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This study aims to enhance growth characteristics and quality parameters for tomato plants (Lycopersicon esculentum) by applying different doses of Crezacin (synthetic) and Energene (natural) as growth regulators instead of Chemical fertilization. A specific experiment has been carried out to study the effect of two types of plant growth regulators Crezacin: Active substances (475 g/L): Orth-o-cresoxyacetic acid triethanolammonium salt with applied doses (100, 200 and 300 ppm) and Energene: active substances (700 g/kg) humic acid with applied doses (250, 500 and 700 ppm) on growth and physiological characteristics of tomato plants (Kendras F1). Both Crezacin and Energene were applied three times (Soaking tomato seeds for 24 hours before sowing, spraying on plants at 35 DAP, spraying on plants at 70 DAP). Application of humic acid "Ener-700" increased plant height (78.0 cm), number of leaves/plant (57.8), fresh weight (250.2 g), dry weight (75.1 g) of arial parts, flowers number (48.1), fruits number (35.1) and fruit weight (64.0 g). Also using " Ener-700" improved tomato fruit's quality by enhancing level of dry matter (7.6%), sugar contents (5.8 oBrix), Ascorbic acid (26.9 mg 100 g-1), Maturity Index (12.61) and Taste Index (1.09), while level of nitrate rose by increasing humic acid and the maximum level (22.0 mg kg-1) obtained from Ener-700. Applying Ener-500 gave the maximum titratable acidity (0.48%) and carotenoids contents (4.89 mg 100 g-1). [ABSTRACT FROM AUTHOR]

Two biostimulants, RutfarmMaxifol (Ascophyllum nodosum extract 17.5%, amino acids, macro- and microelements, Agromaster, Russia) and Radifarm (polysaccharides, glycosides, amino acids, and micro-elements; Valagro, Italy), were applied at different concentrations on tomato plants of the hybrid cultivar ‘Merlice’, grown under a hydroponic system. Biostimulants were applied in the form of seed soaking and twice as foliar sprayings at flowering and at the initial fruit development stages. Biostimulants were applied as water solutions at concentrations of 2.5, 5.0, and 7.5 mg·L−1. Plant growth, productivity, and fruit quality parameters were determined at three points: 35, 70, and 105 days after seeding. All biostimulant treatments resulted in higher values of growth parameters and yield productivity in relation to the control. The application of biostimulants improved the parameters of the fruits’ quality by increasing the total soluble solids and antioxidants, ascorbic acid, and carotenoid contents but it did not affect tomato fruit acidity; therefore, tomato fruits from the treated plants were tastier than those from control.

Red onion varieties are among the richest sources of food flavonoids derived from quercinus. This study presents material on agrotechnological evaluation of red onion samples. Field experiments were carried out on typical light chestnut soils of the right-bank part of the Lower Volga in the zone of a sharply continental climate with a drip irrigation method. 9 samples of onion of red color of integumentary scales of selection BEJO ZADEN B.V., NETHERLANDS (4 samples) were studied: Red Bull F1, Red Baron F1, Red Ram F1, Robin F1; NUNHEMS B.V., NETHERLANDS (3 samples): NUN 9003 F1 (Merenge), Countach F1, NUN 9005 F1; HAZERA SEEDS, ISRAEL (1 sample): Retano F1; ENZA ZADEN, NETHERLANDS (1 sample): Monastrell F1. The samples were studied according to: characteristics of bulb coloration, morphometric parameters of the bulb, yield and ripeness.

The article discusses the lessons in the safety of personnel cleaning up the accidents at the nuclear power plants (NPPs) in Chernobyl in Ukraine and Fukushima 1 in Japan. It presents several efficient measures to avoid exposure to radiation including conducting daily individual radiation checks. It mentions remote-controlled equipment, such as robotics and pilotless aircraft, as among the effective ways to reduce risk of radiation exposure for these personnel on the accident site.

The article reviews the emergence, development and differentiation of the architecture of research and education facilities on territorial, urban and project levels. The genetic (historical) process underlying different types of such research and education complexes is considered in the contexts of cultural episteme (knowledge system, according to Michel Foucault) and educational paradigms. The latter are categorized into syncretic, pre-industrial, industrial, post-industrial, and modern (“network”). By reviewing research and education facilities of various specializations in different historical periods and different geographic areas, the study identifies their principal architectural and planning prototypes – from sacral spaces to individual functional objects.

Background: The locus coeruleus (LC) noradrenergic system may provide a potential new target for pharmacological insomnia treatment, particularly in patients suffering from elevated distress. The selective α2 noradrenergic agonist dexmedetomidine attenuates LC activity in sub-anesthetic doses, yet no adequate non-parental delivery systems of dexmedetomidine are currently available. To examine the feasibility of oro-mucosal dexmedetomidine administration, we developed two distinct - one sublingual and one buccal - oro-mucosal, fast-disintegrating dexmedetomidine formulas tailored for self-administration. Here we established their pharmacokinetic and pharmacodynamic (PK-PD) profiles., Methods: In a pilot study (sublingual formulation; n=8 good sleepers) and a main study (buccal formulation; n=17 poor sleepers), each following a randomized, double-blind, placebo-controlled, cross-over design, we investigated sub-anesthetic doses (20 & 40 µg) of the two formulas. We complemented the PK assessments with all-night polysomnography, nocturnal cortisol and melatonin measurements, assessments of cardiovascular functions during and after sleep, cortisol awakening response, and post-awakening examination of subjective state and vigilance., Results: Particularly buccal dexmedetomidine was rapidly absorbed and exhibited excellent dose-proportionality with minimal between-subject variation in exposure. In poor sleepers, 40 µg of buccal dexmedetomidine shortened the sleep latency by 11.5 min, increased the time spent in non-rapid-eye-movement (NREM) sleep by 37.2 min, and elevated NREM sleep electroencephalographic slow wave energy (0.75-4.0 Hz) in the first half of the night by roughly 23 %. REM sleep latency was dose-dependently prolonged (20 µg: 55.0 min; 40 µg: 115.3 min). Nocturnal cortisol, melatonin and heart rate, and morning cortisol were not significantly affected by dexmedetomidine, nor did post-awakening orthostatic regulation, subjective sleepiness and mood, and psychomotor vigilance differ among the conditions., Conclusions: The favorable PK-PD profile of oro-mucosal dexmedetomidine delivery warrants further dose-finding and clinical studies, to establish the exact roles of α2 receptor agonism in pharmacological sleep enhancement and as possible novel mechanism to alleviate stress-related insomnia., Competing Interests: CONFLICT OF INTEREST STATEMENT: Dr. Rafael Wespi, Dr. Dario A. Dornbierer, and Dr. Hans-Peter Landolt are listed as inventors on a pending patent on “Dexmedetomidine for the treatment of sleep disorders” (UniTectra Fall-Nr. UZ-231534a) that is assigned to University of Zurich, Zurich, Switzerland. Dr. Dario A. Dornbierer declares that he co-founded Reconnect Labs, an academic spin-off company of the University of Zurich, focused on the development of dexmedetomidine-based products for the treatment of sleep disorders. Dr. Hans-Peter Landolt has received consultation fees from Heel Biologische Heilmittel GmbH., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

The mechanism governing pharmaceutical tablet disintegration is far from fully understood. Despite the importance of controlling a formulation's disintegration process to maximize the active pharmaceutical ingredient's bioavailability and ensure predictable and consistent release profiles, the current understanding of the process is based on indirect or superficial measurements. Formulation science could, therefore, additionally deepen the understanding of the fundamental physical principles governing disintegration based on direct observations of the process. We aim to help bridge the gap by generating a series of time-resolved X-ray micro-computed tomography (μCT) images capturing volumetric images of a broad range of mini-tablet formulations undergoing disintegration. Automated image segmentation was a prerequisite to overcoming the challenges of analyzing multiple time series of heterogeneous tomographic images at high magnification. We devised and trained a convolutional neural network (CNN) based on the U-Net architecture for autonomous, rapid, and consistent image segmentation. We created our own μCT data reconstruction pipeline and parameterized it to deliver image quality optimal for our CNN-based segmentation. Our approach enabled us to visualize the internal microstructures of the tablets during disintegration and to extract parameters of disintegration kinetics from the time-resolved data. We determine by factor analysis the influence of the different formulation components on the disintegration process in terms of both qualitative and quantitative experimental responses. We relate our findings to known formulation component properties and established experimental results. Our direct imaging approach, enabled by deep learning-based image processing, delivers new insights into the disintegration mechanism of pharmaceutical tablets., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Recently, the Amazonian plant medicine "ayahuasca"-containing the psychedelic compound N,N-dimethyltryptamine (DMT) and numerous β-carboline alkaloids, such as harmine-has been suggested to exhibit beneficial effects in patients with affective and other mental health disorders. Although ayahuasca ingestion is considered safe, its pharmacokinetics/pharmacodynamics and tolerability profile pose some challenges and may limit the clinical applicability in vulnerable patient populations. While overdosing and the admixture of intolerable plant constituents may explain some of the common adverse reactions, the peroral route of administration may represent another relevant source of gastro-intestinal intolerabilities and unpredictable pharmacokinetics across users. To overcome these challenges, the present work aimed at creating ayahuasca-analogue formulations with improved pharmacokinetics and tolerability profiles. To this end, we developed peroral formulas and compared them with parenteral formulas specifically designed to circumvent the gastro-intestinal tract. In more detail, peroral administration of a capsule (containing purified DMT and harmine) was tested against a combined administration of an oromucosal harmine tablet and an intranasal DMT spray at two dose levels in an open-label within-subject study in 10 healthy male subjects. Pharmacokinetic and pharmacodynamic profiles were assessed by means of continuous blood sampling, vital sign monitoring, and psychometric assessments. Common side effects induced by traditional herbal ayahuasca such as nausea, vomiting, and diarrhea were significantly attenuated by our DMT/harmine formulations. While all preparations were well tolerated, the combined buccal/intranasal administration of harmine and DMT yielded substantially improved pharmacokinetic profiles, indicated by significantly reduced variations in systemic exposure. In conclusion, the combined buccal/intranasal administration of harmine and DMT is an innovative approach that may pave the way towards a safe, rapid-acting, and patient-oriented administration of DMT/harmine for the treatment of affective disorders. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04716335., Competing Interests: DD, MK, DK, and MS declare that they co-founded Reconnect Labs, an academic spin-off at the University of Zurich, focused on the development of psychedelic medicines for mental health. MM and RR are shareholders of Reconnect Labs. All other co-authors have no conflict of interest to declare related to this work., (Copyright © 2023 Dornbierer, Marten, Mueller, Aicher, Mueller, Boxler, Kometer, Kosanic, von Rotz, Puchkov, Kraemer, Landolt, Seifritz and Scheidegger.)

Porous materials are ubiquitous and exhibit properties suitable for depositing therapeutic compounds. Drug loading in porous materials can protect the drug, control its release rate, and improve its solubility. However, to achieve such outcomes from porous delivery systems, effective incorporation of the drug in the internal porosity of the carrier must be guaranteed. Mechanistic knowledge of the factors influencing drug loading and release from porous carriers allows rational design of formulations by selecting a suitable carrier for each application. Much of this knowledge exists in research areas other than drug delivery. Thus, a comprehensive overview of this topic from the drug delivery aspect is warranted. This review aims to identify the loading processes and carrier characteristics influencing the drug delivery outcome with porous materials. Additionally, the kinetics of drug release from porous materials are elucidated, and the common approaches to mathematical modeling of these processes are outlined., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Drug delivery to the colon offers great promise for local treatment of colonic diseases as it allows bypassing systemic absorption in the small intestine, thereby increasing luminal drug concentrations in the colon. The primary objective of this in vivo pharmaco-scintigraphy study was to assess the colon drug targeting accuracy of a metronidazole benzoate colonic drug delivery system intended for local treatment of Clostridioides difficile infections. Additionally, it was assessed if the concept of mucoadhesion would increase colonic residence time and promote higher drug bioavailability. Two different capsule formulations were designed and tested in healthy human subjects. Capsules contained either non-mucoadhesive (NM) or mucoadhesive (M) microgranules, both loaded with 100 mg metronidazole benzoate (antibiotic prodrug) and 5 mg samarium oxide (scintigraphy tracer). Filled capsules were coated with a colonic-targeting technology consisting of two functional layers, which allow for accelerated drug release mediated by the intestinal pH in combination with colonic bacteria. Coated capsules were neutron-activated to yield the radioisotope 153 Sm prior to administration to 18 healthy subjects. Gamma-scintigraphy imaging was combined with the measurement of drug plasma levels. Formulation NM showed high colon-targeting accuracy. Initial capsule disintegration within the targeted ileocolonic region was observed in 8 out of 9 subjects (89%) with colonic arrival times in the range of 3.5-12 h and reduced systemic exposure. In contrast, the mucoadhesive formulation M showed some inconsistency regarding the site of initial capsule disintegration (targeting accuracy 56%). Variability of drug release was attributed to self-adhesion and agglomeration of the mucoadhesive microparticles within the capsule. Accurate ileocolonic delivery of metronidazole-loaded microgranules was achieved following oral administration of colonic-targeted capsules. Delayed drug release from NM microparticles in the colon leads to a reduced systemic exposure compared to immediate-release data from literature and presumably elevated drug concentrations in the colonic lumen. This approach offers promising options for the local treatment of colonic diseases., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Metamizole is an analgesic and antipyretic drug used intensively in certain countries. Previous studies have shown that metamizole induces cytochrome (CYP) 2B6 and possibly CYP3A4. So far, it is unknown whether metamizole induces additional CYPs and by which mechanism. Therefore, we assessed the activity of 6 different CYPs in 12 healthy male subjects before and after treatment with 3 g of metamizole per day for 1 week using a phenotyping cocktail approach. In addition, we investigated whether metamizole induces CYPs by an interaction with the constitutive androstane receptor (CAR) or the pregnane X receptor (PXR) in HepaRG cells. In the clinical study, we confirmed a moderate induction of CYP2B6 (decrease in the efavirenz area under the plasma concentration time curve (AUC) by 79%) and 3A4 (decrease in the midazolam AUC by 68%) by metamizole. In addition, metamizole weakly induced CYP2C9 (decrease in the flurbiprofen AUC by 22%) and moderately CYP2C19 (decrease in the omeprazole AUC by 66%) but did not alter CYP2D6 activity. In addition, metamizole weakly inhibited CYP1A2 activity (1.79-fold increase in the caffeine AUC). We confirmed these results in HepaRG cells, where 4-MAA, the principal metabolite of metamizole, induced the mRNA expression of CYP2B6, 2C9, 2C19, and 3A4. In HepaRG cells with a stable knockout of PXR or CAR, we could demonstrate that CYP induction by 4-MAA depends on CAR and not on PXR. In conclusion, metamizole is a broad CYP inducer by an interaction with CAR and an inhibitor of CYP1A2. Regarding the widespread use of metamizole, these findings are of substantial clinical relevance., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Amorphous solid dispersions (ASDs) are a promising drug-delivery strategy to overcome poor solubility through formulation. Currently, the understanding of drug absorption mechanisms from ASDs in humans is incomplete. Aiming to gain insights in this matter, we conducted a randomized cross-over design open-label clinical study (NCT03886766) with 16 healthy male volunteers in an ambulatory setting, using micro-dosed efavirenz as a model drug. In three phases, subjects were administered (1) solid ASD of efavirenz 50 mg or (2) dissolved ASD of efavirenz 50 mg or (3) a molecular solution of efavirenz 3 mg (non-ASD) as a control in block-randomized order. Endpoints were the pharmacokinetic profiles (efavirenz plasma concentration vs. time curves) and derived pharmacokinetic parameters thereof ( AUC 0-t , C max , t max , and k a ). Results showed that the dissolved ASD (intervention 2) exhibited properties of a supersaturated solution (compared to aqueous solubility) with rapid and complete absorption of the drug from the drug-rich particles. All interventions showed similar AUC 0-t and were well tolerated by subjects. The findings highlight the potential of particle forming ASDs as an advanced drug-delivery system for poorly soluble drugs and provide essential insights into underlying mechanisms of ASD functioning in humans, partially validating current conceptual models.

There is a high unmet medical need for child-appropriate oral dosage forms. The acceptability of a novel placebo orally dispersible tablet formulation (pODT) was therefore evaluated. Monolithic tablets contain an inorganic calcium carbonate/calcium phosphate carrier material as the main excipient. They were assessed in a cross-sectional acceptability study. The 40 child participants were between 2 to 5 years and 6 to 10 years old. One pODT with 5 mm diameter was administered to each participating child by placement on the tongue or into the buccal cavity. Parents were asked to complete a questionnaire together with the study personnel. The spontaneous reactions of the children were recorded. The ease of administration and children's acceptance of the tablet was rated by research staff on a 4-point acceptability scale and by parents on a 5-point Likert scale. The older subjects answered how they had liked the pODT by pointing to the appropriate face of a Facial Hedonic Scale. pODT had very high acceptability as 93% of parents, and all questioned children reported the formulation to be acceptable or very acceptable. Staff reported administering pODT in these children without problems. None of the children showed distress on receipt of pODT. We conclude that the proposed child-friendly dosage form provides a convenient option for oral drug administration and is expected to enhance drug-adherence in pediatric patients.

Amorphous solid dispersions (ASDs) can increase the oral bioavailability of poorly soluble drugs. However, their use in drug development is comparably rare due to a lack of basic understanding of mechanisms governing drug liberation and absorption in vivo . Furthermore, the lack of a unified nomenclature hampers the interpretation and classification of research data. In this review, we therefore summarize and conceptualize mechanisms covering the dissolution of ASDs, formation of supersaturated ASD solutions, factors responsible for solution stabilization, drug uptake from ASD solutions, and drug distribution within these complex systems as well as effects of excipients. Furthermore, we discuss the importance of these findings on the development of ASDs. This improved overall understanding of these mechanisms will facilitate a rational ASD formulation development and will serve as a basis for further mechanistic research on drug delivery by ASDs.

Despite the wide-spread use of liposomal drug delivery systems, application of these systems for oral purposes is limited due to their large-scale formulation and storage issues. Proliposomes are one of the formulation approaches for achieving solid powders that readily form liposomes upon hydration. In this work, we investigated a dry powder formulation of a model low-soluble drug with phospholipids loaded in porous functionalized calcium carbonate microparticles. We characterized the liposome formation under conditions that mimic the different gastrointestinal stages and studied the factors that influence the dissolution rate of the model drug. The liposomes that formed upon direct contact with the simulated gastric environment had a capacity to directly encapsulate 25% of the drug in situ. The emerged liposomes allowed complete dissolution of the drug within 15 min. We identified a negative correlation between the phospholipid content and the rate of water uptake. This correlation corroborated the results obtained for the rate of dissolution and liposome encapsulation efficiency. This approach allows for the development of solid proliposomal dosage formulations, which can be scaled up with regular processes.

Metal-based nanoparticles are clinically used for diagnostic and therapeutic applications. After parenteral administration, they will distribute throughout different organs. Quantification of their distribution within tissues in the 3D space, however, remains a challenge owing to the small particle diameter. In this study, synchrotron radiation-based hard X-ray tomography (SRμCT) in absorption and phase contrast modes is evaluated for the localization of superparamagnetic iron oxide nanoparticles (SPIONs) in soft tissues based on their electron density and X-ray attenuation. Biodistribution of SPIONs is studied using zebrafish embryos as a vertebrate screening model. This label-free approach gives rise to an isotropic, 3D, direct space visualization of the entire 2.5 mm-long animal with a spatial resolution of around 2 µm. High resolution image stacks are available on a dedicated internet page (http://zebrafish.pharma-te.ch). X-ray tomography is combined with physico-chemical characterization and cellular uptake studies to confirm the safety and effectiveness of protective SPION coatings. It is demonstrated that SRμCT provides unprecedented insights into the zebrafish embryo anatomy and tissue distribution of label-free metal oxide nanoparticles., (© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)