Farmakokinetika u plazmi i režim doziranja cefpirom-sulfata u ovaca

Cefpirome is fourth- generation cephalosporin class of drug with a broad spectrum of activity against Gram- positive and Gram- negative organisms. A pharmacokinetic study of single dose intravenous (IV) and intramuscular (IM) administration of cefpirome sulfate (10 mg/kg body weight) was conducted using High Performance Liquid Chromatography (HPLC) and the pharmacokinetic parameters established were utilized to calculate optimal dosage regimens in ewes. Following IV administration of cefpirome in ewes the mean value of the elimination rate constant (β), elimination half life (t½β), the area under the plasma drug concentration-time curve (AUC0-∞), the area under the first moment of the plasma drug concentration (AUMC), the mean residence time (MRT), the apparent volume of distribution (Vdarea) and total body clearance (ClB) were 0.43 ± 0.04 h-1, 1.68 ± 0.21 h, 82.71 ± 3.76 mg.h/mL, 211.06 ± 23.99 mg.h2/mL, 2.51 ± 0.19 h, 0.28 ± 0.03 L/kg and 0.11 ± 0.00 L/h/kg, respectively, while following IM administration of cefpirome the mean values were 0.33 ± 0.01 h-1, 2.04 ± 0.06 h, 73.27 ± 4.04 mg.h/mL, 229.02 ± 20.32 mg.h2/mL, 3.09 ± 0.12 h, 0.45 ± 0.03 L/kg and 0.14 ± 0.01 L/h/kg, respectively. The bioavailability following IM administration of cefpirome was 88.85 ± 4.07 %. Cefpirome concentration in plasma was maintained above the target MIC (≥0.25 mg/mL) for 12 h. The therapeutic dosage regimen calculated using the pharmacokinetic parameters generated by the intravenous route of drug administration indicated the most appropriate dose of cefpirome to maintain MIC at ≥ 0.25 μg/mL with a dosage interval of 12 h, would be 13.00 mg/kg body weight in ewes.Cefpirom je cefalosporin četvrte generacije lijekova sa širokim spektrom djelovanja protiv gram-pozitivnih i gram-negativnih mikroorganizama. Istraživanje farmakokinetike pojedinačne doze cefpirom-sulfata, primijenjene intravenski (iv.) i intramuskularno (im.) (10 mg/kg tjelesne mase), provedeno je tekućinskom kromatografijom visoke djelotvornosti (HPLC) te su utvrđeni pokazatelji za optimalan režim doziranja u ovaca. Nakon intravenske primjene cefpiroma u ovaca prosječna vrijednost konstante brzine eliminacije (β) bila je 0,43 ± 0,04 h-1, poluvijek eliminacije (t½β) 1,68 ± 0,21 h, područje ispod krivulje odnosa koncentracije u plazmi i vremena (AUC0-∞) 82,71 ± 3,76 mg.h/ mL, područje ispod krivulje prvog momenta koncentracije u plazmi (AUMC) 211,06 ± 23,99 mg.h2/mL. Nadalje, srednja vrijednost vremena zadržavanja (MRT) bila je 2,51 ± 0,19 h, prividni volumen distribucije (Vdarea) 0,28 ± 0,03 L/kg i ukupni tjelesni klirens (ClB) 0,11 ± 0,00 L/h/kg. Srednje vrijednosti tijekom intramuskularne primjene cefpiroma za prethodno navedene parametre bile 0,33 ± 0,01 h-1, 2,04 ± 0,06 h, 73,27 ± 4,04 mg.h/mL, 229,02 ± 20,32 mg.h2/mL, 3,09 ± 0,12 h, 0,45 ± 0,03 L/kg i 0,14 ± 0,01 L/h/kg. Bioraspoloživost nakon intramuskularne primjene cefpiroma bila je 88,85 ± 4,07 %. Koncentracija cefpiroma u plazmi održavana je iznad ciljne vrijednosti MIK-a (≥ 0,25 mg/mL) tijekom 12 sati. Terapijski režim doziranja izračunat na temelju farmakokinetičkih pokazatelja dobivenih intravenskom primjenom lijeka upućuje na optimalnu dozu cefpiroma kojom se može održati MIK pri vrijednosti ≥ 0,25 μg/mL s intervalom doziranja od 12 sati, a ta bi doza u ovaca bila 13,00 mg/kg tjelesne mase

Smartphone-based, rapid, wide-field fundus photography for diagnosis of pediatric retinal diseases

PurposeAn important, unmet clinical need is for cost-effective, reliable, easy-to-use, and portable retinal photography to evaluate preventable causes of vision loss in children. This study presents the feasibility of a novel smartphone-based retinal imaging device tailored to imaging the pediatric fundus.MethodsSeveral modifications for children were made to our previous device, including a child-friendly 3D printed housing of animals, attention-grabbing targets, enhanced image stitching, and video-recording capabilities. Retinal photographs were obtained in children undergoing routine dilated eye examination. Experienced masked retina-specialist graders determined photograph quality and made diagnoses based on the images, which were compared to the treating clinician's diagnosis.ResultsDilated fundus photographs were acquired in 43 patients with a mean age of 6.7 years. The diagnoses included retinoblastoma, Coats' disease, commotio retinae, and optic nerve hypoplasia, among others. Mean time to acquire five standard photographs totaling 90-degree field of vision was 2.3 ± 1.1 minutes. Patients rated their experience of image acquisition favorably, with a Likert score of 4.6 ± 0.8 out of 5. There was 96% agreement between image-based diagnosis and the treating clinician's diagnosis.ConclusionsWe report a handheld smartphone-based device with modifications tailored for wide-field fundus photography in pediatric patients that can rapidly acquire fundus photos while being well-tolerated.Translational relevanceAdvances in handheld smartphone-based fundus photography devices decrease the technical barrier for image acquisition in children and may potentially increase access to ophthalmic care in communities with limited resources

Retroperitoneal ancient neurilemmoma: A nervous rarity.

Neurilemmomas are tumors of neural origin that comprise Schwann cell proliferation in a characteristic pattern. They are benign in nature. Ancient neurilemmomas are usually longstanding growths that exhibit degenerative features that could be mistaken for malignancy. We report a case of ancient neurilemmoma in a 70-year-old male patient in the retroperitoneal area. Retroperitoneal schwannomas are extremely uncommon along with ancient neurilemmoma features making it worth reportin

EPHA2 mutations with oncogenic characteristics in squamous cell lung cancer and malignant pleural mesothelioma.

Squamous cell carcinoma (SCC) and malignant pleural mesothelioma (MPM) are thoracic malignancies with very poor prognosis and limited treatment options. It is an established fact that most of the solid tumors have overexpression of EPHA2 receptor tyrosine kinase. EPHA2 is known to exhibit opposing roles towards cancer progression. It functions in inhibiting cancer survival and migration via a ligand and tyrosine kinase dependent signaling (Y772). Whereas it is known to promote tumor progression and cell migration through a ligand-independent signaling (S897). We analyzed the expression profile and mutational status of the ephrin receptor A2 (EPHA2) in SCC and MPM cell lines and primary patient specimens. The EPHA2 receptor was found to be either overexpressed, mutated or amplified in SCC and MPM. In particular, the EPHA2 mutants A859D and T647M were interesting to explore, A859D Y772 dead mutant exhibited lower levels of phosphorylation at Y772 compared to T647M mutant. Molecular Dynamics simulations studies suggested that differential changes in conformation might form the structural basis for differences in the level of EPHA2 activation. Consequently, A859D mutant cells exhibited increased proliferation as well as cell migration compared to controls and T647M mutant. Kinomics analysis demonstrated that the STAT3 and PDGF pathways were upregulated whereas signaling through CBL was suppressed. Considered together, the present work has uncovered the oncogenic characteristics of EPHA2 mutations in SSC and MPM reinstating the dynamics of different roles of EPHA2 in cancer. This study also suggests that a combination of doxazosin and other EPHA2 inhibitors directed to inhibit the pertinent signaling components may be a novel therapeutic strategy for MPM and Non-small cell lung cancer patients who have either EPHA2 or CBL alterations

The First Gamma-ray Emitting BL Lacertae Object at the Cosmic Dawn

One of the major challenges in studying the cosmic evolution of relativistic jets is the identification of the high-redshift ($z>3$) BL Lacertae objects, a class of jetted active galactic nuclei characterized by their quasi-featureless optical spectra. Here we report the identification of the first $\gamma$-ray emitting BL Lac object, 4FGL~J1219.0+3653 (J1219), beyond $z=3$, i.e., within the first two billion years of the age of the Universe. The optical and near-infrared spectra of J1219 taken from 10.4 m Gran Telescopio Canarias exhibit no emission lines down to an equivalent width of $\sim$3.5 A supporting its BL Lac nature. The detection of a strong Lyman-$\alpha$ break at $\sim$5570 A, on the other hand, confirms that J2119 is indeed a high-redshift ($z\sim3.59$) quasar. Based on the prediction of a recent BL Lac evolution model, J1219 is one of the only two such objects expected to be present within the comoving volume at $z=3.5$. Future identifications of more $z>3$ $\gamma$-ray emitting BL Lac sources, therefore, will be crucial to verify the theories of their cosmic evolution.Comment: Accepted for publication in The Astrophysical Journal Letter

CXCR3 antagonist VUF10085 binds to an intrahelical site distinct from that of the broad spectrum antagonist TAK-779.

BACKGROUND AND PURPOSE: The chemokine receptor CXCR3 is implicated in a variety of clinically important diseases, notably rheumatoid arthritis and atherosclerosis. Consequently, antagonists of CXCR3 are of therapeutic interest. In this study, we set out to characterize binding sites of the specific low MW CXCR3 antagonist VUF10085 and the broad spectrum antagonist TAK-779 which blocks CXCR3 along with CCR2 and CCR5. EXPERIMENTAL APPROACH: Molecular modelling of CXCR3, followed by virtual ligand docking, highlighted several CXCR3 residues likely to contact either antagonist, notably a conserved aspartate in helix 2 (Asp-112(2:63) ), which was postulated to interact with the quaternary nitrogen of TAK-779. Validation of modelling was carried out by site-directed mutagenesis of CXCR3, followed by assays of cell surface expression, ligand binding and receptor activation. KEY RESULTS: Mutation of Asn-132(3.33) , Phe-207 and Tyr-271(6.51) within CXCR3 severely impaired both ligand binding and chemotactic responses, suggesting that these residues are critical for maintenance of a functional CXCR3 conformation. Contrary to our hypothesis, mutation of Asp-112(2:63) had no observable effects on TAK-779 activity, but clearly decreased the antagonist potency of VUF 10085. Likewise, mutations of Phe-131(3.32) , Ile-279(6.59) and Tyr-308(7.43) were well tolerated and were critical for the antagonist activity of VUF 10085 but not for that of TAK-779. CONCLUSIONS AND IMPLICATIONS: This more detailed definition of a binding pocket within CXCR3 for low MW antagonists should facilitate the rational design of newer CXCR3 antagonists, with obvious clinical potential.Arthritis Research UK. Grant Number: #1830

Small molecule chemokine mimetics suggest a molecular basis for the observation that CXCL10 and CXCL11 are allosteric ligands of CXCR3.

BACKGROUND AND PURPOSE: The chemokine receptor CXCR3 directs migration of T-cells in response to the ligands CXCL9/Mig, CXCL10/IP-10 and CXCL11/I-TAC. Both ligands and receptors are implicated in the pathogenesis of inflammatory disorders, including atherosclerosis and rheumatoid arthritis. Here, we describe the molecular mechanism by which two synthetic small molecule agonists activate CXCR3. EXPERIMENTAL APPROACH: As both small molecules are basic, we hypothesized that they formed electrostatic interactions with acidic residues within CXCR3. Nine point mutants of CXCR3 were generated in which an acidic residue was mutated to its amide counterpart. Following transient expression, the ability of the constructs to bind and signal in response to natural and synthetic ligands was examined. KEY RESULTS: The CXCR3 mutants D112N, D195N and E196Q were efficiently expressed and responsive in chemotaxis assays to CXCL11 but not to CXCL10 or to either of the synthetic agonists, confirmed with radioligand binding assays. Molecular modelling of both CXCL10 and CXCR3 suggests that the small molecule agonists mimic a region of the '30s loop' (residues 30-40 of CXCL10) which interacts with the intrahelical CXCR3 residue D112, leading to receptor activation. D195 and E196 are located in the second extracellular loop and form putative intramolecular salt bridges required for a CXCR3 conformation that recognizes CXCL10. In contrast, CXCL11 recognition by CXCR3 is largely independent of these residues. CONCLUSION AND IMPLICATIONS: We provide here a molecular basis for the observation that CXCL10 and CXCL11 are allosteric ligands of CXCR3. Such findings may have implications for the design of CXCR3 antagonists