Macrophage uptake rate of Sonazoid in breast lymphosonography is highly conserved in healthy controls.

Subcutaneous microbubble administration in connection with contrast enhanced ultrasound (CEUS) imaging is showing promise as a noninvasive and sensitive way to detect tumor draining sentinel lymph nodes (SLNs) in patients with breast cancer. Moreover, there is potential to harness the results from these approaches to directly estimate cancer burden, since some microbubble formulas, such as the Sonazoid used in this study, are rapidly phagocytosed by macrophages, and the macrophage concentration in a lymph node is inversely related to the cancer burden. This work presents a mathematical model that can approximate a rate constant governing macrophage uptake of Sonazoid,ki, given dynamic CEUS Sonazoid imaging data. Twelve healthy women were injected with 1.0 ml of Sonazoid in an upper-outer quadrant of one of their breasts and SLNs were imaged in each patient immediately after injection, and then at 0.25, 0.5, 1, 2, 4, 6, and 24 h after injection. The mathematical model developed was fit to the dynamic CEUS data from each subject resulting in a mean ± sd of 0.006 ± 0.005 h-1and 0.4 ± 0.1 h-1for relative lymphatic flow (EFl) andki, respectively. Furthermore, the roughly 25% sd of thekimeasurement was similar to the sd that would be expected from realistic noise simulations for a stable 0.4 h-1value ofki, suggesting that macrophage concentration is highly consistent among cancer-free SLNs. These results, along with the significantly smaller variance inkimeasurement observed compared to relative lymphatic flow suggest thatkimay be a more precise and promising approach of estimating macrophage abundance, and inversely cancer burden. Future studies comparing tumor-free to tumor-bearing nodes are planned to verify this hypothesis.

Intracellular islatravir-triphosphate half-life supports extended dosing intervals.

Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t½) of 3.0 and 8.7 days (72 and 209 hours, respectively); therefore, islatravir is being investigated as a long-acting oral antiretroviral agent. A study was conducted to definitively elucidate the terminal t½ of islatravir and its active form islatravir-triphosphate (islatravir-TP). A single-site, open-label, non-randomized, single-dose phase 1 study was performed to evaluate the pharmacokinetics and safety of islatravir in plasma and the pharmacokinetics of islatravir-TP in peripheral blood mononuclear cells after administration of a single oral dose of islatravir 30 mg. Eligible participants were healthy adult males without HIV infection between the ages of 18 and 65 years. Fourteen participants were enrolled. The median time to maximum plasma islatravir concentration was 1 hour. Plasma islatravir concentrations decreased in a biphasic manner, with a t½ of 73 hours. The t½ (percentage geometric coefficient of variation) of islatravir-TP in peripheral blood mononuclear cells through 6 weeks (~1008 hours) after dosing was 8.1 days or 195 hours (25.6%). Islatravir was generally well tolerated with no drug-related adverse events observed. Islatravir-TP has a long intracellular t½, supporting further clinical investigation of islatravir administered at an extended dosing interval.

Hydroxyurea in the sickle cell disease modern era.

INTRODUCTION: Sickle cell disease is an inherited disorder characterized by hemoglobin S polymerization leading to vaso-occlusion and hemolytic anemia. These result in a variety of pathological events, causing both acute and chronic complications. Millions around the world are affected by sickle cell disease with predominance in sub-Saharan Africa. Hydroxyurea was the first drug approved for use in sickle cell disease to reduce the occurrence of painful crises and blood transfusions in patients with frequent, moderate to severe painful crises. AREAS COVERED: With the development of new therapeutics, the role of hydroxyurea is evolving. This narrative review aims to provide clinical data, safety information, and supplementary evidence for the role of hydroxyurea in the current era of sickle cell disease. A comprehensive literature search of databases, including PubMed and Cochrane Library, was conducted from 1963 to 2024. EXPERT OPINION: Even though new medications have been approved for sickle cell disease, hydroxyurea remains the gold standard. Hydroxyurea is not only a disease modifier but it has additional clinical benefits, it is affordable, and its longevity has prompted expanded research in areas such as underutilization and pharmacogenomics. As the treatment landscape evolves, hydroxyurea's long-standing record of efficacy and safety continues to support its role as a key agent in disease management.

Azithromycin dosing and preterm premature rupture of membranes treatment (ADAPT): a randomized controlled Phase I trial.

BACKGROUND: Seven days of antibiotics are recommended in the setting of preterm premature rupture of membranes to promote latency. Azithromycin has generally replaced a 7-day course of erythromycin in current clinical practice. Azithromycin clears from plasma quickly and concentrates in local tissue, which is why daily dosing is not always needed, and local tissue, rather than plasma, concentrations are used to determine dosing. On the basis of limited pharmacokinetic studies in pregnancy, a 1-time dose of 1 g azithromycin may not maintain local (amniotic fluid) drug concentrations above minimum inhibitory concentrations for common genitourinary pathogens (50-500 ng/mL). OBJECTIVE: We aimed to compare the pharmacokinetics of 1-time vs daily dosing of azithromycin in the setting of preterm prelabor rupture of membranes. STUDY DESIGN: This is a randomized clinical trial of singletons with preterm prelabor rupture of membranes randomized to 1 g oral azithromycin once or 500 mg oral azithromycin daily for 7 days. The primary outcome was amniotic fluid azithromycin concentrations over 8 days. Secondary outcomes included plasma azithromycin trough concentrations. Plasma was collected at 1-4 hours and 12-24 hours after the first dose and then every 24 hours through 8 days. Amniotic fluid was collected opportunistically throughout the day noninvasively with Always Flex foam pads. We aimed to enroll 20 participants to achieve n=5 still pregnant through 8 days in each group. Continuous variables were compared using the Mann-Whitney U test, and the relationship between azithromycin concentration and time was assessed using linear regression. RESULTS: The study was halted after 6 enrolled because of lagging enrollment, with 3 in each group. The mean gestational age of enrollment was 27.1±1.7 weeks in the 1 g group and 31.0±1.4 weeks in the 500 mg daily group. One participant in each group had latency to delivery >7 days. Regarding amniotic fluid azithromycin concentration, there was a difference in change in amniotic fluid azithromycin concentration over time between groups (P<.001). The amniotic fluid concentration of azithromycin was relatively stable in the 1 g once group (B,-0.07; 95% confidence interval, -0.44 to 0.31; P=.71), whereas amniotic fluid concentration (ng/mL) increased over time (hours) in the 500 mg daily group (B, 1.3; 95% confidence interval, 0.7-1.9; P<.001). By ≥96 hours, median amniotic fluid levels of azithromycin were lower in the 1 g once group (median, 11; interquartile, 7-56) compared with 500 mg daily (median, 46; interquartile, 23-196), with a median difference of -27 (interquartile,-154 to -1; P=.03). In plasma, there was higher azithromycin concentration during the first 24 hours with 1 g once vs 500 mg daily (median difference, 637 ng/mL; 101-1547; P=.01); however, by ≥96 hours plasma azithromycin declined and was virtually undetectable in the 1 g once group, whereas trough plasma levels in the 500 mg remained elevated (median difference -207 ng/mL; interquartile, -271 to -155; P=.03). CONCLUSION: Approximately 500 mg daily dosing of azithromycin maintains higher amniotic fluid concentrations and more consistently greater than common minimum inhibitory concentrations over 8 days compared with 1 g once in the setting of PPROM. El resumen está disponible en Español al final del artículo.

Buprenorphine vs. morphine: impact on neonatal opioid withdrawal syndrome (NOWS) outcomes in a single center retrospective study.

OBJECTIVES: To compare clinical outcomes for infants with neonatal opioid withdrawal syndrome (NOWS) treated with buprenorphine or morphine. STUDY DESIGN: Retrospective study of infants born ≥35 weeks' gestation and admitted to the NICU for NOWS treatment between 2011 and 2022. Length of treatment, length of stay in the hospital, and the need for secondary medications were compared between buprenorphine and morphine treated neonates. Multiple regression analysis was performed, adjusting for baseline differences and confounders. RESULTS: 417 neonates were treated with morphine and 232 with buprenorphine. The buprenorphine group had shorter treatment days [-10.8 days; 95% CI: -8.08 to -13.53] and shorter hospital stay [-11.8 days; 95% CI: -8.83 to -14.78]. The buprenorphine group was no more likely to receive phenobarbital or clonidine (26% vs. 29%). CONCLUSION: In this large single-center study, buprenorphine was associated with shorter lengths of treatment and hospital stay in the treatment of NOWS compared to morphine.

Pharmacokinetics of apixaban in patients undergoing pancreaticoduodenectomy (PAP-UP).

OBJECTIVE: The impact of pancreaticoduodenectomy on absorption of drugs in the duodenum remains largely unknown. We aim to characterize the pharmacokinetics of apixaban in patients who had previously undergone pancreaticoduodenectomy. MATERIALS AND METHODS: A single 10-mg dose of apixaban was administered to 4 volunteers who underwent pancreaticoduodenectomy at least 6 months prior. The maximum plasma apixaban concentration (Cmax) and area under the plasma concentration time-curve (AUC0-24, AUC0-inf) were compared against healthy historical control subjects (N = 12). Geometric mean ratios (GMR) with 90% confidence interval (CI) were calculated for determination of comparative bioequivalence. RESULTS: In pancreaticoduodenectomy patients, AUC0-24 and AUC0-inf were 1,861 and 2,080 ng×h/mL, respectively. The GMRs of AUC0-24 and AUC0-inf between study subjects and healthy controls were 1.27 (90% CI 0.88 - 1.83) and 1.18 (90% CI 0.82 - 1.72). The mean Cmax of apixaban was 201 ng/mL (SD 15.6) occurring at a median tmax of 3.25 hours (range 2.5 - 4 hours). The GMR of Cmax between study subjects and healthy controls was 1.12 (90% CI 0.77 - 1.63). CONCLUSION: The pharmacokinetic characteristics of apixaban in subjects who had undergone pancreaticoduodenectomy are not significantly different from those of healthy controls. Though the sample size of this study is small, results suggest that no change to apixaban dose regimen is needed in patients who have had a pancreaticoduodenectomy.

The Bioavailability of CHF6563, an Ethanol-Free, Sublingual Neonatal Buprenorphine Formulation: A Bridging Study Conducted in Adults.

OBJECTIVE: Sublingual buprenorphine has demonstrated efficacy for treatment of the neonatal opioid withdrawal syndrome (NOWS), but the current formulation used in clinical practice contains 30% ethanol. Ethanol as a pharmacologically active excipient ideally should be removed from neonatal formulations. The objective of this study was to determine the relative bioavailability of a novel ethanol-free -formulation (CHF6563) compared with the commonly used ethanolic solution in a phase I, open-label, 2-period, -single-dose, crossover study in healthy adults. METHODS: Eighteen adult opioid-naïve volunteers were administered one of the formulations in a randomized crossover treatment. After a 10-day washout period, subjects received the other formulation. Serial blood samples were drawn for pharmacokinetic analysis over 48 hours. RESULTS: The geometric mean ratio (90% CIs) of the ethanol-free buprenorphine solution AUC0-last was 0.80 (0.65-0.99) and Cmax was 0.81 (0.66-0.99) compared with reference ethanolic formulation. The -ethanol-free formulation had a greater degree of intersubject variability than the ethanol-containing -reference formulation (coefficient of variation of 59% vs 31.5%, respectively, for AUC0-last). CONCLUSIONS: In an adult population, a novel ethanol-free formulation of buprenorphine containing widely used excipients demonstrated a slight decrease in bioavailability when compared with an ethanolic solution. These results will inform those seeking to develop ethanol-free pediatric drug formulations.

Bidirectional pharmacokinetics of doravirine, tenofovir, and feminizing hormones in transgender women (IDentify): A randomized crossover trial.

Transgender women may have concerns of drug interactions between feminizing hormone therapy (FHT) and antiretrovirals, leading to nonadherence. This randomized, three-period crossover, open-label, phase I trial assessed the effects of doravirine (DOR) and tenofovir disoproxil fumarate (TDF) on the pharmacokinetics (PKs) of estradiol, spironolactone, and total testosterone and vice versa in healthy transgender women. Volunteers were randomized 1:1 into two sequences containing three treatment groups (DOR, lamivudine [3TC], and TDF alone; estradiol, spironolactone, and placebo; and DOR/3TC/TDF, estradiol, and spironolactone). Eight subjects enrolled in the study and six had completed all study periods. The geometric mean ratios for DOR area under the concentration-time curve from zero to last measured concentration (AUC0-last ), maximum concentration (Cmax ), and concentration at 24 h (C24 ) were similar. However, tenofovir (TFV) AUC0-last , Cmax , and C24 moderately increased by 14%-38%. Last, estradiol AUC0-last , Cmax , and C24 were increased by 10%-13%. Whereas most 90% confidence intervals did not meet the bioequivalence bounds of 80%-125%, the point estimates fell within the intervals. Log-transformed DOR, TFV, and estradiol PK parameters computed with and without co-administration were not statistically different (p > 0.05). There were no serious adverse events. There is not a clinically significant impact of FHT on DOR/TFV PKs. Similarly, there is no observed impact on estradiol PKs and total testosterone following use of DOR/3TC/TDF.

Abstinence scoring algorithms for treatment of neonatal opioid withdrawal syndrome (NOWS).

OBJECTIVE: Chervoneva et al. (2020) developed an abbreviated score (sMNAS-9) derived from full modified Finnegan MOTHER NAS scale (MNAS) for evaluating severity of NOWS. We sought to develop NOWS treatment algorithms for clinical decision rules based on scores utilizing the shorter sMNAS. STUDY DESIGN: This was a retrospective study of 373 infants with NOWS scored with MNAS and treated with morphine between 2007 and 2016. The infants were randomly split into training/test sets. The training set was used to derive optimized cutoff values for sMNAS-9 scores. The independent set evaluated the sMNAS-9 clinical decision rules based on full MNAS in NOWS morphine and buprenorphine treatment algorithms. RESULT: Clinical decision rules based on sMNAS-9 yielded sensitivities of 88% or higher and specificities of 85% or higher for predicting the respective rules based on full MNAS. CONCLUSION: The sMNAS-9 scoring instrument is expected to yield similar clinical decisions in treatment of NOWS.

Aspirin pharmacokinetics and pharmacodynamics through gestation.

BACKGROUND: Low dose aspirin is recommended for prevention of preeclampsia, however there is not consensus on the appropriate dose. Pregnancy specific changes have the potential to impact the pharmacology of aspirin in pregnancy, however there are very limited studies on aspirin pharmacokinetics in pregnancy and none linking pharmacokinetics (PK, drug dose and drug level) to pharmacodynamics (PD, drug dose and physiologic response) in pregnancy. As a result, we do not have a good understanding of the pharmacologic response to aspirin in pregnancy, which has important implications for clinical efficacy. We sought to describe the PK and PD of aspirin through pregnancy and to identify individual covariates that impacted aspirin PK/PD. OBJECTIVE: We sought to describe the PK and PD of aspirin through pregnancy (first and third trimester), to identify covariates that significantly impact aspirin PK and to identify the relationship between aspirin PK and PD. STUDY DESIGN: This is a prospective study of patients at high risk for preeclampsia recommended to take 81 mg aspirin daily. This study involved 3 visits as follows: (1) baseline, first trimester (10-16 weeks of gestation) 6-hour PK visit, done before initiation of aspirin; (2) follow-up 1: 2 to 4 weeks after aspirin initiation; and (3) follow-up 2: third trimester 6-hour PK visit (28-32 weeks of gestation). The following were assessed at each visit: weight or body mass index, platelet function analysis-100 (Siemens), urinary thromboxane B2, serum thromboxane B2, and plasma salicylic acid. The PK visits consisted of blood work done at baseline (predose), administration of 81 mg nonenteric coated aspirin, and then plasma blood level of salicylic acid assessed at 30 minutes and then hourly 1 to 6 hours after dose. Pearson correlation and multivariable regression were used to identify associations between parameters and identify relevant covariates. Log-adjusted values were used for regression analysis. P<.05 was considered statistically significant. RESULTS: Nineteen participants were included with first trimester data, and 16 with third trimester data. There was no statistically significant change in mean PK parameters between the first and third trimester, although there was a trend to lower peak concentration in the third than in the first trimester (P=.08). In multivariable regression, baseline obesity and current body mass index as a continuous measures were negatively associated with log-adjusted peak salicylic acid concentration (-0.28 [-0.46 to -0.11], P=.003 and -0.02 [-0.03 to -0.009], P=.001, respectively) and log-adjusted plasma salicylic acid area under the curve 0 to 6 hours postdose (-0.25 [-0.45 to 0.05], P=.02, -0.04 [-0.07 to -0.01], P=.008 respectively). There was a significant decrease in urinary thromboxane 2 to 4 weeks after aspirin initiation compared with baseline, which correlated with a concomitant increase in platelet function analysis-100 closure time. In multivariable regression model, there was a strong association between plasma salicylic acid concentration (area under the curve 0-6 hours postdose) and urinary thromboxane (B=-3.12 [-5.38 to -1.04], P=.006), and with urinary thromboxane suppression and platelet inhibition, platelet function analysis-100 (-0.23 [-0.31 to -0.14], P<.001). With progressive thromboxane suppression, platelet inhibition (platelet function analysis-100 closure time) increased. Individual comorbidities, including weight, hypertension, and pregestational diabetes (Type I or II), also impacted aspirin response. CONCLUSION: We have demonstrated the relationship between individual factors, plasma concentrations of salicylic acid, thromboxane suppression, and platelet inhibition at a single dose (81 mg) of aspirin taken through pregnancy. Our findings suggest that dose modification of aspirin in pregnancy may help to achieve the optimal response. Our results may be used to facilitate computational modeling to identify optimal dosing, taking into consideration individual factors.

Ondansetron to reduce neonatal opioid withdrawal severity a randomized clinical trial.

OBJECTIVE: To determine if treatment with a 5-HT3 antagonist (ondansetron) reduces need for opioid therapy in infants at risk for neonatal opioid withdrawal syndrome (NOWS). STUDY DESIGN: A multicenter, randomized, placebo controlled, double blind clinical trial of ninety (90) infants. The intervention arms were intravenous ondansetron or placebo during labor followed by a daily dose of ondansetron or placebo in infants for five days. RESULTS: Twenty-two (49%) ondansetron-treated and 26 (63%) placebo-treated infants required pharmacologic treatment (p > 0.05). The Finnegan score was lower in the ondansetron-treated group (4.6 vs. 5.6, p = 0.02). A non-significant trend was noted for the duration of hospitalization. There was no difference in need for phenobarbital or clonidine therapy, or total dose of morphine in the first 15 days of NOWS treatment. CONCLUSIONS: Ondansetron treatment reduced the severity of NOWS symptoms; and there was an indication that it could reduce the length of stay. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01965704.

Platelet protease activated receptor 4 (PAR 4) receptor genotype is associated with an increased risk of preterm birth.

BACKGROUND: Platelet protease activated receptor-4 (PAR4) Thr120 is a common genetic variant associated with increased platelet activity. Increased platelet activity is implicated in the pathogenesis of preeclampsia and preterm birth. OBJECTIVE: Compare the rate of preeclampsia and preterm birth in pregnant individuals homozygous for PAR4 Thr120 variant vs not. STUDY DESIGN: This is a prospective cohort study of patients who delivered November 2020-July 2021. Maternal blood collected on admission for PAR4 genotyping. The primary outcome was the rate of preeclampsia/gestational hypertension in those with Thr/Thr genotype compared with Ala/Thr or Ala/Ala. Secondary outcomes included rates of preterm birth and placental pathology. RESULTS: Three hundred and twenty singletons were included and 52 (16.3%) were PAR4 Thr/Thr. Those PAR4 Thr/Thr were more likely to be Black (67.3% vs 29.5%, p < .001), younger (28 ± 6 vs 31 ± 6, p = .004), and have higher body mass index (35.2 ± 6.8 vs 33.1 ± 7.4, p = .047). There was no difference in preeclampsia/gestational hypertension (19.2% vs 22.8%, p = .705). Those Thr/Thr had a significantly higher rate of preterm birth (15.4% vs 3.7%, adjusted odds ratio [aOR] 4.04 [1.47-11.10], p = .007), indicated preterm birth because of fetal growth restriction or preeclampsia (5.8% vs 0.4%, aOR 10.03 [1.48-67.87], p = .02), spontaneous preterm birth (7.7% vs 2.2%, aOR 4.81 [1.27-18.27], p = .02), and placental intervillous thrombosis (18.5% vs 7.9%, aOR 4.12 [1.14-14.92], p = .03). CONCLUSION: Platelet receptor PAR4 Thr120 is a common variant associated with an increased risk of placental vascular pathology and preterm birth in homozygous individuals. Although a cohort study cannot establish causation, this strong association warrants further exploration.

Pharmacokinetics of apixaban and tacrolimus or cyclosporine in kidney and lung transplant recipients.

Apixaban is frequently used off-label in transplant recipients. However, a potential drug interaction exists with the calcineurin inhibitors. We conducted an open-label drug-drug interaction study to determine the pharmacokinetics of apixaban in lung and kidney transplant recipients who were taking a calcineurin inhibitor. A single dose of apixaban 10 mg was administered orally to kidney and lung transplant recipients maintained on either tacrolimus or cyclosporine, and pharmacokinetic parameters were compared to a reference cohort of 12 healthy subjects who used the same apixaban dose and pharmacokinetic blood sampling. Fourteen participants were enrolled (n = 6 kidney, n = 8 lung), with 10 maintained on tacrolimus and four on cyclosporine. Data from 13 participants was usable. Participants were taking triple therapy immunosuppression and had a mean (SD) of 12 (3) medications. Participants receiving tacrolimus and cyclosporine had area under the plasma concentration-time curve from time zero to infinity (AUC0-inf ) geometric least square means (90% confidence interval [CI]) of 4312 (95% CI 3682, 5049) and 5388 (95% CI 3277, 8858), respectively. Compared to healthy subjects, the associated geometric mean ratios (GMRs) for apixaban maximum plasma concentration (Cmax ), AUC from time zero to the last quantifiable concentration (AUC0-tlast ) and AUC0-inf were 197% (95% CI 153, 295), 244% (95% CI 184, 323), and 224% (95% CI 170, 295) for transplant recipients on tacrolimus. The GMR (90% CI) Cmax , AUC0-tlast , and AUC0-inf of apixaban for patients on cyclosporine were 256% (95% CI 184, 358), 287% (95% CI 198, 415), and 280% (95% CI 195, 401). Kidney and lung transplant recipients receiving tacrolimus had higher apixaban exposure. A similar trend was noted for patients receiving cyclosporine, but additional patients are needed to confirm this interaction. Future studies are needed before apixaban can be safely recommended in this population, and the impact of dose staggering should be investigated. This study highlights the importance of pharmacokinetic studies in actual patient populations.

Is Maternal Methadone Dose Associated with the Severity of Neonatal Abstinence Syndrome?

OBJECTIVE: The aim of the study is to assess the correlation between maternal methadone dose and severity of neonatal abstinence syndrome (NAS) in infants that required pharmacological treatment for NAS. STUDY DESIGN: This is a retrospective analysis of 574 infants ≥35 weeks' gestation exposed to methadone in utero, born between August 2006 and May 2018, and who required pharmacological therapy for NAS. Indicators of NAS severity (duration of morphine treatment, maximum morphine dose, use of phenobarbital, and length of hospitalization) were compared between infants exposed to high (≥200 mg), intermediate (100-199 mg), and low doses (<100 mg) of methadone. Logistic and linear regression models were used to adjust for the covariates. RESULTS: Median (interquartile range) duration of medical treatment with morphine was higher in infants exposed to higher doses of methadone (low dose 23 [14-37] days, intermediate dose 31 [18-45] days, and high dose 35 [20-48] days, p < 0.001). Higher methadone doses were also predictive of longer duration of hospitalization, higher maximum morphine dose, and increased likelihood of treatment with phenobarbital. The association between maternal methadone dose and the severity of NAS persisted in multivariable regression models. CONCLUSION: Infants exposed to higher methadone doses displayed more severe NAS, as indicated by longer durations of treatment, higher maximum morphine dose, longer duration of hospitalization, and increased likelihood of phenobarbital use. KEY POINTS: · Methadone maintenance therapy is used during pregnancy to control maternal withdrawal symptoms.. · Relationship between maternal methadone dose and severity of NAS is not adequately investigated.. · Increased doses of methadone during pregnancy correlate with increased severity of NAS..

Intraperitoneal pharmacokinetics of vancomycin in patients on automated peritoneal dialysis.

It is unclear if the pharmacokinetics of vancomycin are the same during automated peritoneal dialysis (APD), where cycler exchanges may affect the systemic, peritoneal, and urinary disposition of drug. We conducted a prospective pharmacokinetic study evaluating the pharmacokinetics of vancomycin in plasma, dialysis fluid, and urine in peritonitis-negative patients on APD. Patients underwent four drug-free exchanges with 1.5% or 2.5% dextrose following the initial dwell period. Plasma, dialysis fluid, and urine was collected over the course of 7 days for pharmacokinetic analysis. Four patients completed the study with no adverse events. Following a median (range) dwell of 14.6 (14.2-17.6 h), the mean (±SD) observed maximum plasma concentration was 28.7 ± 4.9 mg/L with a mean bioavailability of 98.5 ± 1.4% prior to starting the cycler. The overall mean total plasma clearance estimated from study start to completion was 7.6 ± 1.2 ml/min. Mean total clearance during the dialytic exchange was 13.6 ± 4.9 ml/min. In patients with residual renal function, the mean vancomycin renal clearance was 3.1 ± 1.5 ml/min, representing 21.4%-58.9% of the overall total plasma clearance during the study period. Despite the small sample size, this pilot study suggests that the dwell time has important implications for systemic vancomycin exposure, time to therapeutic plasma concentration, and dosing. Dose is driven by dwell time, whereas the cycler determines the dosing interval. Rapid exchanges from APD will determine the frequency of dosing rather than the adequacy of absorption when vancomycin is given in the peritoneum.

Neonatal opioid withdrawal syndrome: a review of the science and a look toward the use of buprenorphine for affected infants.

Neonates born to mothers taking opioids during pregnancy are at risk for neonatal opioid withdrawal syndrome (NOWS), for which there is no recognized standard approach to care. Nonpharmacologic treatment is typically used as a first-line approach for management, and pharmacologic treatment is added when clinical signs are not responding to nonpharmacologic measures alone. Although morphine and methadone are the most commonly used pharmacotherapies for NOWS, buprenorphine has emerged as a treatment option based on its pharmacologic profile and results from initial single site clinical trials. The objective of this report is to provide an overview of NOWS including a summary of ongoing work in the field and to review the state of the science, knowledge gaps, and practical considerations specific to the use of buprenorphine for the treatment of NOWS as discussed by a panel of experts during a virtual workshop hosted by the National Institutes of Health.

Apixaban Discontinuation for Invasive Or major Surgical procedures (ADIOS): A prospective cohort study.

Background: Apixaban pharmacokinetic properties and some clinical reports suggest cessation 48 hours prior to surgery is safe, but this has not been demonstrated in a naturalistic setting. We sought to measure the residual apixaban exposure in patients who had apixaban held as part of standard of care perioperative management. Methods: This was a prospective, observational study of patients in whom apixaban plasma concentration and anti-Xa activity were measured while at steady state apixaban dosing and again immediately prior to surgery. Clinical management of cessation and resumption of apixaban was at the discretion of the treating physician. Results: Paired blood samples were provided by 111 patients. Ninety-four percent (104/111) of patients had measured apixaban concentrations of ⩽ 30 ng/mL. Only one patient had a value > 50 ng/mL. The median time between the self-reported last dose and presurgery blood sampling was 76 hours (range 32-158) for those who achieved concentrations ⩽ 30 ng/mL and 59 hours (range 49-86) for those > 30 ng/mL. Measured anti-Xa activity correlated well with apixaban exposure. Clinically significant nonmajor bleeding was reported in one patient at 1 week postsurgery. There was one venous thromboembolic event and one stroke in the perioperative period. Conclusion: In a naturalistic setting with a heterogeneous patient population, apixaban discontinuation for at least 48 hours before a procedure resulted in a clinically insignificant degree of anticoagulation prior to a surgical procedure. ClinicalTrials.gov Identifier: NCT02935751.

Phase I double-blind, placebo-controlled trial of dolcanatide (SP-333) 27 mg to explore colorectal bioactivity in healthy volunteers.

Guanylyl cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of the luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Previous studies revealed that linaclotide, an oral GUCY2C agonist formulated for gastric release, did not persist to activate guanylyl cyclase signaling in the distal rectum. Dolcanatide is an investigational oral uroguanylin analog, substituted with select D amino acids, for enhanced stability and extended persistence to activate GUCY2C in small and large intestine. However, the ability of oral dolcanatide to induce a pharmacodynamic (PD) response by activating GUCY2C in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of oral dolcanatide 27 mg daily for 7 d to healthy volunteers did not activate GUCY2C, quantified as accumulation of its product cyclic GMP, in epithelial cells of the distal rectum. These data reveal that the enhanced stability of dolcanatide, with persistence along the rostral-caudal axis of the small and large intestine, is inadequate to regulate GUCY2C across the colorectum to prevent tumorigenesis. These results highlight the importance of developing a GUCY2C agonist for cancer prevention formulated for release and activity targeted to the colorectum.