Hours Of First Administration Research Articles

Predicting persistent fever in patients with cancer using machine learning.

e13552 Background: Sepsis is the leading cause of hospital readmission and death in the developed world. Cancer patients are at high risk due to their underlying disease and therapies. Meanwhile, antimicrobial resistance increases steadily, warranting a more careful administration of antibiotics. Predicting fever persistence 48 hours after initiation of antibiotics could help reduce antibiotic escalation and chest CT scans in patients where fever is predicted to subside within the next 24 hours. Methods: All cancer patients of the University Hospital Essen (UHE) between 1/1/2020-7/1/2023, receiving broad-spectrum i.v. antibiotics, and having persistent fever after 48 hours of first administration were extracted from UHE’s Fast Health Interoperability Resources clinical database. Vital signs, clinically important covariates, as well as lag features of vital signs and laboratory values were included. The binary target to predict was prevalence of body temperature ≥38 °C after 48-72 hours. Gradient boosting machines, a deep learning neural network, logistic regression (LR), random forest (RF) and a voting ensemble classifier were implemented. Hyperparameter tuning and model validation was performed through five-fold stratified cross validation (80/20% train/test split). Results: Analyzing 2.9 million patient records of UHE we obtained approx. 27,000 hospitalized adults with cancer. Restriction to hematology/oncology wards and intravenous broad-spectrum antibiotics resulted in 1,267 cancer patients. Of these, 264 patients had persistent fever after 48 hours, of which 111 patients had solid cancers, 66 lymphomas, and 87 other hematologic malignancies. 72 hours after antibiotic therapy 160 patients (60.2%) had persistent fever. Based on the area under the precision-recall curve (AUPRC) of 81.7%, the voting classifier model had the highest predictive performance. The model shows a sensitivity of 85%, a specificity of 63%, a Negative Predictive Value (NPV) of 75% and a Positive Predictive Value (PPV) of 73% on a cross-validated test set (Table). Conclusions: Machine learning-based algorithms can predict fever evolution and assist in clinical decision-making, potentially contributing to better patient care by preventing unnecessary antibiotics escalations and CT scans. Based on current model performance, 25% of chest CT scans could be obsolete as patients will not have persistent fever after 48 hours. Additional results will be presented at the meeting. [Table: see text]

Intravital Microscopy Reveals Unforeseen Biodistribution Within the Liver and Kidney Mechanistically Connected to the Clearance of a Bifunctional Antibody.

Bifunctional antibody (BfAb) therapeutics offer the potential for novel functionalities beyond those of the individual monospecific entities. However, combining these entities into a single molecule can have unpredictable effects, including changes in pharmacokinetics that limit the compound's therapeutic profile. A better understanding of how molecular modifications affect in vivo tissue interactions could help inform BfAb design. The present studies were predicated on the observation that a BfAb designed to have minimal off-target interactions cleared from the circulation twice as fast as the monoclonal antibody (mAb) from which it was derived. The present study leverages the spatial and temporal resolution of intravital microscopy (IVM) to identify cellular interactions that may explain the different pharmacokinetics of the two compounds. Disposition studies of mice demonstrated that radiolabeled compounds distributed similarly over the first 24 hours, except that BfAb accumulated approximately two- to -three times more than mAb in the liver. IVM studies of mice demonstrated that both distributed to endosomes of liver endothelia but with different kinetics. Whereas mAb accumulated rapidly within the first hour of administration, BfAb accumulated only modestly during the first hour but continued to accumulate over 24 hours, ultimately reaching levels similar to those of the mAb. Although neither compound was freely filtered by the mouse or rat kidney, BfAb, but not mAb, was found to accumulate over 24 hours in endosomes of proximal tubule cells. These studies demonstrate how IVM can be used as a tool in drug design, revealing unpredicted cellular interactions that are undetectable by conventional analyses. SIGNIFICANCE STATEMENT: Bifunctional antibodies offer novel therapeutic functionalities beyond those of the individual monospecific entities. However, combining these entities into a single molecule can have unpredictable effects, including undesirable changes in pharmacokinetics. Studies of the dynamic distribution of a bifunctional antibody and its parent monoclonal antibody presented here demonstrate how intravital microscopy can expand our understanding of the in vivo disposition of therapeutics, detecting off-target interactions that could not be detected by conventional pharmacokinetics approaches or predicted by conventional physicochemical analyses.

Abstract LB-002: SQ3370 enhances the safety of chemotherapeutics via local activation therapy

Abstract With systemic chemotherapy, only 1-2% of the administered dose actually reaches a localized tumor, while the remaining leads to adverse off-target toxicities, including immunosuppression. Hence, there is a critical need to locally deliver cytotoxics directly to the tumor. Our patented approach (SQ3370) consists of: (1) SQL70 - a drug-activating biomaterial carrying no payload (2) SQP33 - a chemically-modified prodrug of doxorubicin (Dox) with attenuated activity. SQL70 is injected at the tumor site followed by SQP33 administered systemically. The prodrug first concentrates to the biomaterial at the tumor site due to their complementary chemical reactivities. The active drug is then spontaneously released over multiple days, providing sustained local delivery directly to the tumor region while reducing systemic side effects. Previously, we have shown that the greater safety of SQP33 allows it to be given at over 38 times the dose of standard Dox in SQL70-injected mice. Pharmacokinetic and biodistribution studies in SQ3370-treated rodents and dogs show that SQP33 disappears from plasma within the first hour of administration, likely due to the rapid concentration to SQL70. Without SQL70, SQP33 shows minimal spontaneous conversion to activated Dox. These studies also indicate that a single injection of SQL70 can activate multiple doses of SQP33, maximizing the local therapeutic index. Recent studies demonstrate that SQ3370 treatment enhances therapeutic response and survival in tumor-bearing mice: In a syngeneic MC38 colorectal cancer model, SQ3370 slowed tumor progression in 8/10 mice, showing improved efficacy compared to standard Dox or anti-PD-1 therapy. In mice bearing dual tumors, with one tumor site injected locally with SQL70, we observed that SQP33 can induce a response in both primary and secondary tumors, suggestive of an anti-tumor immune activation effect. Furthermore, we found that SQ3370 synergizes with anti-PD-1, expanding potential treatment options in the clinic and highlighting the advantages of immune-sparing cytotoxic therapy. Collectively, our results demonstrate that SQ3370 enables delivery of cytotoxic drugs to a target site while limiting exposure in off-target tissues in small and large animals, leading to improvements in both safety and efficacy. Citation Format: Nathan A. Yee, Sangeetha Srinivasan, Maksim Royzen, Jose M. Mejia Oneto. SQ3370 enhances the safety of chemotherapeutics via local activation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-002.

1013. If Blood Cultures Were Not Done Before Starting Antibiotics, Is It of Any Value to Obtain Them Later?

BackgroundObtaining blood cultures before starting antibiotics is one of the pillars of the Surviving Sepsis Campaign (SSC), and delay in obtaining blood cultures (BC) after starting antibiotics is associated with increased mortality (Levy M 2015, Pruinelli L 2018), but we were unable to find data on the relationship between such a delay and a reduction in percentage of positive cultures.MethodsAll adult patients (>18) admitted from the UFHealth Shands Emergency Department (ED) between August 2012 and December 2016 were included in the study (N = 30,743), excluding hospital-hospital transfers. BC were done with BacTec aerobic, anaerobic, and pediatric resin bottles, incubated for 5 days. We calculated the hourly rate of positive BC obtained before and after the start of IV antibiotics by subtracting the time stamp in the electronic medical record (Epic) between the first BC collection time and the start of the first IV antibiotic dose. We considered S. aureus, all Gram-negative rods, β-hemolytic Streptococci and Enterococci as significant pathogens and coagulase negative Staphylococci, S. viridans, Propionibacterium sp., Micrococcus sp. and Bacillus sp. as contaminants hospital ransfers.ResultsThe percentage of BC with significant growth was unchanged during the first hour after starting IV antibiotics, but declined significantly in the period 1–12 hours after IV antibiotics were started. The overall positivity rate before starting IV antibiotics was 1,646/20,867 (7.9%) of patients and declined to 112/3,490 (3.2%), P < 0.0001, in the 1–12 hour period afterwards, but did not decline to 0. Septic patients averaged 1,143/4,923 (23.2%) positive and declined to 65/728 (8.9%), P < 0.0001, while nonseptic patients averaged 503/15,944 (3.15%) positive before antibiotics and declined to 47/2,762 (1.7%) P < 0.0001, 1–12 hours after. It should be pointed out that these are group averages from different patient groups at each hourly time, rather than individual patients with blood cultures drawn serially.ConclusionWe conclude that IV antibiotics dramatically reduce the likelihood of getting a positive blood culture, but not during the first hour of administration; however, the residual positivity rate remains high enough that blood cultures are still clinically worthwhile. Disclosures All authors: No reported disclosures.

Diuretic activity of methanolic extracts from Jodina rhombifolia aerial parts on Wistar rats

Context: Jodina rhombifolia (Hook. &amp; Arn.) Reissek (Santalaceae) it´s used in folk medicine for treat a great diversity of health problems. Aims: To evaluate the diuretic activity of aerial parts methanolic extract (leaves, bark, phloem, and branches of approximately three years) in Wistar rats. Methods: The experimentation was organized with a negative control group (saline solution), a positive control (furosemide; 10 mg/kg) and for each methanolic extract were established three groups of animals that received doses of 125, 250 and 500 mg/kg of weight in normal saline solution. Results: The maximum diuretic activity observed in-group administered with leaves methanolic extract followed of phloem extract. The dose 250 mg/kg of leaves methanolic extract was the more potent and equally important, result the dose 500 mg/kg, which supposes an interesting excretor effect of water for a phytodiuretic. These registers of diuresis in Wistar rats did not show significant statistically results with the positive control group. Furthermore, the onset of diuretic activity of leaves methanolic extract was extremely rapid, within the first hour of administration (for all doses). Conclusions: This study contributes to scientific validation of the ethnomedical use of this botanic species in folk medicine of South America as a diuretic agent, although further studies are necessary to evaluate the mechanisms involved in biological activity and safety following repeated use.

Eptifibatide-induced acute profound thrombocytopenia: a case report

BackgroundThe interactions among cells or among cells and components of the extracellular matrix, is a crucial pathophysiological process involving some molecules collectively known as adhesion molecules (CAMs). Glycoprotein IIb / IIIa receptors are only restricted to blood platelets and they bind fibrinogen and adhesion proteins such as fibronectin, vitronectin, von Willebrand factor to form cross bridges between adjacent platelets. IIb/IIIa receptor antagonists are an object of intense research activity for target therapy worldwide during the last decades. Three GPIIb/IIIa inhibitors, abciximab, tirofiban, and eptifibatide, have been approved for clinical use. Profound thrombocytopenia is an uncommon but clinically important complication of glycoprotein IIb/IIIa inhibitors.Case presentationThis case report discusses a forty-four-year-old male patient with acute coronary syndrome who underwent percutaneous coronary intervention and developed profound thrombocytopenia within 4 hours of first administration of eptifibatide.ConclusionThis report adds another case of eptifibatide-induced thrombocytopenia to the medical literature and endorses the importance of platelet count monitoring after initiating therapy with this agent.

Comparative Hypoglycemic Effects of Three Nigerian Medicinal Plants, Gongronema latifolium, Vernonia amygdalina and Viscum album on Alloxan-Induced Diabetic Mice

A study was carried out to determine the comparative hypoglycemic effects of three Nigerian medicinal plants; Gongronema latifolium, Vernonia amygdalina and Viscum album on alloxan - induced diabetic mice. Oral administration of 100mg/dl of alloxan monohydrate produced diabetic condition in normal albino mice, which increased blood glucose level from 60.5 + 5 mg/dl to156 + 5mg/dl, among others. The leaf extracts of G. latifolium, V. album, V. amygdalina and the combination of the 3 plant extracts had lowering effects on the blood glucose levels of the alloxan induced diabetic mice. This was done by reactivating and restoring the action of the beta-cells of the islet langerherns, which resumed their insulin production. The leaf extract of V. amygdalina and the combined extract became active within first hour of administration, while G. latifolium and V. album became effective in the second hour. The combined extract had more lowering effect on the blood glucose level of the diabetic mice than the other extracts. The glucose-lowering action of the three plant extracts and their combined extracts support their usage in the local treatment of diabetes.

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Introduction: Etomidate is a standard induction agent used during rapid sequence intubation (RSI) in the emergency department (ED). Drug shortages require healthcare professionals to utilize alternative agents such as propofol, though there is limited data to support its use. Methods: This was a retrospective chart review of adult patients in the ED who received propofol or etomidate for induction during RSI. The primary endpoint was hypotension, defined as a systolic blood pressure (SBP) <90mmHg and/or diastolic blood pressure (DBP) <60mmHg, within the first hour of administration of the induction agent. Time to intubation, intensive care unit (ICU) length of stay (LOS), hospital LOS, and in-hospital mortality were also evaluated. Results: Two hundred seventy-five patient charts were reviewed. Of the 98 patients included, 43 patients received propofol and 55 patients received etomidate. Propofol was associated with an increased incidence of hypotension within the first hour of intubation (65.1% vs. 25.5%, p<0.001). There was no difference in the time to intubation, (51.2% vs. 34.6%, p=0.83), or hospital and ICU LOS between the propofol and etomidate groups (7.7 vs. 9.2 days, p= 0.23; 4.2 vs. 6.3 days, p= 0.31). The mortality rate was 11.6% in the propofol group and 27.3% in the etomidate group (p= 0.004). Conclusions: The use of propofol compared to etomidate was safe and effective as an induction agent for RSI, however it was associated with an increased rate of hypotension within the first hour of intubation.

Type 1 Diabetes in Children and Adolescents

Type 1 Diabetes in Children and Adolescents

Slow Response to Clopidogrel Predicts Low Response

The purpose of this study was to determine whether the speed of response to clopidogrel loading predicts the final degree of response. Fast inhibition of platelet aggregation is important in the setting of acute coronary syndromes and percutaneous coronary intervention, but its association with the final degree of inhibition is not well established. We performed a post hoc analysis of the ALBION study; early kinetic profiles of adenosine diphosphate 20 micromol/l maximal platelet aggregation (MPA) and DeltaMPA (with baseline sample as reference) were studied at 8 time points within the 24 h after clopidogrel loading (300, 600, or 900 mg) in non-ST-segment elevation acute coronary syndrome patients. Low response was defined as DeltaMPA <10% over the first 24 h, fast response as DeltaMPA > or =10% at 1 h or before loading (the others being slow responders), and high post-treatment platelet reactivity as MPA > or =56.56% (fourth quartile). Inflammatory markers (PAC-1 and P-selectin) and vasodilator-stimulated phosphoprotein (VASP) were also evaluated according to onset of action. Fifty-five percent of patients were slow responders. Noncurrent smoking and body mass index > or =25 kg/m(2) were associated with slower and lower responses. High post-treatment platelet reactivity was more frequent in slow responders (28% vs. 14%, p < 0.0001). There was a clopidogrel dose-effect relationship on DeltaMPA, with a trend toward faster onset of platelet inhibition in the 900-mg loading dose group. Slow responders had a slower and lower decrease in PAC-1 and P-selectin and higher VASP index at 6 h (76.5% vs. 66.4%, p = 0.019) and 24 h (70.3% vs. 61.5%, p = 0.049). Slow response to clopidogrel, within the first hour of administration, is a reliable marker of low response at 24 h and high post-treatment platelet reactivity.

SR-141716A-induced stimulation of locomotor activity

The central cannabinoid receptor (CB(1)) antagonist, SR-141716A, has been used extensively to ascertain that cannabinoids interact with the CB(1) receptor. SR-141716A has been shown to produce effects opposite of cannabinoids when administered alone. It has been theorized that SR-141716A may act as an inverse agonist at the CB(1) receptor or by disinhibiting an endogenous cannabinoid tone. In an effort to ascertain the exact interaction between SR-141716A and the CB(1) receptor, we have conducted a structure-activity relationship study to compare CB(1) receptor affinity of SR-141716A analogs with their ability to produce an increase in locomotor activity. SR-141716A produced a significant increase in locomotor activity in mice within the first hour of administration. Twenty SR-141716A analogs from five different chemical series were also tested. Our data implicate particular regions of the SR-141716A molecule that may be involved in stimulation and depression of locomotor activity. When the K(I) of the analogs was plotted against the percent stimulation that each analog produced, it is evident that there is no correlation between the ability of the analogs to stimulate locomotor activity and their affinity for the CB(1) receptor. [35S]GTPgammaS binding data indicate that SR-141716A and five of the analogs are inverse agonists. However, none of the analogs demonstrating inverse agonism produce stimulation of locomotor activity. It is therefore concluded that the SR-141716A-induced stimulation in locomotor activity is not the result of inverse agonist activity at the CB(1) receptor or by disinhibition of an endogenous tone.

Inhibitory action of oral thyrotropin-releasing hormone on the glucoregulatory response of the oral glucose tolerance test.

Thyrotropin-releasing hormone (TRH) has been found in the gastrointestinal tract, where it mainly exerts an inhibitory action. We used oral TRH, a stable and powerful formulation, to explore the glucoregulatory response of oral glucose tolerance test (OGTT) on obese patients with impaired glucose tolerance (IGT). Seven obese patients with IGT and eight controls were investigated. Three tests were performed on three separate days. On day 1, An oral TRH test: a 40 mg TRH tablet, was given. Blood samples for blood glucose (BG), proinsulin (PI), insulin (INS), C-peptide (CP), thyroxine (T4), triiodothyronine (T3), and thyrotropin (TSH) were collected every 30 minutes for 3 hours. On day 2, an OGTT with 75 g glucose was performed. On day 3, an oral TRH test was administered 30 minutes before the OGTT, and blood was collected every 30 minutes for 3 hours. Oral-TRH had no effect on basal BG and on pancreatic hormone secretion. Oral TRH, coupled with OGTT in both controls and obese patients, led to a significant inhibition of BG (p < 0.01), of CP (p < 0.001), and of INS (p < 0.001) during the first hour of administration, and afterward, there was only a very slight increase, compared with levels after only OGTT treatment. After OGTT, PI peaked at 90 minutes (9.4+/-3 ng/mL) in controls and at 60 minutes (12.7+/-2.5 ng/mL) in obese patients. TRH application prior to OGTT inhibited PI secretion for 90 minutes in controls, whereas in obese patients PI levels were decreased, not inhibited, during the OGTT. The mechanism of the inhibitory TRH action on OGTT-induced increase of BG and pancreatic hormone secretion is not clear. It could be due to inhibition of gastric motility, and on a paracrine effect that enhances secretion of somatostatin that then suppresses INS, CP, and possibly PI levels. The partial escape of PI from the TRH blockade in obese patients with IGT might indicate a diminished functioning capability of beta-cells and that TRH cannot affect the INS processing within the beta-cells in these patients.

Adsorption of vincristine, vinblastine, doxorubicin and mitozantrone to in-line intravenous filters

The adsorption of four cytotoxic drugs, vinblastine, vincristine, doxorubicin and mitozantrone, to in-line intravenous filters and giving lines has been investigated using the slow administration rates used in clinical practice. Adsorptive losses to polyethylene lines were negligible. The maximal loss to a Polyvinylchloride line was 9% for vincristine during the first hour of administration. Doxorubicin, vinblastine and vincristine were adsorbed to Pall ELD 96 h filters; up to 35% of the potency was lost during the initial hour of delivery. No adsorption could be detected for mitozantrone to the Pall ELD 96 h filter nor for all drugs to filters composed of polysulphone or cellulose acetate. The extent of adsorption for vinblastine, vincristine and doxorubicin to the Pall ELD 96 h filter increased as the pH of their solutions was increased from 4.5 to 7.8.

Pharmacokinetics and pharmacodynamics of obidoxime in sarin-poisoned rats

The pharmacokinetics and pharmacodynamics of the oxime obidoxime (Toxogonin, 50 mg/kg iv) were investigated in anesthetized normal rats and in sarin-poisoned (50 μg/kg iv) rats. The kinetics were described by a two-compartment open model. The elimination half-life ranged from 35 min in normal rats to 86 min in sarin-poisoned rats. Obidoxime excretion occurred predominantly by the renal route, amounting to 4.6% of the administered dose in normal rats and to 0.9% in sarin-poisoned rats within the first hour of administration. The significantly diminished glomerular filtration rate confirmed the retardation of obidoxime exoretion in sarin poisoning. The mean arterial blood pressure (MAP) response to obidoxime, measured in normal rats, was a transient hypotension, but to sarin an immediate hypertension. In sarin-poisoned rats the therapeutic sequence of administration of obidoxime and atropine (5 mg/kg iv) seemed to be important: the administration of atropine 10 min after and of obidoxime 20 min after sarin poisoning exerted a stabilizing effect on MAP. No serum albumin binding was found for obidoxime. Competition experiments at the isolated nicotinic receptor demonstrated the anticholinergic activity of obidoxime. The affinity of obidoxime was 1000 times smaller than that of acetylcholine. It is concluded that obidoxime, due to its prolonged residence time in the organism in sarin poisoning, exerts a “curare-like” inhibition and protection of the nicotinic acetylcholine receptor and, combined with atropine, a synergistic effect on blood pressure normalization.

Bioavailability assessment of a liquid prednisone preparation

To assess the relative bioavailability of a recently developed liquid prednisone preparation, prednisolone pharmacokinetics were evaluated after the administration of three separate steroid preparations. On 3 study days, each 2 wk apart, 12 healthy subjects received in random order, prednisone liquid, prednisone tablet, and prednisolone sodium phosphate. Plasma samples were collected over a 12 hr study period and analyzed for prednisolone concentration by high-pressure liquid chromatography. Tablet data demonstrated a time-to-peak concentration of 1.23 ± 0.68 hr (SD), mean residence time of 5.1 ± 0.49 hr, and absolute bioavailability (tablet/i.v.) of 97.5% ± 17.5%. Liquid data demonstrated a significantly (p < 0.01) shorter time-to-peak concentration, 0.54 ± 0.20 hr, and mean residence time, 4.6 ± 0.34 hr, with no significant difference in absolute bioavailability (liquid/i.v.), 88.2% ± 15.8%. This resulted in significantly (p < 0.05) higher plasma prednisolone concentrations for the liquid preparation in the first 0.75 hr and significantly lower concentrations after 1.5 hr as compared with the tablet. Prednisolone area under the plasma concentration vs time curve for the liquid prednisone formulation was 90.0% ± 13.2% of the tablet preparation. Thus prednisone liquid has comparable bioavailability to the tablet, with an earlier peak plasma prednisolone concentration and significantly higher plasma prednisolone concentrations within the first hour of administration.

The cervix of the sheep and goat during parturition

The change in physical character of the wall of the cervix has been investigated in sheep and goats in relation to the induction of parturition. Two types of observation were made, extension of isolated tissue in vitro and dilation of the cervical canal with balloons in vivo. A decrease in the elastance of the tissue was detectable within 12 hours of first administration of dexamethasone and the decrease was progressive thereafter. This change was unrelated to the plasma concentration of prostaglandins F. There was some relationship in time to changes in circulating concentrations of oestrogen and progesterone but this was not consistent in all animals. Biochemical investigations of cervical wall revealed a marked increase in the liberation of hydroxyproline from collagen and a change in the pattern of extractable glycosaminoglycans, as induction advanced.