Efficacy of ferric carboxymaltose on haemoglobin response among older patients with gastrointestinal bleeding: a randomised clinical trial.

BACKGROUND: Acute gastrointestinal bleeding (AGIB) is common in older patients but the use of iron in this context remains understudied. AIMS: This study aimed to evaluate prospectively the efficacy of ferric carboxymaltose to treat anaemia in older patients after AGIB. METHODS: This randomised double-blinded placebo-controlled clinical trial was conducted in 10 French centres. Eligible patients were 65 years or more, had controlled upper or lower gastrointestinal bleeding and a haemoglobin level of 9-11 g/dl. Patients were randomly assigned, in a 1:1 ratio, to receive either one intravenous iron injection of ferric carboxymaltose or one injection of saline solution. The primary endpoint was the difference in haemoglobin level between day 0 and day 42. Secondary endpoints were treatment-emergent adverse events, serious adverse events, rehospitalisation and improvement of quality of life (QOL) at day 180. RESULTS: From January 2013 to January 2017, 59 patients were included. The median age of patients was 81.9 [75.8, 87.3] years. At day 42, a significant difference in haemoglobin level increase was observed (2.49 g/dl in the ferric carboxymaltose group vs. 1.56 g/dl in the placebo group, P = 0.02). At day 180, QOL, measured on European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, improved by 10.5 points in the ferric carboxymaltose group and by 8.2 points in the placebo group (P = 0.56). Rates of adverse events and rehospitalisation were similar in the two groups. CONCLUSIONS: Intravenous iron seems safe and effective to treat anaemia in older patients after AGIB and should be considered as a standard-of-care treatment. ClinicalTrials.gov (NCT01690585).

Physical compatibility of Xuebijing injection with 53 intravenous drugs during simulated Y-site administration.

OBJECTIVE: Xuebijing injection (XBJ) is a commonly used herbal medicine injection in China. However, the physical compatibility of XBJ with other intravenous drugs remains unclear. The purpose of this research is to evaluate physical compatibility of Xuebijing injection (XBJ) with 53 intravenous drugs (including 31 Chinese medicine injections and 22 chemicals) during simulated Y-site administration. METHODS: Y-site administration was simulated in vitro by admixing 0.33 ml/ml XBJ with an equal volume of other diluted 53 intravenous drugs, respectively. Physical compatibility including visual inspection, Tyndall beam, particle limits, turbidity, pH, chromacity value, spectroscopic absorption of 550 nm and 420 nm (A550 nm and A420 nm) were observed and assessed at 0, 1, 2, and 4 h. Physical compatibility was defined as all solutions with no color changes, no gas evolution, particulate formation and no Tyndall beam within 4 hours, turbidity changes <0.5 nephelometric turbidity unit (NTU) compared to 0 h, particle limits allowed by the Chinese Pharmacopoeia (Ch.P) 2020 edition, pH changes <10% compared to 0, chromacity value changes <200 compared to 0 h, or photometrical changes of A420 nm <0.0400 or A550 nm <0.0100 compared to 0 h. RESULTS: XBJ was physically incompatible with 27 of the 53 intravenous drugs tested, 26 were compatible with XBJ for 4 h. CONCLUSIONS: XBJ should not be simultaneously co-administered with 27 of the 53 intravenous drugs during simulated Y-site. If coadministration was inevitable, flushing tube with NS or D5W before and after infusion of XBJ was needed. Assessment included visual inspection, Tyndall beam, turbidity measurement, particle counts, pH measurement, chromacity value measurement and absorption of A550 nm were proved to be valid and robust for the quality control of infusion and compatibility of Chinese herbal injection.

Amelioration of diabetic nephropathy in mice by a single intravenous injection of human mesenchymal stromal cells at early and later disease stages is associated with restoration of autophagy.

BACKGROUND AND AIMS: Mesenchymal stromal cells (MSCs) a potentially effective disease-modulating therapy for diabetic nephropathy (DN) but their clinical translation has been hampered by incomplete understanding of the optimal timing of administration and in vivo mechanisms of action. This study aimed to elucidate the reno-protective potency and associated mechanisms of single intravenous injections of human umbilical cord-derived MSCs (hUC-MSCs) following shorter and longer durations of diabetes. METHODS: A streptozotocin (STZ)-induced model of diabetes and DN was established in C57BL/6 mice. In groups of diabetic animals, human (h)UC-MSCs or vehicle were injected intravenously at 8 or 16 weeks after STZ along with vehicle-injected non-diabetic animals. Diabetes-related kidney abnormalities was analyzed 2 weeks later by urine and serum biochemical assays, histology, transmission electron microscopy and immunohistochemistry. Serum concentrations of pro-inflammatory and pro-fibrotic cytokines were quantified by ELISA. The expression of autophagy-related proteins within the renal cortices was investigated by immunoblotting. Bio-distribution of hUC-MSCs in kidney and other organs was evaluated in diabetic mice by injection of fluorescent-labelled cells. RESULTS: Compared to non-diabetic controls, diabetic mice had increases in urine albumin creatinine ratio (uACR), mesangial matrix deposition, podocyte foot process effacement, glomerular basement membrane thickening and interstitial fibrosis as well as reduced podocyte numbers at both 10 and 18 weeks after STZ. Early (8 weeks) hUC-MSC injection was associated with reduced uACR and improvements in multiple glomerular and renal interstitial abnormalities as well as reduced serum IL-6, TNF-α, and TGF-ß1 compared to vehicle-injected animals. Later (16 weeks) hUC-MSC injection also resulted in reduction of diabetes-associated renal abnormalities and serum TGF-ß1 but not of serum IL-6 and TNF-α. At both time-points, the kidneys of vehicle-injected diabetic mice had higher ratio of p-mTOR to mTOR, increased abundance of p62, lower abundance of ULK1 and Atg12, and reduced ratio of LC3B to LC3A compared to non-diabetic animals, consistent with diabetes-associated suppression of autophagy. These changes were largely reversed in the kidneys of hUC-MSC-injected mice. In contrast, neither early nor later hUC-MSC injection had effects on blood glucose and body weight of diabetic animals. Small numbers of CM-Dil-labeled hUC-MSCs remained detectable in kidneys, lungs and liver of diabetic mice at 14 days after intravenous injection. CONCLUSIONS: Single intravenous injections of hUC-MSCs ameliorated glomerular abnormalities and interstitial fibrosis in a mouse model of STZ-induced diabetes without affecting hyperglycemia, whether administered at relatively short or longer duration of diabetes. At both time-points, the reno-protective effects of hUC-MSCs were associated with reduced circulating TGF-ß1 and restoration of intra-renal autophagy.

Comprehensive ocular and systemic pharmacokinetics of dexamethasone after subconjunctival and intravenous injections in rabbits.

Even though subconjunctival injections are used in clinics, their quantitative pharmacokinetics has not been studied systematically. For this purpose, we evaluated the ocular and plasma pharmacokinetics of subconjunctival dexamethasone in rabbits. Intravenous injection was also given to enable a better understanding of the systemic pharmacokinetics. Dexamethasone concentrations in plasma (after subconjunctival and intravenous injections) and four ocular tissues (iris-ciliary body, aqueous humour, neural retina and vitreous) were analysed using LC-MS/MS. Population pharmacokinetic modelling for plasma data from both injection routes were used, and for first time the constant rate of absorption of dexamethasone from the subconjunctival space into plasma was estimated (ka,plasma = 0.043 min-1, i.e. absorption half-life of 17.3 min). Non-compartmental analysis was used for the ocular data analysis and resulting in ocular drug exposure of iris-ciliary body (AUC0-∞= 41984 min·ng/g) > neural retina (AUC0-∞= 25511 min·ng/g) > vitreous (AUC0-∞= 7319 min·ng/mL) > aqueous humour (AUC0-∞= 6146 min·ng/mL). The absolute bioavailability values after subconjunctival injection, reported for the first time, were 0.74 % in aqueous humour (comparable to topical dexamethasone suspensions), and 0.30 % in vitreous humour (estimated to be higher than in topical administration). These novel and comprehensive pharmacokinetic data provide valuable information on the potential for exploiting this route in ocular drug development for treating both, anterior and posterior segment ocular diseases. Moreover, the new generated dexamethasone-parameters are a step-forward in building predictive pharmacokinetic models to support the design of new subconjunctival dexamethasone formulations, which may sustain drug effect for longer period of time.

A Neonatal Rodent Model of Retroorbital Vein Injection.

Intravenous (iv) injection is the most used route of drug administration in neonates in the clinical setting. Therefore, retroorbital vein injection is an important method for compound administration in research, where successful proof-of-concept studies can progress into much-needed neonatal clinical trials. Most intravenous studies in neonatal rodents use the superficial temporal/facial vein. However, retroorbital injection becomes unreliable in neonatal rodents older than 2 days after the skin darkens and the vein is no longer visible. In the present protocol, we describe the retroorbital injection of the venous sinus in both the neonatal mouse and rat at ages when the superficial temporal vein is no longer visible, but the eyes have not opened yet. Eye-opening facilitates retro-orbital injection by enabling the researcher to clearly see that they are not perforating the eye when inserting the needle. We demonstrate that this technique can be performed in a reliable and reproducible manner without adverse effects. Additionally, we show that it can be used in many studies, such as administering compounds to study neonatal brain injury.

Pharmacokinetic Study of Ultrasmall Superparamagnetic Iron Oxide Nanoparticles HY-088 in Rats.

BACKGROUND AND OBJECTIVE: HY-088 injection is an ultrasmall superparamagnetic iron oxide nanoparticle (USPIOs) composed of iron oxide crystals coated with polyacrylic acid (PAA) on the surface. The purpose of this study was to investigate the pharmacokinetics, tissue distribution, and mass balance of HY-088 injection. METHODS: The pharmacokinetics of [55Fe]-HY-088 and [14C]-HY-088 were investigated in 48 SD rats by intravenous injection of 8.5 (low-dose group), 25.5 (medium-dose group), and 85 (high-dose group) mg/100 µCi/kg. Tissue distribution was studied by intravenous injection of 35 mg/100 µCi/kg in 48 SD rats, and its tissue distribution in vivo was obtained by ex vivo tissue assay. At the same time, [14C]-HY-088 was injected intravenously at a dose of 25.5 mg/100 µCi/kg into 16 SD rats, and its tissue distribution in vivo was studied by quantitative whole-body autoradiography. [14C]-HY-088 and [55Fe]-HY-088 were injected intravenously into 24 SD rats at a dose of 35 mg/100 µCi/kg, and their metabolism was observed. RESULTS: In the pharmacokinetic study, [55Fe]-HY-088 reached the maximum observed concentration (Cmax) at 0.08 h in the low- and medium-dose groups of SD rats. [14C]-HY-088 reached Cmax at 0.08 h in the three groups of SD rats. The area under the concentration-time curve (AUC) of [55Fe]-HY-088 and [14C]-HY-088 increased with increasing dose. In the tissue distribution study, [55Fe]-HY-088 and [14C]-HY-088 were primarily distributed in the liver, spleen, and lymph nodes of both female and male rats. In the mass balance study conducted over 57 days, the radioactive content of 55Fe from [55Fe]-HY-088 was primarily found in the carcass, accounting for 86.42 ± 4.18% in females and 95.46 ± 6.42% in males. The radioactive recovery rates of [14C]-HY-088 in the urine of female and male rats were 52.99 ± 5.48% and 60.66 ± 2.23%, respectively. CONCLUSIONS: Following single intravenous administration of [55Fe]-HY-088 and [14C]-HY-088 in SD rats, rapid absorption was observed. Both [55Fe]-HY-088 and [14C]-HY-088 were primarily distributed in the liver, spleen, and lymph nodes. During metabolism, the radioactivity of [55Fe]-HY-088 is mainly present in the carcass, whereas the 14C-labeled [14C]-HY-088 shell PAA is eliminated from the body mainly through the urine.

Late/delayed gadolinium enhancement in MRI after intravenous administration of extracellular gadolinium-based contrast agents: is it worth waiting?

The acquisition of images minutes or even hours after intravenous extracellular gadolinium-based contrast agents (GBCA) administration ("Late/Delayed Gadolinium Enhancement" imaging; in this review, further termed LGE) has gained significant prominence in recent years in magnetic resonance imaging. The major limitation of LGE is the long examination time; thus, it becomes necessary to understand when it is worth waiting time after the intravenous injection of GBCA and which additional information comes from LGE. LGE can potentially be applied to various anatomical sites, such as heart, arterial vessels, lung, brain, abdomen, breast, and the musculoskeletal system, with different pathophysiological mechanisms. One of the most popular clinical applications of LGE regards the assessment of myocardial tissue thanks to its ability to highlight areas of acute myocardial damage and fibrotic tissues. Other frequently applied clinical contexts involve the study of the urinary tract with magnetic resonance urography and identifying pathological abdominal processes characterized by high fibrous stroma, such as biliary tract tumors, autoimmune pancreatitis, or intestinal fibrosis in Crohn's disease. One of the current areas of heightened research interest revolves around the possibility of non-invasively studying the dynamics of neurofluids in the brain (the glymphatic system), the disruption of which could underlie many neurological disorders.

Effects of Halloysite Nanotubes and Multi-walled Carbon Nanotubes on Kruppel-like Factor 15-Mediated Downstream Events in Mouse Hearts After Intravenous Injection.

Halloysite nanotubes (HNTs) are nanomaterials (NMs) derived from natural clays and have been considered as biocompatible NMs for biomedical uses. However, the cardiovascular toxicity of HNTs has not been thoroughly investigated. In this study, we compared the cardiotoxicity of HNTs and multi-walled carbon nanotubes (MWCNTs), focusing on the changes in Kruppel-like factor (KLF)-mediated signaling pathways. Mice were intravenously injected with 50 µg NMs, once a day, for 5 days, and then mouse hearts were removed for experiments. While HNTs or MWCNTs did not induce obvious pathological changes, RNA-sequencing data suggested the alterations of KLF gene expression. We further confirmed an increase of Klf15 positive cells, accompanied by changes in Klf15-related gene ontology (GO) terms. We noticed that most of the changed GO terms are related with the regulation of gene expression, and we confirmed that the NMs increased myoneurin (Mynn) but decreased snail family transcriptional repressor 1 (Snai1), two transcription factors (TFs) related with Klf15. Besides, the changed GO terms also include metal ion binding and positive regulation of glucose import, and we verified an increase of phosphoenolpyruvate carboxykinase 1 (Pck1) and insulin receptor (Insr). However, HNTs and MWCNTs only showed minimal impact on cell death signaling pathways, and no increase in apoptotic sites was observed after NM treatment. We concluded that intravenous administration of HNTs and MWCNTs activated a protective TF, namely Klf15 in mouse aortas, to alter gene expression and signaling pathways related with metal ion binding and glucose import.

Gingival-derived mesenchymal stem cell therapy regenerated the radiated salivary glands: functional and histological evidence in murine model.

BACKGROUND: Radiotherapy in head and neck cancer management causes degeneration of the salivary glands (SG). This study was designed to determine the potential of gingival mesenchymal stem cells (GMSCs) as a cell-based therapy to regenerate irradiated parotid SG tissues and restore their function using a murine model. METHODS: Cultured isolated cells from gingival tissues of 4 healthy guinea pigs at passage 3 were characterized as GMSCSs using flow cytometry for surface markers and multilineage differentiation capacity. Twenty-one Guinea pigs were equally divided into three groups: Group I/Test, received single local irradiation of 15 Gy to the head and neck field followed by intravenous injection of labeled GMSCs, Group II/Positive control, which received the same irradiation dose followed by injection of phosphate buffer solution (PBS), and Group III/Negative control, received (PBS) injection only. Body weight and salivary flow rate (SFR) were measured at baseline, 11 days, 8-, 13- and 16-weeks post-irradiation. At 16 weeks, parotid glands were harvested for assessment of gland weight and histological and immunohistochemical analysis. RESULTS: The injected GMSCs homed to degenerated glands, with subsequent restoration of the normal gland histological acinar and tubular structure associated with a significant increase in cell proliferation and reduction in apoptotic activity. Subsequently, a significant increase in body weight and SFR, as well as an increase in gland weight at 16 weeks in comparison with the irradiated non-treated group were observed. CONCLUSION: The study provided a new potential therapeutic strategy for the treatment of xerostomia by re-engineering radiated SG using GMSCs.

Pharmacokinetics of intravenous and topical lidocaine in patients undergoing thoracoscopic pulmonary resection: a comparative study.

OBJECTIVE: Lidocaine was the commonly used local anesthetic. The present study aimed to compare the pharmacokinetics of intravenous and topical lidocaine in patients undergoing thoracoscopic pulmonary resection. PATIENTS AND METHODS: Sixty patients who were scheduled for thoracoscopic pulmonary resection were screened and randomly assigned to the intravenous lidocaine group and topical lidocaine group. After induction, the patient in the intravenous group was given an intravenous bolus of 1.5 mg/kg lidocaine, while the patient in the topical group was given 3.0 mg/kg lidocaine via the "spray-as-you-go" method. Arterial blood was sampled at preset intervals, and plasma concentrations of lidocaine and its metabolites [monoethylglycinexylidide (MEGX) and glycinexylidide (GX)] were measured by ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: Following intravenous administration, plasma lidocaine concentration reached its peak with a time to reach Cmax (Tmax) of 0.05 h and then decreased in a biphasic manner with a very short half-life time (T1/2) of 1.85 h. After topical administration, lidocaine was well absorbed, with Tmax of 0.21 h and bioavailability of 71.02%. The mean Tmax, Cmax, and area under the curve from the time (AUC0-t) of MEGX and GX were higher in the topical group than in the intravenous group. There were no obvious differences in the Cmax, T1/2, clearance, or apparent volume of distribution of lidocaine between the two groups. No obvious adverse events were observed. CONCLUSIONS: Topical administration of 3 mg/kg lidocaine via the "spray-as-you-go" method is an effective and safe technology for patients undergoing thoracoscopic pulmonary resection.

Dose-response relationships of intravenous and perineural dexamethasone as adjuvants to peripheral nerve blocks: a systematic review and model-based network meta-analysis.

BACKGROUND: Superiority of perineural over intravenous dexamethasone at extending nerve block analgesia has been suggested but without considering the dose-response relationships for each route of administration. METHODS: Randomised control studies that evaluated intravenous or perineural dexamethasone as an adjuvant to unilateral peripheral nerve blocks in adults were searched up to October 2023 in MEDLINE, Central, Google Scholar, and reference lists of previous systematic reviews. The Cochrane Risk-of-Bias tool was used. A maximum effect (Emax) model-based network meta-analysis was undertaken to evaluate the dose-response relationships of dexamethasone. RESULTS: A total of 118 studies were selected (9284 patients; 35 with intravenous dexamethasone; 106 with perineural dexamethasone; dose range 1-16 mg). Studies with unclear or high risk of bias overestimated the effect of dexamethasone. Bias-corrected estimates indicated a maximum fold increase in analgesia duration of 1.7 (95% credible interval (CrI) 1.4-1.9) with dexamethasone, with no difference between perineural and intravenous routes. Trial simulations indicated that 4 mg of perineural dexamethasone increased the mean duration of analgesia for long-acting local anaesthetics from 11.1 h (95% CrI 9.4-13.1) to 16.5 h (95% CrI 14.0-19.3) and halved the rate of postoperative nausea and vomiting. A similar magnitude of effect was observed with 8 mg of intravenous dexamethasone. CONCLUSIONS: Used as an adjuvant for peripheral nerve block, intravenous dexamethasone can be as effective as perineural dexamethasone in prolonging analgesic duration, but is less potent, hence requiring higher doses. The evidence is limited because of the observational nature of the dose-response relationships and the quality of the included studies. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42020141689.

Pharmacokinetics of intranasal and intramuscular flunixin in healthy grower pigs.

Flunixin meglumine is a nonsteroidal anti-inflammatory drug approved to manage pyrexia associated with swine respiratory disease. In the United States, no analgesic drugs are approved for use in swine by the FDA, although they are needed to manage painful conditions. This study evaluated the pharmacokinetics and relative bioavailability of intranasal versus intramuscular flunixin in grower pigs. Six pigs received 2.2 mg/kg flunixin either intranasally via atomizer or intramuscularly before receiving flunixin via the opposite route following a 5-day washout period. Plasma samples were collected over 60 h and analysed using ultra-performance liquid chromatography and tandem mass spectrometry to detect flunixin plasma concentrations. A non-compartmental pharmacokinetic analysis was performed. The median Cmax was 4.0 µg/mL and 2.7 µg/mL for intramuscular and intranasal administration, respectively, while the median AUCinf was 6.9 h µg/mL for intramuscular administration and 4.9 h µg/mL for intranasal administration. For both routes, the median Tmax was 0.2 h, and flunixin was detectable in some samples up to 60 h post-administration. Intranasal delivery had a relative bioavailability of 88.5%. These results suggest that intranasal flunixin has similar, although variable, pharmacokinetic parameters to the intramuscular route, making it a viable route of administration for use in grower swine.

An Explanation of Why Dose-Corrected Area Under the Curve for Alternate Administration Routes Can Be Greater than for Intravenous Dosing.

It is generally believed that bioavailability (F) calculated based on systemic concentration area under the curve (AUC) measurements cannot exceed 1.0, yet some published studies report this inconsistency. We teach and believe, based on differential equation derivations, that rate of absorption has no influence on measured systemic clearance following an oral dose, i.e., determined as available dose divided by AUC. Previously, it was thought that any difference in calculating F from urine data versus that from systemic concentration AUC data was due to the inability to accurately measure urine data. A PubMed literature search for drugs exhibiting F > 1.0 and studies for which F was measured using both AUC and urinary excretion dose-corrected analyses yielded data for 35 drugs. We show and explain, using Kirchhoff's Laws, that these universally held concepts concerning bioavailability may not be valid in all situations. Bioavailability, determined using systemic concentration measurements, for many drugs may be overestimated since AUC reflects not only systemic elimination but also absorption rate characteristics, which is most easily seen for renal clearance measures. Clearance of drug from the absorption site must be significantly greater than clearance following an iv bolus dose for F(AUC) to correctly correspond with F(urine). The primary purpose of this paper is to demonstrate that studies resulting in F > 1.0 and/or greater systemic vs urine bioavailability predictions may be accurate. Importantly, these explications have no significant impact on current regulatory guidance for bioequivalence testing, nor on the use of exposure (AUC) measures in making drug dosing decisions.

Practical use of the central venous access port for contrast-enhanced CT: comparison with peripheral intravenous access regarding enhancement and safety.

AIM: To evaluate the efficacy of using the central venous (CV) port compared with peripheral intravenous access for contrast-material injection for contrast enhancement during the portal venous phase. MATERIALS AND METHODS: Patients were divided into three groups: CV delay, CV routine, and peripheral access (PA) groups. Patients in the CV delay group underwent injection in the arm-down position with an additional delay, while those in the CV routine and PA groups underwent injections with the routine injection protocol for portal venous phase imaging. Contrast enhancement was evaluated by measuring the mean radiodensity (Hounsfield units) values for the aortic arch, abdominal aorta, inferior vena cava, portal vein, and spleen. The peak injection pressure was recorded and compared among the three groups. RESULTS: No complications related to power injection were observed during 119 contrast-material injections performed using the CV port device. The CV delay group showed significantly lower radiodensity values than the PA group (165.7 ± 20.1 versus 181 ± 19 HU [p<0.01] for the portal vein); however, no significant differences in mean radiodensity values were observed between the CV routine and PA groups (p>0.05). The median peak injection pressure was 73.5, 67, and 47 psi in the CV delay, CV routine, and PA groups, respectively (p<0.01). CONCLUSION: The CV port can be used for safe contrast-material injection while maintaining contrast enhancement on portal venous phase comparable to that achieved with peripheral intravenous access.

Comparison of the Effectiveness and Side Effects of Intravenous TPA Injection in Acute Stroke Patients Between 0 and 4.5 Hours and the First 4.5 to 6 Hours From the Onset of Symptoms (P7-5.018).

In the American Academy of Neurology Annual Meeting Abstract "Comparison of the Effectiveness and Side Effects of Intravenous TPA Injection in Acute Stroke Patients Between 0 and 4.5 hours and the First 4.5 to 6 hours From the Onset of Symptoms (P7-5.018)" by Maghbooli et al.,1 Mohammad Bagher Abar should have been included as the second author. The Abstract has been replaced by a corrected version. The authors regret the omission.

Implementation of a tier system for IVIG indications to address IVIG shortage at a tertiary care pediatric medical center.

BACKGROUND: Drug shortages are a common issue that healthcare systems face and can result in adverse health outcomes for patients requiring inferior alternate treatment. The United States recently experienced a national drug shortage of intravenous immunoglobulin (IVIG). Several reported strategies to address the IVIG and other drug shortages have been proposed; however, there is a lack of evidence-based methods for protocol development and implementation. OBJECTIVE: To evaluate the efficacy of introducing a multidisciplinary task force and tier system of indications and to minimize adverse effects during a shortage of IVIG. METHODS: Faculty members across disciplines with expertise in IVIG use were invited to participate in a task force to address the shortage and ensure adequate supply for emergent indications. A tier system of IVIG indications was established according to the severity of diagnosis, urgency of indication, and quality of supporting evidence. Based on inventory, indications in selected tiers were auto-approved. Orders that could not be automatically approved were escalated for task force review. RESULTS: Overall, there were 342 distinct requests for IVIG during the study period (August 1, 2019 to December 31, 2019). All Tier 1 indications were approved. Of all requests, only 2.6% (9) of requests were denied, none of which resulted in adverse effects based on retrospective chart review. Seven patients who regularly receive IVIG had possible adverse effects due to dose reduction or spacing of treatment; however, each complication was multifactorial and not attributed to the shortage or tier system implementation alone. CONCLUSION: Implementation of a multidisciplinary task force and tier system to appropriately triage high-priority indications for limited pharmaceutical agents should be considered in health institutions faced with a drug shortage.

Evaluation of prompt engineering strategies for pharmacokinetic data analysis with the ChatGPT large language model.

To systematically assess the ChatGPT large language model on diverse tasks relevant to pharmacokinetic data analysis. ChatGPT was evaluated with prototypical tasks related to report writing, code generation, non-compartmental analysis, and pharmacokinetic word problems. The writing task consisted of writing an introduction for this paper from a draft title. The coding tasks consisted of generating R code for semi-logarithmic graphing of concentration-time profiles and calculating area under the curve and area under the moment curve from time zero to infinity. Pharmacokinetics word problems on single intravenous, extravascular bolus, and multiple dosing were taken from a pharmacokinetics textbook. Chain-of-thought and problem separation were assessed as prompt engineering strategies when errors occurred. ChatGPT showed satisfactory performance on the report writing, code generation tasks and provided accurate information on the principles and methods underlying pharmacokinetic data analysis. However, ChatGPT had high error rates in numerical calculations involving exponential functions. The outputs generated by ChatGPT were not reproducible: the precise content of the output was variable albeit not necessarily erroneous for different instances of the same prompt. Incorporation of prompt engineering strategies reduced but did not eliminate errors in numerical calculations. ChatGPT has the potential to become a powerful productivity tool for writing, knowledge encapsulation, and coding tasks in pharmacokinetic data analysis. The poor accuracy of ChatGPT in numerical calculations require resolution before it can be reliably used for PK and pharmacometrics data analysis.