The efficacy of topical imiquimod in high-grade cervical intraepithelial neoplasia: A systematic review and meta-analysis.

OBJECTIVE: A major side effect of cervical excision for high-grade cervical intraepithelial neoplasia (CIN) is premature birth. A non-invasive treatment for reproductive age women is warranted. The aim of the present study was to determine the efficacy of topical imiquimod in the treatment of high-grade CIN, defined as a regression to ≤CIN 1, and to determine the clearance rate of high-risk human papillomavirus (hr-HPV), compared with surgical treatment and placebo. METHODS: Databases were searched for articles from their inception to February 2023.The study protocol number was INPLASY2022110046. Original studies reporting the efficacy of topical imiquimod in CIN 2, CIN 3 or persistent hr-HPV infections were included. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses checklist. RESULTS: Five studies were included (n = 463). Histological regression to ≤CIN 1 was 55% in imiquimod versus 29% in placebo, and 93% in surgical treatment. Imiquimod-treated women had a greater odds of histological regression to ≤CIN 1 than placebo (odds ratio [OR] 4.17, 95% confidence interval [CI] 2.03-8.54). In comparison to imiquimod, surgical treatment had an OR of 14.81(95% CI 6.59-33.27) for histological regression to ≤CIN 1. The hr-HPV clearance rate was 53.4% after imiquimod and 66% after surgical treatment (95% CI 0.62-23.77). CONCLUSIONS: The histological regression rate is highest for surgical treatment followed by imiquimod treatment and placebo.

Concepts of Lactate Metabolic Clearance Rate and Lactate Clamp for Metabolic Inquiry: A Mini-Review.

Lactate is known to play a central role in the link between glycolytic and mitochondrial oxidative metabolism, as well as to serve as a primary gluconeogenic precursor. Blood lactate concentration is sensitive to the metabolic state of tissues and organs as lactate rates of appearance and disposal/disappearance in the circulation rise and fall in response to physical exercise and other metabolic disturbances. The highest lactate flux rates have been measured during moderate intensity exercise in endurance-trained individuals who exhibit muscular and metabolic adaptations lending to superior oxidative capacity. In contrast, a diminished ability to utilize lactate is associated with poor metabolic fitness. Given these widespread implications in exercise performance and health, we discuss the concept of lactate metabolic clearance rate, which increases at the onset of exercise and, unlike flux rates, reaches a peak just below the power output associated with the maximal lactate steady state. The metabolic clearance rate is determined by both disposal rate and blood concentration, two parameters that are mutually interdependent and thus difficult to parse during steady state exercise studies. We review the evolution of the in vivo lactate clamp methodology to control blood lactate concentration and discuss its application in the investigation of whole-body lactate disposal capacities. In conclusion, we assert that the lactate clamp is a useful research methodology for examining lactate flux, in particular the factors that drive metabolic clearance rate.

Factors influencing the efficacy of residual thyroid clearance with 131I for the first time after surgery in patients with differentiated thyroid cancer / 中国医师杂志

Objective:To explore the influencing factors of residual thyroid clearance with 131I after surgery in patients with differentiated thyroid cancer (DTC). Methods:A retrospective analysis was conducted on the clinical data of 100 DTC patients admitted to the Hunan Provincial People′s Hospital from January 2018 to February 2021 who underwent 131I treatment for the first time. The success rates of first thyroidectomy using different doses of 131I, different pathological types, and different treatment times were compared, and logistic regression analysis was conducted to investigate the influencing factors of the efficacy of first postoperative 131I thyroidectomy in DTC patients. Results:A total of 54 patients successfully cleared residual thyroid, 46 patients failed to clear residual thyroid, and the success rate of clearing residual thyroid was 54%. The success rates of first clearance of residual thyroid in patients with 131I doses of 80 mCi, 90 mCi, and 100 mCi were 37.50%(12/32), 52.78%(19/36), and 71.88%(23/32), respectively, with statistically significant differences among the groups ( P<0.05); The success rates of first removal of residual thyroid in patients with follicular carcinoma, mixed papillary follicular carcinoma, and papillary carcinoma were 65.71%(23/35), 39.13%(9/23), and 52.38%(22/42), respectively. There was no statistically significant difference between the groups ( P>0.05); The success rates of first removal of residual thyroid in the group1 of patients (treatment time<3 months), the group2 of patients (treatment time 3-12 months), and the group3 of patients (treatment time>12 months) were 68.09%(32/47), 44.44%(16/36), and 35.30%(6/17), respectively. There was no statistically significant difference between the groups ( P>0.05); There was no statistically significant difference in the success rate of clearing residual thyroid in DTC patients of different genders, ages, pathological stages, and thyroid stimulating hormone (TSH) levels (all P>0.05); The difference in the success rate of clearing residual thyroid in DTC patients with different metastatic conditions and stimulating thyroid globulin (sTg) was statistically significant (all P<0.05); sTg, postoperative lymph node metastasis, and postoperative distant metastasis were independent risk factors for the efficacy of residual thyroid clearance in DTC patients for the first time after surgery (all P<0.05). Conclusions:The influencing factors for the efficacy of the first 131I in removing residual thyroid include differences in 131I dosage, presence or absence of metastatic lesions during treatment, Tg levels, etc. Reducing Tg levels is an important factor in improving remission rate, and controlling lymph nodes and distant metastasis is a key factor for the successful efficacy of the first 131I in removing residual thyroid.

Four-Compartment Diffusion Model of Cortisol Disposition: Comparison With 3 Alternative Models in Current Clinical Use.

Context: Estimated rates of cortisol elimination and appearance vary according to the model used to obtain them. Generalizability of current models of cortisol disposition in healthy humans is limited. Objective: Development and validation of a realistic, mechanistic model of cortisol disposition that accounts for the major factors influencing plasma cortisol concentrations in vivo (Model 4), and comparison to previously described models of cortisol disposition in current clinical use (Models 1-3). Methods: The 4 models were independently applied to cortisol concentration data obtained for the hydrocortisone bolus experiment (20 mg) in 2 clinical groups: healthy volunteers (HVs, n = 6) and corticosteroid binding globulin (CBG)-deficient (n = 2). Model 4 used Fick's first law of diffusion to model free cortisol flux between vascular and extravascular compartments. Pharmacokinetic parameter solutions for Models 1-4 were optimized by numerical methods, and model-specific parameter solutions were compared by repeated measures analysis of variance. Models and respective parameter solutions were compared by mathematical and simulation analyses, and an assessment tool was used to compare performance characteristics of the four models evaluated herein. Results: Cortisol half-lives differed significantly between models (all P < .001) with significant model-group interaction (P = .02). In comparative analysis, Model 4 solutions yielded significantly reduced free cortisol half-life, improved fit to experimental data (both P < .01), and superior model performance. Conclusion: The proposed 4-compartment diffusion model (Model 4) is consistent with relevant experimental observations and met the greatest number of empiric validation criteria. Cortisol half-life solutions obtained using Model 4 were generalizable between HV and CBG-deficient groups and bolus and continuous modes of hydrocortisone infusion.

Obesity and anesthetic pharmacology: simulation of target-controlled infusion models of propofol and remifentanil.

The prevalence of obesity is increasing, resulting in an increase in the number of surgeries performed to treat obesity and diseases induced by obesity. The associated comorbidities as well as the pharmacokinetic and pharmacodynamic changes that occur in obese patients make it difficult to control the appropriate dose of anesthetic agents. Factors that affect pharmacokinetic changes include the increase in adipose tissue, lean body weight, extracellular fluid, and cardiac output associated with obesity. These physiological and body compositional changes cause changes in the pharmacokinetic and pharmacodynamic parameters. The increased central volume of distribution and alterations in the clearance of drugs affect the plasma concentration of propofol and remifentanil in the obese population. Additionally, obesity can affect pharmacodynamic properties, such as the 50% of maximal effective concentration and the effect-site equilibration rate constant (ke0). Conducting a simulation of target-controlled infusions based on pharmacokinetic and pharmacodynamic models that include patients that are obese can help clinicians better understand the pharmacokinetic and pharmacodynamic changes of anesthetic drugs associated with this population.

Urate levels and clearance in renal patients under peritoneal dialysis.

Hemodialysis adequately controls serum uric acid (UA) levels, making UA-lowering drugs unnecessary; scant data are available for peritoneal dialysis (PD). We analyzed blood, 24 h urine and dialysis fluid from twenty patients under PD, to assess UA levels and clearances, and factors associated with better performance and maintenance of target levels (<6mg/dL). Median serum UA was 5.4 mg/dL (p25-75 4.4-5.8), mainly achieved through peritoneal clearance (3.0 mL/min/1.73m2, 71.2% of total UA clearance); 75% of participants was on UA targets. Continuous cycling peritoneal dialysis showed highest UA clearance and target achievements. These findings may be of interest for end-stage renal patients with gout.

Decreased maximal cortisol secretion rate in patients with cirrhosis: Relation to disease severity.

BACKGROUND & AIMS: Hepatic enzymes play a major role in the metabolic elimination of cortisol, and reduced rates of cortisol clearance have been consistently observed in patients with chronic liver disease. It is less clear whether there are concomitant abnormalities of adrenocortical function in patients with cirrhosis. In the present study, we sought to assess adrenocortical function in patients with cirrhosis using measures of free cortisol appearance and elimination rates that are independent of serum concentrations of cortisol binding proteins. METHODS: Post hoc analysis used computer-assisted numerical and modelling methods with serial total and free cortisol concentration data to obtain rates of free cortisol appearance and elimination. Rate parameters were obtained in 114 patients with chronic liver disease, including Child-Pugh (CP) ≤8 (n = 53) and CP >8 (n = 61). RESULTS: Maximal cortisol secretion rate (CSRmax) was significantly decreased (p = 0.01) in patients with cirrhosis with CP >8 (0.28 nM/s; 95% CI 0.24-0.34) compared with those with CP ≤8 (0.39 nM/s; 95% CI 0.33-0.46), and CSRmax was negatively correlated with CP score (r = -0.19, p = 0.01). Free cortisol elimination rate was significantly (p = 0.04) decreased in the CP >8 group (0.16 ± 0.20 min-1) compared with that in the CP ≤8 group (0.21 ± 0.21 min-1), and free cortisol elimination rates were negatively correlated with CP score (r = -0.23, p = 0.01). A significant correlation between CSRmax and free cortisol elimination rate (r = 0.88, p <0.001) was observed. CONCLUSIONS: CSRmax and free cortisol elimination rates were significantly reduced according to severity of cirrhosis. In contrast to stimulated total cortisol concentrations, CSRmax estimates were independent of cortisol-binding protein concentrations. Results provide additional evidence of subnormal adrenocortical function in patients with cirrhosis. LAY SUMMARY: We applied numerical analytic methods to characterise adrenocortical function in patients with varying stages of chronic liver disease. We found that patients with more severe cirrhosis have decreased rate of free cortisol elimination and decreased maximal cortisol secretion rate, which is a measure of adrenocortical function. In contrast to conventional measures of adrenocortical function, those obtained using numerical methods were not affected by variation in corticosteroid binding globulin and albumin concentrations. We conclude that patients with cirrhosis demonstrate measurable abnormalities of adrenocortical function, evidence of which supports aspects of the hepatoadrenal syndrome hypothesis.

Evaluation of renal drug dosing adjustment in chronic kidney disease patients at two university hospitals in Lebanon.

BACKGROUND: Inappropriate medication dosing in patients with chronic kidney disease can cause toxicity or ineffective therapy. Patients are at a high risk of developing related adverse events caused by the altered effect of drugs in conjunction with the use of polypharmacy to treat comorbid conditions. This necessitates adequate renal dosing adjustments. OBJECTIVE: The current study aims at assessing whether appropriate dosing adjustments were made in hospitalized patients with chronic kidney disease. METHODS: A retrospective descriptive study was conducted at two university hospitals in Beirut between January and December 2016. All adult CKD patients with creatinine clearance less than 60 ml/min and receiving at least one medication that require renal dosing adjustment were included. Kidney function was estimated from serum creatinine using Cockcroft-Gault equation, and dose appropriateness was determined by comparing practice with specific guidelines. The rates of renal drug dosing adjustment were investigated, in addition to the influence of possible determinants, such as the severity of renal impairment, reason of hospital admission, and other patient characteristics. RESULTS: 2138 patients admitted in 2016 were screened. 223 adults receiving 578 drug orders that require adjustment were included. Among the 578 orders, 215 (37%) were adjusted adequately, 284 (49%) were adjusted inadequately, and 79 (14%) were not adjusted at all. Beta-blockers were the most inadequately dosed (83.6%) class of medication, whereas lipid-lowering agents had the highest percentage of adequate dosing (65.1%). As per patient, 84.3% of patients appeared to be receiving at least one inappropriate drug dose. CONCLUSIONS: Our study confirms that physicians are not prescribing appropriate dosing adjustments in chronic kidney disease inpatients, which may have deleterious effects. This highlights the need for more nephrology consultation and the implementation of physician education programs.

Clinical Pharmacology of Antibiotics.

Antimicrobial pharmacology and its effect on prescribing is quite complex. Selecting an antibiotic that will optimally treat an infection while minimizing adverse effects and the development of resistance is only the first step, as one must also consider the patient's individual pharmacokinetic alterations and the pharmacodynamic properties of the drug when prescribing it as well. Patients with CKD may have alterations in their protein binding, volumes of distribution, kidney clearance, and nonrenal clearance that necessitates antibiotic dose adjustments to prevent the development of toxicity. Knowledge of a drug's pharmacodynamics, defined as the relationship between drug exposure and antibacterial efficacy, provides some guidance regarding the optimal way to make dose adjustments. Different pharmacodynamic goals, such as maximizing the time that free (unbound) drug concentrations spend above the minimum inhibitory concentration (MIC) for time dependent drugs (e.g., ß-lactams) or maximizing the free peak-to-MIC ratio for concentration-dependent antibiotics (e.g., aminoglycosides), require different adjustment strategies; for instance, decreasing the dose while maintaining normal dosing frequency or giving normal (or even larger) doses less frequently, respectively. Patients receiving hemodialysis have other important prescribing considerations as well. The nephrologist or patient may prefer to receive antibiotics that can be administered intravenously toward the end of a dialysis session. Additionally, newer dialysis technologies and filters can increase drug removal more than originally reported. This review will discuss the place in therapy, mechanism of action, pharmacokinetic, pharmacodynamic, and other pharmacologic considerations encountered when prescribing commonly used antibiotics in patients with chronic kidney disease or ESKD.

Validated analytical study of the effect of Lycopene on the pharmacokinetics of Paracetamol and Chlorzoxazone in rats

Lycopene was reported to influence some cytochrome P450 enzymes activity. The present study investigates the effect of lycopene on the pharmacokinetics of paracetamol and chlorzoxazone. Lycopene (20 mg/kg) was intra-peritoneally administered to two groups of rats for eight consecutive days and two other groups were given vehicle. On the eighth day, chlorzoxazone and paracetamol were separately intravenously administered to a lycopene group and a control group. Blood samples were collected at different time intervals, treated and analyzed using HPLC. The HPLC method used for paracetamol analysis was based on isocratic elution using a mobile phase consisting of water: methanol, (77:23 v/v) at a flow rate 1 mL min−1, Kromasil C18 column, and UV detection at 254 nm using caffeine as internal standard. About chlorzoxazone, separation was carried out using water: acetonitrile (60: 40, v/v) as the mobile phase at a flow rate 1 mL min−1, Inertsil ODS-3 C18 column, UV detection at 283 nm and esomeprazole as internal standard. Statistical analysis of the pharmacokinetic data using student t test showed a significant increase in AUC 0-t , AUC 0-Inf and t1/2 of paracetamol (P<0.05) and of chlorzoxazone (P<0.05) in the groups pretreated with lycopene (20 mg/kg), significant increase in the volume of distribution of paracetamol (P < 0.05), but no significant difference in that of chlorzoxazone. In other words, paracetamol and chlorzoxazone showed significant decrease (P < 0.05), respectively. These results demonstrate that treatment of rats with Lycopene (20mg/kg, ip) has a significant effect on the metabolic clearance and the pharmacokinetics of both drugs

Beta-cell Function and Metabolic Clearance Rate of Glucose in Patients with Major Mental Health Disorders on Antipsychotic Drug Treatment.

BACKGROUND: Insulin resistance and metabolic alteration continue to be essential features of major mental health disorders (MMHD) with poorly understood and multifaceted mechanisms. This study was carried out to provide information on insulin resistance, beta-cell function, metabolic clearance rate of glucose and their possible interplay with duration of antipsychotic use in patients with major mental health disorders. METHODOLOGY: Plasma levels of glucose and insulin were determined in 124 patients with MMHD after an overnight fast and at 30 and 120 min of standard Oral Glucose Tolerance Test. Thereafter, indices of insulin resistance, beta-cell function and estimated metabolic clearance rate of glucose (eMCR) were calculated appropriately. Statistical analysis was done using ANOVA, Kruskal Wallis, independent Student's t-test and Mann-Whitney U. P-values less than 0.05 were considered as statistically significant. RESULTS: Metabolic factors (fasting and postprandial glucose and insulin), indices of insulin sensitivity and ß-cell function were not significantly different when patients with schizophrenia, bipolar and depression were compared with one another. Postprandial insulin level at 30 min (30 min PPI), estimated First and Second Phases of Insulin Release (eFPIR, eSPIR) were significantly lower in patients on atypical antipsychotic drugs [18.15 (3.57-40.35) µIU/ml), 617.63 (320.06-911.31) pmol/l, 180.30 (114.82-249.39) pmol/l] compared with patients on typical antipsychotic drugs [27.48 (13.33-47.68) µIU/ml, 767.69 (530.58-1198.35) pmol/l, 209.89 (154.01-310.97) pmol/l]. Furthermore, the mean waist circumference and body mass index were significantly higher in patients who have been on anti-psychotic drug for more than 10 years compared with patients with less than 5 years history of anti-psychotic use. eMCR of glucose progressively declined with increasing duration of antipsychotic use and it was significantly lower in patients who have been on antipsychotic drugs for more than 10 years [8.09 (5.90-9.44) ml.kg-1.min-1] compared with patients who have been on the drugs for less than 5 years [9.03 (7.47-10.04) ml.kg-1.min-1]. CONCLUSION: Patients on atypical antipsychotics seem to have insulin secretion phases consistent with ß-cell dysfunction. Also, chronicity of antipsychotic treatment predisposes patients with major mental health disorders to central adiposity and low metabolic clearance rate of glucose, a forerunner of glucose intolerance.

Characterization of Cortisol Secretion Rate in Secondary Adrenal Insufficiency.

CONTEXT: In secondary adrenal insufficiency (SAI), chronic deficiency of adrenocorticotropin (ACTH) is believed to result in secondary changes in adrenocortical function, causing an altered dose-response relationship between ACTH concentration and cortisol secretion rate (CSR). OBJECTIVE: We sought to characterize maximal cortisol secretion rate (CSRmax) and free cortisol half-life in patients with SAI, compare results with those of age-matched healthy controls, and examine the influence of predictor variables on ACTH-stimulated cortisol concentrations. DESIGN: CSRmax was estimated from ACTH1-24 (250 µg)-stimulated cortisol time-concentration data. Estimates for CSRmax and free cortisol half-life were obtained for both dexamethasone (DEX) and placebo pretreatment conditions for all subjects. SETTING: Single academic medical center. PATIENTS: Patients with SAI (n = 10) compared with age-matched healthy controls (n = 21). INTERVENTIONS: The order of DEX vs placebo pretreatment was randomized and double-blind. Cortisol concentrations were obtained at baseline and at intervals for 120 minutes after ACTH1-24. MAIN OUTCOME MEASURES: CSRmax and free cortisol half-life were obtained by numerical modeling analysis. Predictors of stimulated cortisol concentrations were evaluated using a multivariate model. RESULTS: CSRmax was significantly (P < 0.001) reduced in patients with SAI compared with controls for both placebo (0.17 ± 0.09 vs 0.46 ± 0.14 nM/s) and DEX (0.18 ± 0.13 vs 0.43 ± 0.13 nM/s) conditions. Significant predictors of ACTH1-24-stimulated total cortisol concentrations included CSRmax, free cortisol half-life, and baseline total cortisol, corticosteroid-binding globulin, and albumin concentrations (all P < 0.05). CONCLUSIONS: Our finding of significantly decreased CSRmax confirms that SAI is associated with alterations in the CSR-ACTH dose-response curve. Decreased CSRmax contributes importantly to the laboratory diagnosis of SAI.

Measuring the Pharmacokinetic Properties of Drugs with a Novel Surgical Rat Model.

Purpose/aim of the study: The pharmacokinetic (PK) parameters in animal models can help optimize novel candidate drugs prior to human trials. However, due to the complexity of pharmacokinetic experiments, their use is limited in academia. We present a novel surgical rat model for investigation of pharmacokinetic parameters and its use in an anti-obesity drug development program. MATERIALS AND METHODS: The model uses anesthetized male Wistar rats, a jugular, a femoral catheter, and an insulin pump for peptide infusion. The following pharmacokinetic parameters were measured: metabolic clearance rate (MCR), half-life, and volume of distribution (Vd). Glucagon-like peptide 1 (GLP-1), glucagon (GCG), and exendin-4 (Ex-4) were used to validate the model. The pharmacokinetic parameters of anti-obesity drug candidates X1, X2, and X3 were measured. RESULTS: GLP-1 had a significantly higher MCR (83.9 ± 14.1 mL/min/kg) compared to GCG (40.7 ± 14.3 mL/min/kg) and Ex-4 (10.1 ± 2.5 mL/min/kg) (p < .01 and p < .001 respectively). Ex-4 had a statistically significant longer half-life (35.1 ± 7.4 min) compared to both GCG (3.2 ± 1.7 min) and GLP-1 (1.2 ± 0.4 min) (p < .01 for both GCG and GLP-1). Ex-4 had a statistically significant higher volume of distribution (429.7 ± 164.9 mL/kg) compared to both GCG (146.8 ± 49.6 mL/kg) and GLP-1 (149.7 ± 53.5 mL/kg) (p < .01 for both GCG and GLP-1). Peptide X3 had a statistically significant longer half-life (21.3 ± 3.5 min) compared to both X1 (3.9 ± 0.4 min) and X2 (16.1 ± 2.8 min) (p < .001 for both X1 and X2). CONCLUSIONS: We present an affordable and easily accessible platform for the measurement of PK parameters of peptides. This novel surgical rat model produces consistent and reproducible results while minimizing animal use.

Association between Helicobacter pylori infection and creatinine clearance rate in elderly hypertensive patients / 中华老年医学杂志

Objectives To reveal the association between Helicobacter pylori infection and creatinine clearance rate in elderly patients with hypertension.Methods A total of 600 elderly hypertensive patients with different degrees of renal impairment and helicobacter pylori(HP)infection were randomly selected from Department of Health Care,General Hospital of Tianjin Medical University from 2010 to 2015.Serum creatinine concentration detection was conducted and creatinine clearance rate was calculated.Patients were divided into HP infection group(n =254)and non-HP-infection group (n =346).The multiple logistic regression analysis showed the correlation between Helicobacter pylori infection and decreased creatinine clearance rate.Results Creatinine clearance rate was significantly lower in HP-infection group[(61.1 ± 12.7)ml/min] than in non-HP-infection group[(78.5 ± 11.9) ml/min,P =0.014].Multifactorial logistic analysis revealed that Helieobacter pylori infection was significantly associated with decreased creatinine clearance rate(OR=3.5 18,95 ％ CI:1.105～4.918,P =0.011).Conclusions Helicobacter pylori infection is significantly related with decreased creatinine clearance rate in elderly patients with hypertension.

N-linked glycan truncation causes enhanced clearance of plasma-derived von Willebrand factor.

Essentials von Willebrands factor (VWF) glycosylation plays a key role in modulating in vivo clearance. VWF glycoforms were used to examine the role of specific glycan moieties in regulating clearance. Reduction in sialylation resulted in enhanced VWF clearance through asialoglycoprotein receptor. Progressive VWF N-linked glycan trimming resulted in increased macrophage-mediated clearance. Click to hear Dr Denis discuss clearance of von Willebrand factor in a free presentation from the ISTH Academy SUMMARY: Background Enhanced von Willebrand factor (VWF) clearance is important in the etiology of both type 1 and type 2 von Willebrand disease (VWD). In addition, previous studies have demonstrated that VWF glycans play a key role in regulating in vivo clearance. However, the molecular mechanisms underlying VWF clearance remain poorly understood. Objective To define the molecular mechanisms through which VWF N-linked glycan structures influence in vivo clearance. Methods By use of a series of exoglycosidases, different plasma-derived VWF (pd-VWF) glycoforms were generated. In vivo clearance of these glycoforms was then assessed in VWF-/- mice in the presence or absence of inhibitors of asialoglycoprotein receptor (ASGPR), or following clodronate-induced macrophage depletion. Results Reduced amounts of N-linked and O-linked sialylation resulted in enhanced pd-VWF clearance modulated via ASGPR. In addition to this role of terminal sialylation, we further observed that progressive N-linked glycan trimming also resulted in markedly enhanced VWF clearance. Furthermore, these additional N-linked glycan effects on clearance were ASGPR-independent, and instead involved enhanced macrophage clearance that was mediated, at least in part, through LDL receptor-related protein 1. Conclusion The carbohydrate determinants expressed on VWF regulate susceptibility to proteolysis by ADAMTS-13. In addition, our findings now further demonstrate that non-sialic acid carbohydrate determinants expressed on VWF also play an unexpectedly important role in modulating in vivo clearance through both hepatic ASGPR-dependent and macrophage-dependent pathways. In addition, these data further support the hypothesis that variation in VWF glycosylation may be important in the pathophysiology underlying type 1C VWD.

Aging and ABO blood type influence von Willebrand factor and factor VIII levels through interrelated mechanisms.

UNLABELLED: Essentials von Willebrand factor (VWF) and factor VIII (FVIII) levels are modulated by age and ABO status. The effect of aging and ABO blood type on VWF and FVIII was assessed in 207 normal individuals. Aging and ABO blood type showed combined and bidirectional influences on VWF and FVIII levels. Aging and ABO blood type influence VWF levels through both secretion and clearance mechanisms. SUMMARY: Background The effect of aging and ABO blood type on plasma levels of von Willebrand factor (VWF) and factor VIII (FVIII) have been widely reported; however, a comprehensive analysis of their combined effect has not been performed and the mechanisms responsible for the age-related changes have not been determined. Objectives To assess the influence of aging and ABO blood type on VWF and FVIII levels, and to evaluate the contribution of VWF secretion and clearance to the age-related changes. Methods A cross-sectional observational study was performed in a cohort of 207 normal individuals, whose levels of VWF, FVIII, VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio and blood type A antigen content on VWF (A-VWF) were quantified. Results Aging and ABO blood type exerted interrelated effects on VWF and FVIII plasma levels, because the age-related increase in both proteins was significantly higher in type non-O individuals (ß = 0.011 vs. 0.005). This increase with age in non-O subjects drove the differences between blood types in VWF levels, as the mean difference increased from 0.13 U/mL in the young to 0.57 U/mL in the old. Moreover, A-VWF was associated with both VWF antigen (ß = 0.29; 95% confidence interval [CI], 0.09, 0.50) and VWF clearance (ß = -0.15; 95% CI, -0.25, -0.06). We also documented an effect of ABO blood type on VWF secretion with aging, as old individuals with blood type non-O showed higher levels of VWFpp (mean difference 0.29 U/mL). Conclusions Aging and ABO blood type have an interrelated effect on VWF and FVIII levels, where the effect of one is significantly influenced by the presence of the other.

CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects.

AIMS: Ketamine analgesia is limited by low intrinsic efficacy compounded by large interindividual variability in drug responses, possibly due to the heterogeneity in drug concentration. The CYP2B6*6 allele is associated with substantially reduced ketamine metabolism in vitro and, therefore, may affect ketamine clearance. Our aims were to examine the impact of the CYP2B6*6 allele on ketamine plasma clearance and on adverse effects in chronic pain patients. METHODS: CYP2B6 genotypes were identified in 49 chronic pain patients who received 24 h continuous subcutaneous infusions of ketamine. Steady-state plasma concentrations of ketamine (Css,k ) and norketamine (Css,nk ) were determined using HPLC. RESULTS: The median plasma clearance of ketamine after 100 mg 24 h(-1) dose was significantly lower in patients with the CYP2B6*6/*6 (21.6 l h(-1) ) and CYP2B6*1/*6 (40.6 l h(-1) ) genotypes compared with patients with the CYP2B6*1/*1 genotype (68.1 l h(-1) , P < 0.001). The ketamine : norketamine plasma metabolic ratio was significantly higher in patients with the CYP2B6*6/*6 genotype than in those with the CYP2B6*1/*6 and the CYP2B6*1/*1 genotypes (P < 0.001). Patients who experienced adverse effects had lower plasma clearance (45.6 l h(-1) ) than those who did not (52.6 l h(-1) , P = 0.04). The CYP2B6*6 genotype and age, and their combined impact explained 40%, 30% and 60% of the variation in Css,k , respectively. Similar results were observed after higher doses. CONCLUSIONS: The CYP2B6*6 allele is associated with a substantial decrease in steady-state ketamine plasma clearance in chronic pain patients. The decreased clearance and resultant higher plasma concentrations may be associated with a higher incidence of ketamine adverse effects.

von Willebrand factor arginine 1205 substitution results in accelerated macrophage-dependent clearance in vivo.

BACKGROUND: Enhanced von Willebrand factor (VWF) clearance is important in the etiology of type 1 and type 2 von Willebrand disease (VWD). More than 20 different VWF point mutations have already been reported in patients with enhanced clearance. These include the VWD-Vicenza variant, which is characterized by an Arg1205His substitution in the VWF D3 domain. Critically, however, the molecular mechanisms through which single amino acid substitutions in VWF result in enhanced clearance of this complex multimeric glycoprotein have not been defined. OBJECTIVES: In this study, we have investigated the biological basis underlying the enhanced clearance of the VWF-R1205H variant. METHODS: Using VWF(-/-) mice, in vivo clearance rates were determined for a series of full-length and truncated recombinant VWF variants. In addition, the role of macrophages in modulating enhanced VWD-Vicenza clearance was investigated using clodronate liposome administration. RESULTS: Our findings demonstrate that substitutions of R1205 with histidine, cysteine or serine all result in markedly reduced survival of full-length recombinant VWF. Importantly, D'A3 fragments containing these same R1205 substitutions also demonstrated significantly enhanced clearance. In contrast to the reduced in vivo survival observed with R1205H, clearance of R1204H was not enhanced. Recent studies have demonstrated that hepatic and splenic macrophages play key roles in regulating VWF clearance. Importantly, macrophage-depletion also served to markedly attenuate the enhanced clearance phenotypes associated with VWF-R1205H, VWF-R1205S and VWF-R1205C. CONCLUSIONS: Collectively, these novel findings demonstrate a specific and critical role for the R1205 residue in modulating macrophage-mediated clearance of VWF in vivo.