Normal Hepatic Function Research Articles

Cutaneous-hemolytic loxoscelism following brown recluse spider envenomation: new understandings

Background: Brown recluse spider (BRS) (Loxosceles reclusa) envenomation can cause local dermonecrotic lesions, constitutional symptoms, and potentially fatal hemolysis (i.e., cutaneous-hemolytic loxoscelism). As the incidence of hemolysis is low and the spider habitat is limited, little is known regarding the clinical course of cutaneous-hemolytic loxoscelism.Methods: We performed a retrospective observational study of patients following BRS envenomation over an eight-year period. Demographics, clinical course, laboratories, and interventions were assessed. Wilcoxon rank-sum tests and Pearson chi-square tests were used in the univariate analyses. Logistic regression assessed the independent contribution of symptoms in a multivariate analysis.Results: Of the 97 patients, 40.2% (n = 39) developed hemolysis; the majority (66.7%) were 18 years old or younger. Univariate analysis revealed that constitutional symptoms were associated with hemolysis, but multivariate analysis showed only myalgia (aOR: 7.1; 95% CI: 2.2–22.7; p < .001) and malaise (aOR: 12.76; 95% CI: 1.4–119.9; p = .026) were independently associated with hemolysis. The median time to hemolysis onset was 1.0 days (IQR: 1.0–2.5) and all occurred within a week of envenomation. Hemolysis durations were longer in patients DAT positive for IGG antibodies (7.5 vs. 4.0 days; p = .042). Most (76.9%) of hemolyzing patients received blood. In patients with cutaneous-hemolytic loxoscelism, hematuria occurred in 32.4%, rhabdomyolysis occurred in 60.9%, and elevated transaminases with normal hepatic synthetic function occurred in 29.4% but all of these patients developed rhabdomyolysis. Hemolysis was both intravascular and extravascular. Complications (hyperkalemia, INR ≥2.0, metabolic acidosis requiring bicarbonate, hypotension requiring vasopressors, and hypoxia requiring intubation) occurred only in patients with profound hemolytic anemia (hemoglobin <4 g/dL); one patient died.Conclusions: Constitutional symptoms occur in both cutaneous and cutaneous-hemolytic loxoscelism, although they occur more frequently in patients who develop hemolysis. Children may be at a higher risk of hemolysis after envenomation. Renal involvement (as evidenced by hematuria) and rhabdomyolysis may occur more frequently than has been previously reported. Hemolysis was both intravascular and extravascular.

Comparision of Radiochemotherapy Applications that Committing with Two Different Chemotherapies Route in Locally Advanced Lung Cancer.

This study investigated pre- and post-treatment tumor and lymph node dimension response rates and differences between side-effect profiles in patients with locally advanced inoperable nonsmall-cell lung cancer (NSCLC) receiving radiotherapy (RT) and concurrent chemotherapy (CT). A total of 30 inoperable patients who had not previously received RT and having a mean age of 58.73±8.65 years with sufficient hematological reserves and normal hepatic and renal functions were included in the study. Those with pleural effusion, supraventricular lymph node metastasis, and N3 lymph node involvement were excluded. Group I (n=15) received a 21-day 75 mg/m2 cisplatin (D1) and 15 mg/m2 vinorelbine (D1, D8), whereas Group II (n=15) received 45 mg/m2 paclitaxel and AUC2 carboplatin weekly. RT was administered using a linear accelerator device with the 3D conformal RT technique at 6-18 MV energy with a 1.8-2 Gy fraction for 6-7 weeks. Patients were randomized into Group I receiving RT and concurrent cisplatin-vinorelbine and Group II receiving weekly paclitaxel-carboplatin CT. Pre- and post-treatment tumor and lymph node dimensions significantly differed in both groups (p<0.001 and p<0.01, respectively). No significant change was observed in post-RT tumor and lymph node dimensions in terms of applied CT regimens (p>0.05). The significant response achieved with concurrent RT and CT in groups I and II in the local advanced stage of NSCLC is important for local tumor control. Responses to treatment in the group of two arms did not differ.

Analysis of hematologic adverse events (HeAEs) in trifluridine/tipiracil (FTD/TPI)-treated patients (pts) with or without renal/hepatic impairment (RI/HI): Pooled safety analyses from TAGS and RECOURSE.

145 Background: FTD/TPI has shown clinical benefit and consistent safety in pretreated pts with metastatic colorectal cancer (mCRC) and metastatic gastric or gastroesophageal junction cancer (mGC/GEJC) in the phase 3 RECOURSE and TAGS trials, respectively. HeAEs were the most frequent AEs with FTD/TPI treatment. Methods: Pts in this analysis received ≥1 FTD/TPI dose in the TAGS and RECOURSE trials. Subgroups included pts with normal renal function (nRF; CrCl ≥90 mL/min), mild RI (CrCl 60–89 mL/min), moderate (mod) RI (CrCl 30–59 mL/min), normal hepatic function (nHF) and mild HI (total bilirubin &lt;1.5 X ULN, or AST &gt;ULN). Results: FTD/TPI was administered to 868 pts in the overall pooled population (OPP; n=335, TAGS [mGC/GEJC]; n=533, RECOURSE [mCRC]); 52%, 36%, and 11% had nRF, mild and moderate RI, and 66% and 33% had nHF and mild HI, respectively. Frequencies of any-cause grade (gr) ≥3 HeAEs were similar across subgroups and the OPP, except for gr ≥3 anemia and gr ≥3 leukopenia, which were higher with mod RI (table). In the OPP, most gr 3/4 neutropenia events occurred within the first 2 cycles (median time to onset [mTTO], 49 d). Median time to resolution (mTTR) was 8 d. Gr 3/4 neutropenia TTO and TTR in most subgroups were consistent with the OPP, except with mod RI (mTTO, 29 d). HeAE management and correlative efficacy analyses will be presented. Conclusions: In this pooled analysis of pts with mCRC and mGC/GEJC, HeAEs with FTD/TPI in pts with mild to mod RI and mild HI were manageable and not largely different from those in the OPP. Clinical trial information: NCT02500043 and NCT01607957. [Table: see text]

Effect of laparoscopy on liver enzymes

Background: Laparoscopic procedures have gained popularity in recent days because of advantages like small incision, less postoperative pain and discomfort, short hospital stay, early ambulation and early discharge. Very few studies are available to correlate Laparoscopic Surgeries and liver enzyme elevation. This effect may be due to either CO2 pneumoperitoneum, diathermy extruding liver, injury to branch of the hepatic artery or general anesthesia. This study was done to evaluate the changes in liver enzymes pre-operatively and post-operatively following laparoscopy.Methods: This prospective study included 103 patients who underwent various laparoscopic surgeries over a period of 2 years in Bharati Hospital &amp; Research Centre, Pune, India. Serum AST, ALT and bilirubin levels were measured preoperatively and on post-operative day 1 and post-operative day 3. Patients with coexisting liver disease, Patients on long term use of hepatotoxic drugs, patients who developed complications such as CBD injury, obstruction, infection, leakage and high grade fever during surgery and in the post-operative period were excluded.Results: All laparoscopic procedures cause a transient elevation of serum bilirubin and liver enzymes. Elevation in the liver enzymes correlated directly with the duration of pneumoperitoneum. Elevation in the serum bilirubin but doesn’t correlates with the duration of pneumoperitoneum. These elevations do not have clinical significance in patients with normal hepatic function preoperatively.Conclusions: Duration of laparoscopic procedure should be kept to minimum and undue prolongation should be avoided. Decision to convert the operation to open surgery from a laparoscopic surgery should be prompt.

Hepatic Complications in Preeclampsia.

In cases of preeclampsia with severe features and hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome, hepatic complications portend significant short-term and long-term maternal health implications. In this section, we will discuss the physiology of normal hepatic function in pregnancy, the pathophysiology of the abnormalities noted in hepatic function during the process of preeclampsia development, the diagnosis and management of preeclampsia, imitators of HELLP syndrome, the utility of various biomarkers in the diagnosis and prognosis of the preeclampsia disease spectrum, possible underlying genetic factors predisposing women to developing hepatic abnormalities with preeclampsia, and finally prognosis and management of a subcapsular hematoma.

Emerging Roles for Lymphatics in Chronic Liver Disease.

Chronic liver disease (CLD) is a global health epidemic causing ∼2 million deaths annually worldwide. As the incidence of CLD is expected to rise over the next decade, understanding the cellular and molecular mediators of CLD is critical for developing novel therapeutics. Common characteristics of CLD include steatosis, inflammation, and cholesterol accumulation in the liver. While the lymphatic system in the liver has largely been overlooked, the liver lymphatics, as in other organs, are thought to play a critical role in maintaining normal hepatic function by assisting in the removal of protein, cholesterol, and immune infiltrate. Lymphatic growth, permeability, and/or hyperplasia in non-liver organs has been demonstrated to be caused by obesity or hypercholesterolemia in humans and animal models. While it is still unclear if changes in permeability occur in liver lymphatics, the lymphatics do expand in number and size in all disease etiologies tested. This is consistent with the lymphatic endothelial cells (LEC) upregulating proliferation specific genes, however, other transcriptional changes occur in liver LECs that are dependent on the inflammatory mediators that are specific to the disease etiology. Whether these changes induce lymphatic dysfunction or if they impact liver function has yet to be directly addressed. Here, we will review what is known about liver lymphatics in health and disease, what can be learned from recent work on the influence of obesity and hypercholesterolemia on the lymphatics in other organs, changes that occur in LECs in the liver during disease and outstanding questions in the field.

Effect of different doses of Moringa oleifera in postprandial glucose. Influence of participants’ glucose control status

AbstractThe multipurpose plant Moringa oleifera (MO) has shown a variety of in vitro activities potentially beneficial for health and evidences are also numerous in animal models. However, the exact composition of the plant is highly variable depending on the area, culture and post harvesting conditions and the effects in humans are scarcely studied. This is a pilot study of the effect of different doses of MO from an Iberian Peninsula cultivar on postprandial glucose level in non-diabetic subjects. Five adult subjects (40 to 70 years, 3 males) with normal renal and hepatic function were included. Two had normal fasting glucose and 3 had pre-diabetic fasting glucose. A standard breakfast plus, respectively, one placebo capsule (PLC), or 1, 3 and 6 capsules containing 400 mg of MO dry leaf powder (MO-1cap, -3cap and -6cap) were consumed by each subject on 4 consecutive visits, one week apart. The basal and postprandial (30, 60, 90, 120, 150 and 180 min) glucose was measured. The mean glucose change from baseline (ΔGlc) at each measure time was calculated and compared between treatments with the Wilcoxon tests and considered significant at P &lt; 0.05 level. The postprandial curves were also studied separately in pre-diabetic subjects. A difference was found 90 min after breakfast in ΔGlc for the MO-6cap compared to the MO-1cap, being lower in MO-6cap. No more significant differences were observed due to the small number of subjects and high variability in glucose values among subjects. However, the graphical representation of separated curves for the three pre-diabetic participants showed that all three MO doses led to values always below those with PLC. In addition, during the first experimental hour all MO doses showed lower ΔGlc than PLC while this was not the case when all subjects were studied. No adverse events occurred during the experiment. The study, thus, showed a trend to lower glycemic postprandial response with MO leaf powder which seems to be more evident in pre-diabetic subjects than in normoglycemic subjects and especially during the first postprandial hour. The MO-6cap seems to be the election daily dose for a long term intervention study on the glycemic control with MO in pre-diabetic subjects.

Application of Impedance-Based Techniques in Hepatology Research.

There are a variety of end-point assays and techniques available to monitor hepatic cell cultures and study toxicity within in vitro models. These commonly focus on one aspect of cell metabolism and are often destructive to cells. Impedance-based cellular assays (IBCAs) assess biological functions of cell populations in real-time by measuring electrical impedance, which is the resistance to alternating current caused by the dielectric properties of proliferating of cells. While the uses of IBCA have been widely reported for a number of tissues, specific uses in the study of hepatic cell cultures have not been reported to date. IBCA monitors cellular behaviour throughout experimentation non-invasively without labelling or damage to cell cultures. The data extrapolated from IBCA can be correlated to biological events happening within the cell and therefore may inform drug toxicity studies or other applications within hepatic research. Because tight junctions comprise the blood/biliary barrier in hepatocytes, there are major consequences when these junctions are disrupted, as many pathologies centre around the bile canaliculi and flow of bile out of the liver. The application of IBCA in hepatology provides a unique opportunity to assess cellular polarity and patency of tight junctions, vital to maintaining normal hepatic function. Here, we describe how IBCAs have been applied to measuring the effect of viral infection, drug toxicity/IC50, cholangiopathies, cancer metastasis and monitoring of the gut-liver axis. We also highlight key areas of research where IBCAs could be used in future applications within the field of hepatology.

Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects With Normal and Impaired Hepatic Function

Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non‐RA subjects (n = 24) in an open‐label, parallel‐group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions. Plasma PK parameters were measured for peficitinib and its metabolites H1 (sulfate and methylated metabolite), H2 (sulfate metabolite), and H4 (methylated metabolite) in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. The peficitinib area under the plasma‐concentration–time curve from time 0 to infinity (AUCinf) and maximum observed concentration (Cmax) were not markedly different in subjects with mild hepatic impairment versus normal hepatic function. In subjects with moderate hepatic impairment versus normal hepatic function, the geometric mean ratios for peficitinib AUCinf and Cmax, were 1.92 (90% CI: 1.39, 2.66) and 1.82 (90% CI: 1.24, 2.69), respectively. Five treatment‐emergent adverse events (TEAEs) were experienced by 3 subjects, 1 in each group. There were no deaths, no serious TEAEs, and no TEAEs leading to withdrawal. In summary, the PK profile was unaltered in subjects with mild hepatic impairment after a single clinically relevant dose of peficitinib, but exposure almost doubled in subjects with moderate hepatic impairment. Peficitinib dose reduction may be considered in RA patients with moderate hepatic impairment.

MKL1 promotes endothelial-to-mesenchymal transition and liver fibrosis by activating TWIST1 transcription

Excessive fibrogenic response in the liver disrupts normal hepatic anatomy and function heralding such end-stage liver diseases as hepatocellular carcinoma and cirrhosis. Sinusoidal endothelial cells contribute to myofibroblast activation and liver fibrosis by undergoing endothelial-mesenchymal transition (EndMT). The underlying mechanism remains poorly defined. Here we report that inhibition or endothelial-specific deletion of MKL1, a transcriptional modulator, attenuated liver fibrosis in mice. MKL1 inhibition or deletion suppressed EndMT induced by TGF-β. Mechanistically, MKL1 was recruited to the promoter region of TWIST1, a master regulator of EndMT, and activated TWIST1 transcription in a STAT3-dependent manner. A small-molecule STAT3 inhibitor (C188-9) alleviated EndMT in cultured cells and bile duct ligation (BDL) induced liver fibrosis in mice. Finally, direct inhibition of TWIST1 by a small-molecule compound harmine was paralleled by blockade of EndMT in cultured cells and liver fibrosis in mice. In conclusion, our data unveil a novel mechanism underlying EndMT and liver fibrosis and highlight the possibility of targeting the STAT3-MKL1-TWIST1 axis in the intervention of aberrant liver fibrogenesis.

Dotinurad: a clinical pharmacokinetic study of a novel, selective urate reabsorption inhibitor in subjects with hepatic impairment

BackgroundDotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1 (URAT1). We compared the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad in subjects with hepatic impairment and normal hepatic function.MethodsThis was a multicenter, open-label, single dose study. A total of 24 subjects were divided into four groups: the normal hepatic function group and the mild, moderate, and severe hepatic impairment groups. The primary endpoints were changes in plasma dotinurad levels and PK parameters.ResultsThe geometric mean ratio of the maximum plasma concentration (Cmax) [two-sided 90% confidence interval (CI)] of dotinurad in in the mild, moderate, and severe hepatic impairment groups relative to that in the normal hepatic function group was 0.840 (0.674–1.047), 0.798 (0.653–0.976), and 0.747 (0.570–0.979), respectively, showing a lower Cmax in the moderate and severe hepatic impairment groups. Following adjustment for body weight, only the moderate hepatic impairment group had a lower Cmax than the normal hepatic function group. No meaningful differences in other PK parameters were observed between the groups. Regarding the PD of dotinurad, the changes in serum uric acid levels after dosing were similar in all groups. As for safety, no noteworthy concerns were raised in relation to any group.ConclusionThe study revealed no clinically meaningful influence of hepatic impairment on the PK, PD, or safety of dotinurad. These findings indicate possibility that dotinurad can be used without dose adjustment in patients with hepatic impairment.

Hepatic Impairment Study in Subjects With Normal Hepatic Function and Subjects With Varying Degrees of Hepatic Impairment

Hepatic Impairment Study in Subjects With Normal Hepatic Function and Subjects With Varying Degrees of Hepatic Impairment

Impact of hepatic and renal impairment on the pharmacokinetics and tolerability of eliglustat therapy for Gaucher disease type 1

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) who have extensive (EM), intermediate (IM), or poor (PM) CYP2D6 metabolizer phenotypes. It was initially not recommended in GD1 patients with hepatic or renal impairment due to insufficient data. Two Phase 1 studies (NCT02536937/NCT02536911) evaluated the effects of hepatic and renal impairment on pharmacokinetics and tolerability following a single 84-mg dose of eliglustat. Compared to matched healthy EM subjects (n = 7 for both studies), geometric means for eliglustat maximum concentration (Cmax) and area under the plasma concentration versus time curve extrapolated to infinity (AUC) were not substantially different in EMs with mild hepatic impairment (n = 6), higher in EMs with moderate hepatic impairment (n = 7), and similar in EMs with severe renal impairment (n = 7). Higher exposures of eliglustat at steady-state were predicted using a physiologically-based pharmacokinetic (PBPK) model in EMs with mild or moderate hepatic impairment compared with normal hepatic function after repeated 84-mg eliglustat doses. Higher exposures of eliglustat were also predicted in EMs with mild hepatic impairment after coadministration with a CYP2D6 or CYP3A inhibitor with repeated doses. Based on these results, the eliglustat drug label was revised for patients with hepatic or renal impairment.

EPID-25. HOW MANY PATIENTS IN A REAL WORLD GLIOBLASTOMA POPULATION MEET ELIGIBILITY CRITERIA IN CLINICAL TRIALS?

Abstract In population series of glioblastoma (GBM) the median survival is &lt; 1 year. For patients eligible for combined oncological treatment (surgery, radiotherapy (RT) and temozolomide (TMZ)) the median survival raises to 15 months. These patients are younger, have higher performance status and less comorbidity compared to the total GBM population. The extent of selection bias of GBM patients enrolled in clinical trials is, however, unclear. Using the Cancer Registry of Norway and the Brain Tumor Database of Oslo University Hospital, all patients diagnosed with GBM between 2012 and 2016 within a defined geographical area that received all oncological treatment at Oslo University Hospital were identified. Their hospital charts were retrospectively investigated and all patients were evaluated for the possibility to be included in clinical trials according to standard criteria from recent published phase 3 studies. We defined three time points for possible enrollment in trials: before-, halfway through-, and after concomitant RT/TMZ. We identified 424 patients of whom 26 (6.1%) did not undergo surgery. The median survival in the population was 11.7 months. Of the patients that underwent surgery (biopsy or resection), the median survival progressively increased with additional oncological treatment; no RT/TMZ 1.1 months, only RT 7.9 months, RT/TMZ 13.9 months. A potential study patient group≥18 years undergoing surgery for a supratentorial GBM with ECOG ≤2, with normal bone marrow, hepatic and renal function and no severe comorbidity or oncological disease constituted 54% of the population before start of RT/TMZ. Patients adhering to RT/TMZ-treatment and without tumor progression represented 46% and 43% of the population halfway through- and after concomitant RT/TMZ, respectively. The survival of patients that could be included in clinical trials was significantly higher (p&lt; 0.001) than patients not fulfilling standard criteria. Our data suggest a significant patient selection in clinical trials from a real-world GBM population.

A Study of Apalutamide in Participants With Severe Hepatic Impairment Compared With Participants With Normal Hepatic Function

A Study of Apalutamide in Participants With Severe Hepatic Impairment Compared With Participants With Normal Hepatic Function

The relationship between tyramine levels and inflammation in metabolic syndrome.

Background Metabolic syndrome (MetS) is an important contributor to both type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). Although MetS affects one third of American adults, its pathogenesis remains to be elucidated. Tyramine, a derivative of tyrosine, has been shown to act as a catecholamine releasing agent in the human body. The aim of this study is to investigate the role of tyramine as an early biomarker for nascent MetS without the confounding of T2DM, ASCVD or smoking. Patients and methods This was an exploratory study of 28 patients with nascent MetS and 20 matched controls carried out in 2018. Metabolites were evaluated from patient's frozen early morning urine samples and were correlated with biomarkers of inflammation and adipokines. They were assayed by the National Institutes of Health (NIH) Western Metabolomics Center using liquid chromatography/mass spectrometry (LC/MS) and standardized to urinary creatinine. All patients had normal hepatic and renal function. Results Tyramine concentrations were significantly reduced in patients with MetS compared to controls, p = 0.0009. In addition, tyramine was significantly inversely correlated with multiple biomarkers of inflammation and cardiometabolic risk factors such as RBP4, monocyte TLR-4 abundance and P38MAPKinase activity, body mass index (BMI) and blood pressure (BP) (both systolic and diastolic). Conclusion In conclusion, low levels of tyramine could contribute to the proinflammatorty state of MetS.

722. Pharmacokinetics (PK) and Safety of Lefamulin (LEF) After Single Intravenous Dose Administration in Subjects With Impaired Hepatic Function

BackgroundPatients with chronic liver disease (CLD) have impaired immune function, are prone to community-acquired bacterial pneumonia (CABP), and experience greater morbidity/mortality and healthcare costs than CABP patients without CLD. LEF, a novel pleuromutilin antibiotic (IV/oral) with primary liver elimination, was generally well tolerated and noninferior to moxifloxacin in two phase 3 studies of adults with CABP. We investigated the PK and safety of LEF and its main metabolite, BC-8041, in subjects with hepatic impairment.MethodsIn this open-label study, subjects were allocated to 1 of 3 groups based on hepatic function level; Moderate (Child-Pugh score 7–9) or Severe subjects (Child-Pugh score ≥10) were matched (gender, age, and weight) to subjects in the Normal group (normal hepatic function, no liver cirrhosis). Subjects received a single 1-hour 150 mg LEF infusion. Blood and urine samples were collected predose and over a 48-hour period postdose for PK analysis; plasma and urine were assayed for LEF and BC-8041 using validated assays. Safety assessments included treatment-emergent adverse events (TEAEs), labs, vital signs, and electrocardiograms.Results27 subjects enrolled in and completed the study (n = 11, Normal; n = 8, Moderate; n = 8, Severe). Mean LEF and BC-8041 plasma concentration profiles were comparable across all hepatic function groups through the first 12 hours following the start of infusion. Subjects with hepatic impairment had slightly slower rates of elimination in the later elimination phases. LEF and BC-8041 exposures were similar across all hepatic function groups (table), and the majority of LEF and BC-8041 were excreted nonrenally. TEAEs were reported in 2 (18.2%) subjects in the Normal group, 2 (25%) in the Moderate group, and 1 (12.5%) in the Severe group. None of the TEAEs were serious or led to study drug discontinuation. No subject met Hy’s law criteria. Within 4 hours postdose, the maximum mean change from baseline in the QTcF interval was 12.4, 19.2, and 14.1 msec in the Normal, Moderate, and Severe groups, respectively.ConclusionNo dosage adjustment for LEF appears to be required when treating subjects with hepatic impairment. LEF was generally well tolerated in all subjects regardless of hepatic functional status. Disclosures All authors: No reported disclosures

731. Pharmacokinetics of Gepotidacin (GSK2140944) in Subjects with Hepatic Impairment

BackgroundGepotidacin (GEP), a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor, inhibits bacterial replication and has in vitro and in vivo efficacy activity against key pathogens, including drug-resistant strains, associated with a range of infections. In a previous absorption, distribution, metabolism, and excretion study for GEP, the mean recovery of radioactivity in urine and feces accounted for approximately 31.2% and 52.5%, respectively, of [14C]-GEP administered as a single oral dose. GEP was eliminated mainly as parent in urine, accounting for approximately 20% of the administered dose. Elimination via metabolism accounted for a total of 13% to 19% of the dose. Average total intravenous clearance of approximately 43 L/hour and renal clearance (CLr) of approximately 16 L/hour provides a hepatic clearance of 27 L/hour, suggesting that hepatic clearance is a major route of elimination of GEP.MethodsParticipants with normal and varying degrees of hepatic impairment (HI) received a single oral dose of GEP 1,500 mg. PK collections of blood, urine and saliva were performed.ResultsRelative to normal hepatic function, GEP Cmax and AUC(0-∞) in plasma were increased by 1.2-fold in subjects with moderate, and between 1.7-fold to 1.9-fold in severe HI. The fraction of dose excreted in urine increased with an increase in hepatic impairment. GEP urine concentrations remained high over a 12-hour period. Saliva concentrations displayed a linear relationship with plasma (both total and unbound) concentrations (R2 = 0.76). The geometric mean ratio of saliva AUC to unbound plasma AUC values ranged from 0.746 to 0.839 across all groups. Administration of 1,500 mg oral GEP was generally tolerated.ConclusionAn increase in the dosing interval or dose reduction may be required in patients with severe hepatic impairment. Disclosures All authors: No reported disclosures.

Metabolic Encephalopathy - Part II

Normal neurologic function requires a constantly balanced environment of electrolytes. Normal hepatic and renal function is critical in maintaining this balance while removing toxins, maintaining a physiologic pH and regulating the excretion of electrolytes. Nutritional intake provides essential nutrients but deficiencies can lead to characteristic syndromes such as Wernicke's encephalopathy and pellagra and exposure to neurotoxic substances such as heavy metals can lead to encephalopathy. Thyroid and adrenal dysfunction are common endocrine causes of encephalopathy and symptoms can often improve rapidly with treatment. A subset of idiopathic encephalopathy is increasingly being recognized as having an autoimmune basis, often presenting as a paraneoplastic process, and having a constellation of symptoms which can aide in the diagnosis. Timely recognition and treatment of the autoantibodies which target neural structures, with immunosuppressive therapy, can improve outcome in these patients. This review contains 4 figures, 3 tables, and 42 references. Key words: osmotic demyelination syndrome,hepatic encephalopathy, renal failure, triphasic waves, dialysis disequilibrium syndrome, Wernicke encephalopathy, Korsakoff syndrome, myxedema coma, Hashimoto encephalopathy

Metabolic Encephalopathy - Part II

Normal neurologic function requires a constantly balanced environment of electrolytes. Normal hepatic and renal function is critical in maintaining this balance while removing toxins, maintaining a physiologic pH and regulating the excretion of electrolytes. Nutritional intake provides essential nutrients but deficiencies can lead to characteristic syndromes such as Wernicke's encephalopathy and pellagra and exposure to neurotoxic substances such as heavy metals can lead to encephalopathy. Thyroid and adrenal dysfunction are common endocrine causes of encephalopathy and symptoms can often improve rapidly with treatment. A subset of idiopathic encephalopathy is increasingly being recognized as having an autoimmune basis, often presenting as a paraneoplastic process, and having a constellation of symptoms which can aide in the diagnosis. Timely recognition and treatment of the autoantibodies which target neural structures, with immunosuppressive therapy, can improve outcome in these patients. This review contains 4 figures, 3 tables, and 42 references. Key words: osmotic demyelination syndrome,hepatic encephalopathy, renal failure, triphasic waves, dialysis disequilibrium syndrome, Wernicke encephalopathy, Korsakoff syndrome, myxedema coma, Hashimoto encephalopathy