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The pH-dependent solubility of the weakly basic TYK2 inhibitor 1 posed a risk to its advancement, given that drugs with such profiles have exhibited drug-drug interaction (DDI) with stomach acid-reducing agents in humans. In a rat model of pH dependence, preadministration of famotidine caused a 2.4-fold lower exposure of 1 when compared to control rats, implying that pH-dependent oral absorption can reduce the active drug's exposure and translate to subtherapeutic treatment. As part of risk mitigation, a prodrug strategy was explored by synthesizing solubility-enhancing prodrugs, resulting in the identification of lead prodrug 3c with acceptable stability and solubility profiles. In rats, the prodrug eliminated the significant difference in AUC and C max between pentagastrin and famotidine arms, thereby effectively mitigating the impaired drug absorption at the elevated pH relevant for absorption and DDI with famotidine. The prodrug also facilitated dose-proportional systemic exposure of 1 following dose escalation in rats and monkeys.

Malaria is a major public health problem in developing countries. The burden of malaria in fragile and conflict-affected states (FCAS) is increasing year by year. Moreover, the population living in FCAS is often the most vulnerable and at high risk of malaria due to factors, such as deteriorating healthcare system, mass relocations, and reduced resilience to shocks. Therefore, this scoping review aims to map the interventions that are conducted at the FCAS on malaria prevention among the general population. In addition, this review can help policy-makers and international health bodies, providing a comprehensive overview that can lead to more targeted, effective, and context-specific interventions. Databases, such as PubMed, EBSCO-CINAHL, Web of Science, ProQuest, and Cochrane Central Register of Controlled Trials, were searched using specified search terms. A total of 3601 studies were retrieved from the search. After screening, 62 studies were included in the synthesis that met the eligibility criteria. Narrative analysis of the findings was done. The results revealed that in fragile countries, interventions for children below 5 years of age included IPTi, TDA, and ACT. In conflicted countries, interventions for children below 5 years of age included TDA, LLINs, SMC, drug trials, and vaccination. Similar interventions were reported for other age groups and populations. Despite ongoing conflicts, malaria interventions have been maintained in these countries, but a persistent high burden of malaria remains. To achieve the goals of malaria elimination, the results of the review highlight the need for continued research and evaluation of malaria control interventions to assess their effectiveness and impact. Strengthening health systems, building partnerships, utilizing digital health technologies, and conducting context-specific research are recommended to improve healthcare access and reduce the burden of malaria in FCAS., (© 2024. The Author(s).)

Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14 , which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Introduction: There are no formal guidelines for whether CT-guided or fluoroscopy-guided TFESI should be undertaken for patients with symptoms of lumbar nerve root irritation and corresponding nerve impingement. Here, we sought to compare the efficacy, safety and cost of computer tomography (CT)-guided and fluoroscopically guided transforaminal epidural steroid injection (TFESI)., Materials and Methods: All patients who underwent lumbar TFESI at our institution between June 2016 and June 2018 were identified. Six-week follow-up outcomes were categorised. The radiation doses and associated cost was retrieved from our institution's costing system., Results: One hundred and sixteen patients were included (CT-50; fluoroscopy-56). There were no complications. More patients were discharged 6 weeks after CT-guided lumbar TFESI when compared with fluoroscopically guided TFESI (CT-23, fluoroscopy-14 (P = 0.027)). There was no difference in the number of patients who were referred to surgery (P = 0.18), for further pain management (P = 0.45), or for further TFESI (P = 0.43). The effective radiation dose was significantly higher for CT-guided TFESI (CT-5.73 mSv (3.87 to 7.76); fluoroscopy-0.55 mSv (0.11 to 1.4) (P < 0.01)). The total cost for CT-guided lumbar TFESI was £237.50 (£235 to £337), over £800 less than under fluoroscopic guidance (£1052 (£892.80 to £1298.00), P < 0.01)). Removing cost associated with staff and theatre use (staffing, theatre, medical indemnity and overheads) revealed CT-guided lumbar TFESI to be less expensive than if the procedure was fluoroscopy-guided-CT-guided: £132.6 (130.8 to 197.5); fluoroscopy: £237.4 (£209.2 to £271.9) (P = 0.019)., Conclusions: CT-guided TFESI was associated with a higher discharge rate, a lower cost, but a ten times higher radiation dose when compared with fluoroscopically guided TFESI. Prospective studies are required to compare the efficacy of these procedures and to investigate how the radiation dose of CT-guided TFESI can be reduced without jeopardising efficacy or safety., (© 2022. The Author(s).)

Biologics manufacturers must continually monitor the attachment of carbohydrates, called glycans, to their products, because any variability can impact safety and efficacy. To help the industry meet this challenge, the United States Pharmacopeial Convention (USP) offers glycan reference standards and validated methods for glycoprofiling using high-performance liquid chromatography (HPLC). The industry has recently adopted more advanced technologies for glycan analysis, including ultra-high performance liquid chromatography (UHPLC) and mass spectrometry. In this study, we confirm that USP's glycan reference standards are compatible with UHPLC by demonstrating comparable peak separation and glycan identification to HPLC methods. The improved resolving power and shorter run-times of UHPLC also allowed us to identify many of the minor glycan components present in USP's glycan reference standards. These more comprehensively characterized glycan reference standards will enable manufacturers to assess the micro-heterogeneity that can negatively impact the safety and efficacy of biological products., (Copyright © 2020 United States Pharmacopeial Convention. Published by Elsevier Inc. All rights reserved.)

Background: There are very limited data available on 30-day readmissions for ethnic minority patients with cirrhosis. The aim of the study was to identify the risk factors for 30-day readmission in ethnic minority patients admitted for cirrhosis., Methods: We did a retrospective review of 1,373 electronic medical records of patients with cirrhosis admitted from 2009 to 2011. Several parameters including alcohol use history, discharge location and cirrhosis severity scores - model for end-stage liver disease (MELD) score and Child-Pugh-Turcotte (CPT) at first admission were assessed. Statistical analysis was done using Chi-square test and t -test for categorical and continuous variables, respectively., Results: There were 79 patients in the readmission group (63% male, 54% Hispanics and 22% African Americans) and 104 in the no readmission group (62% male, 58% Hispanics and 24% African Americans). History of alcohol use within a month prior to admission (55% vs. 33%, P = 0.002), platelet count at discharge (89,000 vs. 124,000, P = 0.003), and discharge with more than seven medications per day (7.3 vs. 5.2, P = 0.005) were identified as risk factors for readmissions by multivariate analysis., Conclusion: Platelet count, active alcohol use and more than seven medications at discharge are predictors of readmission. These parameters can guide future interventions to reduce readmission rate and health care costs related to cirrhosis readmissions., Competing Interests: The authors have no conflict of interest to disclose., (Copyright 2020, Patel et al.)

Breast cancer is the prime cause for cancer mortality in women worldwide. The importance of diverse natural and dietary agents to reduce the risk of developing breast cancer is well established. Berberine, a natural isoquinoline alkaloid found in many medicinal plants is widely used in traditional Indian and Chinese medicine. Because of its capability to seize the cell cycle and induce apoptosis of numerous malignant cells, berberine has received considerable attention as a potential anticancer agent. In the present study, breast cancer was induced in Sprague Dawley (SD) rats by intragastric administration of 7, 12-dimethylbenz[a]anthracene (DMBA) at a dose of 80mg/kg of body weight. Treatment of berberine (50mg/kg BW) to breast tumor bearing rats was found to be effective against DMBA induced mammary carcinoma. The increased levels of lipid peroxide (malonaldehyde), pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), enzymatic antioxidants (SOD and CAT), non-enzymatic antioxidants (GSH and vitamin C) and transcription factor NF-κB were decreased significantly by administration of berberine. Furthermore, RT-PCR and western blot analysis showed the down-regulation of NF-κB and PCNA in breast tumors. Histopathological studies validated that berberine is effective against DMBA induced ductal carcinoma & invasive carcinoma. Altogether, these findings demonstrate the preventive role of berberine against DMBA induced mammary carcinoma in SD rats., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Despite pronounced increases in central pulse wave velocity (PWV) with aging, reflected wave transit time (RWTT), traditionally defined as the timing of the inflection point (TINF) in the central pressure waveform, does not appreciably decrease, leading to the controversial proposition of a "distal-shift" of reflection sites. TINF, however, is exceptionally prone to measurement error and is also affected by ejection pattern and not only by wave reflection. We assessed whether RWTT, assessed by advanced pressure-flow analysis, demonstrates the expected decline with aging., Methods and Results: We studied a sample of unselected adults without cardiovascular disease (n=48; median age 48 years) and a clinical population of older adults with suspected/established cardiovascular disease (n=164; 61 years). We measured central pressure and flow with carotid tonometry and phase-contrast MRI, respectively. We assessed RWTT using wave-separation analysis (RWTTWSA) and partially distributed tube-load (TL) modeling (RWTTTL). Consistent with previous reports, TINF did not appreciably decrease with age despite pronounced increases in PWV in both populations. However, aging was associated with pronounced decreases in RWTTWSA (general population -15.0 ms/decade, P<0.001; clinical population -9.07 ms/decade, P=0.003) and RWTTTL (general -15.8 ms/decade, P<0.001; clinical -11.8 ms/decade, P<0.001). There was no evidence of an increased effective reflecting distance by either method. TINF was shown to reliably represent RWTT only under highly unrealistic assumptions about input impedance., Conclusions: RWTT declines with age in parallel with increased PWV, with earlier effects of wave reflections and without a distal shift in reflecting sites. These findings have important implications for our understanding of the role of wave reflections with aging., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Lung cancer is the foremost cause of cancer mortality and is a growing economic burden worldwide. Chemoprevention, employing the use of natural, dietary or synthetic agents has become an appealing strategy to combat the increasing cases of cancers worldwide. The present study was designed to investigate the mechanism-based chemopreventive nature of hesperetin (HSP) against B[a]P induced lung carcinogenesis in Swiss albino mice. We analyzed the chemopreventive potential of HSP by estimating the status of lipid peroxidation (LPO), enzymic (SOD, CAT, GPx, GR, and GST), nonenzymic antioxidants (GSH, Vit C and Vit E), proinflammatory cytokine (TNF-α), western blotting (CYP1A1, PCNA, Nrf2 and NF-κB expression) and histopathology of lung tissues of control and experimental mice. Administration of B[a]P (50 mg/kg, p.o.) resulted in an increase in lung weight, LPO with concomitant decrease in body weight, enzymic (SOD, CAT, GPx, GR, and GST) and non-enzymic (GSH, Vit C and Vit E) antioxidants. Histological examination of lungs revealed severe alveolar and bronchiolar damages in B[a]P-induced mice. Further, elevated levels of TNF-α along with activated expression of NF-κB, PCNA and CYP1A1, and downregulation of Nrf2 was observed in B[a]P intoxicated animals. Pre- and post-treatment with HSP effectively suppressed B[a]P induced lung carcinoma and the associated preneoplastic lesions by alleviating LPO, modulating antioxidants and decreasing the expression of NF-κB, PCNA and CYP1A1. These findings demonstrate that HSP possesses a potential chemopreventive activity against B[a]P induced lung cancer and this is attributed to its free radical scavenging, antioxidant, anti-inflammatory and antiproliferative properties., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Avascular necrosis (AVN) of the femoral head is a serious complication in the management of developmental dislocation of the hip. Increasing the abduction angle increases its stability but compromises the vascularity of the femoral head. From our database of 240 children treated for developmental dislocation of hip by the two senior authors between 1998 and 2008, we defined two groups of children who underwent closed or medial open reduction of the hip after a failed Pavlik treatment or if patients presented late. In group 1, the reduced hip was immobilized in around 90° flexion, 60° abduction, and 0-10° internal rotation. In group 2 the hip was immobilized in around 45° of hip abduction with flexion and internal rotation as before. The first and second authors independently analysed these two groups blinded to the hip abduction angle. Our hypothesis was that a reduction in the hip abduction angle would reduce the incidence of AVN in the second group without compromising the stability. All eligible children were included, and there were 42 children in group 1 and 44 children in group 2. An almost equal number of children underwent closed and medial open reduction in both the groups. The age at reduction was a mode of 6 months (range 6-13 months) and 7 months (range 7-12 months), respectively. The abduction angle in the first group had a mode of 60° (range 52-70°) and the second group had a mode of 45° (range 38-50°). Radiographic evidence of AVN as described by Salter and colleagues was seen in eight children (19%) in the first group and seven children (16%) in the second group (P=0.78). Redislocation occurred in one child in the second group and none in the first group. In summary, the results show a nonsignificant reduction in the incidence of AVN when the hip abduction angle was reduced with no significant increased risk of redislocation.

N-Hetereocyclic carbenes (NHCs) were found to be efficient catalysts for the cyclization of propargylic alcohols and isocyanates. Domino cyclization reactions were carried out using isopropyl-substituted imidazolium salt as a precatalyst, and a wide range of substituted oxazolidinones were obtained in high yields.

This meta-analysis evaluates the quality of life in post-traumatic amputees in comparison with limb salvage. Studies included in this meta-analysis had a minimum of 24 months of follow-up and used a validated quality-of-life outcome assessment scale (Short Form-36 or Sickness Impact Profile) for physical and psychological outcomes. Two reviewers performed the search and data extraction independent of each other. A total of 214 studies were identified; 11 fulfilled the inclusion criteria; thus, 1138 patients were available for meta-analysis (769 amputees and 369 cases of reconstruction). The meta-analysis demonstrated that lower limb reconstruction is more acceptable psychologically to patients with severe lower limb trauma compared with amputation, even though the physical outcome for both management pathways was more or less the same., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Intricatinol and intricatin, the two homoisoflavonoids isolated from Hoffmanosseggia intricata, and two analogs have been synthesized from pyrogallol in three steps. The spectral data of synthetic intricatinol are in good agreement with those of natural metabolite, but the spectral data of intricatin are not corroborative with those of the natural product. The structure of intricatin has been thus revised to 8-methoxybonducellin, a compound isolated from Caesalpinia pulcherrima. The antioxidant activity of all the four homoisoflavonoids was determined by superoxide (NBT) and DPPH free radical scavenging methods. The synthetic analog 7,8-dihydroxy-3-[(3,4-dihydroxyphenyl)methylene]chroman-4-one displayed excellent activity in both methods.

Two new homoisoflavonoids, (E)-7-methoxy-3-(4'-methoxybenzylidene)chroman-4-one (1) and (E)-7-hydroxy-3-(3',4',5'-trimethoxybenzylidene)chroman-4-one (5), along with three known homoisoflavonoids (Z)-7-hydroxy-3-(4'-methoxybenzylidene)chroman-4-one (isobon ducellin) (2), (E)-7-hydroxy-3-(4'-methoxybenzylidene)chroman-4-one (bonducellin) (3) and (E)-7-hydroxy-3-(2',4'-dimethoxybenzylidene)chroman-4-one (4) were isolated from the whole plant of Caesalpinia pulcherrima. The structures of these new compounds were elucidated by electron impact mass spectrometry (EI-MS) and 1D and 2D-NMR spectral studies. Antimicrobial activity of the new compounds was evaluated.

Two new 5-deoxyflavonoids, 7,2',3',4'-tetramethoxyflavone (1) and 7,2',3',4'-tetramethoxyflavanone (2) together with a known flavone 7,4'-dimethoxy-3'-hydroxyflavone (3) were isolated from the whole plant of Calliandra inermis. The structures of these new compounds were elucidated by high resolution electron impact mass spectrometry (HR-EI-MS) and 1D and 2D-NMR spectral studies including 1H-1H correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond connectivity (HMBC) and nuclear Overhauser enhancement spectroscopy (NOESY).