Peak Serum Concentrations Research Articles

Acute Quetiapine Intoxication: Relationship Between Ingested Dose, Serum Concentration and Clinical Presentation-Structured Literature Review and Analysis.

Over the past decade, quetiapine has become one of the most commonly used psychotropic drugs in acute intoxication events worldwide. A structured literature review and analysis were conducted to assess the relationship between the kinetic and dynamic profiles in acute quetiapine intoxication. The correlation between dose and peak serum concentration (cmax) was determined using Pearson's correlation coefficient. Binary logistic regression was used to evaluate dose and cmax as predictors of the most common clinical events, signs and symptoms. One hundred and thirty-four cases of acute quetiapine ingestion were included in the analysis, with a median ingested dose of 10 g and a median cmax of 4 mg/L. The typical half-life was estimated to be 16.5 h, significantly longer than at therapeutic doses. For the immediate-release formulation, a biphasic disposition could not be excluded. Dose and cmax demonstrated a weak but significant correlation (r = 0.256; N = 63; p = 0.043). Central nervous system depression and tachycardia were the most common clinical signs. Higher doses and concentrations increased the risk of severe intoxication and were good predictors of intubation, tachycardia, hypotension, QTc prolongation and seizures, but not QRS prolongation, arrhythmia, heart block, hypokalaemia or acidosis. The thresholds for dose and cmax that increased the risk for individual signs and symptoms varied widely. However, doses > 3 g or cmax > 2 mg/L can be considered as alert levels that represent a high risk for severe clinical course of acute quetiapine intoxication.

The trajectory of serum salicylate concentrations after ingestion of medicinal oil containing methyl salicylate

Introduction The toxicokinetics of methyl salicylate after unintentional or intentional ingestion of medicinal oil containing methyl salicylate has not been well studied. We aimed to characterize the trajectory of serum salicylate concentrations and to evaluate factors associated with the peak serum salicylate concentration and the time from ingestion to peak concentration. Methods This was a retrospective cohort study of consecutive patients reported to the Hong Kong Poison Control Centre for laboratory-confirmed methyl salicylate poisoning by all local public emergency departments between 1 July 2008 and 30 June 2023. We analyzed cases with at least three serum salicylate concentrations. Multivariable generalized linear regression was used to identify factors significantly associated with the peak serum concentration and the time from ingestion to peak concentration. Results We included 41 patients (median age 81.0 years; 32 women and nine men). The median time from ingestion to the first peak serum salicylate concentration was 5.6 h (IQR: 3.2–10.8 h). Multiple regression showed that gastric aspiration (adjusted regression coefficient [β] − 2.50; 95% CI: −3.93 to −1.08; P = 0.001) and single-dose activated charcoal (adjusted β − 1.22; 95% CI: −2.02 to −0.42; P = 0.003) were significantly associated with a lower peak concentration, after adjusting for patient age, sex, exposure due to intentional self-harm, reported ingested dose, time from ingestion to emergency department presentation, vomiting, concurrent use of aspirin (acetylsalicylic acid) and other medications that affect gastric emptying or gastric acid secretion, blood pH, serum albumin concentration, and creatinine clearance. Discussion The serum salicylate concentration did not peak as quickly as generally believed, highlighting the importance of continued monitoring. Gastric aspiration and single-dose activated charcoal may help reduce gastrointestinal absorption, but their impact on clinical outcomes remains unclear. Conclusions Given the median time of 5.6 h (IQR: 3.2–10.8 h) from ingestion to the peak salicylate concentration, gastric aspiration and single-dose activated charcoal can be considered in patients up to a few hours after medicinal oil ingestion when the airway is protected.

Pharmacokinetics, Safety, Tolerability, and Immunogenicity of BP02 (Trastuzumab Biosimilar) Compared to EU- and US-Approved Trastuzumab in Healthy Adult Male Volunteers: A Phase 1, Randomized, Double-Blind Study.

This study evaluated the pharmacokinetic (PK) equivalence between BP02 (a proposed trastuzumab biosimilar) and the reference trastuzumab approved in the EU (EU-trastuzumab) and the US (US-trastuzumab). In this phase 1, double-blind, parallel-group trial, 111 healthy male volunteers were randomized 1:1:1 to receive a single 6-mg/kg intravenous infusion of BP02, EU-trastuzumab, or US-trastuzumab and were evaluated for 78days. Serum drug concentration-time data were analyzed by non-compartmental methods. The PK similarity of BP02 to the two reference products, and between EU-trastuzumab and US-trastuzumab, was determined using the standard 80-125% bioequivalence criteria. Baseline demographics for the 111 subjects with evaluable pharmacokinetics were similar across all treatment groups. PK profiles were similar for the three products. The 90% confidence intervals (CIs) for the ratios of area under the serum concentration-time curve (AUC) from the time of dosing to infinity (AUC0-inf), AUC from the time of dosing until the time of the last quantifiable concentration (AUC0-t), and peak serum concentration of trastuzumab (Cmax) were within 80% to 125% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms, with treatment-related AEs reported by 73.0%, 73.0%, and 89.2% of the subjects in the BP02, EU-trastuzumab, and US-trastuzumab groups, respectively. The most common AEs were headache, infusion-related reactions, and upper-respiratory-tract infections. Four subjects-three in the US-trastuzumab group and one in the BP02 group-discontinued the study due to AEs. All post-dose samples except for two tested negative for anti-drug antibodies. This study demonstrates the PK similarity among BP02, EU-trastuzumab, and US-trastuzumab. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab. ANZCTR number: ACTRN12621000573853.

Trimethoprim-sulfamethoxazole dosing and outcomes of pulmonary nocardiosis.

Nocardia often causes pulmonary infection among those with chronic pulmonary disease or immunocompromising conditions. Trimethoprim-sulfamethoxazole (TMP-SMX) is recommended as first-line treatment, though little data exists regarding outcomes of different dosing regimens. We performed a multicenter retrospective cohort study of adult patients with non-disseminated pulmonary nocardiosis initially treated with TMP-SMX monotherapy. Patients' initial TMP-SMX dosing was categorized as high- (> 10mg/kg/day), intermediate- (5-10mg/kg/day) or low-dose (< 5mg/kg/day). Outcomes included one-year mortality, post-treatment recurrence, and dose adjustment or early discontinuation of TMP-SMX. SMX serum concentrations and their effect on management were also assessed. Inverse probability of treatment weighting was applied to Cox regression analyses. Ninety-one patients were included with 24 (26.4%), 37 (40.7%), and 30 (33.0%) treated with high-, intermediate-, and low-dose TMP-SMX, respectively. Patients who initially received low-dose (HR 0.07, 95% CI 0.01-0.68) and intermediate-dose TMP-SMX (HR 0.27, 95% CI 0.07-1.04) had lower risk of one-year mortality than the high-dose group. Risk of recurrence was similar between groups. Nineteen patients had peak SMX serum concentrations measured which resulted in 7 (36.8%) dose changes and was not associated with one-year mortality or recurrence. However, 66.7% of the high-dose group required TMP-SMX dose adjustment/discontinuation compared to 24.3% of the intermediate-dose and 26.7% of the low-dose groups (p = 0.001). Low- and intermediate-dose TMP-SMX for non-disseminated pulmonary nocardiosis were not associated with poor outcomes compared to high-dose therapy, which had a higher rate of dose adjustment/early discontinuation. Historically used high-dose TMP-SMX may not be necessary for management of isolated pulmonary nocardiosis.

Standard versus fractionated high-dose cisplatin plus radiation for locally advanced head and neck cancer: Results of the CisFRad (GORTEC 2015-02) randomized phase II trial

BackgroundChemoradiotherapy with high-dose cisplatin (HD-Cis: 100 mg/m2 q3w for three cycles) is the standard of care (SOC) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Cumulative delivered dose of cisplatin is prognostic of survival, even beyond 200 mg/m2 but high toxicity compromises its delivery. AimCisplatin fractionation may allow, by decreasing the peak serum concentration, to decrease toxicity. To date, no direct comparison was done of HD-Cis versus fractionated high dose cisplatin (FHD-Cis). MethodsThis is a multi-institutional randomized phase II trial, stratified on postoperative or definitive chemoradiotherapy, comparing HD-Cis to FHD-Cis (25 mg/m2/d d1-4 q3w for 3 cycles) in patients with LA-HNSCC. The primary endpoint was the cumulative delivered cisplatin dose. ResultsBetween December 2015 and April 2018, 124 patients were randomized. Median cisplatin cumulative delivered dose was 291 mg/m2 (IQR: 251;298) in the FHD-Cis arm and 274 mg/m2 (IQR: 198;295) in the HD-Cis arm (P = 0.054). The proportion of patients receiving a third cycle of cisplatin was higher, with a lower proportion of grade 3–4 acute AEs in the FHD-Cis arm compared to the HD-Cis arm: 81 % vs. 64 % (P = 0.04) and 10 % vs. 17 % (P = 0.002), respectively.With a median follow-up of 48 months (IQR: 41;55), locoregional failure rate, PFS and OS were similar between the two arms. ConclusionAlthough the primary endpoint was not met, FHD-Cis allowed more cycles of cisplatin to be delivered with lower toxicity, when compared to SOC. FHD-Cis concurrently with RT is a treatment option which deserves further consideration.

Abstract 7167: Impact of patient specific factors on exposures of tarlatamab, a half-life extended DLL3-directed bispecific T-cell engager in patients with advanced small cell lung cancer

Abstract Background: Tarlatamab is a first in class, half-life extended delta-like ligand (DLL3) targeted bispecific T-cell engager (BiTE) immunotherapy that has shown antitumor activity with durable objective responses and promising survival outcomes in the ongoing studies in patients with previously treated small-cell lung cancer (NCT03319940, NCT05060016) (Ahn et al, 2023; Paz-Ares et al, 2023). Here we describe the effects of patient specific factors [age, sex, bodyweight, ethnicity, estimates of renal and hepatic function, prior lines of therapy, baseline disease status, emergence of anti-drug antibodies (ADA)] on tarlatamab exposures. Methods: Tarlatamab serum concentrations were available from 420 subjects (8509 samples) pooled across the ongoing Phase 1 DeLLphi-300 study (dose range 0.003 mg to 100 mg Q2W and 200 mg Q3W) and Phase 2 DeLLphi-301 study (10 mg and 100 mg Q2W). The data were analyzed using a nonlinear-mixed effects modeling approach implemented in NONMEM (v7.5) software. Model selection and evaluation was guided by standard statistical and graphical approaches. Impact of key baseline demographic variables on tarlatamab clearance and volume of distribution were evaluated. Results: Tarlatamab exposures increased in a dose-proportional manner and were not impacted by age, sex, ethnicity, estimates of renal and hepatic function, prior lines of therapy or baseline disease status. Asian race resulted in 14% higher peak serum concentrations relative to Caucasian subjects. Higher body weight (99 kg; 90th percentile) was associated with a 24% decrease in Day 28 pre-dose concentration (Ctrough) relative to median bodyweight (73 kg). Lower body weight (54 kg; 10th percentile) was associated with a 27% increase in Ctrough relative to median bodyweight. Positive ADA status resulted in a 24% decrease in Ctrough. However, at the recommended dose of 10 mg Q2W, neither body weight nor ADA status had a clinically relevant impact on tarlatamab efficacy or safety measures (Ahn et al, 2023). Conclusion: Overall, based on these analyses, no dose adjustment for tarlatamab is required based on age, sex, bodyweight, ethnicity, estimates of renal and hepatic function, prior lines of therapy, baseline disease status or emergence of ADA. Citation Format: Stephanie M. Kong, Mukul Minocha, Po-Wei Chen, Pablo Martinez, Erik S. Anderson, Amanda Parkes, Brett E. Houk, Chih-Wei Lin. Impact of patient specific factors on exposures of tarlatamab, a half-life extended DLL3-directed bispecific T-cell engager in patients with advanced small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7167.

Isoniazid urine spectrophotometry for prediction of serum pharmacokinetics in adults with TB.

Isoniazid (INH) is an important drug in many TB regimens, and unfavorable treatment outcomes can be caused by suboptimal pharmacokinetics. Dose adjustment can be personalized by measuring peak serum concentrations; however, the process involves cold-chain preservation and laboratory techniques such as liquid chromatography (LC)/mass spectrometry (MS), which are unavailable in many high-burden settings. Urine spectrophotometry could provide a low-cost alternative with simple sampling and quantification methods. We enrolled 56 adult patients on treatment for active TB. Serum was collected at 0, 1, 2, 4, 6, and 8 h for measurement of INH concentrations using validated LC-MS/MS methods. Urine was collected at 0-4, 4-8, and 8-24 h intervals, with INH concentrations measured using colorimetric methods. The median peak serum concentration and total serum exposure over 24 h were 4.8 mg/L and 16.4 mg*hour/L, respectively. Area under the receiver operator characteristic curves for urine values predicting a subtherapeutic serum concentration (peak <3.0 mg/L) were as follows: 0-4 h interval (AUC 0.85, 95% CI 0.7-0.96), 0-8 h interval (AUC 0.85, 95% CI 0.71-0.96), and 0-24 h urine collection interval (AUC 0.84, 95% CI 0.68-0.96). Urine spectrophotometry may improve feasibility of personalized dosing in high TB burden regions but requires further study of target attainment following dose adjustment based on a urine threshold.

The Subcutaneous Administration of Beta-Lactams: A Case Report and Literary Review-To Do Small Things in a Great Way.

The subcutaneous (s.c.) route is a commonly used method for delivering various drugs, although its application in the administration of antibiotics is relatively uncommon. In this case, we report a successful treatment of nosocomial pneumonia using piperacillin/tazobactam via continuous subcutaneous administration. Furthermore, this article provides an overview of the current literature regarding the s.c. administration of beta-lactam antibiotics. Based on our analysis, we identified only 15 studies that described the s.c. use of beta-lactam antibiotics in human subjects. Among these studies, cephalosporins were the most extensively investigated antibiotic class, with 10 available studies. According to the study findings, all three antibiotic classes (cephalosporins, penicillins, and carbapenems) demonstrated a similar pharmacokinetic profile when administered via the subcutaneous route. The subcutaneous route appears to be associated with a lower peak serum concentration (Cmax) but a comparable minimum blood concentration (Cmin) and an extended half-life (t1/2) when compared to conventional routes of antibiotic administration. Further research is necessary to determine whether subcutaneously administered beta-lactam antibiotics in human subjects achieve pharmacodynamic targets and demonstrate clinical efficacy.

Investigating serum concentration profiles of orally ingested short-chain fatty acid supplements.

Acetate, propionate, and butyrate are naturally-occurring short-chain fatty acids (SCFAs) derived from bacterial metabolism of dietary fibre and have been associated with numerous positive health outcomes. All three acids have been shown to offer unique physiological and metabolic effects and, therefore, could be targeted for co-ingestion as part of a nutritional/medicinal plan. However, a better understanding of the outcomes of supplementing in combination on circulating concentration profiles is necessary to confirm uptake efficacy. This study sought to investigate the acute circulating concentration profiles of acetate, propionate, and butyrate following oral supplementation. Three experimental trials were conducted including investigations to understand the impact of capsule coating on circulating concentration profiles, the effect of supplementation dose on uptake kinetics, and the outcome of a short, repeated, supplementation routine on circulating levels. Serum samples were analysed for SCFA content using a quantitative GC-MS assay. It was observed that an acid-resistant coated capsule caused a delayed and blunted blood concentration response, with the non-acid resistant trial displaying earlier and more intense peak serum concentrations. For dose comparison investigations, all SCFAs peaked within 60 min and returned to baseline concentrations by 120 min post-supplementation. A graded dose relationship was present for propionate and butyrate when considering the total circulating exposure across a 240 min monitoring period. In addition, a one-week, twice-daily, repeated supplementation protocol resulted in no changes in basal serum SCFA concentrations. Overall, these data indicate that acetate, propionate, and butyrate display relatively similar circulating concentration profiles following oral co-ingestion, adding knowledge to help inform supplementation strategies for future outcomes where acute elevation of circulating SCFAs is desired.

Evaluation of prolonged magnesium infusion after allogeneic hematopoietic cell transplant.

Calcineurin inhibitor use after allogeneic hematopoietic cell transplantation (allo-HCT) is associated with significant magnesium wasting. Utilization of a prolonged magnesium infusion is thought to lead to a lower serum peak concentration and therefore, decreased renal wasting of magnesium. In November 2017, our institution implemented a modification to our inpatient electrolyte replacement protocol for allo-HCT recipients that extended the magnesium infusion rate from 4g/2h to 4g/4h based on this theoretical advantage. The primary objective of this study was to compare the median magnesium requirements per day of admission between patients who received magnesium 4g/2h to patients who received magnesium 4g/4h. Secondary objectives included a comparison of the per-patient median serum magnesium concentration during admission, as well as the median incremental difference in serum magnesium concentration after intravenous replacement per patient per admission. Allo-HCT recipients who received prolonged infusion magnesium infusions were compared to a historical cohort of allo-HCT patients who received shorter IV magnesium infusions. Admissions were included if the patient had received an allo-HCT within 100days prior, was admitted to the Transplant and Cellular Therapy Unit at WVU Medicine J.W. Ruby Memorial Hospital, and received at least one magnesium infusion and one dose of cyclosporine or tacrolimus. Admissions were excluded if the patient received oral magnesium, total parenteral nutrition, aminoglycosides, amphotericin, carboplatin, cisplatin, or foscarnet. The pre-implementation group consisted of 81 admissions (n = 64 patients), while the post-implementation group consisted of 90 admissions (n = 60 patients). Median magnesium requirements per day of admission were not different between groups at 1.4g of magnesium in the pre-implementation group and 1.9g of magnesium in the post-implementation group (P = 0.25). Median serum magnesium concentrations and median incremental difference in serum magnesium concentration after intravenous replacement were also not different between groups: 1.65mg/dL vs 1.60mg/dL (P = 0.65) and 0.30mg/dL vs 0.28mg/dL (P = 0.67), respectively. Prolonged infusion of magnesium in allo-HCT recipients receiving CNI therapy does not result in improvement in magnesium retention.

Selection of clinically relevant drug concentrations for in vitro studies of candidates drugs for cancer repurposing: a proposal.

Drug repurposing of widely prescribed patent-off and cheap drugs may provide affordable drugs for cancer treatment. Nevertheless, many preclinical studies of cancer drug repurposing candidates use in vitro drug concentrations too high to have clinical relevance. Hence, preclinical studies must use clinically achievable drug concentrations. In this work, several FDA-approved cancer drugs are analyzed regarding the correlation between the drug inhibitory concentrations 50% (IC50) tested in cancer cell lines and their corresponding peak serum concentration (Cmax) and area under the curve (AUC) reported in clinical studies of these drugs. We found that for most targeted cancer drugs, the AUC and not the Cmax is closest to the IC50; therefore, we suggest that the initial testing of candidate drugs for repurposing could select the AUC pharmacokinetic parameter and not the Cmax as the translated drug concentration for in vitro testing. Nevertheless, this is a suggestion only as experimental evidence does not exist to prove this concept. Studies on this issue are required to advance in cancer drug repurposing.

Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma.

Bile duct cancer (cholangiocarcinoma, CCA) has a poor prognosis for patients, and despite recent advances in targeted therapies for other cancer types, it is still treated with standard chemotherapy. Anaplastic lymphoma kinase (ALK) has been shown to be a primary driver of disease progression in lung cancer, and ALK inhibitors are effective therapeutics in aberrant ALK-expressing tumors. Aberrant ALK expression has been documented in CCA, but the use of ALK inhibitors has not been investigated. Using CCA cell lines and close-to-patient primary cholangiocarcinoma cells, we investigated the potential for ALK inhibitors in CCA. ALK, cMET, and ROS1 expression was determined in CCA patient tissue by immunohistochemistry and digital droplet polymerase chain reaction, and that in cell lines was determined by immunoblot and immunofluorescence. The effect on cell viability and mechanism of action of ALK, cMet, and ROS1 inhibitors was determined in CCA cell lines. To determine whether ceritinib could affect primary CCA cells, tissue was taken from four patients with biliary tract cancer, without ALK rearrangement, mutation, or overexpression, and grown in three-dimensional tumor growth assays in the presence or absence of humanized mesenchymal cells. ALK and cMet but not ROS were both upregulated in CCA tissues and cell lines. Cell survival was inhibited by crizotinib, a c-met/ALK/ROS inhibitor. To determine the mechanism of this effect, we tested c-Met-specific and ALK/ROS-specific inhibitors, capmatinib and ceritinib, respectively. Whereas capmatinib did not affect cell survival, ceritinib dose-dependently inhibited survival in all cell lines, with IC50 ranging from 1 to 9 µM and co-treatments with gemcitabine and cisplatin further sensitized cells, with IC50 ranging from IC50 0.60 to 2.32 µM. Ceritinib did not inhibit cMet phosphorylation but did inhibit ALK phosphorylation. ALK was not mutated in any of these cell lines. Only ceritinib inhibited 3D growth of all four patient samples below mean peak serum concentration, in the presence and absence of mesenchymal cells, whereas crizotinib and capmatinib failed to do this. Ceritinib appeared to exert its effect more through autophagy than apoptosis. These results indicate that ceritinib or other ALK/ROS inhibitors could be therapeutically useful in cholangiocarcinoma even in the absence of aberrant ALK/ROS1 expression.

Pharmacokinetics of a Single Transdermal Dose of Mirtazapine in Rhesus Macaques (Macaca mulatta).

Decreased appetite is a common clinical problem in captive rhesus macaques (Macaca mulatta). Mirtazapine, a tetracyclic antidepressant originally developed for humans, has shown promise as a safe and effective promoter of weight gain and appetite in several veterinary species including rhesus and cynomolgus macaques. Although mirtazapine is available as oral formulations, transdermal delivery in macaques with reduced appetite would allow quick, painless, topical application. Here we describe the pharmacokinetics of a single application of a widely available veterinary transdermal mirtazapine formulation in 6 rhesus macaques. A dose of 0.5 mg/kg of transdermal mirtazapine ointment that has proven to be effective in rhesus was applied to the caudal pinnae of 3 female and 3 male young adult macaques. Serum was collected at 0, 0.5, 1, 3, 6, 8, 12, 24, 36, 48, and 72 h after administration. Our data indicate transdermal mirtazapine is absorbed at a lower level in rhesus as compared with published values in domestic cats (rhesus peak serum concentration: 1.2 ± 0.3 ng/mL), while drug half-life is longer than that reported in cats (rhesus: 33 ± 7 h). Mirtazapine reaches peak plasma concentrations in rhesus at 16 ± 10 h after administration; our model indicates that up to 5 d of serial dosing may be necessary to reach steady state. Our preliminary data also suggest that sex differences may contribute to efficacy and/or indicate sex-based differences, as male macaques reached Tmax more quickly than females (19 ± 2 h in females and 8 ± 3 h in males) and showed higher variation in half-life (33 ± 4 h in females and 34 ± 11 h in males). While previous work indicates clinical efficacy of the 0.5-mg/kg dosage in macaques, further investigation is warranted to determine if rhesus may benefit from higher recommended doses than companion animal species.

Assessment and predictive ability of the absolute neutrophil count in peripheral blood for in vivo CAR T cells expansion and CRS

BackgroundChimeric antigen receptor (CAR) T cell therapy is an advanced and effective immunotherapy for relapsed or refractory B-cell malignancies. High expansion of CAR T cells in vivo and durable antitumor...

PSI-A-9 A Comparison in Vaginal Gene Expression and Circulating Hormone Concentration in Pre-Pubertal Gilts Achieving Puberty at Different Ages

Abstract A known predictor of reproductive success in swine breeding herds is age at puberty. Early puberty is associated with improved long-term reproductive performance and more high-quality offspring. The objective of this study was to compare vaginal gene expression in gilts that achieved estrus early (160 to 181 d of age), average (181 to 202 d of age), late (202 to 215 d of age) and anestrus. Pre-pubertal gilts (n = 13) were followed from 70 d of age until first estrus or 214 ± 1 d. Vaginal epithelia was collected using a swabbing method at five time points during reproductive development [70 (on-farm arrival), 100 (mid-folliculogenesis), 130, 160 (start of boar exposure) d of age and standing estrus or end of trial]. At 140 d of age, females received an indwelling titanium catheter for daily blood collection during boar exposure. Following detected standing estrus, a blood sample was collected every 2 hours for 96 hours to characterize the peak serum concentration of luteinizing hormone that occurs at ovulation. At the conclusion of the trial, 3 gilts displayed early estrus (169 to 171 d of age), 3 gilts were deemed average estrus (194 to 195 d of age), 3 gilts were deemed late estrus (203 to 213 d of age), 3 gilts were deemed anestrus and 1 was identified as having a ‘silent’ estrus after 200 d of age. Total RNA were isolated from vaginal epithelia and relative gene expression insulin-like growth factor-1 (IGF-1), and estrogen receptor (ER)-alpha was quantified by real time RT-PCR, relative to the expression of RPLP0. to D70 was preformed using the PCR package offered in RStudio (version 1.2.5025). There was an increase in ER-alpha expression in the average estrus group (P = 0.03) at 130 d of age. Early estrus females had a greater expression of IGF-1 at 130 d of age compared with anestrus females (P = 0.01). Of the 9 females placed with an indwelling catheter, 2 catheters were nonpatent, and blood sample could not be collected at standing estrus. Of the 7 females where blood sample was collected at standing estrus, all females achieved an luteinizing hormone (LH) peak within 12 h after recorded standing estrus. Identification of key differences in the vaginal epithelium in concert with LH values provides biological evidence that those deemed achieving estrus based on behavior did successfully achieve estrus. These vaginal epithelium differences may serve as putative biomarkers to detect early estrus in pre-pubertal gilts.

Candida causes recurrent vulvovaginal candidiasis by forming morphologically disparate biofilms on the human vaginal epithelium

BackgroundRecurrent vulvovaginal candidiasis (RVVC) is a recalcitrant medical condition that affects many women of reproductive age. The importance of biofilm formation by Candida in RVVC has been recently questioned. This study aimed to elucidate the fundamental growth modes of Candida in the vagina of patients with RVVC or sporadic vulvovaginal candidiasis (VVC) and to assess their roles in the persistence of RVVC. MethodsVaginal tissues were sampled from twelve patients clinically and microbiologically diagnosed as RVVC or VVC at a post-antifungal-treatment and asymptomatic period. High-resolution scanning electron microscopy, fluorescence in situ hybridization in combination with Candida-specific 18S rRNA probes and viable fungal burden were used to qualitatively and quantitatively evaluate Candida growth in the human vagina. The presence of Candida biofilm extracellular polymeric substances was examined using confocal laser scanning microscopy and biopsy sections pre-stained with Concanavalin A. Histopathological analysis was carried out on infected vaginal tissues stained with hematoxylin and eosin. Lastly, the susceptibility of epithelium-associated Candida biofilms to fluconazole at the peak serum concentration was evaluated. ResultsCandida species grew on the vaginal epithelium of RVVC patients as morphologically disparate biofilms including monolayers, microcolonies, and macro-colonies, in addition to sporadic adherent cells. Candida biofilm growth on the vaginal epithelium was associated with mild lymphocytic infiltration of the vaginal mucosa. These epithelium-based Candida biofilms presented an important characteristic contributing to the persistence of RVVC that is the high tolerance to fluconazole. ConclusionsIn summary, our study provides direct evidence to support the presence of Candida biofilms in RVVC and an important role of biofilm formation in disease persistence.

Selection of Nemolizumab Clinical Dosage for Atopic Dermatitis.

Nemolizumab is a monoclonal antibody directed against the interleukin-31 receptor A subunit, which is involved in the pathogenesis of pruritus and inflammation in atopic dermatitis (AD). Clinical trial results were combined with population PK (popPK) and pharmacokinetic/ pharmacodynamic (PK/PD) models to optimize nemolizumab dosing. Phase 1 and 2a clinical studies indicated that weight-based nemolizumab dosing reduced pruritus in patients with moderate-to-severe AD with good safety and tolerability even at the highest dose (3 mg/kg single dose and 2 mg/kg multiple doses). Nemolizumab PK profile was characterized by a slow absorption with peak serum concentrations reached 4.5-9.2 days post-dose, and a long terminal half-life ranging from 12.6 to 16.5 days. A change from weight-based dosing to flat dose was supported by an additional phase 2b study sponsored by Galderma. Flat dosing provides several practical advantages, including ease of preparation for self- or auto-injection and reduced chance of dosing errors. Doses of 10, 30, and 90 mg were selected based on popPK and PK/PD simulations to result in nemolizumab serum concentrations sufficient to achieve efficacy. Loading doses were administrated at the 2 lower doses in order to achieve target systemic concentrations from the first injection. The efficacy of Nemolizumab in improving cutaneous signs of inflammation and pruritus in AD and its safety profile, combined with popPK and PK/PD analyses, supported selection of the flat-dose regimen of 30 mg (with a 60 mg loading dose) given every 4 weeks subcutaneously for 16 weeks in the phase 3 ARCADIA studies sponsored by Galderma. J Drugs Dermatol. 2023;22(10):1017-1020 doi:10.36849/JDD.7437R1.

Altered State of Consciousness and Mental Imagery as a Function of N, N-dimethyltryptamine Concentration in Ritualistic Ayahuasca Users.

Consumption of the psychedelic brew ayahuasca is a central ritualistic aspect of the Santo Daime religion. The current observational, baseline controlled study was designed to assess whether members (n = 24) of the Santo Daime church would show enhanced capacity for mental imagery during an ayahuasca experience. In addition, this study assessed whether the effects of ayahuasca on consciousness and mental imagery were related to peak serum concentration of N, N-dimethyltryptamine (DMT), the main psychoactive component. Measures of altered states of consciousness (5-Dimensional Altered States of Consciousness Questionnaire) and ego dissolution (Ego Dissolution Inventory [EDI]) as well as measures of mental imagery (visual perspective shifting, vividness of visual imagery, cognitive flexibility, associative thinking) were taken on 2 subsequent days on which members of Santo Daime were sober or drank a self-selected volume of ayahuasca. Measures of altered states of consciousness revealed that feelings of oceanic boundlessness, visual restructuralization, and EDI increased most prominently after drinking and shared a positive correlation with peak DMT concentration. Measures of mental imagery did not noticeably differ between the baseline and ayahuasca condition, although subjective ratings of cognitive flexibility were lower under ayahuasca. Two measures related to mental imagery, that is, perspective shifts and cognitive flexibility, were significantly correlated to peak DMT concentrations. Peak concentrations of DMT and other alkaloids did not correlate with ayahuasca dose. These findings confirm previous notions that the primary phenomenological characteristics of ayahuasca are driven by DMT. Compensatory or neuroadaptive effects associated with long-term ayahuasca intake may have mitigated the acute impact of ayahuasca in Santo Daime members on mental imagery.

Single-agent activity of the anti-GD2 antibody dinutuximab beta given as a long-term infusion in relapsed and refractory neuroblastoma (APN311-304).

10034 Background: Severe pain is a common side effect associated with short-term infusions of anti-GD2 antibodies in combination with cytokines and isotretinoin and was reduced by the long-term infusison (LTI) strategy. We investigated efficacy and tolerability of a single-agent dinutuximab beta (DB)-LTI in patients with primary refractory or relapsed (R/R) stage 4 neuroblastoma (NB). Methods: Patients with R/R-NB were enrolled into an open label phase II trial. Previous anti-GD2 antibody therapies were allowed, if anti-DB antibody could not be detected. Patients received 5 cycles of DB-LTI (100 mg/m2/10 days). The primary endpoint was objective INRC response 24 weeks after the end of cycle 5. A sample size of 40 patients provides at least 80% power to reject the null hypothesis of an objective response in &lt; 10% of patients if the true objective response rate observed was 25% (overall 1-sided significance level 0.05, exact binomial test). Secondary endpoints included safety, morphine use, best response and duration of response, pharmacodynamics and pharmacokinetics, 3-year progression-free (PFS) and overall survival (OS). Results: 40 patients were treated and 38 patients had evaluable response. The objective response rate 24 weeks after the end of cycle 5 was 26% (10/38) (CR/PR) (p = 0.0034) and 32% (12/38) (CR/PR/MR), with a higher response rate in refractory vs. relapsed patients (50% vs 25%; p = 0.0159). The best response rate was 53% (20/38). Of 14 patients with bone marrow involvement, 13 patients responded (93%) (12 CR, 1 PR). The median duration of response (CR/PR) was 238 days (95% CI [108-290d]). The 3-year probability of PFS was 31% (95% CI [0.17–0.47]) and of OS was 66% (95% CI [0.47–0.79]). Survival was higher for patients with refractory compared to relapsed disease (PFS 47% vs 19%, OS 93% vs 50%; p = 0.015). Grade 3 treatment emergent adverse events (TEAE) were pain (18%), diarrhea (5%), and hypokalemia (5%) and grade 3 hypotension, capillary leak and neurotoxicity were not observed. In patients who experienced pain, mean pain scores (scale 0–10, where 0 is no pain) were low and decreased between cycles 1 and 2: pain score at rest decreased from 1.01 to 0.30, and at stress from 1.45 to 0.28. There were no grade 4 or 5 TEAEs. The morphine usage decreased from cycle 2 to 5 (C2 95%; C3 12%; C4 0%; C5 0%). DB peak serum concentration in cycle 1 was 10.8±0.7 µg/ml and patients showed 7- and 11-fold increase of antibody-dependent cell-mediated (ADCC) and complement-dependent cytotoxicity (CDC), respectively. Anti-DB antibodies were found in 24% of patients. There was no association and no trend between exposure to DB (area under the curve, peak ot trough level) and response rate or survival in this cohort. Conclusions: Single-agent treatment with single agent dinutuximab beta given as long LTI without cytokines and without isotretinoin is effective and highly tolerable in R/R-NB. Clinical trial information: NCT02743429 .

Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration.

Mycobacterium tuberculosis (M.tb) has infected one-quarter of the world's population and led to the deaths of 1.6 million individuals in 2021 according to estimates from the World Health Organization. The rise in prevalence of multidrug-resistant and extensively drug-resistant M.tb strains coupled with insufficient therapies to treat such strains has motivated the development of more effective treatments and/or delivery modalities. Bedaquiline, a diarylquinoline antimycobacterial agent, effectively targets mycobacterial ATP synthase but may lead to systemic complications upon oral delivery. Targeted delivery of bedaquiline to the lungs represents an alternative strategy to harness the sterilizing benefits of the drug against M.tb while mitigating off-target side effects. Two pulmonary delivery modalities were developed herein, including dry powder inhalation and liquid instillation. Despite bedaquiline's poor water solubility, spray drying was performed in predominantly aqueous conditions (≥80%) to avoid a closed-loop, inert system. Aerosols of spray-dried bedaquiline with L-leucine excipient outperformed spray-dried bedaquiline alone, demonstrating superior fine particle fraction metrics (~89% of the emitted dose below <5 µm), suitable for inhalation therapies. Furthermore, the use of a 2-hydroxypropyl-β-cyclodextrin excipient allowed a molecular dispersion of bedaquiline in an aqueous solution for liquid instillation. Both delivery modalities were successfully administered to Hartley guinea pigs for pharmacokinetic analysis and were well-tolerated by the animals. Intrapulmonary liquid delivery of bedaquiline led to adequate serum absorption and appropriate peak serum concentrations of the drug. The liquid formulation was superior in systemic uptake compared to the powder formulation. The predominant route via which M.tb bacilli enter the body is aerosol droplets that are deposited onto airway surfaces. For this reason, we believe that further studies should focus on inhalation or intrapulmonary therapies that target the site of entry and primary site of infection for M.tb.