Dose-fractionation studies of a Plasmodium phosphatidylinositol 4-kinase inhibitor in a humanized mouse model of malaria.

UCT594 is a 2-aminopyrazine carboxylic acid Plasmodium phosphatidylinositol 4-kinase inhibitor with potent asexual blood-stage activity, the potential for interrupting transmission, as well as liver-stage activities. Herein, we investigated pharmacokinetic/pharmacodynamic (PK/PD) relationships relative to blood-stage activity toward predicting the human dose. Dose-fractionation studies were conducted in the Plasmodium falciparum NSG mouse model to determine the PK/PD indices of UCT594, using the in vivo minimum parasiticidal concentration as a threshold. UCT594 demonstrated concentration-dependent killing in the P. falciparum-infected NSG mouse model. Using this data and the preclinical pharmacokinetic data led to a low predicted human dose of <50 mg. This makes UCT594 an attractive potential antimalarial drug.

Teratogenicity is more likely a function of primary and secondary pharmacology than caused by chemically reactive metabolites: a critical evaluation of 40 years of scientific research.

The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives.Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms.Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted.

Teaching Old Polymers New Tricks: Improved Synthesis and Anomalous Crystallinity for a Lost Semi-Fluorinated Polyaryl Ether via Interfacial Polymerization of Hexafluoroacetone Hydrate and Diphenyl Ether.

A practical and direct electrophilic polymerization of hexafluoroacetone hydrate with diphenyl ether toward the preparation of semi-fluorinated polyaryl ethers (PAE) is reported. Electrophilic aromatic substitution (EAS) polymerization under interfacial conditions with phase transfer catalyst (Aliquat 336) proceeds in trifluoromethanesulfonic anhydride by generation of trifluoromethanesulfonic acid and the protonated hexafluoroacetone (HFA) in situ affording 1,1,1,3,3,3-hexafluoroisopropylidene (6F) PAE with high regioselectivity (4,4'-DPE) and high molecular weight (≈60 kDa). Although first reported in a 1966 US Patent by DuPont using harsh conditions, improved synthetic methods or modern characterization has not been disclosed until now. Despite the presence of the 6F group, known to impart disordered morphology, this simple semi-fluorinated PAE exhibits anomalous crystallinity with polymorphic melting points (Tm ) ranging from 230-309 °C, high solubility in common organic solvents, a glass transition (Tg ) of 163 °C, and thermo-oxidative stability above 500 °C. Tough optically clear films prepared from solution give transmittance higher than 90% throughout the visible region. Synthesis, mechanistic aspects, and characterization including surface and dielectric properties are discussed.

Through a computer monitor darkly: artificial intelligence in absorption, distribution, metabolism and excretion science.

Artificial Intelligence (AI) is poised or has already begun to influence highly absorption, distribution, metabolism and excretion (ADME) science. It is not in the area expected, that of superior modelling of ADME data to increase its predictive power. It is influencing traditional exhaustive and careful literature research by providing almost perfect summaries of existing information. This will highly influence how people study, graduate and progress in the ADME sciences. The literature contains many flaws, protein binding influence on unbound drug concentration, is one of the examples cited, and without direction AI may help to popularise them.ADME science has a relatively small number of key assays and values but these are produced under widely varying conditions so large data sets, the best substrate for artificial intelligence, are not readily available to produce new more predictive systems. The use of AI to enrich the data bases may be a near term goal.AI is already contributing in other areas such as technical skill assimilation, maintenance of complex instruments (combined with virtual reality) and the processing of pharmacovigilance.

Ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ): tunable halogenation and quinone formation using NaX/Oxone.

Ring-fused benzimidazolequinones are well-known anti-tumour agents, but dimeric ring-fused adducts are new. The alicyclic [1,2-a] ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ) intermediate allows late-stage functionalization of bis-p-benzimidazolequinones. DMBBQs are chlorinated and brominated at the p-dimethoxybenzene site using nontoxic sodium halide and Oxone in HFIP/water. X-ray crystallography is used to rationalize site preference in terms of the discontinuity in conjugation in the DMBBQ system. Quinone formation occurs by increasing in situ halogen generation and water. Conversely, radical trifluoromethylation occurs at the quinone of the DMBBQ.

An in vitro toolbox to accelerate anti-malarial drug discovery and development.

BACKGROUND: Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. METHODS: Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC-MS/MS. RESULTS: Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds. CONCLUSIONS: This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug-drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.

Intracellular and Intraorgan Concentrations of Small Molecule Drugs: Theory, Uncertainties in Infectious Diseases and Oncology, and Promise.

The distribution of a drug within the body should be considered as involving movement of unbound drug between the various aqueous spaces of the body. At true steady state, even for a compound of restricted lipoidal permeability, unbound concentrations in all aqueous compartments (blood, extracellular, and intracellular) are considered identical, unless a compartment has a clearance/transport process. In contrast, total drug concentrations may differ greatly, reflecting binding or partitioning into constituents of each compartment. For most highly lipid permeable drugs, this uniform unbound concentration is expected to apply. However, many compounds have restricted lipoidal permeability and are subjected to transport/clearance processes causing a gradient between intracellular and extracellular unbound concentrations even at steady state. Additional concerns arise where the drug target resides in a site of limited vascularity. Many misleading assumptions about drug concentrations and access to drug targets are based on total drug. Correction, if made, is usually by measuring tissue binding, but this is limited by the lack of homogenicity of the organ or compartment. Rather than looking for technology to measure the unbound concentration it may be better to focus on designing high lipoidal permeable molecules with a high chance of achieving a uniform unbound drug concentration. It is hoped this paper will stimulate greater understanding of the path from circulation to cell interior, and thereby in part avoid or minimize the need to provide the experimentally very determining, and sometimes still questionable, answer to this problem.

US daily temperature records past, present, and future.

Observed temperature extremes over the continental United States can be represented by the ratio of daily record high temperatures to daily record low minimum temperatures, and this ratio has increased to a value of about 2 to 1, averaged over the first decade of the 21st century, albeit with large interannual variability. Two different versions of a global coupled climate model (CCSM4), as well as 23 other coupled model intercomparison project phase 5 (CMIP5) models, show larger values of this ratio than observations, mainly as a result of greater numbers of record highs since the 1980s compared with observations. This is partly because of the "warm 1930s" in the observations, which made it more difficult to set record highs later in the century, and partly because of a trend toward less rainfall and reduced evapotranspiration in the model versions compared with observations. We compute future projections of this ratio on the basis of its estimated dependence on mean temperature increase, which we find robustly at play in both observations and simulations. The use of this relation also has the advantage of removing dependence of a projection on a specific scenario. An empirical projection of the ratio of record highs to record lows is obtained from the nonlinear relationship in observations from 1930 to 2015, thus correcting downward the likely biased future projections of the model. For example, for a 3 °C warming in US temperatures, the ratio of record highs to lows is projected to be ∼15 ± 8 compared to the present average ratio of just over 2.

UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria.

The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2Rγ null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation Plasmodium PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.

Safety Assessment of Acyl Glucuronides-A Simplified Paradigm.

While simple O- (ether-linked) and N-glucuronide drug conjugates generally are unreactive and considered benign from a safety perspective, the acyl glucuronides that derive from metabolism of carboxylic acid-containing xenobiotics can exhibit a degree of chemical reactivity that is dependent upon their molecular structure. As a result, concerns have arisen over the safety of acyl glucuronides as a class, several members of which have been implicated in the toxicity of their respective parent drugs. However, direct evidence in support of these claims remains sparse, and due to frequently encountered species differences in the systemic exposure to acyl glucuronides (both of the parent drug and oxidized derivatives thereof), coupled with their instability in aqueous media and potential to undergo chemical rearrangement (acyl migration), qualification of these conjugates by traditional safety assessment methods can be very challenging. In this Commentary, we discuss alternative (non-acyl glucuronide) mechanisms by which carboxylic acids may cause serious adverse reactions, and propose a novel, practical approach to compare systemic exposure to acyl glucuronide metabolites in humans to that in animal species used in preclinical safety assessment based on relative estimates of the total body burden of these circulating conjugates.

Effectiveness of an Educational Intervention on Reducing Misconceptions Among Ethnic Minorities With Complicated Mild to Severe Traumatic Brain Injury.

OBJECTIVE: To evaluate the effectiveness of an educational intervention designed to reduce traumatic brain injury (TBI)-related misconceptions among blacks and Latinos with complicated mild to severe TBI. DESIGN: Randomized controlled trial with masked 1-month follow-up. SETTING: Community. PARTICIPANTS: Persons (N=52) with complicated mild to severe TBI (mean best day 1 Glasgow Coma Scale score, 11.27±3.89) were randomly recruited from 141 eligible participants (mean age, 37.71±13.88y; age range, 19-66y; mean months postinjury, 24.69±11.50); 25 participants (48.1%) of participants were black and 27 (51.9%) were Hispanic/Latino. Of the Hispanic/Latino participants, 18 (66.7%) were non-U.S. born and 12 (44.4%) spoke Spanish as their primary language. Twenty-seven individuals were randomized to the educational intervention group and 25 were randomized to the wait-list control group. INTERVENTIONS: Single-session educational intervention with written materials provided in English or Spanish. MAIN OUTCOME MEASURES: Forty-item Common Misconceptions about Traumatic Brain Injury Questionnaire administered at baseline and 1-month follow-up. RESULTS: After controlling for ethnic and language differences, a significant between-group main effect (P=.010) and a significant time-group interaction for the Common Misconceptions about Traumatic Brain Injury Questionnaire were noted (Wilks Λ=.89; F1,46=6.00; P=.02). The intervention group showed a decrease in TBI misconception percentages, whereas the wait-list control group maintained similar percentages. At 1-month follow-up, the wait-list control group reported more misconceptions than did the intervention group (P=.019). CONCLUSIONS: An educational intervention developed to address the recovery process, common symptoms, and ways to handle the symptoms provides promise as a tool to decrease TBI misconceptions among persons from ethnically and educationally diverse backgrounds. The effects of therapist characteristics and the client-therapist relation on outcomes should be further explored.

Passive lipoidal diffusion and carrier-mediated cell uptake are both important mechanisms of membrane permeation in drug disposition.

Recently, it has been proposed that drug permeation is essentially carrier-mediated only and that passive lipoidal diffusion is negligible. This opposes the prevailing hypothesis of drug permeation through biological membranes, which integrates the contribution of multiple permeation mechanisms, including both carrier-mediated and passive lipoidal diffusion, depending on the compound's properties, membrane properties, and solution properties. The prevailing hypothesis of drug permeation continues to be successful for application and prediction in drug development. Proponents of the carrier-mediated only concept argue against passive lipoidal diffusion. However, the arguments are not supported by broad pharmaceutics literature. The carrier-mediated only concept lacks substantial supporting evidence and successful applications in drug development.

Risk Factors for Severe Maternal Morbidity Among Women Enrolled in Mississippi Medicaid.

Importance: Mississippi has one of the highest rates of severe maternal morbidity (SMM) in the US, and SMMs have been reported to be more frequent among Medicaid-insured women. A substantial proportion of pregnant women in Mississippi are covered by Medicaid; hence, there is a need to identify potential risk factors for SMM in this population. Objective: To examine the associations of health care access and clinical and sociodemographic characteristics with SMM events among Mississippi Medicaid-enrolled women who had a live birth. Design, Setting, and Participants: A nested case-control study was conducted using 2018 to 2021 Mississippi Medicaid administrative claims database. The study included Medicaid beneficiaries aged 12 to 55 years who had a live birth and were continuously enrolled throughout their pregnancy period and 12 months after delivery. Individuals in the case group had SMM events and were matched to controls on their delivery date using incidence density sampling. Data analysis was performed from June to September 2022. Exposure: Risk factors examined in the study included sociodemographic factors (age and race), health care access (distance from delivery center, social vulnerability index, and level of maternity care), and clinical factors (maternal comorbidity index, first-trimester pregnancy-related visits, and postpartum care). Main Outcomes and Measures: The main outcome of the study was an SMM event. Adjusted odds ratio (aORs) and 95% CIs were calculated using conditional logistic regression. Results: Among 13 485 Mississippi Medicaid-enrolled women (mean [SD] age, 25.0 [5.6] years; 8601 [63.8%] Black; 4419 [32.8%] White; 465 [3.4%] other race [American Indian, Asian, Hispanic, multiracial, and unknown]) who had a live birth, 410 (3.0%) were in the case group (mean [SD] age, 26.8 [6.4] years; 289 [70.5%] Black; 112 [27.3%] White; 9 [2.2%] other race) and 820 were in the matched control group (mean [SD] age, 24.9 [5.7] years; 518 [63.2%] Black; 282 [34.4%] White; 20 [2.4%] other race). Black individuals (aOR, 1.44; 95% CI, 1.08-1.93) and those with higher maternal comorbidity index (aOR, 1.27; 95% CI, 1.16-1.40) had higher odds of experiencing SMM compared with White individuals and those with lower maternal comorbidity index, respectively. Likewise, an increase of 100 miles (160 km) in distance between beneficiaries' residence to the delivery center was associated with higher odds of experiencing SMM (aOR, 1.14; 95% CI, 1.07-1.20). Conclusions and Relevance: The study findings hold substantial implications for identifying high-risk individuals within Medicaid programs and call for the development of targeted multicomponent, multilevel interventions for improving maternal health outcomes in this highly vulnerable population.

Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen.

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.

Which metabolites circulate?

Characterization of the circulating metabolites for a new chemical entity in humans is essential for safety assessment, an understanding of their contributions to pharmacologic activities, and their potential involvement in drug-drug interactions. This review examines the abundance of metabolites relative to the total parent drug [metabolite-to-parent (M/P) ratio] from 125 drugs in relation to their structural and physicochemical characteristics, lipoidal permeability, protein binding, and fractional formation from parent (fm). Our analysis suggests that fm is the major determinant of total drug M/P ratio for amine, alcohol, N- and S-oxide, and carboxylic acid metabolites. Passage from the hepatocyte to systemic circulation does not appear to be limiting owing to the vast majority of metabolites formed being relatively lipid permeable. In some cases, active transport plays an important role in this process (e.g., carboxylic acid metabolites). Differences in total parent drug clearance and metabolite clearance are attenuated by the reduction in lipophilicity introduced by the metabolic step and resultant compensatory changes in unbound clearance and protein binding. A small subclass of these drugs (e.g., terfenadine) is unintentional prodrugs with very high parent drug clearance, resulting in very high M/P ratios. In contrast, arenol metabolites show a more complex relationship with fm due largely to the new metabolic routes (conjugation) available to the metabolite compared with the parent drug molecule. For these metabolites, a more thorough understanding of the elimination clearance of the metabolite is critical to discern the likelihood of whether the phenol will constitute a major circulating metabolite.

A comparison of polymer substrates for photolithographic processing of flexible bioelectronics.

Flexible bioelectronics encompass a new generation of sensing devices, in which controlled interactions with tissue enhance understanding of biological processes in vivo. However, the fabrication of such thin film electronics with photolithographic processes remains a challenge for many biocompatible polymers. Recently, two shape memory polymer (SMP) systems, based on acrylate and thiol-ene/acrylate networks, were designed as substrates for softening neural interfaces with glass transitions above body temperature (37 °C) such that the materials are stiff for insertion into soft tissue and soften through low moisture absorption in physiological conditions. These two substrates, acrylate and thiol-ene/acrylate SMPs, are compared to polyethylene naphthalate, polycarbonate, polyimide, and polydimethylsiloxane, which have been widely used in flexible electronics research and industry. These six substrates are compared via dynamic mechanical analysis (DMA), thermogravimetric analysis (TGA), and swelling studies. The integrity of gold and chromium/gold thin films on SMP substrates are evaluated with optical profilometry and electrical measurements as a function of processing temperature above, below and through the glass transition temperature. The effects of crosslink density, adhesion and cure stress are shown to play a critical role in the stability of these thin film materials, and a guide for the future design of responsive polymeric materials suitable for neural interfaces is proposed. Finally, neural interfaces fabricated on thiol-ene/acrylate substrates demonstrate long-term fidelity through both in vitro impedance spectroscopy and the recording of driven local field potentials for 8 weeks in the auditory cortex of laboratory rats.

Evolution of ADME science: where else can modeling and simulation contribute?

The commentary describes progress in modeling and simulation in ADME science and focuses on lipoidal permeability as a central driver of drug molecule disposition. The tension between screening and in silico is outlined with practical suggestions on how to improve multiparameter models. The limitations on modeling drug metabolism and its enzymes are highlighted together with key features in molecules that lead to drug transport. Reservations about the quality of data and the imprecise classification of drug molecules are explained. Encouragement to move modeling and simulation to the forefront of project start-up is provided after examining the complexity of macromolecule-small molecule conjugate prodrugs.

Return to primary service among bone marrow transplant rehabilitation inpatients: an index for predicting outcomes.

OBJECTIVE: To assess rehabilitation inpatient risk of return to primary (RTP) service in patients with bone marrow transplant (BMT). DESIGN: Retrospective review. SETTING: Inpatient rehabilitation unit within a tertiary referral-based cancer center. PARTICIPANTS: All patients with BMT (131) who were admitted a total of 147 times to inpatient rehabilitation between January 1, 2002, and April 30, 2010. INTERVENTIONS: None. MAIN OUTCOME MEASURES: We analyzed RTP service and demographic information, cancer characteristics, medications, hospital admission characteristics, and laboratory values. RESULTS: A total of 61 (41%) of 147 of BMT admissions were transferred from the inpatient rehabilitation unit back to the primary service. Of those transferred back, 23 (38%) of 61 died after being transferred back to the primary service. Significant or near-significant relationships were found for a platelet count of <43,000 per microliter (P<.01); a creatinine level of >0.9 milligrams/deciliter (P<.01); the presence of an antiviral agent (P=.0501); the presence of an antibacterial agent (P=.0519); the presence of an antifungal agent (P<.05); and leukemia, lymphoma, or multiple myeloma diagnosis (P<.05). Using 5 of these factors, the RTP-BMT index was formulated to determine the likelihood of return to the primary team. CONCLUSIONS: Patients with BMT have a high rate of transfer from the inpatient rehabilitation unit back to the primary service. The RTP-BMT index score can be a useful tool to help clinicians predict the likelihood of return to the primary acute care service.