Comparison of PUFA profiles in the blood and in follicular fluid and its association with follicular dynamics after PGF2α induced luteolysis in dairy cows

The objectives of the present study were to examine the fatty acid (FA) profiles in serum and in the follicular fluid (FF) and the association between polyunsaturated fatty acid level (PUFA) and follicular growth dynamics following induced luteolysis in dairy cows. A total of 29 dairy cows (CL>25mm, follicle approximate to 15mm) at d0 (start of the experiment) were submitted to ultrasound guided transvaginal follicular aspiration for FF collection from the largest follicle and were injected with 500 mu g of cloprostenol. The cows were subdivided into Group A1 (n=11) and Group A2 (n=8) resuming follicular growth either from a secondary follicle less than or larger than 8.5mm, respectively, present at the moment of aspiration and Group A0 (n=10) not resuming follicular growth. Follicular development was monitored daily by ultrasonography until the next dominant follicle reached approximate to 15mm and was subsequently punctured in Group A1 and A2 (d1). Serum and FF samples for FA determination were taken at d0 from all cows and at d1 in Group A1 and A2. No differences were observed between the FA profile in serum nor in FF between sampling days. Regarding the PUFA levels, the serum linoleic acid (C18:2n6) levels at d0 and d1 were significantly higher than in FF, while alpha linolenic acid (C18:3n3) was lower in the serum than in FF, both at d0 and d1. At d0, a tendency for negative correlation between serum and the FF C18:2n6 with subsequent daily follicular growth rate was observed, while, at d1 there was a strong negative correlation between the serum C18:2n6 and daily growth rate (r=-0.71; p=0.0006). The present study revealed similarities of the FA profiles in the serum and in the FF and association between serum and FF PUFA content with the follicular dynamics after induced luteolysis

Tailoring Atomoxetine Release Rate from DLP 3D-Printed Tablets Using Artificial Neural Networks: Influence of Tablet Thickness and Drug Loading

Various three-dimensional printing (3DP) technologies have been investigated so far in relation to their potential to produce customizable medicines and medical devices. The aim of this study was to examine the possibility of tailoring drug release rates from immediate to prolonged release by varying the tablet thickness and the drug loading, as well as to develop artificial neural network (ANN) predictive models for atomoxetine (ATH) release rate from DLP 3D-printed tablets. Photoreactive mixtures were comprised of poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) 400 in a constant ratio of 3:1, water, photoinitiator and ATH as a model drug whose content was varied from 5% to 20% (w/w). Designed 3D models of cylindrical shape tablets were of constant diameter, but different thickness. A series of tablets with doses ranging from 2.06 mg to 37.48 mg, exhibiting immediate- and modified-release profiles were successfully fabricated, confirming the potential of this technology in manufacturing dosage forms on demand, with the possibility to adjust the dose and release behavior by varying drug loading and dimensions of tablets. DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction) and microscopic analysis showed that ATH remained in a crystalline form in tablets, while FTIR spectroscopy confirmed that no interactions occurred between ATH and polymers

Modification of the standard 7-day Ovsynch protocol to increase the luteolytic and synchronization risks in dairy cows

We hypothesized that a single dose of PGF2α belatedly injected on day 8 after GnRH-1 in cows receiving a 7-day Ovsynch-56 protocol (GnRH – 7 days – PGF2α – 56h – GnRH – 16h – timed AI) will increase the proportion of cows with complete luteolysis. At day 35±3 postpartum, 70 lactating Holstein cows from one herd were scored for body condition and pre-synchronized with PGF2α and GnRH (3 days apart) and 7 days later submitted to an Ovsynch-56 protocol for first AI after random assignment to two treatments: (1) OV-7 (n=35) with an injection of PGF2α either on day 7; or (2) OV-8 (n=35) on day 8 after G1, respectively. Blood was collected before the first PGF2α, at day 7 and day 8 in OV-7 and OV-8, respectively, at AI and at 7 days after AI to assess progesterone concentration. Ten cows were classified as acyclic and were excluded from the analysis resulting in 60 cows (OV-8, n=27; OV-7, n=33). In total, more (P=0.01) OV-8 cows and more (P=0.04) primiparous OV-8 cows had complete luteolysis compared with their OV-7 herd mates. In addition, more (P=0.008) OV-8 cows with BCS<2.75 had complete luteolysis compared with their OV-7 herd mates, whereas no difference was observed between treatments among cows with BCS ≥2.75. In conclusion, delaying the application of PGF2α by 1 day reduced the percentage of primiparous cows and cows with poorer BCS having incomplete luteal regression at the time of AI

Oral dosage forms with carvedilol fabricated by selective laser sintering (SLS) 3D printing technique

1. INTRODUCTION When it comes to pharmacy, 3D printing has gained immense popularity in recent years due to its revolutionary use in printing drugs tailored to individual patient needs [1,2]. Selective laser sintering (SLS) is an industrial 3D printing technique which uses a powder bed to build up the 3D object thanks to a laser which binds the powder particles together. Advantages of SLS technique include the fact that it is a solvent-free process and offers relatively fast production. Until today, a limited number of studies investigating the production of drug dosage forms using SLS have been reported [2,3]. 2. MATERIALS AND METHODS 2.1. Materials Carvedilol (CRV) was used as a model substance in this study and it was donated by Hemofarm (Vršac, Serbia). The following excipients used to obtain 3D printing tablets: polyvinyl alcohol (PVA, Merck), mannitol (Parteck® M, Merck), Ludipress® (coprocessed excipient consisting of 93% lactose monohydrate, 3.5% crospovidone (Kollidon® CL) and 3.5% povidone K30 (Kollidon® 30), BASF), talc (Merck) and candurin (Candurin® Gold Sheen, Merck). 2.2. Preparation of formulations The compositions of the formulations are shown in Table 1. Table 1. Composition of the formulations Material Formulation 1 Formulation 2 CRV 10% 10% PVA 55% 55% Parteck® M 30% / Ludipress® / 30% Talc 2% 2% Candurin® Gold Sheen 3% 3% Powder for 3D printing was obtained by mixing all the components of the formulation and sifting through a sieve with a diameter of 180 μm. 2.3. 3D printing of oral dosage forms A cylindrical 3D models of the printed tablets (8.00 mm diameter and 2.00 mm thickness) were designed with Autodesk Fusion 360 software version 2.0.8809 (Autodesk Inc, San Rafael, CA, USA), exported as a stereolithography file (.stl) and printed with Sintratec Kit 3D printer (Sintratec AG, Switzerland). The printing parameters were controlled using Sintratec 3D printer software. After a series of variations in temperature and laser speed, the optimal values of these parameters used in the 3D printing process were established and shown in Table 2. Table 2. SLS 3D printing process parameters Surface Temperature ( ◦C) Chamber Temperature ( ◦C) Laser speed (mm/s) Hatch space 80 ºC 70 ºC 60 250 μm 2.4. Mechanical properties of 3D tablets Tablets (n = 10) were weighed on a Sartorius BP 210 D analytical balance (Sartorius, Goettingen, Germany) and measured (diameter and thickness) using a digital caliper (Vogel, Kevelaer, Germany). 2.5. Powder X-ray diffraction analysis (PXRD) PXRD analysis was performed to assess whether the laser induced amorphization of any of the compounds, especially amorphization of poorly soluble CRV. Samples were collected using a Philips PW-1050 (Philips, The Netherlands) diffractometer, operated at 40 kV and 30 mA, using Ni-filtered Cu Kα radiation. 2.6. Dissolution and Drug Release Analysis Dissolution testing was performed under nonsink conditions using mini paddle apparatus (Erweka DT 600, Germany) with a paddle rotation speed of 50 rpm for 8 h, in 100 ml of phosphate buffer (pH 6.8). The amount of dissolved CRV was determined by HPLC method using Dionex Ultimate 3000 (Thermo Scientific, USA) HPLC system. 3. RESULTS AND DISCUSSION 3.1. 3D printing process It was shown that SLS printer was able to fabricate 3D tablets with CRV, as well as that success of the printing process depended on the used printing parameters. 3.2. Mechanical properties of 3D tablets The dimensions of the obtained 3D tablets were in accordance with the defined values of the created 3D models (F1: 8.10 ± 0.08 mm diameter and 2.10 ± 0.13 mm thickness, F2: 8.13 ± 0.09 mm diameter and 2.10 ± 0.12 mm thickness). Significant variations in tablet weight between formulations were not observed (m1=0.146 ± 0.04; m2=0.136 ± 0.03). 3.3. Powder X-ray diffraction analysis (PXRD) Figure 1. The X-ray powder diffraction of F1 and F2. 3.4. Dissolution and Drug Release Analysis Figure 2. Dissolution profiles of 3D printing tablets 4. CONCLUSION SLA represents a new chapter in 3D printing of solid oral dosage forms and in individualized therapy in particular. By adjusting the formulation and process parameters, it was possible to produce SLS tablets with coamorphous CRV and PVA as a main polymer. Complete drug release was achieved under non sink conditions after 8 hours in phosphate buffer. The tailoring of drug release might be achieved by varying formulation factors as well as process parameters, although it could be governed by the composition of the whole formulation.9th BBBB International Conference on Pharmaceutical Sciences Pharma Sciences of Tomorrow Ljubljana, Slovenia, 15th-17th September, 202

Primena fotopolimerizacione tehnike 3D štampe lekova u izradi dvoslojnih tableta

In recent years, introduction of modern technologies, such as 3D printing, has opened a new chapter and caused a paradigm shift from manufacturing of large-scale to small batches of medicines tailored accordingly to the specific needs of patients (1). The aim of this study was to formulate and fabricate two-layered tablets using digital light processing (DLP) technique, which utilizes light irradiation to create solid objects from photoreactive liquid resin in a layer-by-layer manner. Hydrochlorothiazide (HHT, 5%,w/w) and warfarin sodium (VRN, 5%,w/w) were selected as model drugs, commonly used together in the treatment of cardiovascular diseases. 3D printing process was initiated with 0.10% of photoinitiator, at a constant ratio of poly(ethylene glycol)diacrylate and poly(ethylene glycol) 400, 1:1, with the addition of water (10%,w/w). 3D tablets, with each of the active substances in a separate layer, 8.00 mm in diameter and 1.50 mm thick, as well as combined two-layered tablets with HHT and VRN in individual layers, were successfully printed with Wanhao D8 printer. Dissolution test results showed immediate, but incomplete release of VRN (81.47 ± 1.47%, after 45 min) from individual layers, while the release of HHT was prolonged and complete (98.17 ± 3.11%, after 8 h). Significantly slower and incomplete release of VRN and HHT from combined tablets was observed. The absence of interactions and the presence of a layered structure were confirmed. DLP technique has a potential to provide fast fabrication of combined tablets, while further optimization of formulation factors is necessary in order to achieve complete drug release.Poslednjih godina, uvođenjem savremenih tehnologija, poput 3D štampe, otvorilo se novo poglavlje u načinu proizvodnje lekova i uslovilo razvoj fundamentalnih promena, pri čemu serijska proizvodnja velikih šarži pretenduje da bude zamenjena malim serijama lekova prilagođenih specifičnim potrebama pacijenata (1). Cilj ovog istraživanja bio je da se formulišu i izrade dvoslojne tablete primenom tehnike digitalne obrade svetlosti (DLP) koja omogućava dobijanje objekata mehanizmom nanošenja materijala “sloj po sloj” iz tečne fotopolimerizacione smole pod uticajem svetlosti. Hidrohlortiazid (HHT, 5%, m/m) i varfarin-natrijum (VRN, 5%, m/m) odabrani su kao model lekovite supstance, koje se obično primenjuju zajedno u lečenju kardiovaskularnih bolesti. Proces 3D štampanja sproveden je u prisustvu 0,10% fotoinicijatora, pri konstantnom masenom odnosu poli(etilen glikol)diakrilata i poli(etilen glikola) 400, 1:1, uz dodatak 10% vode. 3D tablete, sa svakom od aktivnih supstanci u posebnom sloju, prečnika 8,00 mm i debljine 1,50 mm, kao i kombinovane dvoslojne tablete sa HHT i VRN u pojedinačnim slojevima, uspešno su odštampane u Wanhao D8 štampaču. Prilikom ispitivanja brzine rastvaranja lekovite supstance iz pojedinačnih slojeva, došlo je do trenutnog (81,47 ± 1,47% nakon 45 min), ali nepotpunog oslobađanja VRN, dok je HHT u potpunosti oslobođen, prateći kinetiku produženog oslobađanja (98,17 ± 3,11%, nakon 8 h). Zapaženo je znatno sporije i nepotpuno oslobađanje VRN i HHT iz kombinovanih dvoslojnih tableta, nakon 8 h. Potvrđeno je odsustvo interakcija i prisustvo slojevite strukture. DLP tehnika ima potencijal da obezbedi brzu izradu kombinovanih tableta, pri čemu je neophodna dalja optimizacija formulacionih faktora u cilju postizanja potpunog oslobađanja lekovite supstance.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Digital light processing 3D printing of Hydrochlorothiazide with modified release

Additive manufacturing also known as 3D printing gains more attention in scientific research due to its great advantages in simple and fast producing custom-designed products. 3D models created with computer-aided design (CAD) are presented to the printers and with different techniques, printing layer-by-layer desired products are made. Most used techniques in additive manufacturing are fused deposition modeling (FDM), material and ink jetting, sintering and vat polymerization techniques. Stereolithography (SLA) and digital light processing (DLP) are the most frequently used techniques in vat polymerization due to their advantages. In DLP technique, a digital micromirror is used for gradually exposing and solidifying a layer of liquid photopolymer solution following a layer-by-layer mechanism (Adamov et al., 2022; Zhu et al., 2020). Nowadays additive manufacturing finds its place in medicine by producing medical devices, implants, prostheses and medical equipment. 3D printing has enormous potential in personalized medicine as a result of different possibilities in production of dosage forms with desired shapes that contain one or more active compounds that can have different release profiles. 3D printing helps in overcoming the problem with permeability and solubility of some drugs and enables using drugs from different BCS classes.14th Central European Symposium on Pharmaceutical Technology, 28th - 30th September, Ohrid, N. Macedonia, 202

3D printing of carvedilol oral dosage forms using selective laser sintering technique

The adjustment of the dose according to the individual needs of the patient is a unique advantage of 3D printing technology, which is of particular importance for the pediatric and geriatric population, due to the diverse needs and characteristics of these groups of patients (Kotta et al., 2018). Selective laser sintering (SLS) is one of the newest 3D printing techniques that uses powder materials, where the powder particles are connected under the influence of laser beams. The main disadvantage of SLS 3D printing is the high process temperature, which can lead to the degradation of active substances. On the other hand, this technique has many advantages, such as high resolution, the possibility of powder recycling and the absence of pre- processing (Fina et al., 2018; Thakkar et al., 2021).14th Central European Symposium on Pharmaceutical Technology, 28th - 30th September, Ohrid, N. Macedonia, 202

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV

Calibration of the CMS hadron calorimeters using proton-proton collision data at root s=13 TeV

Methods are presented for calibrating the hadron calorimeter system of theCMSetector at the LHC. The hadron calorimeters of the CMS experiment are sampling calorimeters of brass and scintillator, and are in the form of one central detector and two endcaps. These calorimeters cover pseudorapidities vertical bar eta vertical bar ee data. The energy scale of the outer calorimeters has been determined with test beam data and is confirmed through data with high transverse momentum jets. In this paper, we present the details of the calibration methods and accuracy.Peer reviewe

Probing effective field theory operators in the associated production of top quarks with a Z boson in multilepton final states at root s=13 TeV

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