There is a need for innovation in plant-derived pharmaceuticals, food supplements and nutraceutical products regarding the use of more eco-sustainable solvents for their extraction. Furthermore, the ...poor oral bioavailability of several phytochemicals with health promoting effects stimulates the research in the field of pharmaceutical formulations. Natural Deep Eutectic Solvents (NADES) are formed by natural compounds, and can be considered as future solvents being especially useful for the preparation of nutraceuticals and food-grade extracts. In this paper various NADES were prepared using sugars, aminoacids and organic acids. Rutin (quercetin-3-
-α-l-rhamnopyranosyl-(1→6))-β-d-glucopyranose) was used as a model compound to study NADES. Moreover, the effect of various eutectic mixtures on rutin's water solubility was studied. Proline/glutamic acid (2:1) and proline/choline chloride (1:1) mixtures have a solubility comparable to ethanol. The proline/glutamic acid (2:1) eutectic containing rutin was used in a pharmacokinetic study in Balb/c mice while bioavailability was compared to oral dosing of water suspension. Plasmatic levels of rutin were measured by HPLC-MS/MS showing increased levels and longer period of rutin permanence in plasma of NADES treated animals. This paper reports the possible use of non-toxic NADES for pharmaceutical and nutraceutical preparations.
Epilepsy is known as one of the most frequent neurological diseases, characterized by an enduring
predisposition to generate epileptic seizures. Oxidative stress is believed to directly participate ...in pathways
leading to neurodegeneration, which serves as the most important propagating factor, leading to the epileptic
condition and cognitive decline. Moreover, there is also a growing body of evidence showing the disturbance
of antioxidant system balance and consequently increased production of reactive species in patients with
epilepsy. A meta-analysis, conducted in the present review confirms an association between epilepsy and
increased lipid peroxidation. Furthermore, it was also shown that some of the antiepileptic drugs could potentially be
responsible for additionally increased lipid peroxidation. Therefore, it is reasonable to propose that during the epileptic
process neuroprotective treatment with antioxidants could lead to less sever structural damages, reduced epileptogenesis
and milder cognitive deterioration. To evaluate this hypothesis studies investigating the neuroprotective therapeutic
potential of various antioxidants in cells, animal seizure models and patients with epilepsy have been reviewed. Numerous
beneficial effects of antioxidants on oxidative stress markers and in some cases also neuroprotective effects were observed
in animal seizure models. However, despite these encouraging results, till now only a few antioxidants have been further
applied to patients with epilepsy as an add-on therapy. Based on the several positive findings in animal models, a strong
need for more carefully planned, randomized, double-blind, cross-over, placebo-controlled clinical trials for the evaluation
of antioxidants efficacy in patients with epilepsy is warranted.
Aims
This study aimed to develop a population pharmacokinetic model for quantitative evaluation of the influence of genetic variants in metabolic enzymes and transporters on lamotrigine ...pharmacokinetics while taking into account the influence of various clinical, biochemical and demographic factors.
Methods
We included 100 patients with epilepsy on stable dosing with lamotrigine as mono or adjunctive therapy. Lamotrigine and lamotrigine N‐2‐glucuronide concentrations were determined in up to two plasma samples per patient. Patients were genotyped for UGT1A4, UGT2B7, ABCB1 and SLC22A1. Population pharmacokinetic analysis was performed by non‐linear mixed effects modelling. Prior knowledge from previous pharmacokinetic studies was incorporated to stabilize the modelling process. A parent–metabolite model was developed to get a more detailed view on the covariate effects on lamotrigine metabolism.
Results
With a base model absorption rate (interindividual variability) was estimated at 1.96 h−1 (72.8%), oral clearance at 2.32 l h−1 (41.4%) and distribution volume at 77.6 l (30.2%). Lamotrigine clearance was associated with genetic factors, patient's weight, renal function, smoking and co‐treatment with enzyme inducing or inhibiting drugs. In patients with UGT2B7–161TT genotype clearance was lower compared with GT and GG genotypes. Clearance was particularly high in patients with UGT2B7 372 GG genotype (compared with AA genotype it was 117%; 95% CI 44.8, 247% higher).
Conclusions
Variability in lamotrigine pharmacokinetics is large and quantification of its sources may lead to more precise individual treatment. Genotyping for UGT2B7 may be useful in various clinical settings.
In the present study results related to the in vivo administration of Natural Deep Eutectic Solvents (NADES)-solubilized berberine are reported for the first time. NADES are mixtures of small natural ...compounds having a melting point significantly lower than that of any individual component. Such solvents have gained much attention of the scientific community in the green chemistry area, being considered useful alternatives to common organic solvents. NADES can be used also as administration vehicles, and this can be attractive for nutraceutical products when eutectics are formed with food grade ingredients. In this work, different NADES were prepared using mainly food grade constituents and were tested as solvents for the alkaloid berberine. Three selected NADES/berberine solutions and an aqueous suspension were orally administered to mice with in dose of 50 mg/Kg. Blood levels of berberine were measured by a LC-MS/MS method. The pharmacokinetic analysis revealed a 2-20 fold increase in blood concentration of NADES/berberine with significant changes in pharmacokinetic profile. Natural Deep Eutectic Solvents may thus be considered attractive solubilizing agents and may also play a role in the increase of absorption of poorly bioavailable natural products such as berberine.
Psychotropic prescription drugs are commonly involved in intoxication events. The study's aim was to determine a comparative risk for intoxication in relation to prescribing rates for individual ...drugs. This was a nationwide observational study in Slovenian adults between 2015 and 2021. Intoxication events with psychotropic drugs were collected from the National Register of intoxications. Dispensing data, expressed in defined daily doses, were provided by the Health Insurance Institute of Slovenia. Intoxication/prescribing ratio values were calculated. The correlation between trends in prescribing and intoxication rates was assessed using the Pearson correlation coefficient. In total, 2640 intoxication cases with psychotropic prescription drugs were registered. Anxiolytics and antipsychotics were the predominant groups. Midazolam, chlormethiazole, clonazepam, sulpiride, and quetiapine demonstrated the highest risk of intoxication, while all antidepressants had a risk several times lower. The best trend correlation was found for the prescribing period of 2 years before the intoxication events. An increase of 1,000,000 defined daily doses prescribed resulted in an increase of fifty intoxication events for antipsychotics, twenty events for antiepileptics, and five events for antidepressants. Intoxication/prescribing ratio calculation allowed for a quantitative comparison of the risk for intoxication in relation to the prescribing rates for psychotropic drugs, providing additional understanding of their toxicoepidemiology.
Background and Objectives
Risk assessment related to bioequivalence study outcome is critical for effective planning from the early stage of drug product development. The objective of this research ...was to evaluate the associations between solubility and acido-basic parameters of an active pharmaceutical ingredient (API), study conditions and bioequivalence outcome.
Methods
We retrospectively analyzed 128 bioequivalence studies of immediate-release products with 26 different APIs. Bioequivalence study conditions and acido-basic/solubility characteristics of APIs were collected and their predictive potential on the study outcome was assessed using a set of univariate statistical analyses.
Results
There was no difference in bioequivalence rate between fasting and fed conditions. The highest proportion of non-bioequivalent studies was for weak acids (10/19 cases, 53%) and neutral APIs (23/95 cases, 24%). Lower non-bioequivalence occurrence was observed for weak bases (1/15 cases, 7%) and amphoteric APIs (0/16 cases, 0%). The median dose numbers at pH 1.2 and pH 3 were higher and the most basic acid dissociation constant (p
K
a) was lower in the non-bioequivalent group of studies. Additionally, APIs with low calculated effective permeability (cPeff) or low calculated lipophilicity (clogP) had lower non-bioequivalence occurrence. Results of the subgroup analysis of studies under fasting conditions were similar as for the whole dataset.
Conclusion
Our results indicate that acido-basic properties of API should be considered in bioequivalence risk assessment and reveal which physico-chemical parameters are most relevant for the development of bioequivalence risk assessment tools for immediate-release products.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Monoclonal antibodies (mAbs) have been extensively developed over the past few years, for the treatment of various inflammatory diseases. They are large molecules characterized by complex ...pharmacokinetic and pharmacodynamic properties. Therapeutic drug monitoring (TDM) is routinely implemented in the therapy with mAbs, to monitor patients' treatment response and to further guide dose adjustments. Serum has been the matrix of choice in the TDM of mAbs and its sampling requires the visit of the patients to laboratories that are not always easily accessible. Therefore, dried blood spots (DBS) and various microsampling techniques have been suggested as an alternative. DBS is a sampling technique in which capillary blood is deposited on a special filter paper. It is a relatively simple procedure, and the patients can perform the home-sampling. The convenience it offers has enabled its use in the quantification of small-molecule drugs, whilst in the recent years, studies aimed to develop microsampling methods that will facilitate the TDM of mAbs. Nevertheless, hematocrit still remains an obstacle that hinders a more widespread implementation of DBS in clinical practice. The introduction of novel analytical techniques and contemporary microsampling devices can be considered the steppingstone to the attempts made addressing this issue.
The antiepileptic drug lamotrigine (LTG) shows high pharmacokinetic variability due to genotype influence and concomitant use of glucuronidation inducers and inhibitors, both of which may be ...frequently taken by elderly patients. Our goal was to develop a reliable quantification method for lamotrigine and its main glucuronide metabolite lamotrigine-N2-glucuronide (LTG-N2-GLU) in dried blood spots (DBS) to enable routine therapeutic drug monitoring and to identify altered metabolic activity for early detection of drug interactions possibly leading to suboptimal drug response.
The analytical method was validated in terms of selectivity, accuracy, precision, matrix effects, haematocrit, blood spot volume influence, and stability. It was applied to a clinical study, and the DBS results were compared to the concentrations determined in plasma samples. A good correlation was established for both analytes in DBS and plasma samples, taking into account the haematocrit and blood cell-to-plasma partition coefficients. It was demonstrated that the method is suitable for the determination of the metabolite-to-parent ratio to reveal the metabolic status of individual patients.
The clinical validation performed confirmed that the DBS technique is a reliable alternative for plasma lamotrigine and its glucuronide determination.
Dietary intake is the predominant route of human exposure to bisphenol A and one of the important food commodities is milk. The aim of our study was to preliminarily evaluate the bisphenol A exposure ...and disposition in sheep milk after repeated dietary and subcutaneous administration of a relatively low dose (100 µg/kg of b. w./day) of bisphenol A to a sheep. On the basis of blood plasma sampling, milk sampling and HPLC analysis, we developed the toxicokinetic model. With the toxicokinetic model we showed that most likely only free bisphenol A passes into the mammary gland and is subsequently conjugated there. The percentage of the dose eliminated with milk was less than 0.1%, regardless of the route of bisphenol A administration. It is proven that the bisphenol A is eliminated through the milk of lactating sheep. However, the amounts excreted in the milk that were detected in this study are minimal.
Oxidative Stress in Schizophrenia Grabnar, Iztok; Vovk, Tomas; Kores Plesnicar, Blanka ...
Current neuropharmacology,
2011-June, 2011-Jun, 2011-06-01, 20110601, Letnik:
9, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Increasing evidence indicates that oxidative damage exists in schizophrenia. Available literature about possible mechanisms of oxidative stress induction was reviewed. Furthermore, possibilities of ...measuring biomarkers of schizophrenia outside the central nervous system compartment, their specificity for different types of schizophrenia and potential therapeutic strategies to prevent oxidative injuries in schizophrenia were discussed. Data were extracted from published literature found in Medline, Embase, Biosis, Cochrane and Web of Science, together with hand search of references. Search terms were: schizophrenia, oxidative stress, antipsychotics, antioxidants and fatty acids. Finding a sensitive, specific and non invasive biomarker of schizophrenia, which could be measured in peripheral tissue, still stays an important task. Antioxidant enzymes, markers of lipid peroxidation, oxidatively modified proteins and DNA are most commonly used. As it considers the supplemental therapy, according to our meta-analysis vitamin E could potentially improve tardive dyskinesia, while for the effect of therapy with polyunsaturated fatty acids there is no clear evidence. Oxidative stress is a part of the pathology in schizophrenia and appears as a promising field to develop new therapeutic strategies. There is a need for well designed, placebo controlled trials with supplementation therapy in schizophrenia.
PDF
