bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective Functionalizations of Cycloalkene‐Fused β‐Lactams and their Transformations into Densely‐Substituted Three‐Dimensional Molecular Entities
Authors: Nonn Melinda , Kiss Loránd
Published: October 2023

Highly‐functionalized, three‐dimensional molecules have had an increasing impact in synthetic organic chemistry and pharmaceutical research over the past decades. Their syntheses and the development of novel synthetic approaches towards versatile, small molecules with chemical and structural diversity have generated great interest. We have designed various selective and stereocontrolled methodologies for the functionalization of cycloalkene‐fused β‐lactams with a common C−C bond, as three‐dimensional, functionalized scaffolds, involving the transformation of their ring olefin bond. The synthetic methodologies developed to access various pharmacologically interesting derivatives with multiple chiral centers might be valuable protocols for the preparation of other classes of organic compounds as well.
Two CPR Awards Nominations Deadlines: Mid‐November, and Early Next Month
Authors: Bleemer Russ
Published: October 2023

Time is tight: The deadline for nominations for the written 2023 CPR Awards arrives on Friday, Nov. 17, soon followed by the Dec. 15 deadline for the diversity and leadership awards.
Microwave‐Responsive Flexible Room‐Temperature Phosphorescence Materials Based on Poly(vinylidene fluoride) Polymer
Authors: Zhang Yongfeng , Zhang Wei , Xia Junming , Xiong Chenchen , Li Gengchen , Li Xiaodong , Sun Peng , Shi Jianbing , Tong Bin , Cai Zhengxu , Dong Yuping
Published: October 2023

The development of flexible, room‐temperature phosphorescence (RTP) materials remains challenging owing to the quenching of their unstable triplet excitons via molecular motion. Therefore, a polymer matrix with Tg higher than room temperature is required to prevent polymer segment movement. In this study, a RTP material was developed by incorporating a 4‐biphenylboronic acid (BPBA) phosphor into a poly(vinylidene fluoride) (PVDF) matrix (Tg=−27.1 °C), which exhibits a remarkable UV‐light‐dependent oxygen consumption phosphorescence with a lifetime of 1275.7 ms. The adjustable RTP performance is influenced by the crystallinity and polymorph (α, β, and γ phases) fraction of PVDF, therefore, the low Tg of the PVDF matrix enables the polymeric segmental motion upon microwave irradiation. Consequently, a reduction in the crystallinity and an increase in the α phase fraction in PVDF film induces RTP after 2.45 GHz microwave irradiation. These findings open up new avenues for constructing crystalline and phase‐dependent RTP materials while demonstrating a promising approach toward microwave detection.
A Self‐Assembled Capsule for Propylene/Propane Separation
Authors: Zhou Chuang‐Wei , Wang Xue‐Zhi , Xie Mo , Xia Ri‐Qin , Luo Dong , Lian Zhao‐Xia , Ning Guo‐Hong , Lu Weigang , Zhou Xiao‐Ping , Li Dan
Published: October 2023

The development of energy‐saving technology for the efficient separation of olefin and paraffin is highly important for the chemical industry. Herein, we report a self‐assembled Fe4L6 capsule containing a hydrophobic cavity, which can be used to encapsulate and separate propylene/propane. The successful encapsulation of propylene and propane by the Fe4L6 cage in a water solution was documented by NMR spectroscopy. The binding constants K for the Fe4L6 cage toward propylene and propane were determined to be (5.0±0.1)×103 M−1 and (2.1±0.7)×104 M−1 in D2O at 25 °C, respectively. Experiments and theoretical studies revealed that the cage exhibited multiple weak interactions with propylene and propane. The polymer‐grade propylene (>99.5 %) can be obtained from a mixture of propylene and propane by using the Fe4L6 cage as a separation material in a U‐shaped glass tube. This work provides a new strategy for the separation of olefin/paraffin.
Unraveling the Solvent Effect on Solid‐Electrolyte Interphase Formation for Sodium Metal Batteries
Authors: Wang Shiyang , Weng Suting , Li Xinpeng , Liu Yue , Huang Xiangling , Jie Yulin , Pan Yuxue , Zhou Hongmin , Jiao Shuhong , Li Qi , Wang Xuefeng , Cheng Tao , Cao Ruiguo , Xu Dongsheng
Published: October 2023

Ether‐based electrolytes are considered as an ideal electrolyte system for sodium metal batteries (SMBs) due to their superior compatibility with the sodium metal anode (SMA). However, the selection principle of ether solvents and the impact on solid electrolyte interphase formation are still unclear. Herein, we systematically compare the chain ether‐based electrolyte and understand the relationship between the solvation structure and the interphasial properties. The linear ether solvent molecules with different terminal group lengths demonstrate remarkably distinct solvation effects, thus leading to different electrochemical performance as well as deposition morphologies for SMBs. Computational calculations and comprehensive characterizations indicate that the terminal group length significantly regulates the electrolyte solvation structure and consequently influences the interfacial reaction mechanism of electrolytes on SMA. Cryogenic electron microscopy clearly reveals the difference in solid electrolyte interphase in various ether‐based electrolytes. As a result, the 1,2‐diethoxyethane‐based electrolyte enables a high Coulombic efficiency of 99.9 %, which also realizes the stable cycling of Na||Na3V2(PO4)3 full cell with a mass loading of ≈9 mg cm−2 over 500 cycles.
A Gene‐Editable Palladium‐Based Bioorthogonal Nanoplatform Facilitates Macrophage Phagocytosis for Tumor Therapy
Authors: Feng Shujun , Zhang Yu , Gao Yanfeng , Liu Yuta , Wang Yanyi , Han Xin , Zhang Tao , Song Yujun
Published: October 2023

Macrophage phagocytosis of tumor cells has emerged as an attractive strategy for tumor therapy. Nevertheless, immunosuppressive M2 macrophages in the tumor microenvironment and the high expression of anti‐phagocytic signals from tumor cells impede therapeutic efficacy. To address these issues and improve the management of malignant tumors, in this study we developed a gene‐editable palladium‐based bioorthogonal nanoplatform, consisting of CRISPR/Cas9 gene editing system‐linked Pd nanoclusters, and a hyaluronic acid surface layer (HBPdC). This HBPdC nanoplatform exhibited satisfactory tumor‐targeting efficiency and triggered Fenton‐like reactions in the tumor microenvironment to generate reactive oxygen species for chemodynamic therapy and macrophage M1 polarization, which directly eliminated tumor cells, and stimulated the antitumor response of macrophages. HBPdC could reprogram tumor cells through gene editing to reduce the expression of CD47 and adipocyte plasma membrane‐associated protein, thereby promoting their recognition and phagocytosis by macrophages. Moreover, HBPdC induced the activation of sequestered prodrugs via bioorthogonal catalysis, enabling chemotherapy and thereby enhancing tumor cell death. Importantly, the Pd nanoclusters of HBPdC were sufficiently cleared through basic metabolic pathways, confirming their biocompatibility and biosafety. Therefore, by promoting macrophage phagocytosis, the HBPdC system developed herein represents a highly promising antitumor toolset for cancer therapy applications.
Dimensional and Optoelectronic Tuning of Lead‐free Perovskite Cs3Bi2I9−nBrn Single Crystals for Enhanced Hard X‐ray Detection
Authors: Li Xiang , Zhang Guodong , Hua Yunqiu , Cui Fucai , Sun Xue , Liu Jiaxin , Liu Hongjie , Bi Yanxiao , Yue Zhongjie , Zhai Zhongjun , Xia Haibing , Tao Xutang
Published: October 2023

Inorganic Bi‐based perovskites have shown great potential in X‐ray detection for their large absorption to X‐rays, diverse low‐dimensional structures, and eco‐friendliness without toxic metals. However, they suffer from poor carrier transport properties compared to Pb‐based perovskites. Here, we propose a mixed‐halogen strategy to tune the structural dimensions and optoelectronic properties of Cs3Bi2I9−nBrn (0≤n≤9). Ten centimeter‐sized single crystals are successfully grown by the Bridgman technique. Upon doping bromine to zero‐dimensional Cs3Bi2I9, the crystal transforms into a two‐dimensional structure as the bromine content reaches Cs3Bi2I8Br. Correspondingly, the optoelectronic properties are adjusted. Among these crystals, Cs3Bi2I8Br exhibits negligible ion migration, moderate resistivity, and the best carrier transport capability. The sensitivities in 100 keV hard X‐ray detection are 1.33×104 and 1.74×104 μC Gyair−1 cm−2 at room temperature and 75 °C, respectively, which are the highest among all reported bismuth perovskites. Moreover, the lowest detection limit of 28.6 nGyair s−1 and ultralow dark current drift of 9.12×10−9 nA cm−1 s−1 V−1 are obtained owing to the high ionic activation energy. Our work demonstrates that Br incorporation is an effective strategy to enhance the X‐ray detection performance by tuning the dimensional and optoelectronic properties.
Piezoelectric properties of noncovalently functionalized 2D nanomaterials incorporated poly(vinylidene fluoride) nanocomposites
Authors: Adaval Akanksha , Khurana Vaibhav , Bhatt Bharat B. , Singh Shiva , Gupta Dipti , Maji Pradip K. , Aslam Mohammed , Turney Terence W. , Simon George P. , Bhattacharyya Arup R.
Published: October 2023

We report here for the first time the role of noncovalently functionalized 2D nanomaterials on the ferroelectric and piezoelectric behavior of poly(vinylidene fluoride) (PVDF) nanocomposites. Graphene oxide (GO), expanded graphite (EG) and hexagonal boron nitride (h‐BN) were noncovalently modified via Li‐salt of 6‐amino hexanoic acid (Li‐AHA), denoted as m‐GO, m‐EG and m‐BN, in order to de‐agglomerate and de‐stack them, which were subsequently incorporated into the PVDF matrix via solution mixing, followed by compression molding. Simultaneously, PVDF nanocomposites with unmodified 0.08 wt% of 2D nanomaterials were also prepared using the same methodology. PVDF/m‐BN nanocomposite showed a higher extent of polar phase (~36%) associated with PVDF phase as compared to PVDF/m‐GO and PVDF/m‐EG nanocomposites. Further, the highest permittivity (~58 at 10−1 Hz) was achieved in PVDF/m‐BN nanocomposite, which was also reflected in higher remnant polarization (~61 nC/cm2) and a significantly higher d33 value (~53 pm/V). Moreover, a higher output peak to peak voltage (~13 V) was obtained for the sensor device fabricated from PVDF/m‐BN nanocomposite. Thus, the role of Li‐AHA‐modified 2D nanomaterials in improving the morphology, dielectric, ferroelectric, and piezoelectric characteristics of the PVDF nanocomposites was clearly established.
Neosetophomone B induces apoptosis in multiple myeloma cells via targeting of AKT/SKP2 signaling pathway
Authors: Kuttikrishnan Shilpa , Ahmad Fareed , Mateo Jericha M. , Prabhu Kirti S. , El‐Elimat Tamam , Oberlies Nicholas H. , Pearce Cedric J. , Akil Ammira S. Alshabeeb , Bhat Ajaz A. , Alali Feras Q. , Uddin Shahab
Published: October 2023

Multiple myeloma (MM) is a hematologic malignancy associated with malignant plasma cell proliferation in the bone marrow. Despite the available treatments, drug resistance and adverse side effects pose significant challenges, underscoring the need for alternative therapeutic strategies. Natural products, like the fungal metabolite neosetophomone B (NSP‐B), have emerged as potential therapeutic agents due to their bioactive properties. Our study investigated NSP‐B's antitumor effects on MM cell lines (U266 and RPMI8226) and the involved molecular mechanisms. NSP‐B demonstrated significant growth inhibition and apoptotic induction, triggered by reduced AKT activation and downregulation of the inhibitors of apoptotic proteins and S‐phase kinase protein. This was accompanied by an upregulation of p21Kip1 and p27Cip1 and an elevated Bax/BCL2 ratio, culminating in caspase‐dependent apoptosis. Interestingly, NSP‐B also enhanced the cytotoxicity of bortezomib (BTZ), an existing MM treatment. Overall, our findings demonstrated that NSP‐B induces caspase‐dependent apoptosis, increases cell damage, and suppresses MM cell proliferation while improving the cytotoxic impact of BTZ. These findings suggest that NSP‐B can be used alone or in combination with other medicines to treat MM, highlighting its importance as a promising phytoconstituent in cancer therapy.
Enhanced Hydroxyl Adsorption in Ultrathin NiO/Cr2O3 In‐Plane Heterostructures for Efficient Alkaline Methanol Oxidation Reaction
Authors: Yang Wenlong , Chen Ping , Niu Xueqing , Fan Yu , Gao Hongtao , Luo Xiliang
Published: October 2023

The exploration of advanced nickel‐based electrocatalysts for alkaline methanol oxidation reaction (MOR) holds immense promise for value‐added organic products coupled with hydrogen production, but still remain challenging. Herein, we construct ultrathin NiO/Cr2O3 in‐plane heterostructures to promote the alkaline MOR process. Experimental and theoretical studies reveal that NiO/Cr2O3 in‐plane heterostructures enable a favorable upshift of the d‐band center and enhanced adsorption of hydroxyl species, leading to accelerated generation of active NiO(OH)ads species. Furthermore, ultrathin in‐plane heterostructures endow the catalyst with good charge transfer ability and adsorption behavior of methanol molecules onto catalytic sites, contributing to the improvement of alkaline MOR kinetics. As a result, ultrathin NiO/Cr2O3 in‐plane heterostructures exhibit a remarkable MOR activity with a high current density of 221 mA cm−2 at 0.6 V vs Ag/AgCl, which is 7.1‐fold larger than that of pure NiO nanosheets and comparable with other highly active catalysts reported so far. This work provides an effectual strategy to optimize the activity of nickel‐based catalysts and highlights the dominate efficacy of ultrathin in‐plane heterostructures in alkaline MOR.
Application of Seeded Membrane Distillation Crystallization for Zero Liquid Discharge
Authors: Flatscher Stefanie , Hlawitschka Mark W. , Samhaber Wolfgang M. , Hell Florian , Lahnsteiner Josef
Published: October 2023

Zero liquid discharge (ZLD) is a crucial requirement in industrial operations concerned with water scarcity and environmental protection. This study investigates the feasibility of using membrane distillation combined with crystallization (MDC) as a potential solution for ZLD. High‐saline NaCl solutions were used to evaluate the performance of a seeded MDC system, which demonstrated excellent recovery rates for both water (over 95 %) and salt (over 95.5 %). The presence of seeding crystals in the MDC system was found to inhibit membrane wetting. The MDC system achieved an average thermal efficiency of 61.5 %, showcasing its potential for long‐term processes. These results indicate that introducing seed crystals to the membrane's feed side enhances the MDC system's viability as a promising solution for ZLD. Additionally, the MDC system offers the prospect of high water and salt recovery, making it a sustainable approach to wastewater treatment and water reclamation.
Synthesis of Long‐Chain Oligomeric Donor and Acceptors via Direct Arylation for Organic Solar Cells†
Authors: Wu Yu , He Xin‐Yu , Huang Xu‐Min , Yang Ling‐Jun , Liu Peng , Chen Na , Li Chang‐Zhi , Liu Shi‐Yong
Published: October 2023

Comprehensive Summary

The rapid synthesis of structurally complicated electron donors & acceptors still remains a major challenge in organic solar cells (OSC). In this work, we developed a highly efficient strategy to access long‐chain oligomeric donor and acceptors for OSC applications. A series of cyclopentadithiophene (CPDT) and benzothiadiazole (BT)‐based π‐conjugated oligomers, i.e., three oligomeric acceptors (BTDT)n‐IC (n = 1—3) and one long‐chain oligomeric donor (BTDT)4‐RD, are facilely synthesized by an atom‐ and step‐economical, and labor‐saving direct C—H arylation (DACH) reaction (i.e., C—H/C—Br cross coupling). Note that (BTDT)4‐RD involving five CPDT, four BT and two rhodamine (RD) building blocks is the longest oligomeric donor in the fullerene‐free OSC devices ever reported. The dependence of the structure‐property‐performance correlation of (BTDT)n‐IC (n = 1—3) and (BTDT)4‐RD on the π‐conjugation lengths is thoroughly investigated by opto‐electrochemical measurements, bulk heterojunction (BHJ) OSC devices and microscopies. The (BTDT)1‐IC:PBDB‐T and (BTDT)4‐RD:Y6 BHJs achieve power conversion efficiencies of 9.14% and 4.51%, respectively. Our findings demonstrate that DACH reaction is a powerful tool to tune the opto‐electronic properties and device performances by regulating the lengths of π‐conjugated oligomers with varied numbers of repeating units.
Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones
Authors: Mihalovits Levente M. , Kollár Levente , Bajusz Dávid , Knez Damijan , Bozovičar Krištof , Imre Tímea , Ferenczy György G. , Gobec Stanislav , Keserű György M.
Published: October 2023

Heterocyclic thiones have recently been identified as reversible covalent warheads, consistent with their mild electrophilic nature. Little is known so far about their mechanism of action in labelling nucleophilic sidechains, especially cysteines. The vast number of tractable cysteines promotes a wide range of target proteins to examine; however, our focus was put on functional cysteines. We chose the main protease of SARS‐CoV‐2 harboring Cys145 at the active site that is a structurally characterized and clinically validated target of covalent inhibitors. We screened an in‐house, cysteine‐targeting covalent inhibitor library which resulted in several covalent fragment hits with benzoxazole, benzothiazole and benzimidazole cores. Thione derivatives and Michael acceptors were selected for further investigations with the objective of exploring the mechanism of inhibition of the thiones and using the thoroughly characterized Michael acceptors for benchmarking our studies. Classical and hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations were carried out that revealed a new mechanism of covalent cysteine labelling by thione derivatives, which was supported by QM and free energy calculations and by a wide range of experimental results. Our study shows that the molecular recognition step plays a crucial role in the overall binding of both sets of molecules.
Optical Genome Mapping for Oncology Applications
Authors: Sahajpal Nikhil Shri , Mondal Ashis K. , Hastie Alex , Chaubey Alka , Kolhe Ravindra
Published: October 2023

Optical genome mapping (OGM) is a next‐generation cytogenomic technology that has the potential to replace standard‐of‐care technologies used in the genetic workup of various malignancies. The ability to detect various classes of structural variations that include copy number variations, deletions, duplications, balanced and unbalanced events (insertions, inversions, and translocation) and complex genomic rearrangements in a single assay and analysis demonstrates the utility of the technology in tumor research and clinical application. Herein, we provide the methodological details for performing OGM and pre‐ and post‐analytical quality control (QC) checks and describe critical steps that should be performed with caution, probable causes for specific QC failures, and potential method modifications that could be implemented as part of troubleshooting. The protocol description and troubleshooting guide should help new and current users of the technology to improve or troubleshoot the problems (if any) in their workflow. © 2023 Wiley Periodicals LLC.

This article was corrected on 10 November 2023. See the end of the full text for details.

Basic Protocol: Optical genome mapping
Predictors, mediators, and moderators of response to digital interventions for eating disorders: A systematic review
Authors: McClure Zoe , Fuller‐Tyszkiewicz Matthew , Messer Mariel , Linardon Jake
Published: October 2023

Objective

Digital interventions show promise as an effective prevention or self‐management option for eating disorders (EDs). However, it remains unclear how, for whom, and through what mechanisms they work in this population, as a synthesis of outcome predictors, moderators, and mediators is lacking. This systematic review synthesized empirical research investigating predictors, mediators, and moderators of response to digital interventions for EDs.

Method

Six databases were searched (PROSPERO CRD42022295565) for studies that assessed predictors, moderators, or mediators of response (i.e., uptake, drop‐out, engagement, and symptom level change) to a digital prevention or treatment program for EDs. Variables were grouped into several overarching categories (demographic, symptom severity, psychological, etc.) and were synthesized qualitatively across samples without a formally diagnosed ED (typically prevention‐focused) and samples with a formally diagnosed ED (typically treatment‐focused).

Results

Eighty‐six studies were included. For studies recruiting samples without a formal diagnosis (n = 70 studies), most predictors explored were statistically unrelated to outcome, although participant age, baseline symptom severity, confidence to change, motivation, and program engagement showed preliminary evidence of prognostic potential. No robust moderators or mediators were identified. Few studies recruiting samples with a formal diagnosis emerged (n = 16), of which no reliable predictors, moderators, or mediators were identified.

Discussion

It remains unclear how, for whom, and under what circumstances digital programs targeting EDs work. We offer several recommendations for future research with the aim of advancing understanding of client characteristics and intervention elements that signal success from this intervention modality.

Public Significance

Digital interventions have shown potential as an effective, scalable, and accessible intervention option for EDs. However, responsiveness varies, so advancing understanding of predictors, mediators, and moderators of outcome to digital interventions for EDs is needed. Such knowledge is important for enabling safe and efficient treatment matching, and for informing future development of effective digital interventions.
Book Review
Authors: Jenne John W.
Published: October 2023

Genetic Factors in Drug Therapy. Clinical and Molecular Pharmacogenetics, by David A. Price Evans
Multiple‐Dose, Placebo‐Controlled, Phase I Study of Oral Dolasetron
Authors: Hunt Thomas L. , Cramer Michael , Christy‐Bittel Janna , Shah Ajit K. , Meyerson Laura J. , Benedict Claude R. , Hahne William E
Published: October 2023

Study Objectives. To evaluate the safety, tolerability, and pharmacokinetics of increasing dose levels of oral dolasetron mesylate, a new 5‐HT3 antagonist.

Design. Double‐blind, placebo‐controlled, dose‐ranging phase I study.

Setting. A clinical research center.

Patients. Forty healthy male volunteers.

Interventions. Eight subjects at each dose level were randomized in a ratio of 3:1 to receive either dolasetron mesylate 25, 50, 100, 150, or 200 mg in a single oral dose on days 1 and 9, and twice/day on days 2–8, or placebo for 9 days.

Measurements and Main Results. Dolasetron was well tolerated at all dose levels. The adverse event rates for dolasetron‐ and placebo‐treated subjects who experienced at least one adverse event were 80% and 50%, respectively. Most frequently reported by subjects receiving dolasetron were headache, constipation, flatulence, and lightheadedness. They generally were mild, and none was severe. No dose‐response relationship was apparent for any adverse event. There were no clinically significant changes in mean laboratory values or vital signs. Asymptomatic treatment‐related electrocardiographic changes were consistent with the drug's electrophysiologic properties. These changes have been well characterized and have thus far been clinically unimportant. Pharmacokinetics of the reduced metabolite were dose independent, and multiple‐dose exposure of this metabolite can be predicted from its single‐dose values.

Conclusion. Oral dolasetron mesylate was well tolerated when administered in doses up to 200 mg/day for 9 days in healthy volunteers.
Possible Role of the Intestinal P‐450 Enzyme System in a Cyclosporine‐Clarithromycin Interaction
Authors: Sketris Ingrida S. , Wright Matthew R. , West Michael L.
Published: October 2023

Clarithromycin is a macrolide antibiotic similar in structure to erythromycin, but suggested to have fewer drug interactions. Although a pharmacokinetic interaction between clarithromycin and cyclosporine was recently reported, its magnitude and mechanism have not been explored. A 43‐year‐old renal transplant recipient receiving cyclosporine was treated with clarithromycin because of pneumonia. A cyclosporine pharmacokinetic study was performed 8 days after the initiation of the clarithromycin and 14 days after stopping the drug. Clarithromycin coadministration caused an approximately 2‐fold increase in the area under the whole blood concentration versus time curve of cyclosporine. The oral clearance of cyclosporine was halved by clarithromycin, but the terminal elimination rate constant decreased only 15% and mean residence time 20%. These observations suggest that clarithromycin inhibits not only the hepatic metabolism but also the intestinal metabolism of cyclosporine. Caution is advised when administering the two drugs concurrently, and additional studies are necessary to elucidate the mechanism of this interaction.
Current Perspectives on β‐Receptor Antagonists in the Treatment of Symptomatic Ventricular Dysfunction
Authors: Adams Kirkwood F.
Published: October 2023

Even though therapeutic advances have occurred, heart failure is still associated with significant morbidity and mortality. Digitalis, diuretics, and angiotensin‐converting enzyme inhibitors have proven effective, but in many patients still do not prevent progressive and debilitating heart failure. Many hormonal factors are involved, but two, the renin‐angiotensin‐aldosterone (RAA) axis and the autonomic nervous system, apparently are critical in the pathophysiology of progressive ventricular dysfunction. Pharmacologic suppression of the RAA system is associated with significant clinical benefit, suggesting that antagonism of sympathetic nervous activity with β‐receptor‐blocking agents might also be efficacious. Major alterations of the autonomic nervous system are characteristic of heart failure, with excessive sympathetic activity one of the earliest adaptations to the condition, and important in promoting the heart failure state and the progression of ventricular dysfunction. Certain β‐antagonists administered early by careful and slow up‐titration from small starting dosages proved effective in small trials. Large‐scale, randomized, placebo‐controlled studies continue to document that β‐blockers improve ventricular function and symptoms, and preliminary results suggest mortality and morbidity reductions as well. Although intolerance to β‐antagonism does occur, the majority of patients can be successfully treated with these agents.
Combination Therapy with Low‐Dose Lovastatin and Niacin Is as Effective as Higher‐Dose Lovastatin
Authors: Gardner Stephanie F. , Schneider Eric F. , Granberry Mark C. , Carter Inge R.
Published: October 2023

Study Objectives. To determine if low‐dose lovastatin in combination with niacin causes a greater percentage reduction in low‐density lipoprotein (LDL) cholesterol than lovastatin alone, and to determine if the combination increases the risk of serious adverse effects.

Design. Prospective, randomized, open‐label, clinical trial.

Setting. Family medicine clinic of a university‐affiliated hospital.

Patients. Patients with fasting LDL cholesterol concentrations of at least 150 mg/dl after 4 weeks of dietary stabilization and washout of any cholesterol‐lowering drugs.

Interventions. Twenty‐eight patients received lovastatin 20 mg/day for 4 weeks after dietary stabilization and washout. If LDL cholesterol remained above 130 mg/dl (100 mg/dl in patients with coronary artery disease), they were randomized to receive either lovastatin 40 mg/day or a combination of lovastatin 20 mg/day and niacin 500 mg 3 times/day.

Measurements and Main Results. There was no difference in actual or percentage reductions of LDL cholesterol, total cholesterol, and triglycerides between the groups. A greater increase in high‐density lipoprotein (HDL) cholesterol occurred with combination therapy (p=0.024). There was no difference in liver function tests, glucose, or uric acid between the therapies. Based on drug‐acquisition cost, combination therapy is approximately 40% less expensive than monotherapy.

Conclusion. Low‐dose niacin plus low‐dose lovastatin was as effective as higher‐dose lovastatin in lowering total cholesterol, LDL cholesterol, and triglyceride levels. The combination may offer benefit in raising HDL cholesterol levels.
CYP2D6, N‐Acetylation, and Xanthine Oxidase Activity in Cystic Fibrosis
Authors: Bosso John A. , Liu Qing , Evans William E. , Relling Mary V.
Published: October 2023

Study Objective. To determine the activity of CYP2D6, N‐acetylation, and xanthine oxidase, three drug‐metabolizing enzyme systems, in patients with cystic fibrosis and compare the findings with those in individuals without the disease.

Design. Prospective cohort study.

Setting. General pediatrics service.

Patients. Fifty‐nine patients with cystic fibrosis and 480 healthy Caucasian volunteers.

Interventions. Enzyme activity was determined based on urinary molar metabolite ratios of caffeine and dextromethorphan probes.

Measurements and Main Results. The percentage of poor metabolizers of CYP2D6 in patients with cystic fibrosis was not different from that in the control group (p=0.45). N‐Acetylation activity was significantly lower in the patients (p=0.007), but no statistically significant difference was found in xanthine oxidase activity (p=0.12).

Conclusion. The activity of these drug‐metabolic pathways does not appear to be increased in cystic fibrosis. Whether the activity of other pathways is increased, thus providing a partial explanation for the generally increased drug clearance in this disease, remains to be determined.
Prospective Validation of an Optimal Sparse Plasma‐Sampling Strategy for Estimating Ciprofloxacin Pharmacokinetics
Authors: Amsden Guy W. , Ballow Charles H.
Published: October 2023

Data obtained from 23 critically ill patients treated with intravenous ciprofloxacin in two clinical trials were used to validate prospectively a previously developed maximum a posteriori (MAP)‐Bayesian estimator and optimal plasma‐sampling strategy (OSS). Dosages ranged from 200 mg every 12 hours to 400 mg every 8 hours. Each patient had 8–16 samples taken, either as large gold standard sampling sets or as a mix of gold standard sets and OSSs. The MAP‐Bayesian estimator used a two‐compartment model and identified apparent volumes of distribution of the central and peripheral compartments, distributional clearance, and the slope and intercept of the relationship between creatinine clearance and total body clearance. Fit parameters were used to derive the apparent volume of distribution at steady state and the 24‐hour area under the curve. All parameters derived from the OSS using the MAP‐Bayesian estimates matched up almost identically to those obtained from modeling the gold standard sets. There was no systematic bias, and good precision was seen among all the parameters. These data demonstrate the usefulness and validity of the current OSS and MAP‐Bayesian estimator, and provide further evidence of the utility of optimal sampling theory.
Methotrexate Elimination in a Patient with an Orthotopic Neobladder with and without a Urethral Catheter
Authors: Wire Patrick D. , Dupuis Robert E. , Mohler James L. , Bernard Stephen A. , Lindley Celeste M.
Published: October 2023

Placement of a urethral catheter has been recommended to ensure adequate methotrexate elimination in patients with a neobladder; however, the need for this and its impact on methotrexate elimination have not been determined. A 53‐year‐old man with a cecal continent urinary diversion received intravenous methotrexate 30 mg/m2 on two occasions, with and without urethral catheter drainage of the neobladder. Serum methotrexate concentrations declined at a rate that resulted in 24‐ and 48‐hour values falling below the accepted toxic concentration threshold of 5–50 μmol/L and 0.05 μmol/L, respectively. In this man, who received low‐dose methotrexate, catheterization of the neobladder did not alter methotrexate elimination sufficiently to justify its cost, risk, and inconvenience.
Risperidone: Effects of Formulations on Oral Bioavailability
Authors: Gutierrez Rolando , Lee Peter I. D. , Huang May‐Lynn , Woestenborghs Robert
Published: October 2023

The bioavailability of risperidone was evaluated in an open‐label, randomized, two‐way, crossover study comparing a 1‐mg tablet with a 1‐mg/ml oral solution. Both formulations were administered as a single 1‐mg dose with a 10‐day washout period between treatments. Of 26 healthy men who entered the study, 23 completed both treatment periods. Plasma concentrations of risperidone and the active moiety (risperidone plus its active metabolite, 9‐hydroxyrisperidone) were determined by radioimmunoassays. For key pharmacokinetic values (Cmax, AUC), the 90% CIs on the relative bioequivalence of risperidone, 9‐hydroxyrisperidone, and the active moiety were contained within the equivalence range of 80–120% (80–125% for log‐transformed data). The results demonstrate that the 1‐mg/ml oral solution and the 1‐mg tablet are bioequivalent.
Comparison of Intravenous Diltiazem and Verapamil for the Acute Treatment of Atrial Fibrillation and Atrial Flutter
Authors: Phillips Bradley G. , Gandhi Ashesh J. , Sanoski Cynthia A. , Just Vicki L. , Bauman Jerry L.
Published: October 2023

Study Objectives. To compare the efficacy and safety of intravenous diltiazem and verapamil in controlling ventricular rate in patients with atrial fibrillation or flutter, and to evaluate the effects of these agents on left ventricular systolic function.

Design. Prospective, randomized, double‐blind, crossover study.

Setting. University‐affiliated hospital and Veterans Administration hospital.

Patients. Seventeen men with atrial fibrillation or flutter with a ventricular rate of 120 beats/minute or higher and a systolic blood pressure of 100 mm Hg or greater.

Interventions. Patients received up to two intravenous boluses of either diltiazem or verapamil, followed by an 8‐hour continuous infusion if a therapeutic response was achieved (phase I). After a washout period, patients who responded were crossed over to receive the other drug in a similar fashion (phase II).

Measurements and Main Results. At the end of each infusion, the patient's ejection fraction was assessed by gated angiography. Of the 17 men initially randomized, 8 successfully completed both phases I and II. In these patients, baseline mean (± SD) ventricular rates before treatment with intravenous diltiazem and verapamil were 138 ± 15 and 132 ± 9 beats/minute, respectively (NS). At 2 minutes after the initial bolus dose, the mean ventricular rate decreased to 100 ± 13 beats/minute in the diltiazem group compared with 114 ± 17 beats/minute in those receiving verapamil (p<0.05). Mean ventricular rates of 96 ± 11 and 97 ± 9 beats/minute were maintained during the 8‐hour continuous infusion of diltiazem and verapamil, respectively (NS). On completion of the bolus dose(s) and during continuous infusions, there were no significant differences in blood pressures between the groups. Mean ejection fractions were 35.6 ± 13.6% and 35.5 ± 15.4% in the diltiazem and verapamil groups, respectively (NS). For the 17 patients, the mean maximum percentage decreases in blood pressure were not significantly different between groups. However, three patients developed symptomatic hypotension all of whom were randomized to receive verapamil initially.

Conclusion. Intravenous diltiazem and verapamil are comparable in terms of efficacy and effect on systolic function in patients with rapid atrial fibrillation and flutter. However, hypotension may limit therapy with verapamil in some patients.
Pharmacokinetics of Amiloride after Inhalation and Oral Administration in Adolescents and Adults with Cystic Fibrosis
Authors: Jones Kristen M. , Liao Edward , Hohneker Kathy , Turpin Stephen , Henry Marianna M. , Selinger Krzysztof , Hsyu Poe‐Hirr , Boucher Richard C. , Knowles Michael R. , Dukes George E.
Published: October 2023

Study Objective. To compare the pharmacokinetics and systemic exposure of nebulized and oral amiloride in adolescents and adults with mild to moderate cystic fibrosis (CF).

Design. Open‐label, randomized, two‐way crossover, single‐dose pharmacokinetic study.

Setting. University hospital clinical research unit.

Patients. Nine adolescents and 10 adults with mild to moderate CF (forced expiratory volume in 1 sec > 50% predicted, Brasfield score ≥ 15).

Interventions. Patients received amiloride solution orally (10 mg of amiloride 1‐mg/ml solution) and by inhalation [4.5 ml amiloride of 1‐mg/ml solution in 12% saline (∼ 3.8 mmol/L) by DeVilbiss 646 nebulizer] during two study phases separated by a 7‐ to 28‐day washout period. Serial blood and urine samples were collected for 48 and 72 hours, respectively.

Measurements and Main Results. After oral dosing, the mean ± SD maximum peak concentration (Cmax) was 20.6 ± 10.0 ng/ml at 3.2 ± 1.2 hours in adults and 21.7 ± 4.88 at 2.9 ± 0.6 hours in the adolescents. Mean area under the concentration‐time curve (AUC) from time zero to infinity hours was 275 ± 115 and 254 ± 60 ng•hr/ml in the adult and adolescent groups; half‐life was 16.0 ± 0.7 and 13.4 ± 1.4 hours, respectively. After nebulization, 14 of 19 subjects exhibited two concentration peaks (Cmax1 and Cmax2) with mean values of 1.57 ± 1.67 ng/ml at 0.5 ± 0.2 hours and 1.37 ± 1.21 ng/ml at 4.0 ± 1.0 hours for adults, and 1.49 ± 0.99 ng/ml at 0.5 ± 0.1 hours and 1.52 ± 0.81 ng/ml at 3.3 ± 0.5 hours for adolescents. Estimated mean ± SD dose nebulized was 1.91 ± 0.66 and 2.28 ± 0.30 mg in the adult and adolescent groups, respectively. Mean ± SD AUC from time zero to the last measurable plasma amiloride concentration after inhalation was 14.4 ± 17.6 and 15.4 ± 10.1 ng•hr/ml in the adults and adolescents. No significant adverse events occurred during the study. Pharmacokinetic parameters were not statistically different between the adolescent and adult groups by route of administration. However significant differences in peak amiloride concentration, AUC, and urinary amiloride excretion were evident when comparing oral versus inhalation administration within each group.

Conclusions. Mean amiloride plasma concentration peaks and AUC after inhalation were significantly lower than after oral dosing. In addition, the second amiloride plasma concentration peak may be due to oral ingestion of the nebulized amiloride, whereas the earlier Cmax1 after inhalation may be due to pulmonary absorption of amiloride. These results suggest that single‐dose amiloride inhalation in patients with mild to moderate CF results in minimal systemic exposure compared with oral dosing, and that drug disposition is similar in adolescents and adults with CF.
A Randomized, Prospective Evaluation of an Interventional Program to Discontinue Intravenous Antibiotics at Two Tertiary Care Teaching Institutions
Authors: Bailey Thomas C. , Ritchie David J. , McMullin S. Troy , Kahn Michael , Reichley Richard M. , Casabar Ed , Shannon William , Dunagan William Claiborne
Published: October 2023

To evaluate a program to discontinue intravenous antibiotics at two teaching hospitals, 102 inpatients meeting eligibility criteria were randomly assigned to two groups. In one group, patients' physicians were contacted by pharmacists with recommendations to discontinue intravenous antibiotic therapy; in the other, patients were simply observed. Measured outcomes were antibiotic costs, length of stay, need to restart intravenous antibiotics, in‐hospital mortality, and 30‐day readmissions. The intervention significantly reduced mean antibiotic costs per patient ($19.82 vs $35.84, p=0.03), but related labor costs exceeded this benefit. Readmissions were significantly more frequent in the intervention group than in the control group (29% vs 9.8% p=0.02), but they were not infection related. No impact was demonstrated on the other measured outcomes. Institutions considering such programs or with one in place should conduct similar evaluations.
Stenotrophomonas (Xanthomonas) maltophilia: A Multidrug‐Resistant Nosocomial Pathogen
Authors: Penzak Scott R. , Abate Betty J.
Published: October 2023

Stenotrophomonas (Xanthomonas) maltophilia is emerging as a multidrug‐resistant nosocomial pathogen. In general, the organism is opportunistic, colonizing or infecting patients with predisposing risk factors such intensive care unit residence, malignancy, mechanical ventilation, and previous antibiotic exposure. It can cause a variety of infections depending on underlying patient‐specific medical conditions. It is often part of multimicrobial infections, and determining its role as a pathogen is difficult. Trimethoprim‐sulfamethoxazole (TMP‐SMX) has traditionally been the most active agent against S. maltophilia. Other classes of antibiotics, with few exceptions, have not been effective. Synergistic antimicrobial combinations are now being investigated due to the bacteriostatic nature of TMP‐SMX, and increasing reports of resistance to TMP‐SMX. The combination of ticarcillinclavulanate plus TMP‐SMX appears to be the most promising regimen studied thus far.
Prevention by Calcium Antagonists of Profibrillatory Effects of Class I Antiarrhythmic Drugs in Acute Myocardial Ischemia: Study in Pig Heart In Situ
Authors: Bui‐Xuan Bernard , Aupetit Jean F. , Freysz Marc , Faucon Georges , Timour Quadiri
Published: October 2023

Class I antiarrhythmic drugs do not decrease, but increase, the risk of ventricular fibrillation in the ischemic myocardium. On the contrary, vulnerability to fibrillation related to ischemia appears to be substantially reduced by calcium antagonists. We assessed whether the calcium antagonist diltiazem (0.50 mg/kg bolus plus 0.02 mg/kg/min infusion) could prevent the profibrillatory effect or even partially restore the antifibrillatory effect of a class I antiarrhythmic drug, flecainide (1 mg/kg bolus plus 0.04 mg/kg/min infusion) in the ischemic myocardium of anesthetized, open‐chest pigs. Ischemia was obtained by completely occluding the left anterior descending coronary artery near its origin. Vulnerability to fibrillation was assessed by electrical fibrillation threshold (EFT), measured with diastolic impulses of 100 msec duration delivered at a rate of 180 beats/minute. Diltiazem did not oppose the rise in EFT induced by flecainide in the absence of ischemia (6.8 ± 1.2 to 9.9 ± 0.9 mA, p<0.001). It limited the fall in EFT observed under the dual influence of ischemia and flecainide (4.2 ± 0.9 vs 1.3 ± 0.6 mA, p<0.001). By reducing calcium entry into myocardial fibers, diltiazem delayed ischemic depolarization, as evidenced by reduced shortening of the monophasic action potential duration from 215 ± 7 to 200 ± 4 msec, instead of 178 ± 6 (p<0.001), and reduced lengthening of intraventricular conduction time from 33 ± 5 to 43 ± 4 msec, instead of 53 ± 4 (p<0.01). Therefore, diltiazem is likely to prevent the loss and even the reversal of the antifibrillatory properties of flecainide due to myocardial ischemia in dosages that do not adversely affect myocardial contractility or atrioventricular conduction to a large extent.
Reduced Serum Theophylline Concentrations after Discontinuation of Azithromycin: Evidence for an Unusual Interaction
Authors: Pollak Paul Timothy , Slayter Kathryn L.
Published: October 2023

A 68‐year‐old man receiving long‐term therapy with oral sustained‐release theophylline 450 mg twice/day was admitted to the hospital after failing treatment with azithromycin for an acute exacerbation of obstructive lung disease. Peak serum theophylline concentration was 20 μg/ml (normal 10–20 μg/ml). Azithromycin was discontinued and the theophylline dosage reduced by 33%. The subsequent 80% decrease in serum theophylline to 4.6 μg/ml was unexpectedly large. Two rechallenges produced similar transient depressions of serum theophylline concentrations after withdrawal of azithromycin, suggesting an interaction. Withdrawal of azithromycin may leave an increased number of active enzyme sites available as the drug is cleared from the system. In some circumstances, it may be useful for pharmacokinetic interaction studies to continue measuring concentrations after the suspected interacting agent is stopped.
Herbal Therapies for Perimenopausal and Menopausal Complaints
Authors: Israel Debra , Youngkin Ellis Quinn
Published: October 2023

Consumer use of alternative medicines in the United States is growing rapidly. Included in this phenomenon are herbal therapies instead of or as adjuncts with traditional medicine for perimenopausal and menopausal complaints. Of significant concern is the safety of these herbs. Since many women are using herbal therapies, clinicians must be knowledgeable about their use, quality, and safety. There are currently no government standards on the quality of herbal products in the United States, and some products are either unsafe or little is known scientifically about them. Selected herbal therapies touted in the lay press for common perimenopausal and menopausal complaints are examined, with advice on their use and safety based on scientific sources. (Pharmacotherapy 1997;17(5):970–984)
Population Pharmacokinetics of Glyburide in Patients with Well‐Controlled Diabetes
Authors: Tracewell William G. , Stalker Dennis J. , Maloley Pierre A. , Gallagher Thomas F. , Gwilt Peter R.
Published: October 2023

Study Objectives. To investigate glyburide pharmacokinetics in patients with well‐controlled noninsulin‐dependent diabetes mellitus (NIDDM), and test the hypothesis that intersubject variability in the glyburide dose is due to patient differences in the drug's pharmacokinetics.

Methods. Prospective, open‐label study.

Setting. University‐affiliated, internal medicine outpatient clinic.

Patients. Fifty‐one patients with NIDDM (11 women, 40 men, mean age 56.7 ± 15.3 yrs) receiving oral glyburide and with well‐controlled glycohemoglobin levels 10.0% or below.

Intervention. After fasting overnight, patients ingested their regular morning dose of glyburide and then ate breakfast. Blood samples were drawn before dosing and between 0.5–2 hours, 2–5 hours, and 5–10 hours after dosing.

Measurements and Main Results. Serum glyburide was assayed by high‐performance liquid chromatography and pharmacokinetics by NONMEM. Glyburide clearance was proportional to weight and greater in older patients (> 60 yrs).

Conclusion. Variability in the glyburide dose was not primarily due to intersubject differences in the drug's pharmacokinetics.