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Thrombosis and inflammation are primary contributors to the onset and progression of ischemic stroke. The contactkinin pathway, initiated by plasma kallikrein (PK) and activated factor XII (FXIIa), functions bidirectionally with the coagulation and inflammation cascades, providing a novel target for therapeutic drug development in ischemic stroke. In this study, we identified a bat-derived oligopeptide from Myotis myotis (Borkhausen, 1797), designated LE6 (Leu-Ser-Glu-Glu-Pro-Glu, 702 Da), with considerable potential in stroke therapy due to its effects on the contact kinin pathway. Notably, LE6 demonstrated significant inhibitory effects on PK and FXIIa, with inhibition constants of 43.97 μmol/L and 6.37 μmol/L, respectively. In vitro analyses revealed that LE6 prolonged plasma recalcification time and activated partial thromboplastin time. In murine models, LE6 effectively inhibited carrageenan-induced mouse tail thrombosis, FeCl3-induced carotid artery thrombosis, and photochemically induced intracerebral thrombosis. Furthermore, LE6 significantly decreased inflammation and stroke injury in transient middle cerebral artery occlusion models. Notably, the low toxicity, hemolytic activity, and bleeding risk of LE6, along with its synthetic simplicity, underscore its clinical applicability. In conclusion, as an inhibitor of FXIIa and PK, LE6 offers potential therapeutic benefits in stroke treatment by mitigating inflammation and preventing thrombus formation. [ABSTRACT FROM AUTHOR]

An appropriately designed pharmacokinetic (PK) assay that is sensitive for antidrug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, was developed based on its mechanism of action (MoA). Using critical monoclonal anti-idiotypic (anti-ID) antibody positive controls as ADA surrogates, the impact on exposure was evaluated pre-clinically. In a phase I clinical trial (NCT02324257), initial data suggest that the combination of ADA and PK assays for correlation of the ADA response with cibisatamab exposure. To understand the neutralizing potential of patient-derived ADAs on drug activity, advanced ADA characterization has been performed. Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. For this purpose, relevant patient ADA binding features were identified and compared with the specific monoclonal anti-ID antibody-positive controls. Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs and allows a correlation between ADA response and loss of exposure. Therefore, the described study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure. [ABSTRACT FROM AUTHOR]

The author conducted weekly online group psychokinesis (PK) experiments between Aug. 9, 2019 and Feb. 25, 2023, with the goal of experiencing collective PK. Participant observation experiments were designed to uncover variables associated with group PK experiences rather than prove the existence of PK. Early experiments seemed to increase individual propensity for spontaneous anomalous experience. The group began attempting to influence pinwheel turning on June 12, 2020. Direct observation seemed to reduce pinwheel turning. Certain conversational elements, such as emotion and discussion of psychical research, seemed to enhance turning. A motionactivated Blink camera was incorporated into the protocol on November 8, 2021, allowing documentation of 44 pinwheel experiments. Experiences involved ostensible anomalous pinwheel turning, equipment failures, poltergeist-like events, and trickster effects. Quantitative results included: (1) Significantly more pinwheel turning, as measured by camera activations, during group meetings compared to equivalent nongroup periods; (2) Certain discussion topics were associated with rapid turning: occult traditions, psychic readings, psychical research; and (3) Other variables were associated with reduced turning: direct observation, relaxation exercise, miscellaneous discussion topics. Participants felt that the pinwheels exhibited a form of intelligence due to the pinwheel response to group discussion. Trickster effects included turning patterns that changed over time, unusual equipment failures, and 'hiding' behavior thwarting full verification. These features suggest that the replicability of findings may be limited, although a series of methodological guidelines are suggested to increase success. Grounded theory strategies allow theory development, and a new model is proposed to account for the phenomena in question. [ABSTRACT FROM AUTHOR]

The STAR GATE archive included an experiment from China of psicho-physical claim reportedly conducted on aqueous object (Wu et al, 1991). Over a time-lapse of approximately 208 seconds, total 7 phases of significant temperature deviation from the baseline temperature of 25 °C may be identified, without an explainable source of thermal generation. Not questioning the genuineness of the experiment, this work analyzes the thermal-energy transfer on the test-object that could have caused the reported temperature changes. A non-adiabatic single-compartment produces first-order low-pass responses between a thermal-input and the object's temperature. Whereas the input determines the steady-state condition, the thermal dissipation dictates the dynamics. Under the assumption of ONLY first-order responses and adjusting the input parameters including DC and AC magnitudes and time-constant of the single-compartment responses, multi-phase temperature changes resembling the reported patterns could be reconstructed. One rising phase and three falling phases with apparent oscillation were reconstructed by considering the thermal input to contain modulatory patterns of 0.4-0.5 Hz in frequency. Such modeled modulation of the thermal inputs would correspond to a correlation coefficient of 0.95 between the DC and AC magnitudes at a varying AC/ DC modulation-depth of ≤94%. The low-frequency may suggest relevance to altered neuro-electro-physiology. [ABSTRACT FROM AUTHOR]

Microbial keratitis in a post-transplant cornea should be considered a distinct entity from microbial keratitis in a non-transplant cornea. Firstly, the use of immunosuppressive treatments and sutures in corneal transplants changes the etiology of keratitis. Secondly, corneal transplant has an impact on corneal biomechanics and structure, which facilitates the spread of infection. Finally, the emergence of lamellar transplants has introduced a new form of keratitis known as interface keratitis. Given these factors, there is a clear need to update our understanding of and management strategies for microbial keratitis following corneal transplantation, especially in the era of lamellar transplants. To address this, a comprehensive review is provided, covering the incidence, risk factors, causes, and timing of microbial keratitis, as well as both clinical and surgical management approaches for its treatment in cases of penetrating and lamellar corneal transplants. [ABSTRACT FROM AUTHOR]

The use of available treatments for Fabry disease (FD) (including enzyme replacement therapy [ERT]) may be restricted by their limited symptom improvement and mode of administration. Lucerastat is currently being investigated in the MODIFY study as oral substrate reduction therapy for the treatment of FD. By reducing the net globotriaosylceramide (Gb3) load in tissues, lucerastat has disease-modifying potential to improve symptoms and delay disease progression. MODIFY is a multicenter, double-blind, randomized, placebo-controlled, parallel-group Phase 3 study (ClinicalTrial.gov: NCT03425539); here we present the rationale and design of this study. Eligible adults with a genetically confirmed diagnosis of FD and FD-specific neuropathic pain entered screening. Patients were randomized (2:1) to receive either oral lucerastat twice daily or placebo for 6 months; treatment allocation was stratified according to sex and ERT treatment status. The main objectives of MODIFY are to assess the effects of lucerastat on neuropathic pain, gastrointestinal (GI) symptoms, FD biomarkers, and determine its safety and tolerability. Neuropathic pain and GI symptoms are key features of FD that have a significant impact on quality of life. Despite various tools available to assess pain and GI symptoms, there are currently limited tools available to assess neuropathic and GI symptoms in FD, validated according to health authority guidelines. Based on FDA recommendations, we undertook a patient-reported outcome (PRO) validation study, using a novel eDiary-based PRO tool to assess the validity of evaluating neuropathic pain as a primary efficacy endpoint in MODIFY. Results from the PRO validation study are included. To date, MODIFY is the largest Phase 3 clinical study conducted in patients with FD. Enrollment to MODIFY is now complete, with 118 patients randomized. Results will be presented in a separate publication. Long-term effects of lucerastat are being assessed in the ongoing open-label extension study (NCT03737214).

BACKGROUND: Isoniazid (INH) is an important drug in many TB regimens, and unfavorable treatment outcomes can be caused by suboptimal pharmacokinetics. Dose adjustment can be personalized by measuring peak serum concentrations; however, the process involves cold-chain preservation and laboratory techniques such as liquid chromatography (LC)/mass spectrometry (MS), which are unavailable in many high-burden settings. Urine spectrophotometry could provide a low-cost alternative with simple sampling and quantification methods. METHODS: We enrolled 56 adult patients on treatment for active TB. Serum was collected at 0, 1, 2, 4, 6, and 8 h for measurement of INH concentrations using validated LC-MS/MS methods. Urine was collected at 0–4, 4–8, and 8–24 h intervals, with INH concentrations measured using colorimetric methods. RESULTS: The median peak serum concentration and total serum exposure over 24 h were 4.8 mg/L and 16.4 mg*hour/L, respectively. Area under the receiver operator characteristic curves for urine values predicting a subtherapeutic serum concentration (peak

An appropriately designed pharmacokinetic (PK) assay that is sensitive for anti-drug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, was developed based on its mechanism of action (MoA). Using critical monoclonal anti-idiotypic (anti-ID) antibody positive controls as ADA surrogates, the impact on exposure was evaluated pre-clinically. In a phase I clinical trial (NCT02324257), initial data suggest that the combination of ADA and PK assays for correlation of the ADA response with cibisatamab exposure. To understand the neutralizing potential of patient-derived ADAs on drug activity, advanced ADA characterization has been performed. Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. For this purpose, relevant patient ADA binding features were identified and compared with the specific monoclonal anti-ID antibody-positive controls. Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs and allows a correlation between ADA response and loss of exposure. Therefore, the described study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure.

Purpose: To assess and contrast the visual and refractive results of Descemetic deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PK) in the treatment of advanced keratoconus. Design: Retrospective, comparative, interventional study. Methods: This study enrolled eyes affected by keratoconus with preoperative mean keratometry ≥ 60 diopters (D) that were treated with either Descemetic DALK (30 eyes) or PK (29 eyes) by using always the same corneal diameters (8.00mm recipient; 8.25mm donor cornea) and the same suture technique (10– 0 nylon double-running 12-bites continuous suture). The outcome measures were postoperative uncorrected distance visual acuity (UDVA), best-corrected distance visual acuity (CDVA), subjective refractive astigmatism (SRAst), and keratometric astigmatism at 3mm area (SimK), spherical equivalent (SEq). Results: Postoperative visual acuity significantly improved in both groups. Mean CDVA was higher in the DALK group 3 months (DALK 0.61, PK 0.42, p< 0.05), 6 months (DALK 0.69, PK 0.44, p< 0.05), and 12 months (DALK 0.72, PK 0.45, p< 0.05) postoperatively. However, 6 months after suture removal, CDVA was not statistically different between the two groups (DALK 0.71, PK 0.75, p> 0.05). Final SRAst and SimK also were comparable between the two groups (respectively DALK 2.97, PK:2.81, p> 0.05; DALK 3.91, PK 2.37, p> 0.05). No significant statistical differences were noted for UCVA and SEq data during the entire follow-up period between the two groups. Conclusion: Both methods of corneal transplantation resulted in a notable enhancement of visual and refractive outcomes in eyes afflicted by advanced keratoconus. Descemetic DALK demonstrated superior visual acuity before suture removal, whereas DALK and PK exhibited comparable results in terms of visual acuity, refractive correction, and keratometric astigmatism after suture removal. [ABSTRACT FROM AUTHOR]

Introduction: Veterinary hemp products containing cannabidiol (CBD) and negligible psychoactive (THC) have increased popularity since hemp (with <0.3% THC) was removed from schedule 1 substances under the Controlled Substances Act in 2018. This was accompanied by increased CBD research, mostly on the short-term safety and efficacy for inflammatory and neurological conditions. It is imperative to understand how CBD is metabolized or accumulated in the body long-term, thus the goal of the present work was to determine monthly plasma CBD concentrations, as well as changes in pharmacokinetic (PK) parameters in chronically dosed dogs. Methods: The study was a masked, placebo-controlled, randomized design. Six adult beagles were assigned to placebo, 5 and 10 mg/kg/day CBD treatment groups. Dogs received oral oil treatment once daily for 36 weeks. Blood was collected once every 4 weeks pre- and postprandially for CBD plasma determination (at 0 and 2 h). Pharmacokinetics were conducted at 0, 18 and 36 weeks. Pharmacokinetics and monthly CBD plasma data of dogs who received CBD were analyzed as repeated measures over time using a mixed model, with significance at α = 0.05. Results: Average plasma CBD at 5 and 10 mg/kg were 97.3 ng/mL and 236. 8 ng/mL pre-prandial, 341 ng/mL and 1,068 ng/mL postprandial, respectively. PK parameters suggested CBD accumulation over time, with significant increases in Cmax and AUC at both the 18 and 36-week timepoints. Cmax and AUC were dose proportional. Half-life demonstrated large inter-individual variations and increased (p < 0.05) at weeks 18 and 36 compared to baseline. Volume of distribution was not affected by time or treatment, while MRT increased, and clearance decreased over time (p < 0.05). Conclusions and clinical importance: Chronic administration of CBD to healthy adult dogs led to a dose-proportional accumulation in the body for 36 weeks, which was confirmed by an increased half-life, total exposure, mean residence time and plasma peak. Our data also suggests that CBD plasma levels may have less daily variation if administered twice daily. [ABSTRACT FROM AUTHOR]

Abstract Background Vilobelimab, a complement 5a (C5a)-specific monoclonal antibody, reduced mortality in critically ill COVID-19 patients in a phase 3 multicentre, randomized, double-blind, placebo-controlled study. As part of the study, vilobelimab concentrations and C5a levels as well as antidrug antibodies (ADAs) to vilobelimab were analysed. Results From Oct 1, 2020 to Oct 4, 2021, 368 invasively mechanically ventilated COVID-19 patients were randomized: 177 patients were randomly assigned to receive vilobelimab while 191 patients received placebo. Pharmacokinetic sampling was only performed at sites in Western Europe. Blood samples for vilobelimab measurements were available for 93 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. On day 8, after three infusions, mean vilobelimab (trough) concentrations ranged from 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). Blood samples for C5a measurements were available for 94 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. At screening, C5a levels were highly elevated and comparable between groups. In the vilobelimab group, median C5a levels were 118.3 ng/mL [IQR 71.2–168.2 ng/mL] and in the placebo group, median C5a levels were 104.6 ng/mL [IQR 77.5–156.6 ng/mL]. By day 8, median C5a levels were reduced by 87% in the vilobelimab group (median 14.5 ng/mL [IQR 9.5–21.0 ng/mL], p

LNA-i-miR-221 is a novel microRNA(miRNA)-221 inhibitor designed for the treatment of human malignancies. It has recently undergone phase 1 clinical trial (P1CT) and early pharmacokinetics (PKs) data in cancer patients are now available. We previously used multiple allometric interspecies scaling methods to draw inferences about LNA-i-miR-221 PKs in humans and estimated the patient dose based on the safe and pharmacodynamic (PD) active dose observed in mice, therefore providing a framework for the definition of safe starting and escalation doses for the P1CT. The preliminary data collected during the P1CT showed that the LNA-i-miR-221 anticipated doses, according to our human PK estimation approach, were indeed well tolerated and effective. PD data demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets as well as stable disease in 8 (50.0%) patients and partial response in 1 (6.3%) colorectal cancer case. Here, we detail the experimentally evaluated PK parameters of LNA-i-miR-221 in human, using both a non-compartmental and a population PKs approach. The population approach was adequately described by a three-compartments model with first-order elimination. The recorded age, sex and body weight of patients were evaluated as potential covariates. The estimated typical population parameter values were clearance (CL = 200 mL/h/kg), central volume of distribution (V1 = 45 mL/kg), peripheral volume of distribution (V2 = 200 mL/kg, volume of the second peripheral compartment V3 = 930 mL/h/kg) and inter-compartmental clearance (Q2 = 480 mL/h/kg and Q3 = 68 mL/h/kg). Age was found to be a predictor of Q3, with a statistically significant correlation. This work aimed also at retrospectively comparing the measured plasmatic clearance values with those predicted by different allometric scaling approaches. Our comparative analysis showed that the most accurate prediction was achieved by applying the single species allometric scaling approach and that the use of more than one species in allometric scaling to predict therapeutic oligonucleotides PKs would not necessarily generate the best prediction. Finally, our predictive approach was found accurate not only in predicting the main PK parameters in human but suggesting the range of effective and safe dose to be applied in the next clinic phase 2.

ABSTRACTAspartic acid (Asp) isomerization is a spontaneous non-enzymatic post-translation modification causing a change in the structure of the protein backbone, which is commonly observed in therapeutic antibodies during manufacturing and storage. The Asps in Asp–Gly (DG), Asp–Ser (DS), and Asp–Thr (DT) motifs in the structurally flexible regions, such as complementarity-determining regions (CDRs) in antibodies, are often found to have high rate of isomerization, and they are considered “hot spots” in antibodies. In contrast, the Asp-His (DH) motif is usually considered a silent spot with low isomerization propensity. However, in monoclonal antibody mAb-a, the isomerization rate of an Asp residue, Asp55, in the aspartic acid-histidine-lysine (DHK) motif present in CDRH2 was found to be unexpectedly high. By determining the conformation of DHK motif in the crystal structure of mAb-a, we found that the Cgamma of the Asp side chain carbonyl group and the back bone amide nitrogen of successor His were in proximal contact, which facilitates the formation of succinimide intermediate, and the +2 Lys played an important role in stabilizing such conformation. The contributing roles of the His and Lys residues in DHK motif were also verified using a series of synthetic peptides. This study identified a novel Asp isomerization hot spot, DHK, and the structural-based molecular mechanism was revealed. When 20% Asp55 isomerization in this DHK motif occurred in mAb-a, antigen binding activity reduced to 54%, but the pharmacokinetics in rat was not affected significantly. Although Asp isomerization of DHK motif in CDR does not appear to have a negative impact on PK, DHK motifs in the CDRs of antibody therapeutics should be removed, considering the high propensity of isomerization and impact on antibody activity and stability.

Certain classes of antibiotics show "concentration dependent" antimicrobial activity; higher concentrations result in increased bacterial killing rates, in contrast to "time dependent antibiotics", which show antimicrobial activity that depends on the time that antibiotic concentrations remain above the MIC. Aminoglycosides and fluoroquinolones are still widely used concentration-dependent antibiotics. These antibiotics are not hydrolyzed by beta-lactamases and are less sensitive to the inoculum effect, which can be defined as an increased MIC for the antibiotic in the presence of a relatively higher bacterial load (inoculum). In addition, they possess a relatively long Post-Antibiotic Effect (PAE), which can be defined as the absence of bacterial growth when antibiotic concentrations fall below the MIC. These characteristics make them interesting complementary antibiotics in the management of Multi-Drug Resistant (MDR) bacteria and/or (neutropenic) patients with severe sepsis. Global surveillance studies have shown that up to 90% of MDR Gram-negative bacteria still remain susceptible to aminoglycosides, depending on the susceptibility breakpoint (e.g., CLSI or EUCAST) being applied. This percentage is notably lower for fluoroquinolones but depends on the region, type of organism, and mechanism of resistance involved. Daily (high-dose) dosing of aminoglycosides for less than one week has been associated with significantly less nephro/oto toxicity and improved target attainment. Furthermore, higher-than-conventional dosing of fluoroquinolones has been linked to improved clinical outcomes. Beta-lactam antibiotics are the recommended backbone of therapy for severe sepsis. Since these antibiotics are time-dependent, the addition of a second concentration-dependent antibiotic could serve to quickly lower the bacterial inoculum, create PAE, and reduce Penicillin-Binding Protein (PBP) expression. Inadequate antibiotic levels at the site of infection, especially in the presence of high inoculum infections, have been shown to be important risk factors for inadequate resistance suppression and therapeutic failure. Therefore, in the early phase of severe sepsis, effort should be made to optimize the dose and quickly lower the inoculum. In this article, the authors propose a novel concept of "Inoculum Based Dosing" in which the decision for antibiotic dosing regimens and/or combination therapy is not only based on the PK parameters of the patient, but also on the presumed inoculum size. Once the inoculum has been lowered, indirectly reflected by clinical improvement, treatment simplification should be considered to further treat the infection. [ABSTRACT FROM AUTHOR]

This paper proposes a framework that supports both free will and anomalous mind-matter interaction (psychokinesis). I begin by considering the argument by the physicist Sean Carroll that the laws of physics as we understand them rule out psychokinesis (and other modes of psi), and find his claims problematic, in part due to misunderstandings of arguments borrowed from David Hume. I proceed to consider a more dispositional notion of causality (in contrast to one characterized by universal and necessary laws) which is more hospitable to both psychokinesis and free will. I then incorporate recent work from the philosophy of mind and science to arrive at a framework that supports real volition and psychokinesis, which are intimately linked. This approach is fundamentally dispositional but grounded in an ontologically prior field of awareness and potentiality. I also consider that the regularities (or causal natures) we observe in our physical world are ultimately supported by teleological “intentions” within a nonlocal, mind-like quantum ground.

Background: Vilobelimab, a complement 5a (C5a)-specific monoclonal antibody, reduced mortality in critically ill COVID-19 patients in a phase 3 multicentre, randomized, double-blind, placebo-controlled study. As part of the study, vilobelimab concentrations and C5a levels as well as antidrug antibodies (ADAs) to vilobelimab were analysed. Results: From Oct 1, 2020 to Oct 4, 2021, 368 invasively mechanically ventilated COVID-19 patients were randomized: 177 patients were randomly assigned to receive vilobelimab while 191 patients received placebo. Pharmacokinetic sampling was only performed at sites in Western Europe. Blood samples for vilobelimab measurements were available for 93 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. On day 8, after three infusions, mean vilobelimab (trough) concentrations ranged from 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). Blood samples for C5a measurements were available for 94 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. At screening, C5a levels were highly elevated and comparable between groups. In the vilobelimab group, median C5a levels were 118.3 ng/mL [IQR 71.2–168.2 ng/mL] and in the placebo group, median C5a levels were 104.6 ng/mL [IQR 77.5–156.6 ng/mL]. By day 8, median C5a levels were reduced by 87% in the vilobelimab group (median 14.5 ng/mL [IQR 9.5–21.0 ng/mL], p < 0.001) versus an 11% increase in the placebo group (median 119.2 ng/mL [IQR 85.9–152.1 ng/mL]). Beyond day 8, though plasma sampling was sparse, C5a levels did not reach screening levels in the vilobelimab group while C5a levels remained elevated in the placebo group. Treatment-emergent ADAs were observed in one patient in the vilobelimab group at hospital discharge on day 40 and in one patient in the placebo group at hospital discharge on day 25. Conclusions: This analysis shows that vilobelimab efficiently inhibits C5a in critically ill COVID-19 patients. There was no evidence of immunogenicity associated with vilobelimab treatment. Trialregistration ClinicalTrials.gov, NCT04333420. Registered 3 April 2020, https://clinicaltrials.gov/ct2/show/NCT04333420 [ABSTRACT FROM AUTHOR]

IntroductionVeterinary hemp products containing cannabidiol (CBD) and negligible psychoactive (THC) have increased popularity since hemp (with

Dehua Zhao, Xiaoqing Long, Jisheng Wang Department of Clinical Pharmacy, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, People’s Republic of ChinaCorrespondence: Dehua Zhao; Jisheng Wang, Email zhaoyaoshi0566@163.com; wangjishengyaoshi@163.comAbstract: Poly (ADP-ribose) polymerase (PARP) inhibitors are small-molecule inhibitors of PARP enzymes (including PARP1, PARP2, and PARP3) that exhibit activity against tumor cells with defects in DNA repair. In recent years, five PARP inhibitors, olaparib, niraparib, rucaparib, talazoparib and veliparib, have been developed for the treatment of solid tumors, particularly in patients with breast-related cancer antigen (BRCA) 1/2 mutations, or those without a functional homologous recombination repair pathway. These novel treatments exhibit improved efficacy and toxicity when compared to conventional chemotherapy agents. The five PARP inhibitors are eliminated primarily via the liver and kidneys, hepatic or renal impairment may significantly affect their pharmacokinetics (PK). Therefore, it is important to know the effects of hepatic or renal impairment on the PK and safety of PARP inhibitors. In this review, we characterize and summarize the effects of hepatic and renal function on the PK of PARP inhibitors and provide specific recommendations for clinicians when prescribing PARP inhibitors in patients with hepatic or renal impairment.Keywords: PARP inhibitors, cancer, hepatic impairment, renal impairment, PK

Background: Assessment of the safety of heartworm preventatives in dogs with pre-existing patent heartworm (Dirofilaria immitis) infections is necessary because rapid adult worm and microfilarial death can lead to severe clinical complications, including thromboembolism and anaphylactic shock in dogs. The aim of this study was to determine the clinical safety of Simparica Trio® (sarolaner, pyrantel, moxidectin) in heartworm-infected dogs and the degree of microfilaricidal and adulticidal activity of three consecutive monthly treatments of Simparica Trio. Methods: Twenty-four laboratory Beagle dogs were implanted with 10 male and 10 female D. immitis (ZoeKY isolate), and once infection was patent, they were randomized equally among three groups to receive no treatment, 1× or 3× the maximum recommended label dose of Simparica Trio. Dogs in the treated groups received Simparica Trio on days 0, 28 and 56. In-life assessments included body weight, physical examinations, clinical observations, daily general health observations, a quantitative estimate of food consumption and blood collections for pharmacokinetic (PK) analysis, microfilariae (MF) counts and D. immitis antigen testing. At the end of the study the heart, lungs and pleural and peritoneal cavities were examined for adult D. immitis worms. Results: Simparica Trio was generally well tolerated. Emesis occurred at low frequency in all groups including control. Abnormal stool occurred occasionally in the 1× and 3× groups throughout the 3-month study. Fever (> 104 °F/40 °C) was recorded in one 1× and one 3× dog 1 day after the first dose and resolved by the following day. No severe hypersensitivity reactions occurred. The mean number of circulating microfilariae (MF) counts in the control group increased from 12,000/ml at study start (Day 0) to > 20,000/ml at Day 28 and remained > 20,000/ml for the duration of the study. The least squares means of circulating MF were reduced by 69.8% on Day 1 and 97.4% on Day 7 for the 1× group and remained at > 99% lower than the control group for the remainder of the study. Similarly, least squares means of circulating MF were reduced by 85.3% on Day 1 and 93.9% on Day 7 for the 3× group and remained > 98% lower than the control group for the remainder of the study. At the end of the study, the mean number of implanted adult worms recovered was < 10 per sex in all groups with 90%, 85% and 75% of live adult heartworms recovered in control, 1× and 3× treatment groups, respectively. Low numbers of dead adult worms were recovered in 1× and 3×, with none in control. Following each dose, the moxidectin and sarolaner AUC and Cmax had close to dose proportional increases. Conclusions: This study demonstrated that Simparica Trio (sarolaner, pyrantel, moxidectin) was well tolerated when administered to heartworm-positive dogs at 1× and 3× the maximum recommended dose at 28-day intervals for 3 consecutive months. Simparica Trio significantly reduced microfilaria counts in both treatment groups, without significant clinical consequences. At the doses administered, Simparica Trio had minor adulticidal activity but resulted in no clinical sequelae. [ABSTRACT FROM AUTHOR]

A series of amino-2-cyclohexyl ester derivatives were studied for their ion channel blocking and antiarrhythmic actions in the rat and a structure-activity analysis was conducted. The compounds are similar in chemical structure except for ionizable amine groups (pK values 6.1-8.9) and the positional arrangements of aromatic naphthyl moieties. Ventricular arrhythmias were produced in rats by coronary-artery occlusion or electrical stimulation. The electrophysiological effects of these compounds on rat heart sodium channels (Nav1.5) expressed in Xenopus laevis oocytes and transient outward potassium currents (Kv4.3) from isolated rat ventricular myocytes were examined. The compounds reduced the incidence of ischemia-related arrhythmias and increased current threshold for induction of ventricular fibrillo-flutter (VFt) dose-dependently. As pK increased compounds showed a diminished effectiveness against ischemia-induced arrhythmias, and were less selective for ischemia- versus electrically-induced arrhythmias. Where tested, compounds produced a concentration-dependent tonic block of Nav1.5 channels. An increased potency for inhibition of Nav1.5 occurred when the external pH (pHo) was reduced to 6.5. Some compounds inhibited Kv4.3 in a pH-independent manner. Overall, the differences in antiarrhythmic and ion channel blocking properties in this series of compounds can be explained by differences in chemical structure. Antiarrhythmic activity for the amino-2-cyclohexyl ester derivatives is likely a function of mixed ion channel blockade in ischemic myocardium. These studies show that drug inhibition of Nav1.5 occurred at lower concentrations than Kv4.3 and was more sensitive to changes in the ionizable amine groups rather than on positional arrangements of the naphthyl constituents. These results offer insight into antiarrhythmic mechanisms of drug-ion channel interactions.

Background: Capecitabine is one of the fluoropyrimidine anticancer agents which is extensively used in the management of colorectal cancer. We have noticed a discrepancy between the doses we are using in our patients and the recommended dosing regimen. Thus, this study aims to assess the pharmacokinetic parameters of capecitabine and its metabolites in colorectal cancer patients and report some clinical outcomes. Methods: This study is a prospective observational pharmacokinetic study. It was conducted at the Oncology Center at King Saud University Medical City. The study included adult patients who received capecitabine for any stage of colorectal cancer. Blood samples were collected following the oral administration of capecitabine. Capecitabine and its metabolites concentration in plasma were determined using HPLC and pharmacokinetic parameters were estimated using PKanalix software. Results: The study included 30 colorectal cancer patients with a mean age of 58 ± 9.5 years and ECOG Performance Status of 0–1. 60 % of the patients were in stage IV. The average total daily dose was 1265 ± 350 mg/m2/day. Cmax for capecitabine was 5.2 ± 1.3 μg/ mL and Tmax was 1 ± 0.25 h. AUClast for capecitabine was 28 ± 10 μg.h/ mL. Vdobs and Clobs for capecitabine were 186 ± 28 L and 775 ± 213 mL/min, respectively. Calculated half-life (t1/2) was 2.7 h. Half of our patients showed partial tumor response and 20% showed stable disease. Only two patients had to discontinue the treatment because of the toxicity. Conclusion: Despite using lower doses, capecitabine and its metabolites parameters were found to be similar to previous studies except for the longer half-life found in our patients. In addition, lower doses of capecitabine showed acceptable response rate which might indicate that higher doses are not always necessary to achieve desired therapeutic effect.

This study is concerned with the development of an optimum method for identification of supercritical CO2 permeability in thermoplastic films with moderate to excellent barrier properties namely, High-Density Polyethylene (HDPE), Raised-Temperature Polyethylene (PE-RT), Polyvinylidene Fluoride (PVDF) and aliphatic Polyketone (PK) at elevated temperatures (40 °C−82 °C). A high-temperature/high-pressure permeation cell was designed based on the “closed-volume/variable pressure” standard test method. The identified gas transport properties using the time lag method yielded significant error particularly for PVDF and PK, which was ascribed to the sole reliance on the accumulated pressure-rate in steady-state. This error was minimized using the Non-Linear Regression (NLR) by utilizing the full range of measured data including the transient state. The coefficient of determination between the measured and modeled data using NLR was quantified above 0.99 for all the polymers at the entire examined temperature range. The 1.4 % higher degree of crystallinity and 28.5 % smaller spherulite size caused 13.3 % higher diffusivity and 8.6 % lower solubility in PE-RT when compared with HDPE at 82°C. As a result of this trade-off, PE-RT exhibited only 3.5 % higher permeability than HDPE. The developed generalized temperature-dependent model provided the essential data for design optimization of gas barrier performance in multilayer high-temperature pressure-vessels.

A vast evolution of drug modalities has occurred over the last several decades. Novel modalities such as cell and gene therapies have proven to be efficacious for numerous clinical indications–primarily in rare disease and immune oncology. Because of this success, drug developers are heavily investing in these novel modalities. Given the complexity of these therapeutics, a variety of bioanalytical techniques are employed to fully characterize the pharmacokinetics of these therapies in clinical studies. Industry trends indicate that quantitative PCR (qPCR) and multiparameter flow cytometry are both valuable in determining the pharmacokinetics, i.e. cellular kinetics, of cell therapies. This manuscript will evaluate the pros and cons of both techniques and highlight regulatory guidance on assays for measuring cellular kinetics. Moreover, common considerations when developing these assays will be addressed. [ABSTRACT FROM AUTHOR]

The article has discussed a step-by-step algorithm for developing population pharmacokinetics models in the Lixoft Monolix software. Features of population pharmacokinetics study’s methodology have described. Special attention is paid to the advantages of the compartmental approach and nonlinear mixed effects modeling in study of pharmacokinetics. Methods for estimating population pharmacokinetic parameters and its implementation in software are described.

Colored digital images are one of the most important types of digital data to be used in many vital applications, which require a safe way to protect them from hacking operations and the danger of intruders and data thieves. This paper presents an effective and safe method for storing digitally colored images (CASDC). A high level of protection is provided through a complex secret key agreed upon between the sender and the receiver. The secret key consists of nine decimal digits (and can be increased as needed). These digits are processed to extract three values for each color of the three color channels. A left rotation process is performed for the value of each color to produce three new values, where an exclusion process is performed between them to obtain the encrypted value for the color. CASDC is evaluated against a wide range of images to calculate its throughput to show the extent to which this method fulfills encryption and decryption requirements. The Mean Square Error (MSE) values, Peak Signal Noise Ratio (PSNR), and Correlation Coefficient for the three primary channels of the RGB coloring system were analyzed. The practical results of the proposed method are compared with other standard methods such as Data Encryption Standard (DES), Tripple-DES (3DES), Advanced Encryption Standard (AES), and Blow Fish (BF). According to the obtained results, CASDC outperforms all standard methods in terms of efficiency by reducing the time of encryption and decryption and increasing the throughput of the corresponding process. Besides, CASDC is robust against breaks, as the attempts to break the private key will require hundreds of years in the best case.

Purpose: To assess the long-term outcome of graft insertion by taco technique through a 2.8-mm clear corneal incision in patients undergoing Descemet's stripping automated endothelial keratoplasty (DSAEK).Methods: This is a retrospective interventional case series of 77 eyes of 75 patients who underwent DSAEK in a tertiary eye hospital. The DSAEK donor grafts were folded to an uneven 70/30 taco and held at a single point using Utrata forceps. All insertions were through a 2.8-mm clear corneal incision except the two aphakic patients requiring combined SFIOL implantation. All patients underwent a comprehensive eye examination preoperatively and were followed up to 6 years postoperatively. Visual outcomes, graft clarity, and complications of all and endothelial cell loss in 22 patients with available postop specular microscopy were analyzed. Results: Overall, 59 (76.6%) had clear grafts until the final follow-up. Visual acuity improved in 48 (62.3%) from an average of 1.3 to 0.8 logMAR (P = 0.0001). Vision was maintained in seven and worsened in four eyes. Grafts failed in 18 (23.3%) eyes: seven (9%) were primary failures, two post rejection, four done for failed PK did not clear, four due to worsening of preexisting glaucoma, and one noncompliant failed eventually. Average endothelial cell density reduction was 26.3% (mean preop donor 2419 to postop 1779 cells/mm2; P = 0.000). Conclusion: Our study shows good long-term clinical outcome of DSAEK using Taco technique through a 2.8-mm clear corneal incision in a tertiary hospital.

Certain classes of antibiotics show “concentration dependent” antimicrobial activity; higher concentrations result in increased bacterial killing rates, in contrast to “time dependent antibiotics”, which show antimicrobial activity that depends on the time that antibiotic concentrations remain above the MIC. Aminoglycosides and fluoroquinolones are still widely used concentration-dependent antibiotics. These antibiotics are not hydrolyzed by beta-lactamases and are less sensitive to the inoculum effect, which can be defined as an increased MIC for the antibiotic in the presence of a relatively higher bacterial load (inoculum). In addition, they possess a relatively long Post-Antibiotic Effect (PAE), which can be defined as the absence of bacterial growth when antibiotic concentrations fall below the MIC. These characteristics make them interesting complementary antibiotics in the management of Multi-Drug Resistant (MDR) bacteria and/or (neutropenic) patients with severe sepsis. Global surveillance studies have shown that up to 90% of MDR Gram-negative bacteria still remain susceptible to aminoglycosides, depending on the susceptibility breakpoint (e.g., CLSI or EUCAST) being applied. This percentage is notably lower for fluoroquinolones but depends on the region, type of organism, and mechanism of resistance involved. Daily (high-dose) dosing of aminoglycosides for less than one week has been associated with significantly less nephro/oto toxicity and improved target attainment. Furthermore, higher-than-conventional dosing of fluoroquinolones has been linked to improved clinical outcomes. Beta-lactam antibiotics are the recommended backbone of therapy for severe sepsis. Since these antibiotics are time-dependent, the addition of a second concentration-dependent antibiotic could serve to quickly lower the bacterial inoculum, create PAE, and reduce Penicillin-Binding Protein (PBP) expression. Inadequate antibiotic levels at the site of infection, especially in the presence of high inoculum infections, have been shown to be important risk factors for inadequate resistance suppression and therapeutic failure. Therefore, in the early phase of severe sepsis, effort should be made to optimize the dose and quickly lower the inoculum. In this article, the authors propose a novel concept of “Inoculum Based Dosing” in which the decision for antibiotic dosing regimens and/or combination therapy is not only based on the PK parameters of the patient, but also on the presumed inoculum size. Once the inoculum has been lowered, indirectly reflected by clinical improvement, treatment simplification should be considered to further treat the infection.

Objective: Four laboratory studies and an online experiment explored psychophysical (mind-matter) interactions with quantum entangled photons. Method: Entanglement correlation strength measured in real-time was presented via a graph or dynamic images displayed on a computer monitor or web browser. Participants were tasked with mentally influencing that metric. Results: A statistically significant increase in entanglement strength was obtained in experimental conditions in the four lab studies (p < 0.02), with particularly strong results observed in three studies conducted at the Institute of Noetic Sciences (p < 0.0002). Modest results (p < 0.05) were observed in a high-quality subset of entanglement samples in an online experiment. Control experiments using the same equipment and protocols, but without observers present, showed results consistent with chance expectation in both the lab and online studies. Conclusion: These outcomes suggest that the fidelity of entangled states and the nonlocal resource they entail may be mutable in systems that include conscious awareness. This is potentially of interest for quantum information technologies such as quantum computation, encryption, key distribution, and teleportation. The results are also relevant for interpretations of quantum theory, especially if future studies show that entanglement strength can be mentally modulated above the Tsirelson Bound – the upper limit predicted by quantum theory. Such an outcome would suggest that quantum theory in its present form does not hold when physical systems interact with certain mental states. The results of these exploratory experiments justify continued investigation of entangled photons as targets of mind-matter interaction.

Metabolic engineering efforts toward rewiring metabolism of cells to produce new compounds often require the utilization of non-native enzymatic machinery that is capable of producing a broad range of chemical functionalities. Polyketides encompass one of the largest classes of chemically diverse natural products. With thousands of known polyketides, modular polyketide synthases (PKSs) share a particularly attractive biosynthetic logic for generating chemical diversity. The engineering of modular PKSs could open access to the deliberate production of both existing and novel compounds. In this review, we discuss PKS engineering efforts applied at both the protein and cellular level for the generation of a diverse range of chemical structures, and we examine future applications of PKSs in the production of medicines, fuels and other industrially relevant chemicals.

Efforts to improve preservice teacher education have recently focused on developing teachers' adequate pedagogical knowledge (PK), content knowledge (CK), and pedagogical content knowledge (PCK), which are critical elements of teacher's professional knowledge, and important indicators of preparedness to teach. However, the development of the three knowledge domains of Chinese preservice English as a foreign language (EFL) teachers is surprisingly under-researched. To fill this gap, this study examined the development of the three knowledge domains of a group of Chinese preservice EFL teachers at different stages of a teacher education program. Specifically, it explored the relationship among the three knowledge domains, and the effects of learning opportunities on their development. Findings revealed that preservice EFL teachers at a later stage outperformed those at an earlier stage with regard to PK and PCK. Our findings also suggested that there were positive correlations among PK, CK, and PCK at different stages of the teacher education program. Furthermore, the findings showed that courses on CK, PK, and PCK, and teaching experience significantly influenced preservice EFL teachers' professional knowledge. However, the role of classroom observation was not significant. Implications for EFL teacher education and future research were also discussed. [ABSTRACT FROM AUTHOR]

Increasing clinical data on sex-related differences in drug efficacy and toxicity has highlighted the importance of understanding the impact of sex on drug pharmacokinetics and pharmacodynamics. Intrinsic differences between males and females, such as different CYP enzyme activity, drug transporter expression or levels of sex hormones can all contribute to different responses to medications. However, most studies do not include sex-specific investigations, leading to lack of sex-disaggregated pharmacokinetic and pharmacodynamic data. Based available literature, the potential influence of sex on exposure-response relationship has not been fully explored for many drugs used in clinical practice, though population-based pharmacokinetic/pharmacodynamic modelling is well-placed to explore this effect. The aim of this review is to highlight existing knowledge gaps regarding the effect of sex on clinical outcomes, thereby proposing future research direction for the drugs with significant sex differences. Based on evaluated drugs encompassing all therapeutic areas, 25 drugs demonstrated a clinically meaningful sex differences in drug exposure (characterised by ≥ 50% change in drug exposure) and this altered PK was correlated with differential response. [ABSTRACT FROM AUTHOR]

Penelitian ini bertujuan untuk mengevaluasi pengaruh penggunaan Ampas Kelapa (Cocos nucifera L.) dalam Konsentrat dengan Level Berbeda terhadap Produksi Susu Kambing Nubian, dengan menggunakan Rancangan Bujur Sangkar Latin (RBSL) 3 ulangan, 3 perlakuan, dan 3 periode. Perlakuan P0 = hijauan + konsentrat tanpa ampas kelapa, P1 = hijauan + konsentrat dengan 3,55% ampas kelapa, P2 = hijauan + konsentrat dengan 6,85% ampas kelapa. Perlakuan berpengaruh tidak nyata (P>0,05) terhadap konsumsi hijauan segar, BK hijauan, PK hijauan, SK hijauan, air minum dan pertambahan bobot badan. Perlakuan berpengaruh sangat nyata (P

Increasing clinical data on sex-related differences in drug efficacy and toxicity has highlighted the importance of understanding the impact of sex on drug pharmacokinetics and pharmacodynamics. Intrinsic differences between males and females, such as different CYP enzyme activity, drug transporter expression or levels of sex hormones can all contribute to different responses to medications. However, most studies do not include sex-specific investigations, leading to lack of sex-disaggregated pharmacokinetic and pharmacodynamic data. Based available literature, the potential influence of sex on exposure-response relationship has not been fully explored for many drugs used in clinical practice, though population-based pharmacokinetic/pharmacodynamic modelling is well-placed to explore this effect. The aim of this review is to highlight existing knowledge gaps regarding the effect of sex on clinical outcomes, thereby proposing future research direction for the drugs with significant sex differences. Based on evaluated drugs encompassing all therapeutic areas, 25 drugs demonstrated a clinically meaningful sex differences in drug exposure (characterised by ≥ 50% change in drug exposure) and this altered PK was correlated with differential response.

Efforts to improve preservice teacher education have recently focused on developing teachers’ adequate pedagogical knowledge (PK), content knowledge (CK), and pedagogical content knowledge (PCK), which are critical elements of teacher’s professional knowledge, and important indicators of preparedness to teach. However, the development of the three knowledge domains of Chinese preservice English as a foreign language (EFL) teachers is surprisingly under-researched. To fill this gap, this study examined the development of the three knowledge domains of a group of Chinese preservice EFL teachers at different stages of a teacher education program. Specifically, it explored the relationship among the three knowledge domains, and the effects of learning opportunities on their development. Findings revealed that preservice EFL teachers at a later stage outperformed those at an earlier stage with regard to PK and PCK. Our findings also suggested that there were positive correlations among PK, CK, and PCK at different stages of the teacher education program. Furthermore, the findings showed that courses on CK, PK, and PCK, and teaching experience significantly influenced preservice EFL teachers’ professional knowledge. However, the role of classroom observation was not significant. Implications for EFL teacher education and future research were also discussed.

In 2018/19, a study was conducted in the East Gojjam Zone of Northwestern Ethiopia to show the current potato cultivation problems relating to inorganic fertilizers at the farm level. The study used a mixture of 0, 34.5, and 69 kg P2O5 and 0, 100, 200, and 300 kg K2O. RCBD (Randomized Complete Block Design) was used with three replications. Using a mixture of 34.5 kg P2O5 and 200 kg K2O yielded a significant total and marketable yield of 49.14 t ha and 48.32 t ha, respectively (with an Ethiopian birr in the net reward of 236,172.40), In addition, this treatment surpass other treatments and produced a marginal rate of return that was higher than the least acceptable marginal rate of return. As a result, it is recommended that a combined fertilizer application method be used to optimize the economic return from potato production in the study area.

Purpose: The aim of this study was to compare the cost-effectiveness and perform cost-utility analysis of Descemet stripping automated endothelial keratoplasty (DSAEK) vs. penetrating keratoplasty (PK) in Indian population. Methods: This was an institutional, ambispective, observational study. Patients who underwent PK or DSAEK for endothelial dysfunction were included and followed up for 2 years; those with other ocular comorbidities were excluded. The analysis was performed from the patient's perspective receiving subsidized treatment at a tertiary care hospital. Detailed history, ophthalmic examination, total expenditure by patient, and clinical outcomes were recorded. The main outcome measures were best spectacle-corrected visual acuity (BSCVA), graft survival (Kaplan–Meier survival estimates), incremental cost-effectiveness ratio (ICER), and incremental cost-utility ratio (ICUR). Utility values were based on quality-adjusted life years (QALYs) associated with visual acuity outcomes. Statistical analysis was performed using SPSS software package, version 12.1; a value of P < 0.05 was considered statistically significant. Results: A total of 120 patients (PK: 60, DSAEK: 60) were included. At 2 years, for a similar logMAR BSCVA, [PK (0.32 ± 0.02), DSAEK (0.25 ± 0.02); P = 0.078], the overall cost for PK (13511.1 ± 803.3 INR) was significantly more than DSAEK (11092.9 ± 492.1 INR) (difference = 1952.6 INR; P = 0.01). ICER of DSAEK relative to PK was –39,052 INR for improvement in 1 logMAR unit BSCVA. ICUR of DSAEK relative to PK was –1,95,260 INR for improvement in 1 QALY. Conclusion: DSAEK was more cost-effective than PK in patients with endothelial dysfunction at 2 years.

Capecitabine is one of the fluoropyrimidine anticancer agents which is extensively used in the management of colorectal cancer. We have noticed a discrepancy between the doses we are using in our patients and the recommended dosing regimen. Thus, this study aims to assess the pharmacokinetic parameters of capecitabine and its metabolites in colorectal cancer patients and report some clinical outcomes. This study is a prospective observational pharmacokinetic study. It was conducted at the Oncology Center at King Saud University Medical City. The study included adult patients who received capecitabine for any stage of colorectal cancer. Blood samples were collected following the oral administration of capecitabine. Capecitabine and its metabolites concentration in plasma were determined using HPLC and pharmacokinetic parameters were estimated using PKanalix software. The study included 30 colorectal cancer patients with a mean age of 58 ± 9.5 years and ECOG Performance Status of 0–1. 60 % of the patients were in stage IV. The average total daily dose was 1265 ± 350 mg/m2/day. C max for capecitabine was 5.2 ± 1.3 μg/ mL and T max was 1 ± 0.25 h. AUC last for capecitabine was 28 ± 10 μg.h/ mL. Vd obs and Cl obs for capecitabine were 186 ± 28 L and 775 ± 213 mL/min, respectively. Calculated half-life (t 1/2) was 2.7 h. Half of our patients showed partial tumor response and 20% showed stable disease. Only two patients had to discontinue the treatment because of the toxicity. Despite using lower doses, capecitabine and its metabolites parameters were found to be similar to previous studies except for the longer half-life found in our patients. In addition, lower doses of capecitabine showed acceptable response rate which might indicate that higher doses are not always necessary to achieve desired therapeutic effect. [ABSTRACT FROM AUTHOR]

Asem A Alqudah,1 Rami A Al Dwairi,1 Noor M Alqudah,1 Sumayyah K Abumurad2 1Ophthalmology Service, Department of Special Surgery, Faculty of Medicine, Jordan University of Science and Technology (JUST), Irbid, Jordan; 2Department of Neurology, The University of Chicago Medicine, Chicago, IL, USACorrespondence: Asem A AlqudahOphthalmology Service, Department of Special Surgery, Faculty of Medicine, Jordan University of Science and Technology (JUST), P.O. Box 3030, Irbid 22110, JordanTel +962795458496Fax +962-27095010Email asemq981@yahoo.comAbstract: Novel coronavirus or COVID-19 is a viral illness that can cause severe respiratory symptoms. It spreads between people through direct, indirect (through contaminated objects or surfaces), or close contact with infected people via mouth and nose secretions. COVID-19 has caused a worldwide pandemic that necessitated many countries to perform a national lockdown. In Jordan, a complete lockdown was imposed by the government on March 17th, 2020 and continued for more than two months. The lockdown included every single sector in the country. Hospitals were only dealing with outpatient emergency cases, urgent referrals from primary or secondary health institutions and with inpatients whose medical conditions required keeping them admitted. Elective clinics and surgeries were canceled. At the King Abdullah University Hospital (KAUH), which is the only tertiary center in northern Jordan, we dealt with four cases of traumatic eye injury that resulted in a ruptured globe. The four cases were for eyes that had a history of penetrating keratoplasty (PK) and were visually compromised in the involved eye compared to the other eye. The percentage of open globe injuries to the total number of emergency cases presented during the lockdown was significantly higher than the percentage of open globe injuries to the total number of emergency cases presented during the corresponding period in the previous year (p=0.0005). We believe the lockdown inside homes has resulted in higher risk of trauma and rupture globe in this group of patients.Keywords: COVID-19, lockdown, eye injury, PK

A-Long Cui,1,* Wen-Fang Sun,1,2,* Zhao-Jin Zhong,1 Jie Jin,1 Si-Tu Xue,1 Shuo Wu,1,2 Yu-Huan Li,1,2 Zhuo-Rong Li1 1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China; 2CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China*These authors contributed equally to this workCorrespondence: Si-Tu Xue; Shuo Wu Tel +86-10-63027185; +86-10-63010984Email xuesitu@imb.pumc.edu.cn; wushuoimb@126.comIntroduction: Hepatitis B virus (HBV) is a global health concern that can cause acute and chronic liver diseases. Thus, there is an urgent need to research novel anti-HBV agents. Our previous reports show that N-phenylbenzamide derivatives exert broad-spectrum antiviral effects against HIV-1, HCV, and EV71 by increasing intracellular levels of APOBEC3G (A3G). As A3G is capable of inhibiting the replication of HBV, we screened the N-phenylbenzamide derivatives against HBV.Methods: In this study, a new derivative, N-(4-chlorophenyl)-4-methoxy-3-(methylamino) benzamide (IMB-0523), was synthesized and its anti-HBV activity was evaluated in vitro and in vivo. The acute toxicity and pharmacokinetic profiles of IMB-0523 were also investigated.Results: Our results show that IMB-0523 has higher anti-HBV activity in both wild-type HBV (IC50: 1.99 μM) and drug-resistant HBV (IC50: 3.30 μM) than lamivudine (3TC, IC50: 7.37 μM in wild-type HBV, IC50: > 440 μM in drug-resistant HBV). The antiviral effect of IMB-0523 against HBV may be due to an increased level of intracellular A3G. IMB-0523 also showed low acute toxicity (LD50: 448 mg/kg) in mice and promising PK properties (AUC0-t: 7535.10± 2226.73 μg·h/L) in rats. Further, IMB-0523 showed potent anti-HBV activity in DHBV-infected ducks.Conclusion: Thus, IMB-0523 may be a potential anti-HBV agent with different mechanisms than current anti-HBV treatment options.Keywords: anti-HBV activity, APOBEC3G, hepatitis B virus, IMB-0523, PK, toxicity

Dehua Zhao,1 Jing Chen,1 Mingming Chu,2 Xiaoqing Long,1 Jisheng Wang1 1Department of Clinical Pharmacy, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang 621000, People’s Republic of China; 2Department of Clinical Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, People’s Republic of ChinaCorrespondence: Jisheng Wang; Dehua Zhao Email wangjishengyaoshi@163.com; zhaodehua1000@163.comAbstract: Anaplastic lymphoma kinase (ALK) inhibitors are important treatment options for non-small-cell lung cancer (NSCLC), associated with ALK gene rearrangement. Patients with ALK gene rearrangement show sensitivity to and benefit clinically from treatment with ALK tyrosine kinase inhibitors (ALK-TKIs). To date, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and entrectinib have received approval from the US Food and Drug Administration and/or the European Medicines Agency for use during the treatment of ALK-gene-rearrangement forms of NSCLC. Although the oral route of administration is convenient and results in good compliance among patients, oral administration can be affected by many factors, such as food, intragastric pH, cytochrome P450 enzymes, transporters, and p-glycoprotein. These factors can result in increased risks for serious adverse events or can lead to reduced therapeutic effects of ALK-TKIs. This review characterizes and summarizes the pharmacokinetic parameters and drug–-drug interactions associated with ALK-TKIs to provide specific recommendations for oncologists and clinical pharmacists when prescribing ALK-TKIs.Keywords: ALK, TKIs, NSCLC, PK, drug–drug interactions

Thrombosis and inflammation are primary contributors to the onset and progression of ischemic stroke. The contact-kinin pathway, initiated by plasma kallikrein (PK) and activated factor XII (FXIIa), functions bidirectionally with the coagulation and inflammation cascades, providing a novel target for therapeutic drug development in ischemic stroke. In this study, we identified a bat-derived oligopeptide from Myotis myotis (Borkhausen, 1797), designated LE6 (Leu-Ser-Glu-Glu-Pro-Glu, 702 Da), with considerable potential in stroke therapy due to its effects on the contact kinin pathway. Notably, LE6 demonstrated significant inhibitory effects on PK and FXIIa, with inhibition constants of 43.97 μmol/L and 6.37 μmol/L, respectively. In vitro analyses revealed that LE6 prolonged plasma recalcification time and activated partial thromboplastin time. In murine models, LE6 effectively inhibited carrageenan-induced mouse tail thrombosis, FeCl 3 -induced carotid artery thrombosis, and photochemically induced intracerebral thrombosis. Furthermore, LE6 significantly decreased inflammation and stroke injury in transient middle cerebral artery occlusion models. Notably, the low toxicity, hemolytic activity, and bleeding risk of LE6, along with its synthetic simplicity, underscore its clinical applicability. In conclusion, as an inhibitor of FXIIa and PK, LE6 offers potential therapeutic benefits in stroke treatment by mitigating inflammation and preventing thrombus formation.

Background: Arsenic metabolism enzymes can affect the toxic effects of arsenic. However, the effects of different genders on the metabolites and metabolic enzymes in liver arsenic metabolism is still unclear. This study analyzed the gender differences of various arsenic metabolites and metabolic enzymes and further explored the effects of gender differences on arsenic metabolism in liver tissues of rats. Methods: Rats were treated with high/medium/low doses of iAs3+ or iAs5+. Liver pathological changes were observed with electron microscopy. The monomethyl aracid (MMA) and dimethyl aracid (DMA) was determined by high performance liquid chromatography-hydride generation atomic fluorescence spectroscopy. S-adenosylmethionine (SAM), arsenate respiratory reductase (ARR), nicotinamide adenine dinucleotide (NAD), purine nucleoside phosphorylase (PNP), pyruvate kinase (PK), and myeloperoxidase (MPO) SAM, ARR, NAD, PNP, PK, and MPO were determined by enzyme-linked immunoassay. RT-qPCR was used to determine Arsenic (+ 3 oxidation state) methyltransferase (AS3MT). Results: The iAs3+ and iAs5+ at high doses induced pathological changes in the liver, such as increased heterochromatin and lipid droplets. Compared within the same group, MMA and DMA were statistically significant in iAs3 + high, iAs3 + medium and iAs5+ low dose groups (P < 0.05). MMA of male rats in iAs3+ high and medium groups was higher than that of female rats, and the DMA of male rats was lower than that of female rats. As3MT mRNA in the male iAs3+ high group was higher than that of females. Besides, compared between male and female, only in iAS3+ low dose, iAS3+ medium dose, iAS5+ low dose, and iAS5+ medium dose groups, there was significant difference in SAM level (P < 0.05). Compared within the same group, male rats had significantly higher PNP and ARR activities while lower PK activity than female rats (P < 0.05). Between the male and female groups, only the iAS3+ high dose and medium dose group had a statistically significant difference (P < 0.05). The NAD activity of females in iAS3+ high dose group was higher than that of males. Conclusion: The gender differences in the arsenic metabolism enzymes may affect the biotransformation of arsenic, which may be one of the important mechanisms of arsenic toxicity of different sexes and different target organs. [ABSTRACT FROM AUTHOR]

Purpose: To assess the long-term outcome of graft insertion by taco technique through a 2.8-mm clear corneal incision in patients undergoing Descemet's stripping automated endothelial keratoplasty (DSAEK).Methods: This is a retrospective interventional case series of 77 eyes of 75 patients who underwent DSAEK in a tertiary eye hospital. The DSAEK donor grafts were folded to an uneven 70/30 taco and held at a single point using Utrata forceps. All insertions were through a 2.8-mm clear corneal incision except the two aphakic patients requiring combined SFIOL implantation. All patients underwent a comprehensive eye examination preoperatively and were followed up to 6 years postoperatively. Visual outcomes, graft clarity, and complications of all and endothelial cell loss in 22 patients with available postop specular microscopy were analyzed.Results: Overall, 59 (76.6%) had clear grafts until the final follow-up. Visual acuity improved in 48 (62.3%) from an average of 1.3 to 0.8 logMAR (P = 0.0001). Vision was maintained in seven and worsened in four eyes. Grafts failed in 18 (23.3%) eyes: seven (9%) were primary failures, two post rejection, four done for failed PK did not clear, four due to worsening of preexisting glaucoma, and one noncompliant failed eventually. Average endothelial cell density reduction was 26.3% (mean preop donor 2419 to postop 1779 cells/mm2; P = 0.000).Conclusion: Our study shows good long-term clinical outcome of DSAEK using Taco technique through a 2.8-mm clear corneal incision in a tertiary hospital. [ABSTRACT FROM AUTHOR]

Purpose: To identify the causes of failure of the different surgical corneal graft techniques: penetrating keratoplasty (PK), deep anterior lamellar keratoplasty (DALK), Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK). Methods: This multicentric retrospective study enrolled a consecutive cohort of patients who had undergone any type of keratoplasty between 2001 and 2016. The clinical data were obtained from the patient's medical records, following ethical guidelines, permissions and data protection. The main outcome measured in the study was the cause of graft failure, defined as any irreversible loss of graft transparency capable of compromising vision. The main causes of graft failure were classified as follows: (A) primary graft failure (PGF), (B) immunological rejection, (C) non‐rejection (which includes endothelial decompensation without rejection, IOP elevation/glaucoma, diseases of the ocular surface, recurrence of the primary disease, wound dehiscence/hypotonia and trauma, among others) and (D) specific causes of lamellar keratoplasty failure. A descriptive study of the obtained data was carried out. The distribution of the causes of failure was evaluated according to the type of corneal transplant. Results: Our research included a cohort of 571 keratoplasty failures, of which 509 met the inclusion criteria. The analysis of the causes of the PK failure showed that immunological allograft rejection represented the main cause, with 28.2% of the failures, followed by surface diseases (17.8%) and endothelial decompensation without rejection (17.3%). For the PK re‐grafts group, the main cause of failure was immunological allograft rejection (34.0%), followed by diseases of the ocular surface (18.5%). For the DALK group, the failures mainly occurred due to surface diseases such as limbal stem cell insufficiency, infectious keratitis, keratolysis or persistent epithelial defect (37.8%). However, the main reason for failure in the DSAEK group was endothelial decompensation without rejection (31.9%) while primary graft failure was the main cause of failure in the DMEK group (64.1%). Conclusion: The main reason for failure in PK was immunological allograft rejection, both in primary and secondary transplants. The leading causes for failure were diseases of the ocular surface in the DALK population, endothelial decompensation without rejection in DSAEK and primary graft failure in DMEK. [ABSTRACT FROM AUTHOR]