Quantification of sertraline maternal/fetal ratio and amniotic fluid concentration using a pregnancy physiologically based pharmacokinetic model.

AIMS: Selective serotonin reuptake inhibitors (SSRIs) are indicated for a variety of psychiatric conditions which may require treatment during pregnancy. Knowledge of appropriate SSRI dosages that maintain maternal therapeutic benefit and minimize fetal risk are needed. Assessment of fetal exposure to drugs is challenging since sampling is often limited to a single concentration from the umbilical cord at delivery. Physiologically based pharmacokinetic (PBPK) modelling provides a non-invasive approach to quantify exposure in pregnancy. METHODS: We incorporated sertraline clearances mediated by passive diffusion, placental efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) into our previously published pregnancy PBPK model for sertraline. Simulations were performed for various sertraline doses (25-200 mg) at 40 weeks gestational age to predict the minimum (Cmin ), maximum (Cmax ) and average (Cavg ) sertraline maternal and fetal plasma concentrations and evaluated them against observed maternal and cord concentrations obtained at delivery from five clinical studies. RESULTS: The accuracy of the PBPK predictions as indicated by the average fold error (AFE) value for Cmax , Cmin and Cavg for maternal plasma sertraline concentrations at delivery was 1.7, 1.2 and 1.4, respectively. The AFE for the Cmax , Cmin and Cavg for cord blood sertraline concentration at delivery was 1.2, 1 and 1.1, respectively. The AFE for cord-maternal sertraline concentration ratio at delivery for Cmax , Cmin and Cavg was 0.7, 0.9 and 0.8, respectively. CONCLUSIONS: The PBPK model we developed may serve as a guide for maternal sertraline dose adjustment during pregnancy considering changes in exposures for both mother and fetus.

Digital screening and brief intervention for alcohol misuse in college students: A pilot, mixed-methods, cluster randomized controlled trial from a low-resourced setting.

INTRODUCTION: We examined the feasibility and acceptability of digital screening and brief intervention (d-SBI) for alcohol misuse in college students; the effectiveness of d-SBI was our secondary outcome. We also explored the barriers and facilitators of d-SBI. METHODS: The study design is a mixed-methods, pilot, and cluster randomized trial. Five colleges from a northern city in India were randomly allocated to d-SBI and control groups. One hundred and ninety-one students were screened, and 25 (male = 23 and female = 2) participants (age 19.62 ± 2.58 years) fulfilled eligibility. All participants completed follow-up assessments at 3 months. In-depth interviews were done with 11 participants. Alcohol Use Disorder Identification Test (AUDIT) based screening brief intervention was provided on a web portal- or mobile application in the d-SBI group. The control group received digital screening and brief education. Direct questions and usage statistics assessed the measurement acceptability of the intervention. We compared the change in AUDIT scores in the intervention groups over 3 months post-intervention. Thematic analyses of transcripts of interviews were done by inductive coding. RESULTS: Most participants reported that d-SBI was user-friendly (80%), advice was appropriate (80%), and perceived it to be useful (72%). Ninety-six percent of users, who logged in, completed screening. There was a significant decrease in AUDIT scores both in d-SBI (p < .001) and control groups (p < .001). Time and group significantly affected the mean AUDIT score, but time × group interaction was non-significant. Thematic analysis revealed six overarching themes. CONCLUSIONS: Digital SBI for alcohol misuse is acceptable, feasible, and possibly effective among college students from low-resource settings.

Digital screening and brief intervention for illicit drug misuse in college students: A mixed methods, pilot, cluster, randomized trial from India.

BACKGROUND: Adolescence and early adulthood are vulnerable periods for substance use-related disorders later in life. The use of internet-enabled interventions can be useful, especially in low-resource settings. AIMS: To examine the feasibility, acceptability, and preliminary effectiveness of single-session digital screening and brief intervention (d-SBI) for illicit drug misuse in college students and explore barriers and facilitators of d-SBI. METHODS: Design: Mixed-methods, pilot cluster randomized trial. SETTING: Four conveniently selected colleges were randomized into intervention and control groups. PARTICIPANTS: 219 students were screened, and 37 fulfilled eligibility. Twenty-four completed follow-ups. In-depth interviews were done with ten students. Intervention and Comparator: Following a digital screening, Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) based brief intervention was provided in the d-SBI group. The control group received brief education. MEASUREMENTS: Acceptability was assessed by direct questions and usage statistics. ASSIST scores of groups were assessed at baseline and 3 months. Inductive coding of the interview transcript was done. RESULTS: More than 50 % of participants found d-SBI user-friendly, appropriate, and useful. Eighty percent of users, who logged in, completed screening. Per-protocol analysis showed a reduction in cannabis-ASSIST score over 3 months. The mean ASSIST score for other drugs combined did not differ significantly between groups. The difference in risk transition (moderate to low) was not significant. Qualitative analysis revealed three overarching themes- recruitment, engagement, and behavior change. CONCLUSIONS: Digital SBI for drug misuse is feasible among college students. d-SBI might be effective in reducing cannabis use.

Regulation of renal calbindin expression during cisplatin-induced kidney injury.

Since the discovery of calbindin release into the urine during renal injury, there has been growing interest in the utility of this protein as a biomarker of nephrotoxicity. However, little is known about the intrarenal regulation of the release and expression of this calcium-regulating protein during kidney injury. We sought to characterize the time-dependent expression and excretion of the protein calbindin in the distal tubule in comparison to kidney injury molecule-1 (Kim-1), a protein in the proximal tubule, in mice treated with cisplatin. Urine, blood, and kidneys were collected from male C57BL/6 mice treated with vehicle or cisplatin (20 mg/kg ip). Urinary concentrations of calbindin and Kim-1 were elevated by 11.6-fold and 2.5-fold, respectively, within 2 days after cisplatin. Circulating creatinine and blood urea nitrogen levels increased in cisplatin-treated mice by 3 days, confirming the development of acute kidney injury. Time-dependent decreases in intrarenal calbindin protein were observed on Days 3 and 4 and a 200-fold upregulation of calbindin (CALB1) and KIM-1 messenger RNAs (mRNAs) was observed on Day 3. These data suggest that early loss of calbindin protein into the urine along with declines in renal calbindin levels initiates a compensatory induction of mRNA expression at later time points (Days 3 and 4). Understanding the regulation of calbindin during cisplatin nephrotoxicity further enhances its utility as a potential urinary biomarker of kidney damage. The results of the current study support the combined use of a proximal (Kim-1) and distal tubule (calbindin) marker to phenotype acute kidney injury secondary to cisplatin administration.

Time-dependent changes in kidney injury biomarkers in patients receiving multiple cycles of cisplatin chemotherapy.

Proteins secreted into urine following tubular injury are being increasingly used as biomarkers of clinical and subclinical nephrotoxicity. In the present study, we sought to characterize the time-dependent urinary excretion of three promising biomarkers, kidney injury molecule-1 (KIM-1), calbindin, and trefoil factor 3 (TFF3), during two different chemotherapy cycles in 27 patients with solid tumors prescribed the anticancer drug cisplatin (≥25 mg/m2). Urinary biomarkers were evaluated at Days 3 and 10 during an initial and a subsequent cycle of cisplatin chemotherapy. Longitudinal analyses compared the mean difference estimations for biomarker concentrations during and across the initial and subsequent cycles of cisplatin treatment. Traditional biomarkers including serum creatinine, estimated glomerular filtration rate, and blood urea nitrogen were unchanged during and across both cycles of cisplatin therapy. In response to the initial cycle, urinary KIM-1 concentrations increased from baseline and remained elevated through a subsequent cycle of cisplatin chemotherapy. By comparison, urinary levels of calbindin were elevated 10 days after the initial cisplatin treatment, but largely unchanged by cisplatin exposure in a subsequent cycle. Early elevations in urinary TFF3 at 3 days after cisplatin administration were observed consistently in both the initial and subsequent cycle of cisplatin treatment. In conclusion, the longitudinal assessment of biomarker performance in the same cohort of oncology patients reveals different patterns of urinary excretion between initial and subsequent cycles of cisplatin-containing chemotherapy. These data add novel cycle-dependent insight to the growing literature addressing the ability of urinary biomarkers to detect subclinical renal injury in patients receiving cisplatin.

Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients.

PURPOSE: The ability to predict and detect clinical and subclinical nephrotoxicity early in the course of therapy has the potential to improve long-term outcomes in cancer patients receiving cisplatin chemotherapy. Pharmacokinetic parameters could serve as predictors of cisplatin-induced nephrotoxicity. METHODS: Participants [n = 13] were treated with a 1-h cisplatin infusion [30-75 mg/m2]. Blood was collected pre-dose and up to 6 h post-dose. Urinary biomarkers [KIM-1, calbindin, clusterin, GST-pi, ß2M, albumin, NGAL, osteopontin, clusterin, MCP-1, cystatin C, and TFF3] were measured at baseline, days 3 and 10. Total and unbound platinum concentrations were measured using ICP/MS. Noncompartmental analysis was performed, and correlation and regression analyses evaluated the relationships between platinum pharmacokinetics and nephrotoxicity. RESULTS: Peak platinum urinary concentrations correlated with urinary levels of KIM-1, calbindin, clusterin, GST-pi, ß2M, albumin, NGAL, osteopontin, clusterin, cystatin C, and TFF3 at day 10. Unbound platinum plasma concentrations at 2 h also correlated with urinary clusterin, ß2M, cystatin C, NGAL, osteopontin, and TFF3 at day 3. Regression analyses suggested 2-h total plasma platinum concentrations greater than 2000 ng/ml, and peak urinary platinum concentrations above 24,000 ng/ml may serve as potential approximations for elevated risk of nephrotoxicity. Platinum area under the plasma concentration time curve was associated with serum creatinine and estimated glomerular filtration rate. CONCLUSIONS: Peak plasma and urinary platinum concentrations and pharmacokinetic parameters were associated with risk of subclinical cisplatin-induced kidney injury as assessed using novel urinary biomarkers. Future studies will examine these relationships in larger clinical populations of cisplatin-induced acute kidney injury.

Urinary protein biomarkers of kidney injury in patients receiving cisplatin chemotherapy.

Despite recent progress in the development of novel approaches to treat cancer, traditional antineoplastic drugs, such as cisplatin, remain a mainstay of regimens targeting solid tumors. Use of cisplatin is limited by acute kidney injury, which occurs in approximately 30% of patients. Current clinical measures, such as serum creatinine and estimated glomerular filtration rate, are inadequate in their ability to detect acute kidney injury, particularly when there is only a moderate degree of injury. Thus, there is an urgent need for improved diagnostic biomarkers to predict nephrotoxicity. There is also interest by the U.S. Food and Drug Administration to validate and implement new biomarkers to identify clinical and subclinical acute kidney injury in patients during the drug approval process. This minireview provides an overview of the current literature regarding the utility of urinary proteins (albumin, beta-2-microglobulin, N-acetyl-D-glucosaminidase, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and cystatin C) as biomarkers for cisplatin-induced AKI. Many of the well-studied urinary proteins (KIM-1, NGAL, B2M, albumin) as well as emerging biomarkers (calbindin, monocyte chemotactic protein-1, and trefoil factor 3) display distinct patterns of time-dependent excretion after cisplatin administration. Implementation of these biomarker proteins in the oncology clinic has been hampered by a lack of validation studies. To address these issues, large head-to-head studies are needed to fully characterize time-dependent responses and establish accurate cutoff values and ranges, particularly in cancer patients. Impact statement There is growing interest in using urinary protein biomarkers to detect acute kidney injury in oncology patients prescribed the nephrotoxic anticancer drug cisplatin. We aim to synthesize and organize the existing literature on biomarkers examined clinically in patients receiving cisplatin-containing chemotherapy regimens. This minireview highlights several proteins (kidney injury molecule-1, beta-2-microglobulin, neutrophil gelatinase-associated lipocalin, calbindin, monocyte chemotactic protein-1, trefoil factor 3) with the greatest promise for detecting cisplatin-induced acute kidney injury in humans. A comprehensive review of the existing literature may aid in the design of larger studies needed to implement the clinical use of these urinary proteins as biomarkers of kidney injury.

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin.

Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI.

Profiling of Kidney Injury Biomarkers in Patients Receiving Cisplatin: Time-dependent Changes in the Absence of Clinical Nephrotoxicity.

The success of cisplatin-containing regimens to treat solid tumors is limited, in part, by nephrotoxicity. In rodents, several urinary proteins have emerged that are sensitive indicators of cisplatin-induced kidney injury. We sought to characterize time-dependent changes in the urinary concentrations of 12 proteins, including kidney injury molecule-1 (KIM-1), calbindin, beta 2-microglobulin (ß2M), and trefoil factor 3 (TFF3) after cisplatin therapy. Urine was collected at baseline, 3 days (range, 2-5 days), and 10 days (range, 9-11 days) from 57 patients with solid tumors receiving outpatient cisplatin therapy (≥25 mg/m2 ). Serum creatinine was largely unchanged after cisplatin infusion. However, compared with baseline values, several novel biomarkers were significantly increased in the urine, including ß2M, which was threefold higher by day 3 (P < 0.0001). Urinary KIM-1 and TFF3 were elevated twofold by day 10 (P = 0.002 and P = 0.002, respectively), whereas calbindin levels were increased eightfold (P < 0.0001). We report novel time-dependent changes in the urinary excretion of noninvasive markers of subclinical kidney injury after cisplatin treatment.

Role of NOS2 in pulmonary injury and repair in response to bleomycin.

Nitric oxide (NO) is derived from multiple isoforms of the Nitric Oxide Synthases (NOSs) within the lung for a variety of functions; however, NOS2-derived nitrogen oxides seem to play an important role in inflammatory regulation. In this study, we investigate the role of NOS2 in pulmonary inflammation/fibrosis in response to intratracheal bleomycin instillation (ITB) and to determine if these effects are related to macrophage phenotype. Systemic NOS2 inhibition was achieved by administration of 1400W, a specific and potent NOS2 inhibitor, via osmotic pump starting six days prior to ITB. 1400W administration attenuated lung inflammation, decreased chemotactic activity of the broncheoalveolar lavage (BAL), and reduced BAL cell count and nitrogen oxide production. S-nitrosylated SP-D (SNO-SP-D), which has a pro-inflammatory function, was formed in response to ITB; but this formation, as well as structural disruption of SP-D, was inhibited by 1400W. mRNA levels of IL-1ß, CCL2 and Ptgs2 were decreased by 1400W treatment. In contrast, expression of genes associated with alternate macrophage activation and fibrosis Fizz1, TGF-ß and Ym-1 was not changed by 1400W. Similar to the effects of 1400W, NOS2-/- mice displayed an attenuated inflammatory response to ITB (day 3 and day 8 post-instillation). The DNA-binding activity of NF-κB was attenuated in NOS2-/- mice; in addition, expression of alternate activation genes (Fizz1, Ym-1, Gal3, Arg1) was increased. This shift towards an increase in alternate activation was confirmed by western blot for Fizz-1 and Gal-3 that show persistent up-regulation 15 days after ITB. In contrast arginase, which is increased in expression at 8 days post ITB in NOS2-/-, resolves by day 15. These data suggest that NOS2, while critical to the development of the acute inflammatory response to injury, is also necessary to control the late phase response to ITB.