Predicting Drug-Drug Interactions Involving Rifampicin Using a Semi-mechanistic Hepatic Compartmental Model.

AIMS: To develop a semi-mechanistic hepatic compartmental model to predict the effects of rifampicin, a known inducer of CYP3A4 enzyme, on the metabolism of five drugs, in the hope of informing dose adjustments to avoid potential drug-drug interactions. METHODS: A search was conducted for DDI studies on the interactions between rifampicin and CYP substrates that met specific criteria, including the availability of plasma concentration-time profiles, physical and absorption parameters, pharmacokinetic parameters, and the use of healthy subjects at therapeutic doses. The semi-mechanistic model utilized in this study was improved from its predecessors, incorporating additional parameters such as population data (specifically for Chinese and Caucasians), virtual individuals, gender distribution, age range, dosing time points, and coefficients of variation. RESULTS: Optimal parameters were identified for our semi-mechanistic model by validating it with clinical data, resulting in a maximum difference of approximately 2-fold between simulated and observed values. PK data of healthy subjects were used for most CYP3A4 substrates, except for gilteritinib, which showed no significant difference between patients and healthy subjects. Dose adjustment of gilteritinib co-administered with rifampicin required a 3-fold increase of the initial dose, while other substrates were further tuned to achieve the desired drug exposure. CONCLUSIONS: The pharmacokinetic parameters AUCR and CmaxR of drugs metabolized by CYP3A4, when influenced by Rifampicin, were predicted by the semi-mechanistic model to be approximately twice the empirically observed values, which suggests that the semi-mechanistic model was able to reasonably simulate the effect. The doses of four drugs adjusted via simulation to reduce rifampicin interaction.

Amphotericin B concentrations in healthy mallard ducks (Anas platyrhynchos) following a single intratracheal dose of liposomal amphotericin B using an atomizer.

Aspergillosis is a fungal infection that primarily affects the respiratory tract. Amphotericin B has broad antifungal activity and is commonly used to treat aspergillosis, a fungal pneumonia that is a common sequela in oiled waterfowl as well as other birds in wildlife rehabilitation. Pharmacokinetic parameters of nebulized amphotericin B in an avian model have been reported, but those of direct intratracheal delivery have yet to be established. The objective of this study was to evaluate if a single 3 mg/kg dose of liposomal amphotericin B delivered intratracheally using a commercial atomizer would achieve plasma and lung tissue concentrations exceeding targeted minimum inhibitory concentrations (MIC) for Aspergillus species in adult mallard ducks (Anas platyrhynchos). Following intratracheal delivery, amphotericin B was present in lung parenchyma at concentrations above the targeted MIC of 1 µg/g for up to 9 days post-administration; however, distribution of the drug was uneven, with the majority of the drug concentrated in one lung lobe. Concentrations in the contralateral lung lobe and the kidneys were above the targeted MIC 1 day after administration but declined exponentially with a half-life of approximately 2 days. Plasma concentrations were never above the targeted MIC. Histological examination of the trachea, bronchi, lungs, heart, liver, and kidneys did not reveal any toxic changes. Using a commercial atomizer, intratracheal delivery of amphotericin B at 3 mg/kg resulted in lung parenchyma concentrations above 1 µg/ml with no discernable systemic effects. Further studies to establish a system of drug delivery to both sides of the pulmonary parenchyma need to be performed, and the efficacy of this treatment for disease prevention remains to be determined.

Unusual Response of HDL-Chol Level and Body Weight to Atorvastatin: A Case Report.

Atorvastatin is an HMG-CoA reductase inhibitor that is prescribed to prevent adverse cardiovascular events by reducing blood total cholesterol (Chol) and LDL-Chol. Here we report a case related to an unusual response of HDL-Chol upon the administration of atorvastatin following an acute myocardial infarction. While atorvastatin substantially reduced LDL and triglycerides (TAG) of the patient as desired, it also lowered the HDL significantly, and in a dose-dependent manner. It is widely known that statins have several major side effects, but a significant suppression on HDL has been rarely reported so far. In addition, atorvastatin is deemed the likely cause for unintentional weight loss of this subject.

Feasibility of Image Inversion for Ventral Hernia Repair Using the Versius System.

Background: The aim of our technical report is to demonstrate the image inversion technique in the new Versius Robotic System. Methods: We report a step-by-step surgical maneuver for robotic surgeons when performing robotic ventral hernia repair (VHR) with the Versius Robotic System. Technical Report: The image inversion artifice consists in rotating 180° with the scope using the surgeon's master control in a specific rotation command in the right-hand joystick. The assisting surgeon can do a manual inversion of the camera without the console being aware that the scope is inverted. In this scenario, the 30° Up configuration should be used while informing the console that the scope is looking down. The surgeon can reassign instruments to each joystick. This results in the right joystick controlling the left instrument and left control controlling the right instrument. Since the image is inverted, the movements will look natural on the surgeon console. Conclusions: The use of the image inversion technique with the Versius Robotic System is effective in aiding surgeons to perform the hernia defect closure during robotic VHRs.

Reconstitution of early paclitaxel biosynthetic network.

Paclitaxel is an anticancer therapeutic produced by the yew tree. Over the last two decades, a significant bottleneck in the reconstitution of early paclitaxel biosynthesis has been the propensity of heterologously expressed pathway cytochromes P450, including taxadiene 5α-hydroxylase (T5αH), to form multiple products. Here, we structurally characterize four new products of T5αH, many of which appear to be over-oxidation of the primary mono-oxidized products. By tuning the promoter strength for T5αH expression in Nicotiana plants, we observe decreased levels of these proposed byproducts with a concomitant increase in the accumulation of taxadien-5α-ol, the paclitaxel precursor, by three-fold. This enables the reconstitution of a six step biosynthetic pathway, which we further show may function as a metabolic network. Our result demonstrates that six previously characterized Taxus genes can coordinatively produce key paclitaxel intermediates and serves as a crucial platform for the discovery of the remaining biosynthetic genes.

How Appropriate Are Recommendations of Online Chat-Based Artificial Intelligence (ChatGPT) to Common Questions on Ventral Hernia Repair?

ChatGPT is a conversational AI model developed by OpenAI to generate human-like text based on the input it receives. ChatGPT has become increasingly popular, and the general public may use this tool to ask questions about different medical conditions. There is a lack of data to demonstrate ChatGPT is able to provide reliable information on medical conditions. The aim of our study is to assess the accuracy and appropriateness of ChatGPT answers to questions on ventral hernia management.

Predicting pharmacodynamic effects through early drug discovery with artificial intelligence-physiologically based pharmacokinetic (AI-PBPK) modelling.

A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model links the concentration-time profile of a drug with its therapeutic effects based on the underlying biological or physiological processes. Clinical endpoints play a pivotal role in drug development. Despite the substantial time and effort invested in screening drugs for favourable pharmacokinetic (PK) properties, they may not consistently yield optimal clinical outcomes. Furthermore, in the virtual compound screening phase, researchers cannot observe clinical outcomes in humans directly. These uncertainties prolong the process of drug development. As incorporation of Artificial Intelligence (AI) into the physiologically based pharmacokinetic/pharmacodynamic (PBPK) model can assist in forecasting pharmacodynamic (PD) effects within the human body, we introduce a methodology for utilizing the AI-PBPK platform to predict the PK and PD outcomes of target compounds in the early drug discovery stage. In this integrated platform, machine learning is used to predict the parameters for the model, and the mechanism-based PD model is used to predict the PD outcome through the PK results. This platform enables researchers to align the PK profile of a drug with desired PD effects at the early drug discovery stage. Case studies are presented to assess and compare five potassium-competitive acid blocker (P-CAB) compounds, after calibration and verification using vonoprazan and revaprazan.

Asymmetric catalysis at the mesoscale: gold nanoclusters embedded in chiral self-assembled monolayer as heterogeneous catalyst for asymmetric reactions.

Research to develop highly versatile, chiral, heterogeneous catalysts for asymmetric organic transformations, without quenching the catalytic reactivity, has met with limited success. While chiral supramolecular structures, connected by weak bonds, are highly active for homogeneous asymmetric catalysis, their application in heterogeneous catalysis is rare. In this work, asymmetric catalyst was prepared by encapsulating metallic nanoclusters in chiral self-assembled monolayer (SAM), immobilized on mesoporous SiO2 support. Using olefin cyclopropanation as an example, it was demonstrated that by controlling the SAM properties, asymmetric reactions can be catalyzed by Au clusters embedded in chiral SAM. Up to 50% enantioselectivity with high diastereoselectivity were obtained while employing Au nanoclusters coated with SAM peptides as heterogeneous catalyst for the formation of cyclopropane-containing products. Spectroscopic measurements correlated the improved enantioselectivity with the formation of a hydrogen-bonding network in the chiral SAM. These results demonstrate the synergetic effect of the catalytically active metallic sites and the surrounding chiral SAM for the formation of a mesoscale enantioselective catalyst.

Bioequivalence study of ipratropium bromide inhalation aerosol using PBPK modelling.

Aims: Systemic pharmacokinetic (PK) studies can reflect the overall exposure of orally inhaled drug Products (OIDPs) in the blood after inhalation into the lung and can be used to evaluate the bioequivalence of test and reference products. The aim of this article is: (1) to study the PK characteristics and bioequivalence of ipratropium bromide (IB) inhalation aerosol, reference and test products in healthy Chinese subjects; (2) to establish a physiologically based pharmacokinetic (PBPK) model and verify the accuracy of the model in predicting bioequivalence; (3) attempt to use the model to predict the regional distribution of particles in the lung after inhalation, and discuss the effect of gastrointestinal drug absorption of IB on systemic exposure. Methods: The study involved two clinical studies. Clinical study-1 (registration number: CTR20201284) was used with non-clinical data to construct and validate a PBPK model in the B2O simulator, a web-based virtual drug development platform. This model assessed different test and reference products' bioequivalence. Results were compared to a second clinical study (Clinical study-2: registration number CTR20202291). The particles' regional distribution in the lung and the gastrointestinal absorption effect on systemic exposure were discussed based on the simulation results. Results: The established PBPK model successfully simulated the in vivo PK characteristics of IB inhalation aerosol, with r 2 close to 1. Gastrointestinal absorption had a negligible effect on systemic exposure. Particles accumulated in the alveolar area were cleared within an hour, followed by particles in the bronchioles and bronchi. Conclusion: This model provided a reliable method for exploring the correlation between in vitro and in vivo PK studies of IB inhalation aerosols. According to the simulation results, the test and reference products were bioequivalent.

Reconstitution of Early Paclitaxel Biosynthetic Network.

Paclitaxel is an anticancer therapeutic produced by the yew tree. Over the last two decades, a significant bottleneck in the reconstitution of early paclitaxel biosynthesis has been the propensity of heterologously expressed pathway cytochromes P450, including taxadiene 5α-hydroxylase (T5αH), to form multiple products. This diverts metabolic flux away from the paclitaxel precursor, taxadien-5α-ol, thus previous attempts of reconstitution have not yielded sufficient material for characterization, regardless of the heterologous host. Here, we structurally characterized four new products of T5αH, many of which appear to be over-oxidation of the primary mono-oxidized products. By tuning the promoter strength for T5αH expression, levels of these proposed byproducts decrease with a concomitant increase in the accumulation of taxadien-5α-ol by four-fold. This engineered system enabled the reconstitution of a six step biosynthetic pathway to produce isolatable 5α,10ß-diacetoxy-taxadien-13α-ol. Furthermore, we showed that this pathway may function as a metabolic network rather than a linear pathway. The engineering of the paclitaxel biosynthetic network demonstrates that Taxus genes can coordinatively function for the biosynthetic production of key early stage paclitaxel intermediates and serves as a crucial platform for the discovery of the remaining biosynthetic genes.

Materials and Applications of 3D Printing Technology in Dentistry: An Overview.

PURPOSE: This narrative review aims to provide an overview of the mechanisms of 3D printing, the dental materials relevant to each mechanism, and the possible applications of these materials within different areas of dentistry. METHODS: Subtopics within 3D printing technology in dentistry were identified and divided among five reviewers. Electronic searches of the Medline (PubMed) database were performed with the following search keywords: 3D printing, digital light processing, stereolithography, digital dentistry, dental materials, and a combination of the keywords. For this review, only studies or review papers investigating 3D printing technology for dental or medical applications were included. Due to the nature of this review, no formal evidence-based quality assessment was performed, and the search was limited to the English language without further restrictions. RESULTS: A total of 64 articles were included. The significant applications, applied materials, limitations, and future directions of 3D printing technology were reviewed. Subtopics include the chronological evolution of 3D printing technology, the mechanisms of 3D printing technologies along with different printable materials with unique biomechanical properties, and the wide range of applications for 3D printing in dentistry. CONCLUSIONS: This review article gives an overview of the history and evolution of 3D printing technology, as well as its associated advantages and disadvantages. Current 3D printing technologies include stereolithography, digital light processing, fused deposition modeling, selective laser sintering/melting, photopolymer jetting, powder binder, and 3D laser bioprinting. The main categories of 3D printing materials are polymers, metals, and ceramics. Despite limitations in printing accuracy and quality, 3D printing technology is now able to offer us a wide variety of potential applications in different fields of dentistry, including prosthodontics, implantology, oral and maxillofacial, orthodontics, endodontics, and periodontics. Understanding the existing spectrum of 3D printing applications in dentistry will serve to further expand its use in the dental field. Three-dimensional printing technology has brought about a paradigm shift in the delivery of clinical care in medicine and dentistry. The clinical use of 3D printing has created versatile applications which streamline our digital workflow. Technological advancements have also paved the way for the integration of new dental materials into dentistry.

Complex scaffold remodeling in plant triterpene biosynthesis.

Triterpenes with complex scaffold modifications are widespread in the plant kingdom. Limonoids are an exemplary family that are responsible for the bitter taste in citrus (e.g., limonin) and the active constituents of neem oil, a widely used bioinsecticide (e.g., azadirachtin). Despite the commercial value of limonoids, a complete biosynthetic route has not been described. We report the discovery of 22 enzymes, including a pair of neofunctionalized sterol isomerases, that catalyze 12 distinct reactions in the total biosynthesis of kihadalactone A and azadirone, products that bear the signature limonoid furan. These results enable access to valuable limonoids and provide a template for discovery and reconstitution of triterpene biosynthetic pathways in plants that require multiple skeletal rearrangements and oxidations.

Tmem65 is critical for the structure and function of the intercalated discs in mouse hearts.

The intercalated disc (ICD) is a unique membrane structure that is indispensable to normal heart function, yet its structural organization is not completely understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin43 (Cx43) localization and function in cultured mouse neonatal cardiomyocytes. Here, we investigate the functional and cellular effects of Tmem65 reductions on the myocardium in a mouse model by injecting CD1 mouse pups (3-7 days after birth) with recombinant adeno-associated virus 9 (rAAV9) harboring Tmem65 shRNA, which reduces Tmem65 expression by 90% in mouse ventricles compared to scrambled shRNA injection. Tmem65 knockdown (KD) results in increased mortality which is accompanied by eccentric hypertrophic cardiomyopathy within 3 weeks of injection and progression to dilated cardiomyopathy with severe cardiac fibrosis by 7 weeks post-injection. Tmem65 KD hearts display depressed hemodynamics as measured echocardiographically as well as slowed conduction in optical recording accompanied by prolonged PR intervals and QRS duration in electrocardiograms. Immunoprecipitation and super-resolution microscopy demonstrate a physical interaction between Tmem65 and sodium channel ß subunit (ß1) in mouse hearts and this interaction appears to be required for both the establishment of perinexal nanodomain structure and the localization of both voltage-gated sodium channel 1.5 (NaV1.5) and Cx43 to ICDs. Despite the loss of NaV1.5 at ICDs, whole-cell patch clamp electrophysiology did not reveal reductions in Na+ currents but did show reduced Ca2+ and K+ currents in Tmem65 KD cardiomyocytes in comparison to control cells. We conclude that disrupting Tmem65 function results in impaired ICD structure, abnormal cardiac electrophysiology, and ultimately cardiomyopathy.

A Pt-cluster-based heterogeneous catalyst for homogeneous catalytic reactions: X-ray absorption spectroscopy and reaction kinetic studies of their activity and stability against leaching.

The design and development of metal-cluster-based heterogeneous catalysts with high activity, selectivity, and stability under solution-phase reaction conditions will enable their applications as recyclable catalysts in large-scale fine chemicals production. To achieve these required catalytic properties, a heterogeneous catalyst must contain specific catalytically active species in high concentration, and the active species must be stabilized on a solid catalyst support under solution-phase reaction conditions. These requirements pose a great challenge for catalysis research to design metal-cluster-based catalysts for solution-phase catalytic processes. Here, we focus on a silica-supported, polymer-encapsulated Pt catalyst for an electrophilic hydroalkoxylation reaction in toluene, which exhibits superior selectivity and stability against leaching under mild reaction conditions. We unveil the key factors leading to the observed superior catalytic performance by combining X-ray absorption spectroscopy (XAS) and reaction kinetic studies. On the basis of the mechanistic understandings obtained in this work, we also provide useful guidelines for designing metal-cluster-based catalyst for a broader range of reactions in the solution phase.

Stereocontrolled total syntheses of isodomoic acids G and H via a unified strategy.

Marine neuroexcitatory compounds isodomoic acids G and H were efficiently synthesized from a common intermediate using a silicon-based cross-coupling reaction. Dividing each target compound into the core fragment and the side-chain fragment enabled the synthesis to be convergent. The trans-2,3-disubstituted pyrrolidine core fragment was accessed through a diastereoselective rhodium-catalyzed carbonylative silylcarbocyclization reaction of a vinylglycine-derived 1,6-enyne. A stereochemically divergent desilylative iodination reaction was developed to convert the cyclization product to both E- and Z-alkenyl iodides, which would eventually lead to isodomoic acid G and isodomoic acid H, respectively. The late-stage alkenyl-alkenyl silicon-based cross-coupling reaction uniting the core alkenyl iodides and the side-chain alkenylsilanol was achieved under mild conditions. Finally, two mild deprotections afforded the target molecules.

Comparison of 1-Year Morbidity Following Liver Transplant for Acute Alcoholic Hepatitis Versus Alcoholic Cirrhosis.

OBJECTIVES: With limited data on the morbidity profile of liver transplant as therapy for alcoholic hepatitis, we compared 30-day and 1-year morbidity in liver transplant recipients with alcoholic hepatitis versus alcoholic cirrhosis. MATERIALS AND METHODS: We retrospectively reviewed 38 perioperative variables in patients with alcoholic hepatitis (n = 15) and with alcoholic cirrhosis (n = 46). Multivariable analysis was performed to identify factors independently associated with outcomes. RESULTS: Patients with alcoholic hepatitis were younger (43 vs 58 years; P = .001), with higher pretransplant Model for End-Stage Liver Disease scores (36 vs 29; P = .009) and worse Karnofsky scores (20 vs 50; P < .001). All patients with alcoholic hepatitis received standard criteria deceased donor grafts; however, in the alcoholic cirrhosis group, 64% received standard criteria deceased, 11% living, 11% after cardiac death, 9% extended criteria, and 2% split graft donor organ donations (P > .05). The alcoholic hepatitis group had higher degree of steatosis on explant (P < .005), and the alcoholic cirrhosis group had higher 30-day reoperation rate (P = .001); however, 1-year interventions, vascular and biliary complications, graft and patient survival, and all other variables were similar (P > .05). Rates of alcohol relapse, 1-year infection, and 1-year rejection were higher but not significant (P > .05) in the alcoholic hepatitis group. Thirty-day reoperation (odds ratio of 82.63; 95% CI, 8.02-3338.96; P = .002) and Karnofsky scores (odds ratio of 1.18; 95% CI, 1.08-1.36; P = .006) remained significant on multivariate analysis. CONCLUSIONS: Our results showed significant differences between our patient groups, including worse functional status in the alcoholic hepatitis group but significantly higher 30-day reoperation rates and more variable grafts in the alcoholic cirrhosis group, although both groups had similar overall 1-year complication and survival rates. Although not significant, patients with alcoholic hepatitis had higher alcohol relapse and 1-year infection and rejection rates. A larger cohort is necessary to confirm the strength of these findings.

Highly active heterogeneous palladium nanoparticle catalysts for homogeneous electrophilic reactions in solution and the utilization of a continuous flow reactor.

A highly active heterogeneous Pd-nanoparticle catalyst for the intramolecular addition of phenols to alkynes was developed and employed in a continuous flow reaction system. Running the reaction in flow mode revealed reaction kinetics, such as the activation energy and catalyst deactivation, and provides many potential practical advantages.

Sequential Processes in Palladium-Catalyzed Silicon-Based Cross-Coupling.

Although developed somewhat later, silicon-based cross-coupling has become a viable alternative to the more conventional Suzuki-Miyaura, Stille-Kosugi-Migita, and Negishi cross-coupling reactions because of its broad substrate scope, high stability of silicon-containing reagents, and low toxicity of waste streams. An empowering and yet underappreciated feature unique to silicon-based cross-coupling is the wide range of sequential processes available. In these processes, simple precursors are first converted to complex silicon-containing cross-coupling substrates, and the subsequent silicon-based cross-coupling reaction affords an even more highly functionalized product in a stereoselective fashion. In so doing, structurally simple and inexpensive starting materials are quickly transformed into value-added and densely substituted products. Therefore, sequential processes are often useful in constructing the carbon backbones of natural products. In this review, studies of sequential processes involving silicon-based cross-coupling are discussed. Additionally, the total syntheses that utilize these sequential processes are also presented.

Silicon-based cross-coupling reactions in the total synthesis of natural products.

Unlike other variants of transition-metal-catalyzed cross-coupling reactions, those based on organosilicon donors have not been used extensively in natural product synthesis. However, recent advances such as: 1) the development of mild reaction conditions, 2) the expansion of substrate scope, 3) the development of methods to stereoselectively and efficiently introduce the silicon-containing moiety, 4) the development of a large number of sequential processes, and 5) the advent of bifunctional bis(silyl) linchpin reagents, signify the coming of age of silicon-based cross-coupling reactions. The following case studies illustrate how silicon-based cross-coupling reactions play a strategic role in constructing carbon-carbon bonds in selected target molecules.

Apelin increases atrial conduction velocity, refractoriness, and prevents inducibility of atrial fibrillation.

Previous studies have shown an association between elevated atrial NADPH-dependent oxidative stress and decreased plasma apelin in patients with atrial fibrillation (AF), though the basis for this relationship is unclear. In the current study, RT-PCR and immunofluorescence studies of human right atrial appendages (RAAs) showed expression of the apelin receptor, APJ, and reduced apelin content in the atria, but not in plasma, of patients with AF versus normal sinus rhythm. Disruption of the apelin gene in mice increased (2.4-fold) NADPH-stimulated superoxide levels and slowed atrial conduction velocities in optical mapping of a Langendorff-perfused isolated heart model, suggesting that apelin levels may influence AF vulnerability. Indeed, in mice with increased AF vulnerability (induced by chronic intense exercise), apelin administration reduced the incidence and duration of induced atrial arrhythmias in association with prolonged atrial refractory periods. Moreover, apelin decreased AF induction in isolated atria from exercised mice while accelerating conduction velocity and increasing action potential durations. At the cellular level, these changes were associated with increased atrial cardiomyocyte sodium currents. These findings support the conclusion that reduced atrial apelin is maladaptive in fibrillating human atrial myocardium and that increasing apelin bioavailability may be a worthwhile therapeutic strategy for treating and preventing AF.