-
Science Advances May 2024Antibody drug conjugates (ADCs) have made impressive strides in the clinic in recent years with 11 Food and Drug Administration approvals, including 6 for the treatment... (Review)
Review
Antibody drug conjugates (ADCs) have made impressive strides in the clinic in recent years with 11 Food and Drug Administration approvals, including 6 for the treatment of patients with solid tumors. Despite this success, the development of new agents remains challenging with a high failure rate in the clinic. Here, we show that current approved ADCs for the treatment of patients with solid tumors can all show substantial efficacy in some mouse models when administered at a similar weight-based [milligrams per kilogram (mg/kg)] dosing in mice that is tolerated in the clinic. Mechanistically, equivalent mg/kg dosing results in a similar drug concentration in the tumor and a similar tissue penetration into the tumor due to the unique delivery features of ADCs. Combined with computational approaches, which can account for the complex distribution within the tumor microenvironment, these scaling concepts may aid in the evaluation of new agents and help design therapeutics with maximum clinical efficacy.
Topics: Animals; Immunoconjugates; Mice; Neoplasms; Humans; Xenograft Model Antitumor Assays; Translational Research, Biomedical; Disease Models, Animal; Tumor Microenvironment; Cell Line, Tumor; Antineoplastic Agents; Drug Evaluation, Preclinical
PubMed: 38820153
DOI: 10.1126/sciadv.adk1894 -
JAMA Network Open May 2024Direct-to-consumer education reduces chronic sedative use. The effectiveness of this approach for prescription opioids among patients with chronic noncancer pain remains... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Direct-to-consumer education reduces chronic sedative use. The effectiveness of this approach for prescription opioids among patients with chronic noncancer pain remains untested.
OBJECTIVES
To evaluate the effectiveness of a government-led educational information brochure mailed to community-dwelling, long-term opioid consumers to reduce prescription opioid use compared with usual care.
DESIGN, SETTING, AND PARTICIPANTS
This cluster randomized clinical trial was conducted from July 2018 to January 2019 in Manitoba, Canada. All adults with long-term opioid prescriptions were enrolled (n = 4225). Participants were identified via the Manitoba Drug Program Information Network. Individuals receiving palliative care or with a diagnosis of cancer or dementia were excluded. Data were analyzed from July 2019 to March 2020.
INTERVENTION
Participants were clustered according to their primary care clinic and randomized to the intervention (a codesigned direct-to-consumer educational brochure sent by mail) or usual care (comparator group).
MAIN OUTCOMES AND MEASURES
The main outcome was discontinuation of opioid prescriptions at the participant level after 6 months, ascertained by pharmacy drug claims. Secondary outcomes included dose reduction (in morphine milligram equivalents [MME]) and/or therapeutic switch. Reduction in opioid use was assessed using generalized estimating equations to account for clustering, with prespecified subgroup analyses by age and sex. Analysis was intention to treat.
RESULTS
Of 4206 participants, 2409 (57.3%) were male; mean (SD) age was 60.0 (14.4) years. Mean (SD) baseline opioid use was comparable between groups (intervention, 157.7 [179.7] MME/d; control, 153.4 [181.8] MME/d). After 6 months, 235 of 2136 participants (11.0%) in 127 clusters in the intervention group no longer filled opioid prescriptions compared with 228 of 2070 (11.0%) in 124 clusters in the comparator group (difference, 0.0%; 95% CI, -1.9% to 1.9%). More participants in the intervention group than in the control group reduced their dose (1410 [66.0%] vs 1307 [63.1%]; difference, 2.8% [95% CI, 0.0%-5.7%]). Receipt of the brochure led to greater dose reductions for participants who were male (difference, 3.9%; 95% CI, 0.1%-7.7%), aged 18 to 64 years (difference, 3.7%; 95% CI, 0.2%-7.2%), or living in urban areas (difference, 5.9%; 95% CI, 1.9%-9.9%) compared with usual care.
CONCLUSIONS AND RELEVANCE
In this cluster randomized clinical trial, no significant difference in the prevalence of opioid cessation was observed after 6 months between the intervention and usual care groups; however, the intervention resulted in more adults reducing their opioid dose compared with usual care.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03400384.
Topics: Humans; Male; Female; Middle Aged; Analgesics, Opioid; Aged; Patient Education as Topic; Adult; Manitoba; Chronic Pain; Cluster Analysis; Opioid-Related Disorders
PubMed: 38809554
DOI: 10.1001/jamanetworkopen.2024.13698 -
Pharmaceutics May 2024The aim of this study was to develop and validate a fast and sensitive bioanalytical method for the accurate quantification of fosfomycin concentrations in human...
The aim of this study was to develop and validate a fast and sensitive bioanalytical method for the accurate quantification of fosfomycin concentrations in human prostatic tissue. The sample preparation method only required milligrams of tissue sample. Each sample was mixed with two times its weight of water and homogenized. A methanol solution that was three times the volume of the internal standard (fosfomycin-13C3) was added, followed by vortex mixing and centrifugation. After its extraction from the homogenized prostatic tissue, fosfomycin was quantified by means of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) triple quadrupole system operating in negative electrospray ionization and multiple reaction monitoring detection mode. The analytical procedure was successfully validated in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, and stability, according to EMA guidelines. The validation results, relative to three QC levels, were 9.9% for both the within-day and inter-day accuracy (BIAS%); 9.8% for within-day precision; and 9.9 for between-day precision. A marked matrix effect was observed in the measurements but was corrected by normalization with the internal standard. The average total recovery was high (approximatively 97% at the three control levels). The dynamic range of the method was 0.1-20 μg/g (R of 0.999). Negligible carry-over was observed after the injection of highly concentrated samples. F in the sample homogenate extracts was stable at 10 °C and 4 °C for at least 24 h. In the tissue sample freeze-thaw experiments, a significant decrease in F concentrations was observed after only two cycles from -80 °C to room temperature. The novel method was successfully applied to measure fosfomycin in prostatic tissue samples collected from 105 patients undergoing prostatectomy.
PubMed: 38794343
DOI: 10.3390/pharmaceutics16050681 -
Energy & Fuels : An American Chemical... May 2024Pyrolysis of lignocellulosic biomass and waste plastics has been intensely studied in the last few decades to obtain renewable fuels and chemicals. Various pyrolysis...
Pyrolysis of lignocellulosic biomass and waste plastics has been intensely studied in the last few decades to obtain renewable fuels and chemicals. Various pyrolysis devices have been developed for use in a laboratory setting, operated either in batch or continuously at scales ranging from milligrams per hour to tenths of g per hour. We report here the design and operation of a novel staged free-fall (catalytic) pyrolysis unit and demonstrate that the concept works very well for the (catalytic) pyrolysis of pinewood sawdust, paper sludge, and polypropylene as representative feeds. The unit consists of a vertical tube with a pretreatment section, a pyrolysis section, a solid residue collection section, a gas-liquid separation/collection section, and a catalytic reaction section to optionally perform ex situ catalytic upgrading of the pyrolysis vapor. The sample is placed in a tube, which is transported by gravity through various sections of the unit. It allows for rapid testing with semicontinuous feeding (e.g., 50 g h) and the opportunity to perform reactions under an (inert) gas (e.g., N) at atmospheric as well as elevated pressure (e.g., 50 bar). Liquid yields for noncatalytic sawdust pyrolysis at optimized conditions (475 °C and atmospheric pressure) were 63 wt % on biomass intake. A lower yield of 51 wt % (on a biomass basis) was obtained for the noncatalytic pyrolysis of paper sludge, likely due to the presence of minerals (e.g., CaCO) in the feed. The possibility of using the unit for ex situ catalytic pyrolysis (pyrolysis at 475 °C and catalytic upgrading at 550 °C) was also successfully demonstrated using paper sludge as the feed and H-ZSM-5 as the catalyst (21 wt % catalyst on biomass). This resulted in a biphasic liquid product with 25.6 wt % of an aqueous phase and 11 wt % of an oil phase. The yield of benzene, toluene, and xylenes was 1.9 wt % (on a biomass basis). Finally, the concept was also proven for a representative polyolefin (polypropylene), both noncatalytic as well as in situ catalytic pyrolysis using H-ZSM-5 as the catalyst at 500 °C. The liquid yield of thermal, noncatalytic plastic pyrolysis was as high as 77 wt % on plastic intake, while in situ catalytic pyrolysis gave a combined 7.8 wt % yield of benzene, toluene, and xylenes on plastic intake.
PubMed: 38774064
DOI: 10.1021/acs.energyfuels.3c04733 -
Protein Expression and Purification Sep 2024Protein reagents are essential resources for several stages of drug discovery projects from structural biology and assay development through lead optimization. Depending...
Protein reagents are essential resources for several stages of drug discovery projects from structural biology and assay development through lead optimization. Depending on the aim of the project different amounts of pure protein are required. Small-scale expressions are initially used to determine the reachable levels of production and quality before scaling up protein reagent supply. Commonly, amounts of several hundreds of milligrams to grams are needed for different experiments, including structural investigations and activity evaluations, which require rather large cultivation volumes. This implies that cultivation of large volumes of either transiently transfected cells or stable pools/stable cell lines is needed. Hence, a production process that is scalable, speeds up the development projects, and increases the robustness of protein reagent quality throughout scales. Here we present a protein production pipeline with high scalability. We show that our protocols for protein production in Chinese hamster ovary cells allow for a seamless and efficient scale-up with robust product quality and high performance. The flexible scale of the production process, as shown here, allows for shorter lead times in drug discovery projects where there is a reagent demand for a specific protein or a set of target proteins.
Topics: CHO Cells; Cricetulus; Animals; Bioreactors; Recombinant Proteins; Plasmids; Cricetinae
PubMed: 38768672
DOI: 10.1016/j.pep.2024.106505 -
Cureus Apr 2024Background Opioids, commonly used to control pain associated with surgery, are known to prolong the duration of mechanical ventilation and length of hospital stay. A...
Background Opioids, commonly used to control pain associated with surgery, are known to prolong the duration of mechanical ventilation and length of hospital stay. A wide range of adjunctive strategies are currently utilized to reduce postoperative pain, such as local and regional nerve blocks, nerve cryoablation, and adjunctive medications. We hypothesized that dronabinol (a synthetic cannabinoid) in conjunction with standard opioid pain management will reduce opioid requirements to manage postoperative pain. Methods Sixty-eight patients who underwent isolated first-time coronary artery bypass graft surgery were randomized to either the control group, who received only standard opioid-based analgesia, or the dronabinol group, who received dronabinol (a synthetic cannabinoid) in addition to standard opioid-based analgesia. Dronabinol was given in the preoperative unit, before extubation in the ICU, and after extubation on the first postoperative day. Preoperative, intraoperative, and postoperative parameters were compared under an IRB-approved protocol. The primary endpoints were the postoperative opioid requirement, duration of mechanical ventilation, and ICU length of stay, and the secondary endpoints were the duration of inotropic support needed, left ventricular ejection fraction (LVEF), and the change in LVEF. This study was undertaken at Northwest Medical Center, Tucson, AZ, USA. Results Sixty-eight patients were randomized to either the control group (n = 37) or the dronabinol group (n = 31). Groups were similar in terms of demographic features and comorbidities. The total postoperative opioid requirement was significantly lower in the dronabinol group [39.62 vs 23.68 morphine milligram equivalents (MMEs), p = 0.0037], representing a 40% reduction. Duration of mechanical ventilation (7.03 vs 6.03h, p = 0.5004), ICU length of stay (71.43 vs 63.77h, p = 0.4227), and inotropic support requirement (0.6757 vs 0.6129 days, p = 0.7333) were similar in the control and the dronabinol groups. However, there was a trend towards lower durations in each endpoint in the dronabinol group. Interestingly, a significantly better preoperative to postoperative LVEF change was observed in the dronabinol group (3.51% vs 6.45%, p = 0.0451). Conclusions Our study found a 40% reduction in opioid use and a significantly greater improvement in LVEF in patients treated with adjunctive dronabinol. Mechanical ventilation duration, ICU length of stay, and inotropic support requirement tended to be lower in the dronabinol group, though did not reach statistical significance. The results of this study, although limited by sample size, are very encouraging and validate our ongoing investigation.
PubMed: 38765405
DOI: 10.7759/cureus.58566 -
Environmental Science & Technology Jun 2024The presence of organic micropollutants in water and sediments motivates investigation of their biotransformation at environmentally low concentrations, usually in the...
The presence of organic micropollutants in water and sediments motivates investigation of their biotransformation at environmentally low concentrations, usually in the range of μg L. Many are biotransformed by cometabolic mechanisms; however, there is scarce information concerning their direct metabolization in this concentration range. Threshold concentrations for microbial assimilation have been reported in both pure and mixed cultures from different origins. The literature suggests a range value for bacterial growth of 1-100 μg L for isolated aerobic heterotrophs in the presence of a single substrate. We aimed to investigate, as a model case, the threshold level for sulfamethoxazole (SMX) metabolization in pure cultures of strain BR1. Previous research with this strain has covered the milligram L range. In this study, acclimated cultures were exposed to concentrations from 0.1 to 25 μg L of C-labeled SMX, and the C-CO produced was trapped and quantified over 24 h. Interestingly, SMX removal was rapid, with 98% removed within 2 h. In contrast, mineralization was slower, with a consistent percentage of 60.0 ± 0.7% found at all concentrations. Mineralization rates increased with rising concentrations. Therefore, this study shows that bacteria are capable of the direct metabolization of organic micropollutants at extremely low concentrations (sub μg L).
Topics: Sulfamethoxazole; Water Pollutants, Chemical
PubMed: 38761139
DOI: 10.1021/acs.est.4c02191 -
Orthopaedic Journal of Sports Medicine May 2024Although several studies have noted that patients are routinely overprescribed opioids, few have reported usage after arthroscopic surgery.
BACKGROUND
Although several studies have noted that patients are routinely overprescribed opioids, few have reported usage after arthroscopic surgery.
PURPOSE
To determine opioid consumption and allocation for unused opioids after common arthroscopic surgeries.
STUDY DESIGN
Case series; Level of evidence, 4.
METHODS
Patients between the ages of 15 and 40 years who were scheduled to undergo anterior cruciate ligament reconstruction (ACLR), labral repair of the hip or shoulder, meniscectomy, or meniscal repair were prospectively enrolled. Patients were prescribed either 5 mg hydrocodone-325 mg acetaminophen or 5 mg oxycodone-325 mg acetaminophen based on surgeon preference. Patients completed a daily opioid usage survey during the 2-week postoperative period. In addition, patients completed a survey on postoperative day 21 inquiring about continued opioid use and medication disposal, if applicable. Opioid medication consumption was converted to morphine milligram equivalents (MMEs).
RESULTS
Of the 200 patients who were enrolled in the study, 176 patients had sufficient follow-up after undergoing 85 (48%) ACLR, 26 (14.8%) hip labral repair, 34 (19.3%) shoulder labral repair, 18 (10.2%) meniscectomy, and 13 (7.4%) meniscal repair procedures. Mean age was 26.1 years (SD, 7.38); surgeons prescribed a mean of 26.6 pills whereas patients reported consuming a mean of 15.5 pills. The mean MME consumption in the 14 days after each procedure was calculated: ACLR (95.7; 44% of prescription), hip labral repair (84.8; 37%), shoulder labral repair (57.2; 35%), meniscectomy (18.4; 27%), and meniscal repair (32.1; 42%). This corresponded to approximately 39% of the total opioid prescription being utilized across all procedures. Mean MME consumption was greatest on postoperative day 1 in hip, shoulder, and meniscal procedures and on postoperative day 2 in ACLR. Only 7.04% of patients reported continued opioid use in the third postoperative week. Patients had a mean of 11 unused pills or 77.7 MMEs remaining. Of the patients with remaining medication, 24.7% intended to keep their medication for future use.
CONCLUSION
The results of our study indicate that patients who undergo the aforementioned arthroscopic procedures consume <75 MMEs in the 2-week postoperative period, translating into a mean of 10 to 15 pills consumed. Approximately 60% of total opioids prescribed went unused, and one-fourth of patients intended to keep their remaining medication for future usage. We have provided general prescribing guidelines and recommend that surgeons carefully consider customizing their opioid prescriptions on the basis of procedure site to balance optimal postoperative analgesia with avoidance of dissemination of excess opioids.
PubMed: 38757068
DOI: 10.1177/23259671241249688 -
JPGN Reports May 2024Protein-losing enteropathy associated with collagenous colitis (CC) is a rare but described entity in the adult population. However, literature regarding this in the...
Protein-losing enteropathy associated with collagenous colitis (CC) is a rare but described entity in the adult population. However, literature regarding this in the pediatric population is scarce. Here we describe a 2-year-old female who presented with fevers, accompanied by nonbloody, watery diarrhea, and decreased oral intake. Work-up was significant for severe hypoalbuminemia at 1.5 grams per deciliter (g/dL), pancytopenia, and elevated fecal alpha-1-antitrypsin at 1.13 milligrams per grams (mg/g). Gastrointestinal mucosal evaluation was normal endoscopically; however, histology was consistent with CC. She responded to 12-week treatment with budesonide with resolution of symptoms and laboratory values. At this point, she has not had a recurrence 1 year later.
PubMed: 38756128
DOI: 10.1002/jpr3.12051 -
Frontiers in Endocrinology 2024The baseline urinary albumin/creatinine ratio (uACR) has been proven to be significantly associated with the risk of major adverse cardiac events (MACE). However, data...
OBJECTIVE
The baseline urinary albumin/creatinine ratio (uACR) has been proven to be significantly associated with the risk of major adverse cardiac events (MACE). However, data on the association between the longitudinal trajectory patterns of uACR, changes in glycated hemoglobin A1c (HbA1c), and the subsequent risk of MACE in patients with diabetes are sparse.
METHODS
This is a retrospective cohort study including 601 patients with type 2 diabetes mellitus (T2DM; uACR < 300 mg/g) admitted to The First Hospital of Shanxi Medical University and The Second Hospital of Shanxi Medical University from January 2015 to December 2018. The uACR index was calculated as urinary albumin (in milligrams)/creatinine (in grams), and latent mixed modeling was used to identify the longitudinal trajectory of uACR during the exposure period (2016-2020). The deadline for follow-up was December 31, 2021. The primary outcome was the MACE [a composite outcome of cardiogenic death, hospitalization related to heart failure (HHF), non-fatal acute myocardial infarction, non-fatal stroke, and acute renal injury/dialysis indications]. The Kaplan-Meier survival analysis curve was used to compare the risk of MACE among four groups, while univariate and multivariate Cox proportional hazards models were employed to calculate the hazard ratio (HR) and 95% confidence interval (CI) for MACE risk among different uACR or HbA1c trajectory groups. The predictive performance of the model, both before and after the inclusion of changes in the uACR and HbA1c, was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC).
RESULTS
Four distinct uACR trajectories were identified, namely, the low-stable group (uACR = 5.2-38.3 mg/g, = 112), the moderate-stable group (uACR = 40.4-78.6 mg/g, = 229), the high-stable group (uACR = 86.1-153.7 mg/g, = 178), and the elevated-increasing group (uACR = 54.8-289.4 mg/g, = 82). In addition, five distinct HbA1c trajectories were also identified: the low-stable group (HbA1c = 5.5%-6.8%, = 113), the moderate-stable group (HbA1c = 6.0%-7.9%, = 169), the moderate-decreasing group (HbA1c = 7.4%-6.1%, = 67), the high-stable group (HbA1c = 7.7%-8.9%, = 158), and the elevated-increasing group (HbA1c = 8.4%-10.3%, = 94). Compared with the low-stable uACR group, patients in the high-stable and elevated-increasing uACR groups were more likely to be older, current smokers, and have a longer DM course, higher levels of 2-h plasma glucose (PG), HbA1c, N-terminal pro-B-type natriuretic peptide (NT-proBNP), uACR, and left ventricular mass index (LVMI), while featuring a higher prevalence of hypertension and a lower proportion of β-receptor blocker treatment ( < 0.05). During a median follow-up of 45 months (range, 24-57 months), 118 cases (19.6%) of MACE were identified, including 10 cases (1.7%) of cardiogenic death, 31 cases (5.2%) of HHF, 35 cases (5.8%) of non-fatal acute myocardial infarction (AMI), 18 cases (3.0%) of non-fatal stroke, and 24 cases (4.0%) of acute renal failure/dialysis. The Kaplan-Meier survival curve showed that, compared with that in the low-stable uACR group, the incidence of MACE in the high-stable (HR = 1.337, 95% CI = 1.083-1.652, = 0.007) and elevated-increasing (HR = 1.648, 95% CI = 1.139-2.387, = 0.009) uACR groups significantly increased. Similar results were observed for HHF, non-fatal AMI, and acute renal injury/dialysis indications ( < 0.05). The multivariate Cox proportional hazards models indicated that, after adjusting for potential confounders, the HRs for the risk of MACE were 1.145 ( = 0.132), 1.337 ( = 0.007), and 1.648 ( = 0.009) in the moderate-stable, high-stable, and elevated-increasing uACR groups, respectively. In addition, the HRs for the risk of MACE were 1.203 ( = 0.028), 0.872 ( = 0.024), 1.562 ( = 0.033), and 2.218 ( = 0.002) in the moderate-stable, moderate-decreasing, high-stable, and elevated-increasing groups, respectively. The ROC curve showed that, after adding uACR, HbA1c, or both, the AUCs were 0.773, 0.792, and 0.826, which all signified statistically significant improvements ( = 0.021, 0.035, and 0.019, respectively).
CONCLUSION
A long-term elevated uACR is associated with a significantly increased risk of MACE in patients with diabetes. This study implies that regular monitoring of uACR could be helpful in identifying diabetic patients with a higher risk of MACE.
Topics: Humans; Male; Female; Retrospective Studies; Diabetes Mellitus, Type 2; Middle Aged; Albuminuria; Creatinine; Aged; Glycated Hemoglobin; Longitudinal Studies; Risk Factors; Prognosis; Biomarkers; Cohort Studies; Follow-Up Studies
PubMed: 38745945
DOI: 10.3389/fendo.2024.1355149