Prediction of Kidney Drug Clearance: A Comparison of Tubular Secretory Clearance and Glomerular Filtration Rate.

BACKGROUND: Although proximal tubular secretion is the primary mechanism of kidney drug elimination, current kidney drug dosing strategies are on the basis of eGFR. METHODS: In a dedicated pharmacokinetic study to compare GFR with tubular secretory clearance for predicting kidney drug elimination, we evaluated stable outpatients with eGFRs ranging from 21 to 140 ml/min per 1.73 m2. After administering single doses of furosemide and famciclovir (metabolized to penciclovir), we calculated their kidney clearances on the basis of sequential plasma and timed urine measurements. Concomitantly, we quantified eight endogenous secretory solutes in plasma and urine using liquid chromatography-tandem mass spectrometry and measured GFR by iohexol clearance (iGFR). We computed a summary secretion score as the scaled average of the secretory solute clearances. RESULTS: Median iGFR of the 54 participants was 73 ml/min per 1.73 m2. The kidney furosemide clearance correlated with iGFR (r=0.84) and the summary secretion score (r=0.86). The mean proportionate error (MPE) between iGFR-predicted and measured furosemide clearance was 30.0%. The lowest MPE was observed for the summary secretion score (24.1%); MPEs for individual secretory solutes ranged from 27.3% to 48.0%. These predictive errors were statistically indistinguishable. Penciclovir kidney clearance was correlated with iGFR (r=0.83) and with the summary secretion score (r=0.91), with similar predictive accuracy of iGFR and secretory clearances. Combining iGFR with the summary secretion score yielded only modest improvements in the prediction of the kidney clearance of furosemide and penciclovir. CONCLUSIONS: Secretory solute clearance measurements can predict kidney drug clearances. However, tight linkage between GFR and proximal tubular secretory clearance in stable outpatients provides some reassurance that GFR, even when estimated, is a useful surrogate for predicting secretory drug clearances in such patients.

Company Characteristics, Disability Inclusion Practices, and Employment of People with Disabilities in the Post COVID-19 Job Economy: A Cross Sectional Survey Study.

Purpose In the post coronavirus disease 2019 (COVID-19) recession economy, rehabilitation counselors, transition specialists, and other disability service providers must redouble their efforts to connect with employers to create employment opportunities for people with physical and mental impairments. The purpose of the present study was to investigate company characteristics and effective disability inclusion practices that are related to employment of people with disabilities. Methods Four hundred sixty-six employers completed a demographic questionnaire and the Disability Inclusion Profiler. Results Results indicated company characteristics and disability practices were positively related to employment of people with disabilities. Conclusions Findings of the present study can be used by transition specialists, rehabilitation counselors, and other disability service providers to engage and connect with employers to increase employment opportunity for people with disabilities in the post COVID-19 economy. Future research and practice implications are provided.

Glove and instrument changing to prevent bacterial contamination in infected wound debridement and closure procedures: A prospective observational study.

Many surgeons use a single table of instruments for both excisional debridement and coverage/closure of infected wounds. This study investigates the effectiveness of a two-table set-up of sterile instruments, in addition to glove exchange, to reduce instrument cross-contamination during these procedures. This is a prospective, single-site, institutional review board-approved observational study of surgical debridements of infected wounds over a 17-month period. Two separate sterile surgical tables were used for each case: Table A for initial wound debridement (debridement set-up) and Table B for wound coverage/closure (clean set-up). Swabs of each table and its respective instruments were taken after debridement but prior to coverage/closure. The primary outcome of interest was bacterial growth at 48 hours. There were 72 surgical cases included in this study. Culture results of Table A demonstrated bacterial growth in 23 of 72 (32%) cases at 48 hours compared with 5of 72 (7%) from Table B (P = .001). These data suggest that there is significant bacterial contamination of surgical instruments used for debridement of infected wounds. Use of a two-table set-up reduced instrument cross-contamination by 78%, suggesting avoidable re-contamination of the wound.

The American Society of Shoulder and Elbow Therapists' consensus statement on rehabilitation for anatomic total shoulder arthroplasty.

Anatomic total shoulder arthroplasty is the gold standard shoulder replacement procedure for patients with an intact rotator cuff and sufficient glenoid bone to accommodate prosthetic glenoid implant and offers reliable patient satisfaction, excellent implant longevity, and a low incidence of complications. Disparity exists in the literature regarding rehabilitation strategies following anatomic total shoulder arthroplasty. This article presents a consensus statement from experts in the field on rehabilitation following anatomic total shoulder arthroplasty. The goal of this consensus statement is to provide a current evidence-based foundation to inform the rehabilitation process after anatomic total shoulder arthroplasty. These guidelines apply to anatomic total shoulder arthroplasty (replacement of the humeral head and glenoid), hemiarthroplasty (replacing only the humeral head), and hemiarthroplasty with glenoid reaming or resurfacing. The consensus statement integrates an extensive literature review, as well as survey results of the practice patterns of members of the American Society of Shoulder and Elbow Therapists and the American Shoulder and Elbow Surgeons. Three stages of recovery are proposed, which initially protect and then gradually load soft tissue affected by the surgical procedure, such as the subscapularis, for optimal patient outcomes. The proposed guidelines should be used in collaboration with surgeon preferences and patient-specific factors.

The Impact of Risk and Resistance Factors on Quality of Life in Caregivers of Individuals with Dementia.

OBJECTIVES: The present study investigates the effect of caregiver and care recipient risk and resistance factors on caregiver quality of life (QOL). Risk factors are those characteristics that contribute to psychosocial maladjustment of the caregiver and reduce QOL, while resistance factors promote caregiver adjustment and improve QOL. METHODS: One-hundred and three caregiver/care recipient dyads were recruited from a memory assessment clinic in Midwestern United States. Caregivers completed questionnaires estimating perceived social support, spirituality, social problem-solving, and care recipient functional dependence. Care recipients' results from the Mini-Mental State Examination and Animal Naming task were also collected. RESULTS: In the final model, caregiver age, relationship type, social problem-solving, perceived social support, and care recipient functional dependence each accounted for a significant portion of variance in caregiver QOL. The final model accounted for 46.1% of the variance in caregiver QOL. CONCLUSION: Caregiver age, relationship type, social problem-solving, perceived social support, and care recipient functional dependence are important contributors to caregiver QOL. Further research is needed to specify which caregiver and care recipient characteristics are most important to caregiver QOL. CLINICAL IMPLICATIONS: Health professionals should assess caregiver problem-solving skills, social support, and care recipient functional dependence, as these may provide important information about caregiver QOL. Study results also suggest that caregiving has more of a negative impact on caregiver QOL for midlife adult caregivers compared to older adult caregivers, and appears to have a greater negative effect on spouses than on children.

Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation.

Norbuprenorphine (NBUP) is the major active metabolite of buprenorphine (BUP) that is commonly used to treat opiate addiction during pregnancy; it possesses 25% of BUP's analgesic activity and 10 times BUP's respiratory depression effect. To optimize BUP's dosing regimen during pregnancy with better efficacy and safety, it is important to understand how pregnancy affects NBUP disposition. In this study, we examined the pharmacokinetics of NBUP in pregnant and nonpregnant mice by administering the same amount of NBUP through retro-orbital injection. We demonstrated that the systemic clearance (CL) of NBUP in pregnant mice increased ∼2.5-fold compared with nonpregnant mice. Intrinsic CL of NBUP by glucuronidation in mouse liver microsomes from pregnant mice was ∼2 times greater than that from nonpregnant mice. Targeted liquid chromatography tandem-mass spectrometry proteomics quantification revealed that hepatic Ugt1a1 and Ugt2b1 protein levels in the same amount of total liver membrane proteins were significantly increased by ∼50% in pregnant mice versus nonpregnant mice. After scaling to the whole liver with consideration of the increase in liver protein content and liver weight, we found that the amounts of Ugt1a1, Ugt1a10, Ugt2b1, and Ugt2b35 protein in the whole liver of pregnant mice were significantly increased ∼2-fold compared with nonpregnant mice. These data suggest that the increased systemic CL of NBUP in pregnant mice is likely caused by an induction of hepatic Ugt expression and activity. The data provide a basis for further mechanistic analysis of pregnancy-induced changes in the disposition of NBUP and drugs that are predominately and extensively metabolized by Ugts.

Disparities in Adherence to Pediatric Diabetic Ketoacidosis Management Guidelines Across a Spectrum of Emergency Departments in the State of Indiana: An Observational In Situ Simulation-Based Study.

BACKGROUND: Diabetic ketoacidosis (DKA) is a common presentation to an emergency department (ED), with the majority presenting to community EDs. Adherence to clinical guidelines in these EDs can reduce morbidity and mortality. Few methods to describe practice gaps for DKA management have been reported. OBJECTIVES: We hypothesized that high-fidelity in situ simulation can be used to measure and compare the quality of the care provided to pediatric patients with DKA presenting to community EDs in the state of Indiana. METHODS: This observational study examined multiprofessional teams caring for a simulated pediatric patient who presented with DKA to community EDs. The primary outcome was overall adherence to pediatric DKA guidelines as measured by a validated performance checklist. A composite adherence score (CAS) was calculated using the sum of 9 checklist performance parameters. Multivariable logistic regression was used to examine the impact of ED volume and characteristics on the scores. RESULTS: A 49 multiprofessional teams from 13 sites were enrolled. Of the 252 participants, 26 (10.3%) were physicians, 143 (56.7%) registered nurses, 25 (9.9%) respiratory therapists, and 58 (23.0%) were other. The overall CAS for all sites was 55.6% (25th, 75th interquartile range, 44.4%, 66.7%). Excessive intravenous fluid boluses were given by 53.1%, whereas 30.6% and 26.5% incorrectly administered insulin and sodium bicarbonate boluses, respectively. Only 10.2% used an appropriate intravenous fluid rate, and 57.1% performed an hourly glucose. No significant difference in the CAS was found due to pediatric ED volume or presence of an inpatient pediatric service. CONCLUSIONS: Using validated in situ simulation; we revealed high variability in adherence to the pediatric DKA management guidelines at a wide range of community EDs. A statewide education initiative focused on decreasing variation and improving adherence to pediatric DKA guidelines is necessary for patient safety.

Analysis of Wind Pressure Data on Components and Cladding of Low-Rise Buildings.

This paper presents a methodology for analyzing wind pressure data on cladding and components of low-rise buildings. The aerodynamic force acting on a specified area is obtained by summing up pressure time series measured at that area's pressure taps times their respective tributary areas. This operation is carried out for all sums of tributary areas that make up rectangles with aspect ratios not exceeding four. The peak of the resulting area-averaged time series is extrapolated to a realistic storm duration by the translation method. The envelope of peaks over all wind directions is compared with current specifications. Results for one low-rise building for one terrain condition indicate that these specifications can seriously underestimate pressures on gable roofs and walls. Comparison of the proposed methodology with an alternative method for assignment of tributary areas and area averaging is shown as well.

Effect of Coenzyme Q10 on Biomarkers of Oxidative Stress and Cardiac Function in Hemodialysis Patients: The CoQ10 Biomarker Trial.

BACKGROUND: Oxidative stress is highly prevalent in patients with end-stage renal disease and is linked to excess cardiovascular risk. Identifying therapies that reduce oxidative stress has the potential to improve cardiovascular outcomes in patients undergoing maintenance dialysis. STUDY DESIGN: Placebo-controlled, 3-arm, double-blind, randomized, clinical trial. SETTING & PARTICIPANTS: 65 patients undergoing thrice-weekly maintenance hemodialysis. INTERVENTION: Patients were randomly assigned in a 1:1:1 ratio to receive once-daily coenzyme Q10 (CoQ10; 600 or 1,200mg) or matching placebo for 4 months. OUTCOMES: The primary outcome was plasma oxidative stress, defined as plasma concentration of F2-isoprotanes. Secondary outcomes included levels of plasma isofurans, levels of cardiac biomarkers, predialysis blood pressure, and safety/tolerability. MEASUREMENTS: F2-isoprostanes and isofurans were measured as plasma markers of oxidative stress, and N-terminal pro-brain natriuretic peptide and troponin T were measured as cardiac biomarkers at baseline and 1, 2, and 4 months. RESULTS: Of 80 randomly assigned patients, 15 were excluded due to not completing at least 1 postbaseline study visit and 65 were included in the primary intention-to-treat analysis. No treatment-related major adverse events occurred. Daily treatment with 1,200mg, but not 600mg, of CoQ10 significantly reduced plasma F2-isoprostanes concentrations at 4 months compared to placebo (adjusted mean changes of -10.7 [95% CI, -7.1 to -14.3] pg/mL [P<0.001] and -8.3 [95% CI, -5.5 to -11.0] pg/mL [P=0.1], respectively). There were no significant effects of CoQ10 treatment on levels of plasma isofurans, cardiac biomarkers, or predialysis blood pressures. LIMITATIONS: Study not powered to detect small treatment effects; difference in baseline characteristics among randomized groups. CONCLUSIONS: In patients undergoing maintenance hemodialysis, daily supplementation with 1,200mg of CoQ10 is safe and results in a reduction in plasma concentrations of F2-isoprostanes, a marker of oxidative stress. Future studies are needed to determine whether CoQ10 supplementation improves clinical outcomes for patients undergoing maintenance hemodialysis.

P-gp/ABCB1 exerts differential impacts on brain and fetal exposure to norbuprenorphine.

Norbuprenorphine is the major active metabolite of buprenorphine which is commonly used to treat opiate addiction during pregnancy. Norbuprenorphine produces marked respiratory depression and was 10 times more potent than buprenorphine. Therefore, it is important to understand the mechanism that controls fetal exposure to norbuprenorphine, as exposure to this compound may pose a significant risk to the developing fetus. P-gp/ABCB1 and BCRP/ABCG2 are two major efflux transporters regulating tissue distribution of drugs. Previous studies have shown that norbuprenorphine, but not buprenorphine, is a P-gp substrate. In this study, we systematically examined and compared the roles of P-gp and BCRP in determining maternal brain and fetal distribution of norbuprenorphine using transporter knockout mouse models. We administered 1mg/kg norbuprenorphine by retro-orbital injection to pregnant FVB wild-type, Abcb1a-/-/1b-/-, and Abcb1a-/-/1b-/-/Abcg2-/- mice on gestation day 15. The fetal AUC of norbuprenorphine was ∼64% of the maternal plasma AUC in wild-type mice, suggesting substantial fetal exposure to norbuprenorphine. The maternal plasma AUCs of norbuprenorphine in Abcb1a-/-/1b-/- and Abcb1a-/-/1b-/-/Abcg2-/- mice were ∼2 times greater than that in wild-type mice. Fetal AUCs in Abcb1a-/-/1b-/- and Abcb1a-/-/1b-/-/Abcg2-/- mice were also increased compared to wild-type mice; however, the fetal-to-maternal plasma AUC ratio remained relatively unchanged by the knockout of Abcb1a/1b or Abcb1a/1b/Abcg2. In contrast, the maternal brain-to-maternal plasma AUC ratio in Abcb1a-/-/1b-/- or Abcb1a-/-/1b-/-/Abcg2-/- mice was increased ∼30-fold compared to wild-type mice. Protein quantification by LC-MS/MS proteomics revealed significantly higher amounts of P-gp protein in the wild-type mice brain than that in the placenta. These results indicate that fetal exposure to norbuprenorphine is substantial and that P-gp has a minor impact on fetal exposure to norbuprenorphine, but plays a significant role in restricting its brain distribution. The differential impacts of P-gp on norbuprenorphine distribution into the brain and fetus are likely, at least in part, due to the differences in amounts of P-gp protein expressed in the blood-brain and blood-placental barriers. BCRP is not as important as P-gp in determining both the systemic and tissue exposure to norbuprenorphine. Finally, fetal AUCs of the metabolite norbuprenorphine-ß-d-glucuronide were 3-7 times greater than maternal plasma AUCs, while the maternal brain AUCs were <50% of maternal plasma AUCs, suggesting that a reversible pool of conjugated metabolite in the fetus may contribute to the high fetal exposure to norbuprenorphine.

Wind-Pressure Coefficients on Low-Rise Building Enclosures Using Modern Wind-Tunnel Data and Voronoi Diagrams.

External pressure coefficients specified in the ASCE 7-10 Standard, used to determine design wind pressures for the components and cladding of buildings, are developed from wind tunnel test data that date back 30-50 years. In recent decades, advances in pressure measurement and computer technology have made it possible to obtain simultaneous pressure records, with high sampling rates, at many more wind tunnel pressure taps than was the case in the past. This paper proposes a method to calculate external pressure coefficients using aerodynamic wind tunnel databases such as Tokyo Polytechnic University's large, publicly available database. Voronoi diagrams are used to assign tributary areas to irregularly spaced pressure taps. User-defined grids of various sizes and shapes are placed at various offsets over the building surface to perform area-averaging of the pressure time series. Considering all wind directions for which measurements are obtained in the wind tunnel, the peak pressures are determined assuming a Gumbel distribution, and are extrapolated to a standard storm duration. The external peak pressure coefficients are then plotted as functions of their corresponding area for various zones of the building enclosure to produce plots similar to the ASCE 7-10 specifications on components and cladding. Results for three gable buildings analyzed in the paper show that the current ASCE 7-10 specifications can severely underestimate the external pressure coefficients for components and cladding of low-rise buildings.

Solid-State 27Al NMR Spectroscopy of the γ-Al13 Keggin Containing Al Coordinated by a Terminal Hydroxyl Ligand.

We report solid-state 27Al NMR spectroscopic results for the sulfate salt of the γ-Al13 Keggin cluster, γ-[AlO4Al12(OH)25(OH2)11][SO4]3·[H2O]14, that provide a spectroscopic signature for partial hydrolysis of this Keggin-type cluster. In 27Al multiple-quantum magic-angle spinning NMR spectra, all 13 Al positions of the cluster are at least partially resolved and assigned with the aid of density functional theory (DFT) calculations of the 27Al electric field gradients. The isotropic chemical shift of the single tetrahedral site, 75.7 ppm, is nearly identical to that reported for solutions from which the cluster crystallizes. Reflecting broadly similar coordination environments, the octahedral Al show mostly small variations in isotropic chemical shift (+7 to +11 ppm) and quadrupolar coupling constant (CQ; 6-7.5 MHz), except for one resonance that exhibits a much smaller CQ and another site with a larger value. DFT calculations show that deprotonation of a terminal water ligand, to form an η-OH group, causes a large reduction in the 27Al CQ, allowing assignment of a distinct, narrow peak for octahedral Al to this hydroxyl-terminated site. This result suggests a relationship between octahedral 27Al NMR line width and hydrolysis for solids prepared from Keggin-type clusters.

Disability Diversity Training in the Workplace: Systematic Review and Future Directions.

Purpose Misinformation and negative attitudes toward disability contribute to lower employment rates among people with disabilities. Diversity training is an intervention intended to improve intergroup relations and reduce prejudice. We conducted a systematic review to determine the use and effectiveness of disability diversity training aimed at improving employment outcomes for employees with disabilities. Methods Five databases were searched for peer-reviewed studies of disability diversity training interventions provided within the workplace. Studies identified for inclusion were assessed for quality of methodology. Results Of the total of 1322 articles identified by the search, three studies met the criteria for inclusion. Two of the three articles focused specifically on training to improve outcomes related to workplace injuries among existing employees. The other study provided an initial test of a more general disability diversity training program. Conclusions There is currently a lack of empirically validated diversity training programs that focus specifically on disability. A number of disability diversity trainings and resources exist, but none have been well researched. Related literature on diversity training and disability awareness suggests the possibility for enhancing diversity training practices through training design, content, participant, and outcomes considerations. By integrating best practices in workplace diversity training with existing disability training resources, practitioners and researchers may be able to design effective disability diversity training programs.

Dexmedetomidine reduces cranial temperature in hypothermic neonatal rats.

BACKGROUND: The α2-adrenergic agonist dexmedetomidine (DEX) is increasingly used for prolonged sedation of critically ill neonates, but there are currently no data evaluating possible consequences of prolonged neonatal DEX exposure. We evaluated the pharmacokinetics and histological consequences of neonatal DEX exposure. METHODS: DEX was administered (s.c.) to naive (uninjured) neonatal Lewis rats to provide acute (25 µg/kg, ×1) or prolonged (25 µg/kg three times daily, ×2 or ×4 d) exposure. Therapeutic hypothermia was simulated using a water-cooled blanket. Cranial temperatures were measured using an infrared thermometer. DEX concentrations were measured by LC-MS in plasma and homogenized brainstem tissue for pharmacokinetic analysis. Cortex, cerebellum, and brainstem were evaluated for evidence of inflammation or injury. RESULTS: Prolonged neonatal DEX exposure was not associated with renal or brain pathology or indices of gliosis, macrophage activation, or apoptosis in either hypothermic or control rats. Plasma and brain DEX concentrations were tightly correlated. DEX peaked within 15 min in brain and reduced cranial temperature from 32 to 30 °C within 30 min after injection in cooled rats. CONCLUSION: Prolonged DEX treatment in neonatal rats was not associated with abnormal brain histology. These data provide reassuring preliminary results for using DEX with therapeutic hypothermia to treat near-term brain injury.

Reversible, time-dependent inhibition of CYP3A-mediated metabolism of midazolam and tacrolimus by telaprevir in human liver microsomes.

PURPOSE: Telaprevir inhibits CYP3A resulting in drug-drug interactions (DDI) of unprecedented magnitude. We investigated the mechanisms by which telaprevir inhibits the oxidation of midazolam and tacrolimus in human liver microsomes (HLM). METHODS: We performed a static mechanistic DDI prediction to evaluate whether previously reported competitive inhibition of CYP3A by telaprevir and its diastereomeric metabolite - VRT-127394 is sufficient to explain the remarkable reduction in oral clearance observed with oral midazolam and tacrolimus. To further explore the inhibitory mechanisms of telaprevir, we assessed whether telaprevir-mediated inhibition of the oxidation of midazolam and tacrolimus is time-dependent in human liver microsomes, and whether any observed time-dependency was irreversible or reversible in nature. RESULTS: The competitive inhibition model failed to account for the magnitude of telaprevir interactions in human subjects. In comparing HLM incubations with and without a prior 30-min exposure to telaprevir, a respective 4- and 11-fold reduction in IC50 was observed with midazolam and tacrolimus as substrates. This time-dependent inhibition was shown to be NADPH-dependent. Upon dilution of microsomes following pre-incubation with telaprevir, time-dependent inhibition of midazolam metabolism was completely reversed, whereas partial reversal occurred with tacrolimus. CONCLUSIONS: The interaction between telaprevir and midazolam or tacrolimus involves both competitive and time-dependent inhibition. The time-dependent component is not explained by irreversible inactivation of CYP3A. Formation of potent inhibitory metabolites may contribute to the remarkable in vivo inhibitory potency of telaprevir.

Synthesis of the Stable Ordered Conjugated Polymer Poly(dibromodiacetylene) from an Explosive Monomer.

Dibromobutadiyne is an extremely unstable compound that explodes at room temperature, even under inert atmosphere. This instability has limited the studies of dibromobutadiyne almost entirely to spectroscopic characterization. Here we report an approach to control the reactivity of dibromobutadiyne, via topochemical reaction in cocrystals, leading to the ordered polymer poly(dibromodiacetylene), PBDA. At low temperatures (-15 to -18 °C), dibromobutadiyne can form cocrystals with oxalamide host molecules containing either pyridyl or nitrile side groups, in which halogen bonds align the dibromobutadiyne monomers for topochemical polymerization. The cocrystals with the bis(nitrile) oxalamide host undergo complete ordered polymerization to PBDA, demonstrated by solid-state MAS-NMR, Raman, and optical absorption spectroscopy. Once formed, the polymer can be separated from the host; unlike the monomer, PBDA is stable at room temperature.

Recipient pretransplant inosine monophosphate dehydrogenase activity in nonmyeloablative hematopoietic cell transplantation.

Mycophenolic acid, the active metabolite of mycophenolate mofetil (MMF), inhibits inosine monophosphate dehydrogenase (IMPDH) activity. IMPDH is the rate-limiting enzyme involved in de novo synthesis of guanosine nucleotides and catalyzes the oxidation of inosine 5'-monophosphate to xanthosine 5'-monophosphate (XMP). We developed a highly sensitive liquid chromatography-mass spectrometry method to quantitate XMP concentrations in peripheral blood mononuclear cells (PMNCs) isolated from the recipient pretransplant and used this method to determine IMPDH activity in 86 nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) patients. The incubation procedure and analytical method yielded acceptable within-sample and within-individual variability. Considerable between-individual variability was observed (12.2-fold). Low recipient pretransplant IMPDH activity was associated with increased day +28 donor T cell chimerism, more acute graft-versus-host disease (GVHD), lower neutrophil nadirs, and more cytomegalovirus reactivation but not with chronic GVHD, relapse, nonrelapse mortality, or overall mortality. We conclude that quantitation of the recipient's pretransplant IMPDH activity in PMNC lysate could provide a useful biomarker to evaluate a recipient's sensitivity to MMF. Further trials should be conducted to confirm our findings and to optimize postgrafting immunosuppression in nonmyeloablative HCT recipients.

Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil.

A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplantation (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNCs) at 5 time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic-dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory maximum effect model with an IC50 of 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, nonrelapse mortality, and overall mortality. In conclusion, a pharmacokinetic-dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker.

Optimizing twin-screw melt granulation: The role of overflight clearance on granulation behavior.

Twin-screw melt granulation (TSMG) relies on the dispersive and distributive mixing at the kneading zone for granule growth to happen highlighting the critical role played by the kneading elements in TSMG. Despite extensive research conducted on the impact of screw geometry in melt compounding, there is not enough literature for TSMG. Disc width for the kneading elements was 2 mm, contrary to the standard 5 mm. The objective of this study was to evaluate if varying overflight clearance (OC) can alter the paradigm for TSMG. The new elements reduce the peak shear at kneading zone however a higher barrel temperature and degree of fill (DoF) is required to compensate to attain similar granule attributes. The change in DoF was achieved through a combination of modified screw configuration to pre-densify powders before kneading and processing at a lower screw speed. Despite the higher barrel temperature, process optimization of thermally unstable gabapentin was carried out. Using the new elements, compressible granules (Tensile strength > 2 MPa) with low % GABA-L content were manufactured despite increasing OC to 0.4 mm. Granule stability at 40 °C, ambient humidity for 6 months indicated gabapentin was stable (% GABA-L ≪0.4 %) despite a high barrel temperature of 120 °C.