Parenteral Dose Research Articles

Safety and Efficacy of Low-Dose Versus High-Dose Parenteral Ketorolac for Acute Pain Relief in Patients 65 Years and Older in the Emergency Department.

Background There is limited data surrounding acute pain management in elderly ED patients. Ketorolac is a potent non-steroidal anti-inflammatory drug (NSAID) with dose/duration-dependent side effects. There is evidence that an analgesic ceiling effect exists for parenteral ketorolac doses greater than 10 milligrams (mg); however, this has not been studied in patients 65 years and older. Methods This was a retrospective chart review of ED patients 65 years and older who received at least one dose of parenteral ketorolac. Patients were separated into two cohorts based on the ketorolac dose received: 15 mg IV or 30 mg intramuscular (IM) and 30 mg IV or 60 mg IM. The primary objective was to evaluate the analgesic efficacy of parenteral ketorolac doses measured as needing rescue analgesia from 30 minutes to 2 hours after ketorolac administration. Secondary objectives included changes in pain scores and the occurrence of adverse drug events commonly associated with ketorolac. Results Two-hundred and sixty patients received ketorolac doses of 15 mg IV or 30 mg IM, and 52 received 30 mg IV or 60 mg IM. The primary outcome occurred in seven of 52 patients who received ketorolac 30 mg IV or 60 mg IM and 17 of 260 patients who received ketorolac 15 mg IV or 30 mg IM (13.5% vs. 6.5%, p=0094; OR: 2.22, 95% CI: 0.87-5.67). The average change in pain scores were 2.9 (±3.1) and 2.8 (±2.9) for patients who received doses 30 mg IV or 60 mg IM compared to doses 15 mg IV or 30 mg IM, respectively (p=0.154). The occurrence of adverse events was low in both groups. Conclusion Parenteral ketorolac doses of 15 mg IV or 30 mg IM did not demonstrate a greater need for rescue analgesia compared to doses of 30 mg IV or 60 mg IM.

Drug delivery improvements to enable a flexible care setting for monoclonal antibody medications in oncology - Analogue-based decision framework

Introduction : The substantial acceleration in healthcare spending together with the expenditures to manage the COVID-19 pandemic demand drug delivery solutions that enable a flexible care setting for high-dose monoclonal antibodies (mAbs) in oncology. Areas covered : This expert opinion introduces an analogue-based framework applied to guide decision making for associated product improvements for mAb medications that are either already authorized or in late-stage clinical development. The four pillars of this framework comprise (1) the drug delivery profile of current and emerging treatments in the market, (2) the needs and preferences of people treated with mAbs, (3) existing healthcare infrastructures, and (4) country-dependent reimbursement and procurement models. The following product optimization examples for mAb-based treatments are evaluated based on original research and review articles in the field: subcutaneous formulations, an established drug delivery modality to reduce parenteral dosing complexity, fixed-dose combinations, an emerging concept to complement combination therapy, and (connected) on-body delivery systems, an identified future opportunity to support dosing outside of a controlled healthcare institutional environment. Expert opinion : Leveraging existing synergies and learnings from other disease areas is a measure to reduce associated development and commercialization costs and thus to provide sustainable product offerings already at initial launch of a medication.

Zinc oxide calcium silicate composite attenuates acute tramadol toxicity in mice

BackgroundSeizures are considered to be the most common symptom encountered in emergency- rushed tramadol-poisoned patients; accounting for 8% of the drug-induced seizure cases. Although, diazepam clears these seizures, the risk of central respiratory depression cannot be overlooked. Henceforth, three adsorbing composites were examined in a tramadol acute intoxication mouse model.MethodsCalcium Silicate (Wollastonite) either non-doped or wet doped with iron oxide (3%Fe2O3) or zinc oxide (30% ZnO) were prepared. The composites’ adsorption capacity for tramadol was determined in vitro. Tramadol intoxication was induced in Swiss albino mice by a parenteral dose of 120 mg/kg. Proposed treatments were administered within 1 min at 5 increasing doses, i.p. The next 30 min, seizures were monitored as an intoxication symptom. Plasma tramadol concentration was recorded after two hours of administration.ResultsThe 3% Fe2O3-containing composite (CSFe3), was found to be composed of mainly wollastonite with very little alpha–hematite. On the other hand, hardystonite and wellimite were developed in the 30%ZnO-containing composite (CSZn3). Micro-round and irregular nano-sized microstructures were established (The particle size of CS was 56 nm, CSFe3 was 49 nm, and CSZn3 was 42 nm). The CSZn3 adsorption capacity reached 1497 mg of tramadol for each gram. Tramadol concentration was reduced in plasma and seizures were inhibited after its administration to mice at three doses.ConclusionThe calcium silicate composite doped with ZnO presented a good resolution of tramadol-induced seizures accompanied by detoxification of blood, indicating its potential for application in such cases. Further studies are required.

JS-NG-9: PRIMARY HYPERALDOSTERONISM IN A TRIPLET PREGNANCY: CONSIDERATIONS FOR INTRA-PARTUM DIAGNOSIS AND MANAGEMENT

Primary aldosteronism (PA) is an uncommon etiology of hypertension. We report the first known case of PA in a triplet pregnancy to describe the intra-partum considerations in diagnosis, investigation and management of PA. A 33-year-old female G3P0A2 at 10 weeks gestation with triplet pregnancy was admitted for hyperemesis gravidarum and hypertension. Her comorbidities include chronic hypertension, uterine fibroids, and two previous pregnancy losses. Home medications are labetalol 100 mg BID. On presentation, the patient complained of nausea, vomiting and epigastric pain and headache. On examination, her blood pressure was 161/90 and heart rate of 75. The rest of the cardiopulmonary exam was normal. Laboratory values were notable for potassium:2.9 mmol/L (n 3.5–5mmol/L) and bicarbonate 26 mmol/L (n 24–31mmol/L). The platelets, liver function tests and renal function tests were normal. Despite continuous high dose oral and parenteral high dose potassium supplementations, she had hypokalemic episodes (nadir 2.7mmol/L). She remained hypertensive at 140/90 on labetalol 200 mg QID and nifedipine XL 30 mg q12 hours. PA was suspected and testing revealed aldosterone 1280 (n 166–2885), renin 0.49 (n 0.10–1.10), aldosterone-renin ratio (ARR) 2615 (n < 1500), which is indeterminate. Abdominal MRI demonstrated right adrenal mass, measuring 2.7 x 5.2 x 2.9 cm. Repeat testing revealed aldosterone 11,000, renin 0.34, ARR > 30,000, which is highly suggestive of PA. The uterus was too bulky with the triplet pregnancy and uterine fibroids to safely proceed with adrenalectomy. The patient consented to receive eplerenone 25 mg BID for medical management of PA in addition to nefidipine XL 60 mg BID and oral potassium supplementation. She re-presented to hospital at 31 weeks with spontaneous rupture of membranes. She had an emergency caesarian section and delivery three healthy male infants. At one month postpartum, she was switched to spironolactone 25 mg BID from eplerenone, in addition to nefidipine and potassium supplementation, and maintained blood pressure of 130–140/80–90. At five months postpartum, she had testing on doxazosin 4 mg daily, hydralazine 10 mg TID and potassium supplementations, which revealed aldosterone 2360 pmol/L, renin < 2, ARR > 1200. Adrenal vein sampling demonstrated marked lateralization of aldosterone production to the right adrenal gland. A right laparoscopic adrenalectomy was completed and she achieved normotension on post-operative day 2. She was discharged on no antihypertensive medication or potassium supplementation. At 8 months post-adrenalectomy, her blood pressure is 120/96 potassium is 4mmol/L and her aldosterone levels remain low at 252 on no medications. In this case of triplet pregnancy, the diagnosis of PA was difficult to establish given the impact of pregnancy on the renin-angiotensin-aldosterone-system. Treatment with eplerenone resulted in improvement of hypertension and good pregnancy outcome. Postpartum, adrenalectomy resulted in rapid and sustained improvement in hypertension and reversal of hypokalemia.

Real-World Evaluation of the Safety and Effectiveness of Apixaban & Rivaroxaban Lead-in Dosing Compared to Parenteral Lead-in Dosing in the Treatment of Venous Thromboembolism: A Multi-Center Retrospective Cohort Study.

Although parenteral anticoagulation lead-in is not recommended with apixaban and rivaroxaban, parenteral anticoagulation is often used to replace apixaban or rivaroxaban lead-in doses for the initial phase treatment of VTE. Thus, our study compares the safety and effectiveness of lead-in parenteral anticoagulation to lead-in apixaban or rivaroxaban in patients who received apixaban or rivaroxaban for VTE treatment. A multi-center retrospective cohort study included adult patients (aged ≥ 18 years) admitted to the hospital with acute VTE and treated with either apixaban or rivaroxaban. Patients were grouped depending on the lead-in anticoagulation received for initial VTE treatment into the "Direct oral anticoagulation (DOAC) lead-in" group if patients received an appropriate lead-in dose of apixaban and rivaroxaban and patients who received parenteral lead-in the "parenteral lead-in" group. A total of 389 patients were included; the DOAC lead-in group included 296 patients, whereas 93 patients were in the parenteral lead-in group. VTE recurrence (rVTE) during hospitalization and within 30 days was numerically higher in the parenteral lead-in group compared to the DOAC lead-in group (3.3% vs 0.6%; p=0.09 and 1.1% vs 0.7%; p=0.560), with a significantly higher number of patients with rVTE at 90 days (5.4% vs 1.4%; p=0.039). However, none of the patient's characteristics were significantly associated with the incidence of rVTE. In addition, the major bleeding rate during hospitalization was significantly higher among the parenteral lead-in group than in the DOAC lead-in group (14.0% vs 3.7%; p<0.001). Parenteral anticoagulation lead-in before starting maintenance of apixaban and rivaroxaban showed a significantly higher risk of bleeding and a trend toward higher VTE recurrence than the DOAC lead-in. This study adds to the evidence supporting the utilization of the DOAC lead-in regimen in treating patients with VTE. Still, larger studies with robust designs are needed to confirm these findings.

813: OPIOID AND SEDATIVE USE IN ADULT ICUS: ADULT IATROGENIC WITHDRAWAL STUDY IN THE ICU (ALERT-ICU)

Introduction: Iatrogenic withdrawal syndrome (IWS) is associated with large doses and prolonged use of opioids-sedatives. This study aimed to determine current utilization patterns of opioids-sedatives in adult ICUs that may be associated with IWS. We hypothesized that cumulative doses would increase with prolonged ICU stay. Methods: We conducted an international, observational, point prevalence study on a single date between June 1 and September 30, 2021 for adult ICU patients (≥ 18 years). Demographic data, medication exposures in the preceding 24 hours, and outcomes were collected following institutional ethics approval. The primary outcome was the proportion of patients receiving continuous parenteral opioids-sedatives for ≥ 72 hours. We defined continuous use as continuous IV infusion, scheduled intermittent injections, or as needed parenteral doses with at least half of the possible doses administered in 24 hours. Outcomes were compared between patients receiving opioids-sedatives < 72 and ≥ 72 hours. Parametric and nonparametric statistical analyses were performed using IBM SPSS Statistics version 28.0.0 (Armonk, New York) according to level of measurement, data distribution and assumptions. The a priori alpha was 5%. Results: There were 1506 patients who received parenteral opioids-sedatives in 229 ICUs at 87 hospitals in 11 countries. Median ICU stay was 6 (IQR; 12) days, 31% had ARDS, and 71% were invasively mechanically ventilated. Continuous opioids were administered to 50% (647/1305), sedatives to 52% (600/1151), and both to 37% (561/1506) of patients ≥ 72-hr, with 84% receiving continuous IV infusion opioids and 98% sedatives ≥ 72-hr (p< 0.001). All median 24-hr total opioid-sedative doses were significantly greater when used ≥ 72 hr. There was no difference in opioid-sedative dose reduction in the previous 24-hr, but significantly more patients on opioids-sedatives < 72-hr received > 50% dose reductions (61% vs. 38%; p< 0.001) and had enteral opioids-sedatives initiated in the previous 24-hr (24% vs. 15%; p< 0.001). Three of 9 patients assessed had IWS, all of whom received opioids-sedatives ≥ 72-hr. Conclusions: Half of adult ICU patients receive continuous parenteral opioids-sedatives for ≥ 72-hr at higher doses than earlier in admission, which may increase the risk of IWS.

Stable nebulization and muco-trapping properties of regdanvimab/IN-006 support its development as a potent, dose-saving inhaled therapy for COVID-19.

The respiratory tract represents the key target for antiviral delivery in early interventions to prevent severe COVID‐19. While neutralizing monoclonal antibodies (mAb) possess considerable efficacy, their current reliance on parenteral dosing necessitates very large doses and places a substantial burden on the healthcare system. In contrast, direct inhaled delivery of mAb therapeutics offers the convenience of self‐dosing at home, as well as much more efficient mAb delivery to the respiratory tract. Here, building on our previous discovery of Fc‐mucin interactions crosslinking viruses to mucins, we showed that regdanvimab, a potent neutralizing mAb already approved for COVID‐19 in several countries, can effectively trap SARS‐CoV‐2 virus‐like particles in fresh human airway mucus. IN‐006, a reformulation of regdanvimab, was stably nebulized across a wide range of concentrations, with no loss of activity and no formation of aggregates. Finally, nebulized delivery of IN‐006 resulted in 100‐fold greater mAb levels in the lungs of rats compared to serum, in marked contrast to intravenously dosed mAbs. These results not only support our current efforts to evaluate the safety and efficacy of IN‐006 in clinical trials, but more broadly substantiate nebulized delivery of human antiviral mAbs as a new paradigm in treating SARS‐CoV‐2 and other respiratory pathologies.

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood-Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2.

Leucine-rich repeat kinase 2 (LRRK2) is one of the most promising targets for Parkinson’s disease. LRRK2-targeting strategies have primarily focused on type 1 kinase inhibitors, which, however, have limitations as the inhibited protein can interfere with natural mechanisms, which could lead to undesirable side effects. Herein, we report the development of LRRK2 proteolysis targeting chimeras (PROTACs), culminating in the discovery of degrader XL01126, as an alternative LRRK2-targeting strategy. Initial designs and screens of PROTACs based on ligands for E3 ligases von Hippel–Lindau (VHL), Cereblon (CRBN), and cellular inhibitor of apoptosis (cIAP) identified the best degraders containing thioether-conjugated VHL ligand VH101. A second round of medicinal chemistry exploration led to qualifying XL01126 as a fast and potent degrader of LRRK2 in multiple cell lines, with DC50 values within 15–72 nM, Dmax values ranging from 82 to 90%, and degradation half-lives spanning from 0.6 to 2.4 h. XL01126 exhibits high cell permeability and forms a positively cooperative ternary complex with VHL and LRRK2 (α = 5.7), which compensates for a substantial loss of binary binding affinities to VHL and LRRK2, underscoring its strong degradation performance in cells. Remarkably, XL01126 is orally bioavailable (F = 15%) and can penetrate the blood–brain barrier after either oral or parenteral dosing in mice. Taken together, these experiments qualify XL01126 as a suitable degrader probe to study the noncatalytic and scaffolding functions of LRRK2 in vitro and in vivo and offer an attractive starting point for future drug development.

Therapeutic Potential of Quercetin-Loaded Nanoemulsion against Experimental Visceral Leishmaniasis: In Vitro/Ex Vivo Studies and Mechanistic Insights.

Visceral leishmaniasis (VL) is one of the most fatal and neglected tropical diseases caused by Leishmania donovani (L. donovani). The applications of currently available chemotherapy (amphotericin B, miltefosine, and others) in VL treatment have been limited due to their poor bioavailability, unfavorable toxicity profile, and prolonged parenteral dosing. Quercetin (QT), a potent natural antioxidant, is a prominent target when conducting investigations on alternative therapies against L. donovani infections. However, the therapeutic applications of QT have been restricted due to its low solubility and bioavailability. In the present study, we developed and evaluated the antileishmanial activity (ALA) of quercetin-loaded nanoemulsion (QTNE) against L. donovani clinical strains. In vitro anti-promastigote assay results demonstrated that QTNE (IC50 6.6 μM, 48 h) significantly inhibited the growth of parasites more efficiently than the pure QT suspension in a dose- and time-dependent manner. Results of the anti-amastigote assay revealed that the infected macrophages (%) of QTNE were significantly more than those of the pure QT suspension at all concentrations (6.6, 26.4, and 52.8 μM; p < 0.05, p < 0.01 compared to the control). Moreover, the results of in vitro and ex vivo studies assisted in determining the mechanistic insights associated with the ALA of QTNE. The overall findings suggested that QTNE exhibited potential ALA by enhancing the intracellular ROS and nitric oxide levels, inducing distortion of membrane integrity and phosphatidylserine release (AV/PI), rupturing the parasite DNA (late apoptosis/necrosis process), and upregulating the immunomodulatory effects (IFN-γ and IL-10 levels). Additionally, QTNE showed superior biocompatibility against all of the treated healthy cells (PBMCs, PECs, and BMCs) as compared to the control. In conclusion, QTNE acts as a potential antileishmanial agent targeting both promastigote and intracellular amastigote forms of L. donovani, which thus opens a new avenue for the use of QTNE in VL therapy.

A NOVEL METHOD DEVELOPMENT AND VALIDATION FOR THE QUANTIFICATION OF NEFOPAM HYDROCHLORIDE IN PARENTERAL DOSAGE FORM BY RP-HPLC METHOD

Objective: Using RP-HPLC, a simple, accurate, and exact method for estimating the Nefopam Hydrochloride parenteral dose form was devised.&#x0D; Methods: The isocratic mode of the RP-HPLC method used an Inertsil C8 column as the stationary phase and a mobile phase of potassium dihydrogen phosphate with pH 3.0: Acetonitrile (70:30) at a flow rate of 1 ml/min. With UV detection at 220 nm, a flow rate of 1 ml/min was established.&#x0D; Results: The developed RP-HPLC technique revealed acceptable linearity (R2 = 0.9998) and good assay results in the concentration range of 0.004–0.08 mg/ml (103.3 percent). Further forced degradation investigations using 0.1N Hydrochloric acid (acid degradation), 0.1NNaOH (base degradation), and 3 percent H2O2 (Hydrogen peroxide) were carried out using RP-HPLC, and percent degradation values were determined. In peroxide degradation conditions, the medication was shown to be unstable.&#x0D; Conclusion: In compliance with ICH requirements, the developed procedures were validated.

A case of vocal cord dysfunction in the emergency department

We describe the case of a 78-year-old woman admitted to our emergency department for an acute onset of severe dyspnoea with inspiratory wheezing-like sounds. She denied fever, cough, voice change and pain. She referred a similar but less severe episode occurred spontaneously one year before, with complete resolution in few minutes without sequelae. On examination upper airway obstruction was firstly excluded. She was initially treated as having asthma, without response. Parenteral high dose corticosteroids and antihistamines provided no benefit. Point-of-care-ultrasound resulted normal. Flexible laryngoscopy during the episode showed paradoxical vocal cord movement with adduction during both inspiration and expiration. This demonstrated that her dyspnoea was from Vocal Cord Dysfunction (VCD). VCD completely solved after administration of intravenous benzodiazepines.

Estimation the Safety of Parenteral Resveratrol in Mice

Resveratrol is polyphenolic compound has many biochemical and biological effects on several organs. Therefore, resveratrol can be used to treat many diseases. The aim was to evaluate resveratrol safety when used in a parenteral single bolus dose. This study was conducted on 60 mice (30 males and 30 females). Each male and female mice divided into 6 groups (five mice per group). All mice groups given 1% DMSO and five different doses of resveratrol (5, 2.5, 1.25, 0.625, 0.312) gm/kg intraperitonially given to five groups respectively. The mice were continuously monitored during 14 days. The number of deaths, changes in general behavior, changes in physiological activity, and signs of toxicity were reported. On day 15 blood was collected using a jugular vein puncture to obtain blood samples for hematological and biochemical analysis. All mice were euthanized under anesthesia. The heart, lung, liver, kidney, and gonads were dissected and sent for histopathological study. The result showed that at dose 0.312gm/kg neither signs of toxicity nor death were detected. The LD50 dose was 1.18 g/kg for female and 1.07 g/kg for male mice. The body weight change, biochemical and hematological assay, revealed that at doses 1.25 g/kg,0.625,0.312 g/kg for both sexes no significant changes had reported in comparison with a control group (p?0.05). Histopathological examination revealed that at doses 1.25 g/kg for both sexes no significant tissue changes had reported in comparison with a control group (p?0.05). In conclusion resveratrol has dose-dependent toxicity when used intraperitoneally in Swiss Albino mice and the non-observed adverse effect level at dose 0.312 g/kg.

Parenteral vs Oral Vitamin B12 in Children With Nutritional Macrocytic Anemia: A Randomized Controlled Trial

There is limited literature in children on efficacy of different routes of vitamin B12 administration for vitamin B12 deficiency macrocytic-megaloblastic anemia. To compare parenteral with oral vitamin B12 therapy in children with macrocytic-megaloblastic anemia. Single-center, open-label randomized controlled trial. 80 children aged 2 month-18 year with clinical and laboratory features of nutritional macrocytic anemia. All children received an initial single parenteral dose of 1000 µg vitamin B12 followed by randomization to either parenteral or oral vitamin B12 for subsequent doses. Group A was given 1000 µg intramuscular (IM) vitamin B12 (3 doses on alternate days for those aged <10 year, five doses for age >10 year), followed by monthly 1000 µg IM for the subsequent two doses. Group B was given daily oral vitamin B12 1500 µg (500 µg in <2 years age) for three months. Folic acid and iron supple-mentation, and relevant dietary advice were given to both groups in a similar fashion. Improvement in serum vitamin B12 levels and total hemoglobin was compared three months post-treatment. The median(IQR) increase in serum vitamin B12 level was significantly higher in group A [600 (389,775) vs 399 (313, 606) pg/mL; P= 0.016]. The median (IQR) rise of hemoglobin was also more in group A [2.7 (0.4,4.6) vs 0.5 (-0.1,1.2) g/dL; P=0.001]. Increase in serum vitamin B12 levels and hemoglobin was better in children with nutritional macrocytic anemia receiving parenteral as compared to oral vitamin B12.

Bumetanide for neonatal seizures: No light in the pharmacokinetic/dynamic tunnel.

In his editorial, Kevin Staley criticizes our recent work demonstrating the lack of effect of bumetanide in a novel model of neonatal seizures. The main points in our response are that (1) our work is on an asphyxia model, not one on "hypercarbia only"; (2) clinically relevant parenteral doses of bumetanide applied in vivo lead to concentrations in the brain parenchyma that are at least an order of magnitude lower than what would be sufficient to exert any direct effect—even a transient one—on neuronal functions, including neonatal seizures; and (3) moreover, bumetanide's molecular target in the brain is the Na‐K‐2Cl cotransporter NKCC1, which has vital functions in neurons, astrocytes, and oligodendrocytes as well as microglia. This would make it impossible even for highly brain‐permeant NKCC1 blockers to specifically target depolarizing and excitatory actions of γ‐aminobutyric acid in principal neurons of the brain, which is postulated as the rationale of clinical trials on neonatal seizures.

What is the optimum thiamine dose to treat or prevent Wernicke's encephalopathy or Wernicke-Korsakoff syndrome? Results of a randomized controlled trial.

BackgroundThe primary cause of Wernicke–Korsakoff syndrome (WKS) is thiamine deficiency, and more than 90% of cases are reported in alcohol‐dependent patients. While observational studies show parenteral thiamine administration drastically reduced WKS‐related mortality, relevant treatment trials have never been conducted to determine the optimum thiamine dose.MethodsTwo double‐blind, parallel groups, randomized controlled trials (RCTs) were conducted to determine the optimal thiamine dose required for (1) the prevention of Wernicke's encephalopathy (WE), the acute phase of WKS, in asymptomatic but “at‐risk” alcohol misuse patients (Study 1) and (2) the treatment of WE in symptomatic alcohol misuse patients (Study 2). Each study had a dosage regimen comprising three parenteral thiamine doses that were allocated at a ratio of 1:1:1. Study 1: Asymptomatic At‐Risk patients (N = 393) received either 100 mg daily, 100 mg thrice daily, or 300 mg thrice daily, for 3 days. Study 2: Symptomatic patients (N = 127) received either 100 mg thrice daily, 300 mg thrice daily, or 500 mg thrice daily, for 5 days. Cognitive function was the primary outcome, assessed using the Rowland Universal Dementia Assessment Scale, two Cogstate subtests, and an adapted Story Memory Recall test. Secondary analyses examined differences in neurological function (ataxia, oculomotor abnormalities, and confusion) at follow‐up.ResultsNo significant differences were observed between any of the dosage conditions for either Study 1 or Study 2 on cognition or neurological functioning. This real‐world study found that having a clinically unwell target population with high comorbidity and multiple presentations, coupled with challenges in cross‐cultural assessment is likely to complicate RCT findings.ConclusionsThe results of this study showed no clear benefit of high dose thiamine over intermediate or lower doses of thiamine, over the time intervals examined, for the treatment and prevention of cognitive and neurological abnormalities related to WKS. Several study limitations temper the interpretation of these findings. Nevertheless, the absence of conclusive evidence for the superiority of high‐dose thiamine supports a recommendation for patient‐specific treatment, while ensuring that the potential impact of other biochemical factors (e.g., magnesium and other B vitamin deficiencies) are considered and corrected if necessary.

Parenteral Nutrition Total Energy Dosing and Risk for Central Line–Associated Bloodstream Infection: A Case-Control Study

Background: Central line–associated bloodstream infection (CLABSI) is a complication of central venous access devices used for parenteral nutrition (PN). PN overfeeding is associated with increased adverse effects; however, whether risk for CLABSI is influenced by PN dosing is uncertain. Objective: The purpose of the study was to assess differences in CLABSI risk associated with recommended total energy dosing in hospitalized adult patients receiving PN. Methods: A case-control study was conducted in a single United States Veterans Health Administration health system to assess the potential CLABSI risk factor of weight-based PN kilocalorie dosing. Hospitalized adult patients who developed CLABSI while receiving PN were identified and compared to a control group of patients who did not develop CLABSI. The exposures evaluated were overfeeding, defined as greater than 30 kcal/kg/day, and underfeeding, defined as less than 20 kcal/kg/day. Results: Twenty-nine cases of CLABSI were identified and compared with 274 controls. Odds of CLABSI were significantly higher in patients receiving greater than 30 kcal/kg/day (OR, 3.63; 95% CI, 1.55-8.48; P < .01). No significant difference in odds was found for patients receiving less than 20 kcal/kg/day (OR, .74; 95% CI, 0.21-2.57; P = .63). Conclusion: Increased risk for CLABSI in hospitalized adult patients receiving PN was found to be associated with overfeeding, but not underfeeding. These results may aid clinicians in the management of patients requiring PN and in the generation of hypothesis for future investigations.

Newborn Screening in Pediatric Endocrine Disorders

Two endocrine disorders, congenital hypothyroidism (CH) and congenital adrenal hyperplasia (CAH), when untreated, can have devastating, irreversible and fatal outcomes. Permanent cognitive impairment, growth failure and dysmorphic appearance are seen in congenital hypothyroidism (CH) and early infant death in males with salt wasting CAH (as most females are discovered by presence of atypical genital appearance, while males appeared normal). Newborn screening (NBS) for CH was developed with broader engagement of centers, and was more rapidly adopted throughout the US and other large or developed countries, while NBS for CAH was pioneered by relatively few and was not fully adopted in the US until the initiation of Universal Expanded Newborn Screening Panel in 2005. Advances in genetic understanding of CH and CAH continue with NBS. Cost–benefit analysis, showing CH NBS as more successful than CAH NBS, may not fully recognize the cost of a life saved with CAH NBS. Early treatment of CH is much simpler with taking a pill a day unlike CAH requiring multiple medication doses, and possibly surgery apart from enteral and parenteral stress doses during adrenal crisis. CAH management outcomes with gender identity matters in persons with atypical genital appearance and androgen effects are still being studied.

Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing.

3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.

Use of Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict In Vivo Acute Toxicity of Tetrodotoxin in Rodents.

In this study, the ability of a new in vitro/in silico quantitative in vitro–in vivo extrapolation (QIVIVE) methodology was assessed to predict the in vivo neurotoxicity of tetrodotoxin (TTX) in rodents. In vitro concentration–response data of TTX obtained in a multielectrode array assay with primary rat neonatal cortical cells and in an effect study with mouse neuro-2a cells were quantitatively extrapolated into in vivo dose–response data, using newly developed physiologically based kinetic (PBK) models for TTX in rats and mice. Incorporating a kidney compartment accounting for active renal excretion in the PBK models proved to be essential for its performance. To evaluate the predictions, QIVIVE-derived dose–response data were compared with in vivo data on neurotoxicity in rats and mice upon oral and parenteral dosing. The results revealed that for both rats and mice the predicted dose–response data matched the data from available in vivo studies well. It is concluded that PBK modeling-based reserve dosimetry of in vitro TTX effect data can adequately predict the in vivo neurotoxicity of TTX in rodents, providing a novel proof-of-principle for this methodology.

Nutritional management of ICU patients receiving mechanical ventilation: A retrospective cohort study using a medical claims database

<h2>Summary</h2><h3>Background & aims</h3> Because nutritional therapy affects clinical outcomes in critically ill patients, the nutritional management of such patients must be appropriate. However, the nutritional management of critically ill patients in Japan has not been fully characterized. The aim of this study was to describe the nutritional management of inpatients admitted to Japanese intensive care units using a national medical claims database. <h3>Methods</h3> In this retrospective cohort study, we included mechanically ventilated adult patients who were admitted to an ICU in Japan from January 2010 through June 2020 and remained there ≥ 4 days. We determined when nutritional management (i.e., oral intake, enteral nutrition, or parenteral nutrition) was initiated and how that changed during days 1–30. We also identified the prescribed daily doses of parenteral energy, amino acids, and lipids during fasting period from days 1–30. <h3>Results</h3> Of 99147 patients, 28435 (28.7%) were aged ≥ 80 and 16737 (16.9%) had BMI < 18.5. The median (Q1, first quartile; Q3, third quartile) initiation of enteral nutrition was day 4 (2, 6). Of this cohort, 37240 (37.6%) and 73563 (74.2%) patients took food orally or received enteral nutrition on days 3 and 7, respectively; whereas, 89542 (90.3%) and 25584 (25.8%) patients received only parenteral nutrition or glucose/electrolyte infusions on days 1 and 7, respectively. For fasting patients, the prescribed parenteral energy dose began increasing on day 2 and the median (Q1, Q3) dose on day 7 was 10.7 (4.5, 18.9) kcal/kg; prescribed amino acid dose began increasing on day 5 and the median (Q1, Q3) dose on day 7 reached 0.32 (0.00, 0.62) g/kg; and median (Q1, Q3) prescribed lipid caloric proportion of non-protein energy was 8.0% (0.0%, 34.4%) on day 1 and 0.0% after that. <h3>Conclusions</h3> Fasting critically ill patients in Japan were prescribed inadequate doses of parenteral amino acids relative to doses recommended in nutritional guidelines, and almost all of these patients had no parenteral lipids prescribed. The results of this survey of nutritional management in real-world settings should serve as a foundation for future studies determining optimal nutritional management of critically ill patients. <h3>Trial registration</h3> UMIN clinical trial registry, the Japanese clinical trial registry (registration number: UMIN000042607). Registered 1 December 2020 - Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000048553.