of medicated feeds were used to predict profiles obtainable by administering once-daily medicated feeds for 7 consecutive days. The results proved that the feeds containing microemulsified erythromycin provided largely superior oral bioavailability and the advantage of obtaining the same efficacy against bacterial infections with a much lower dose of drug.
Background. Chemotherapy with platinum agent and etoposide for small-cell lung cancer (SCLC) is supposed to be associated with intermediate risk (10-20%) of febrile neutropenia. Primary prophylaxis ...with granulocyte colonystimulating factors (G-CSFs) is not routinely recommended by the treatment guidelines. However, in clinical practice febrile neutropenia is often observed with standard etoposide/platinum regimen. The aim of this analysis was to evaluate the frequency of neutropenia and febrile neutropenia in advanced SCLC patients in the first cycle of standard chemotherapy. Furthermore, we explored the association between severe neutropenia and etoposide peak plasma levels in the same patients.
Methods. The case series based analysis of 17 patients with advanced SCLC treated with standard platinum/etoposide chemotherapy, already included in the pharmacokinetics study with etoposide, was performed. Grade 3/4 neutropenia and febrile neutropenia, observed after the first cycle are reported. The neutrophil counts were determined on day one of the second cycle unless symptoms potentially related to neutropenia occurred. Adverse events were classified according to Common Toxicity Criteria 4.0. Additionally, association between severe neutropenia and etoposide peak plasma concentrations, which were measured in the scope of pharmacokinetic study, was explored.
Results. Two out of 17 patients received primary GCS-F prophylaxis. In 15 patient who did not receive primary prophylaxis the rates of both grade 3/4 neutropenia and febrile neutropenia were high (8/15 (53.3%) and 2/15 (13.3%), respectively), already in the first cycle of chemotherapy. One patient died due to febrile neutropenia related pneumonia. Neutropenic events are assumed to be related to increased etoposide plasma concentrations after a standard etoposide and cisplatin dose. While the mean etoposide peak plasma concentration in the first cycle of chemotherapy was 17.6 mg/l, the highest levels of 27.07 and 27.49 mg/l were determined in two patients with febrile neutropenia.
Conclusions. Our study indicates that there is a need to reduce the risk of neutropenic events in chemotherapy treated advanced SCLC, starting in the first cycle. Mandatory use of primary G-CSF prophylaxis might be considered. Alternatively, use of improved risk models for identification of patients with increased risk for neutropenia and individualization of primary prophylaxis based on not only clinical characteristics but also on etoposide plasma concentration measurement, could be a new, promising options that deserves further evaluation.
A simple, fast, and cost-effective LC-MS/MS method for quantification of rifampicin in human plasma was developed and fully validated. The plasma samples containing rifampicin and isotopically ...labelled internal standard rifampicin D8, were cleaned up using a Captiva ND Lipids filtration plate. Chromatographic separation was achieved on an 1290 Infinity liquid chromatograph coupled to 6460 Triple Quadrupole operated in positive mode on a core-shell Kinetex C18 column (50 × 2.1 mm, 2.6 μm) by gradient elution using 0.1% formic acid in water and acetonitrile as a mobile phase. The proposed method is the fastest method published by now, both in terms of sample preparation (approximately one minute per sample) and chromatographic analysis (total run time 2.4 min). Another key benefit is the outstanding sensitivity and wide analytical range (5-40000 μg/L) with good linearity, accuracy, and precision. The method showed almost complete recovery (92%) and absence of any significant matrix effect as demonstrated by uniform responses from QC samples prepared in blood plasma from 6 volunteers (RSD <5%). The proposed method was successfully applied to rifampicin quantification in 340 patients’ plasma samples, thus demonstrating its suitability for both therapeutic drug monitoring and pharmacokinetic analysis.
Leflunomide is a disease-modifying antirheumatic drug used for the treatment of rheumatoid arthritis (RA). Cytochromes P450, mainly CYP1A2 and CYP2C19, may be involved in the transformation of ...leflunomide to leflunomide metabolite (A77 1726, 2-cyano-3-hydroxy-N-4-(trifluoromethyl)phenyl-2-butenamide). The aim of this study was to investigate whether genetic polymorphisms in CYP1A2 and CYP2C19 influence leflunomide pharmacokinetics, treatment response, and the occurrence of adverse drug reactions (ADRs). The study included 67 patients with RA and 4 patients with polyarthritis resembling RA and psoriasis treated with leflunomide. A77 1726 steady-state plasma concentrations were determined by validated high-performance liquid chromatography with UV detection. A population pharmacokinetic model was developed to estimate the oral clearance (CL/F) and volume of distribution (V/F). A genotyping approach was used to determine C-163A, C-729T, and T-739G in the CYP1A2 gene as well as single nucleotide polymorphisms that characterize CYP2C19*2, *3, *4, and *17 alleles. A large interindividual variability in trough A77 1726 steady-state plasma concentrations was observed (from 1.9 to 156.9 mg/l). A77 1726 CL/F was 71% higher in carriers of the CYP2C19*2 allele compared with noncarriers. The A77 1726 average steady-state plasma concentration was associated with the treatment response. Patients with a greater decrease in C-reactive protein (CRP) had higher average steady-state plasma A77 1726 concentrations: 49.7 +/- 39.0 mg/l in patients with DeltaCRP of more than 8.5 mg/l compared with 24.8 +/- 13.7 mg/l in patients with DeltaCRP of <or=8.5 mg/l (p = 0.015). No association of A77 1726 steady-state plasma concentrations with the occurrence of ADRs was observed. Our results suggest that genetic variability in leflunomide-metabolizing enzymes influences leflunomide metabolite concentrations that are associated with the treatment response but not with leflunomide-induced toxicity.
Two randomized, single dose, 2-period, 2-sequence crossover studies were conducted to evaluate the comparative bioavailability of two clopidogrel formulations under fasting and fed conditions. ...Assessment of bioequivalence was based upon measurement of plasma concentrations of the parent drug, clopidogrel, and its major (inactive) metabolite, clopidogrel carboxylic acid, using improved methanol-free extraction. Bioequivalence of Krka’s formulation to the innovator’s formulation was demonstrated under both fasting and fed conditions on 205 volunteers. Confidence intervals for AUC
, AUC
and C
of clopidogrel and its main metabolite were well within the acceptance range of 80.00 to 125.00 %. Food substantially increased the bioavailability of clopidogrel from both formulations, while no effect of food on the extent and rate of exposure to the metabolite was observed. The effect of food was comparable between the two formulations, as indicated by the same direction and rank of food impact on the bioavailability of both formulations.
Polymorphic multidrug resistant protein 1 (MDR1) transports drugs against a concentration gradient across the blood–brain barrier and reduces their accumulation in the brain. MDR1 may therefore ...influence antipsychotic brain availability contributing to inter-individual differences in treatment response and adverse effects, regardless of plasma concentrations. In the present study we investigated the influence of two common MDR1 polymorphisms on the improvement of psychopathological symptoms and occurrence of extrapyramidal side effects (EPS) in Slovenian schizophrenia patients acutely treated with risperidone. A total of 59 clinically well defined patients with first episode schizophrenia spectrum disorders or after tapering their maintenance treatment were genotyped for MDR1 C3435T and G2677T/A. Steady-state plasma concentrations of risperidone active moiety (sum of risperidone and the 9-hydroxyrisperidone) were determined. G2677T/A and C3435T genotypes were not associated to psychopathological symptoms, efficacy of treatment and risk for parkinsonism. Marginal associations with akathisia (
p
=
0.039 and
p
=
0.042, respectively) and dystonia (
p
=
0.013 and
p
=
0.034, respectively) were observed for both G2677T/A and C3435T genotypes. However, higher AIMS and BARS scores were observed only in heterozygous carriers of G2677T/A and C3435T polymorphisms and there was no tendency of gene–dose effect. The present study does not suggest a major influence of MDR1 G2677T/A and C3435T polymorphisms on treatment response during short-term risperidone therapy in patients with schizophrenia or schizoaffective disorder.
Topiramate pharmacokinetics is influenced by individual factors such as patient age, renal function and co-treatment. The aim of this study was to develop a population pharmacokinetic model of ...topiramate to assist dosage adjustments in individual patients. Steady-state topiramate plasma concentrations in patients with epilepsy were determined by HPLC using fluorescent labelling. Demographic, biochemical data and dosing history including concomitant drug therapy were collected from patients' charts. Nonlinear mixed effects modelling was used to fit a one-compartment pharmacokinetic model. The influence of patient weight and gender, body surface area, age, creatinine clearance, serum transaminases, topiramate daily dose and co-treatment with carbamazepine, valproic acid, benzodiazepines, and risperidone on topiramate pharmacokinetics was evaluated. Additionally, the relationship between topiramate plasma concentration and clinical response was investigated. Volume of distribution of topiramate was 0.518 l/kg. For a typical patient oral clearance was estimated at 1.47 l/h, with interindividual variability of 39.2%. Clearance was 70% higher in patients co-treated with carbamazepine and was found to increase with patient age. Somnolence was the most frequently observed adverse event. Incidence of headache was associated with topiramate plasma concentration. Somnolence, ataxia, tremor, speech disorders and fatigue were associated with adjunctive therapy with carbamazepine, valproic acid, benzodiazepines, risperidone, and clozapine. No association of topiramate plasma concentration with frequency of seizures or patient quality of life was observed. The developed model can be used for Bayesian estimation of pharmacokinetic parameters based on sparse plasma samples and for selection of optimum dosing in routine patient care.
This article presents the results of mapping the Slovenian pharmacy curriculum to evaluate the adequacy of the recently developed and validated European Pharmacy Competences Framework (EPCF). The ...mapping was carried out and evaluated progressively by seven members of the teaching staff at the University of Ljubljana's Faculty of Pharmacy. Consensus was achieved by using a two-round modified Delphi technique to evaluate the coverage of competences in the current curriculum. The preliminary results of the curriculum mapping showed that all of the competences as defined by the EPCF are covered in Ljubljana's academic program. However, because most EPCF competences cover healthcare-oriented pharmacy practice, a lack of competences was observed for the drug development and production perspectives. Both of these perspectives are important because a pharmacist is (or should be) responsible for the entire process, from the development and production of medicines to pharmaceutical care in contact with patients. Nevertheless, Ljubljana's graduates are employed in both of these pharmaceutical professions in comparable proportions. The Delphi study revealed that the majority of differences in scoring arise from different perspectives on the pharmacy profession (e.g., community, hospital, industrial, etc.). Nevertheless, it can be concluded that curriculum mapping using the EPCF is very useful for evaluating and recognizing weak and strong points of the curriculum. However, the competences of the framework should address various fields of the pharmacist's profession in a more balanced way.
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