PK/PD modeling of 5-hydroxytryptophan (5-HTP) challenge test with cortisol measurement in serum and saliva.

This research was planned to build a Pharmacokinetic/Pharmacodynamic (PK/PD) model of 5-hydroxytryptophan (5-HTP) challenge study including a circadian rhythm component of cortisol and to predict serum cortisol based on saliva cortisol. Data from three 5-HTP challenge studies in healthy volunteers were collected. Serum 5-HTP, saliva, and serum cortisol were sampled as PK and PD marker. The population PK/PD modeling approach was applied. A baseline model of serum cortisol was built to assess the circadian rhythm before a pharmacodynamic model was used to evaluate the drug effect of the 5-HTP on cortisol. Finally, linear and power function relationships were tested to predict serum cortisol based on saliva cortisol. The PK of 5-HTP could be described using a one-compartment model with a transit compartment. The typical value for clearance was 20.40 L h-1 and showed inter-study variability. A cosine function was chosen and properly described the circadian rhythm of serum cortisol. A linear approximation model was applied to fit the 5-HTP PD effect on cortisol data with a slope of 4.16 ng mL-1  h. A power function provided a better description than a linear function to relate the saliva and serum cortisol. In conclusion, a circadian rhythm component was built in the PK/PD model of the 5-HTP challenge test which could better improve the understanding of the stimulating effect on HPA with cortisol change. After the 5-HTP challenge, saliva cortisol correlated well with serum cortisol and was predictable by a population PK-PD model.

The Clinical Performance of Monolithic Lithium Disilicate Posterior Restorations After 5, 10, and 15 Years: A Retrospective Case Series.

PURPOSE: Lithium disilicate (LDS) glass-ceramic restorations are routinely used, but results over a period longer than 10 years are rare. The objective of this study was to obtain long-term clinical data on monolithic LDS posterior crowns provided by a single restorative dentist. MATERIALS AND METHODS: Eligible patients who received a circumferential LDS crown in the posterior region between 1997 and 2010 were invited to participate in a clinical examination in 2015. This consisted of intraoral inspection and radiographs, performed by one observer and according to standardized criteria. Probability of survival was estimated using Kaplan-Meier survival analysis. RESULTS: A total of 13 patients (n = 87 restorations) fulfilled the inclusion criteria. Of these, 12 patients were available for clinical evaluation (n = 74 restorations). After 5, 10, and 15 years, the cumulative chance of survival of the restoration was 92%, 85.5%, and 81.9%, respectively, with a median observation period of 12.8 years. Of the 74 restorations, 13 failed: 4 because of secondary caries, 2 because of debonding, and 7 because of fracture of the restoration. CONCLUSION: Lithium disilicate can be regarded as a strong and fracture-load-resistant restorative material providing reliable long-term clinical performance.

Tooth wear: a systematic review of treatment options.

STATEMENT OF PROBLEM: Treatment of tooth wear is increasing. Because no evidence-based guidelines are available, the clinician may have difficulties deciding which treatment option to choose to resolve complex situations. PURPOSE: The purpose of this systematic review was to identify similarities among treatment options for generalized tooth wear and to develop an approach to rehabilitation based on the best evidence available. MATERIAL AND METHODS: A Medline and Cochrane search (for articles published from January 31, 2003, to January 31, 2013) was conducted. Minimally invasive and fully described treatments for generalized tooth wear with esthetically satisfying results were included. Five steps within the treatment procedures were analyzed: diagnostic waxing (DW), occlusal positioning (OP), vertical dimension increase (VDI), restoration, and follow-up. RESULTS: Common threads were established within the 5 treatment steps. Nine studies used DW, and 6 performed diagnostic tooth arrangement (DTA). Centric relation was used in 5 studies, and VDI was tested in 8 studies, 5 of which used a removable appliance. Seven studies implemented a provisional stage, and 5 used composite resin at that time. For definitive treatment, composite resin (6 studies) and glass ceramic (6 studies) were used. Seven studies applied a protective appliance, and 5 scheduled regular posttreatment evaluation as means of aftercare. CONCLUSIONS: Within the limitations of this systematic review, the present evidence is not strong enough to form conclusions, and the presented similarities cannot be substantiated with evidence. Therefore, comprehensive clinical research into the designated treatment of generalized tooth wear is recommended.

Hypothalamic-pituitary-adrenal axis functioning in Huntington's disease mutation carriers compared with mutation-negative first-degree controls.

Neurodegeneration in Huntington's disease (HD) occurs in various brain regions including the hypothalamus. In this cross-sectional study, hypothalamic-pituitary-adrenal (HPA) axis functioning was studied in 26 presymptomatic and 58 symptomatic HD mutation carriers, and 28 controls. HPA axis functioning was measured through salivary cortisol in the day curve, the cortisol awakening response (CAR), the area under the curve (AUC), the morning rise, and the dexamethasone suppression test (DST). Only the CAR was statistically different between the three groups, being explained by higher cortisol concentrations at 45 and 60 min post-awakening for presymptomatic mutation carriers compared to both symptomatic mutation carriers and controls. No differences were found for the AUC, evening and post-DST cortisol concentrations. Our study indicates a mild disturbance in morning cortisol secretion in HD mutation carriers that precedes the onset of motor symptoms.

Explaining variability in ciclosporin exposure in adult kidney transplant recipients.

PURPOSE: Optimal ciclosporin A (CsA) exposure in kidney transplant recipients is difficult to attain because of variability in CsA pharmacokinetics. A better understanding of the variability in CsA exposure could be a good means of individualizing therapy. Specifically, genetic variability in genes involved in CsA metabolism could explain exposure differences. Therefore, this study is aimed at identifying a relationship between genetic polymorphisms and the variability in CsA exposure, while accounting for non-genetic sources of variability. METHODS: De novo kidney transplant patients (n = 33) were treated with CsA for 1 year and extensive blood sampling was performed on multiple occasions throughout the year. The effects of the non-genetic covariates hematocrit, serum albumin concentration, cholesterol, demographics (i.e., body weight), CsA dose interval, prednisolone dose and genetic polymorphisms in genes encoding ABCB1, CYP3A4, CYP3A5, and PXR on CsA pharmacokinetics were studied using non-linear mixed effect modeling. RESULTS: The pharmacokinetics of CsA were described by a two-compartment disposition model with delayed absorption. Body weight was identified as the most important covariate and explained 35% of the random inter-individual variability in CsA clearance. Moreover, concurrent prednisolone use at a dosage of 20 mg/day or higher was associated with a 22% higher clearance of CsA, hence lower CsA exposure. In contrast, no considerable genotype effects (i.e., greater than 30-50%) on CsA clearance were found for the selected genes. CONCLUSIONS: It appears that the selected genetic markers explain variability in CsA exposure insufficiently to be of clinical relevance. Therefore, therapeutic drug monitoring is still required to optimize CsA exposure after administration of individualized doses based on body weight and, as this study suggests, co-administration of prednisolone.

Noninvasive functional liver blood flow measurement: comparison between bolus dose and steady-state clearance of sorbitol in a small-rodent model.

Plasma clearance of D-sorbitol, a nontoxic polyol, occurs predominantly in the liver and has been used to measure functional liver blood flow after bolus and steady- state intravenous administration. However, it is not known which of these two administration methods is superior. Therefore, plasma D-sorbitol clearance was studied in an animal model both after a bolus dose and under steady-state (SS) conditions and compared directly with liver blood flow, under normal conditions, and after the induction of endotoxin (LPS) sepsis. Adult male Wistar rats (526 +/- 38 g body wt; n = 27) were anesthetized and mechanically ventilated. Hemodynamics, hepatic arterial flow, and portal venous flow were measured. Two groups were studied, namely healthy animals that served as controls and a sepsis group that received 5 mg/kg LPS intravenously (Escherichia coli O127:B8). Each animal received either a SS infusion (0.1 mg/100 g body wt per min) or a bolus (3 mg/100 g body wt) of a 5% D-sorbitol solution intravenously in a randomized order. After the initial measurements and a 60-min pause time in between (T(1/2,sorbitol) = 9 min), a crossover was done. The hepatic clearance of D-sorbitol in the control group showed a good correlation between bolus and SS (Spearman's r = 0.7681, P = 0.0004), and both techniques correlated well with total liver blood flow (TLBF) (r = 0.7239, P = 0.0023 and r = 0.7226, P = 0.0023, respectively). Also in the sepsis group there was a good correlation between bolus and SS sorbitol clearance (r = 0.6655, P = 0.0182). In the sepsis group, only the SS clearance correlated with TLBF (r = 0.6434, P = 0.024). In conclusion, in normal and under septic conditions, hepatic clearance of D-sorbitol either by bolus or a SS infusion is comparable. In healthy animals, this also correlated well with TLBF but not in septic conditions. However, this is expected because of the changes in the liver microcirculation, shunting, and decreased hepatocyte function in sepsis.

Central nervous system effects of alcohol at a pseudo-steady-state concentration using alcohol clamping in healthy volunteers.

AIM: In determining the acute effects of alcohol, it is helpful if alcohol concentrations are maintained at stable levels, to facilitate the interpretation of the results. Recently, an alcohol clamping method was developed that resulted in stable alcohol concentrations for hours. The aim of this study was to test a range of central nervous system (CNS) effects under pseudo-steady-state conditions. METHODS: To achieve a pseudo-steady state of 0.6 g l(-1), breath alcohol concentrations (BrAC) were frequently measured and fed back into a spreadsheet-based program to guide intravenous dosing. CNS effects were frequently measured throughout the clamp. RESULTS: The clamping paradigm resulted in a pseudo-steady-state BrAC of 0.61 g l(-1) (coefficient of variation 6.2%). A plateau was maintained from 25 to 300 min and caused significant effects on smooth pursuit eye movements [-9.7%, 95% confidence interval (CI) -12.4, -7.1], adaptive tracking (-3.4%, 95% CI -4.5, -2.2), visual analogue scale (VAS) alertness (-13 mm, 95% CI -20, -6), VAS alcohol effects (16 mm, 95% CI 7, 25) and body sway (21.3%, 95% CI 1.8, 45). Some effects (like smooth pursuit eye movements) closely followed the relatively stable alcohol concentrations, whereas others (such as body sway and VAS alcohol effects) fluctuated during the plateau phase. CONCLUSIONS: Most CNS effects of alcohol showed a trend to change over time, despite stable concentrations. Other variables remained stable under pseudo-steady-state conditions. The intravenous clamping method provides precise control over BrAC levels and allows frequent repetition of different CNS measurements. These features make this technique eminently suitable to study the complex pharmacodynamic effects of acute alcohol administration.

Increased melanogenesis is a risk factor for oxidative DNA damage--study on cultured melanocytes and atypical nevus cells.

Melanin synthesis is an oxygen-dependent process that acts as a potential source of reactive oxygen species (ROS) inside pigment-forming cells. The synthesis of the lighter variant of melanin, pheomelanin, consumes cysteine and this may limit the capacity of the cellular antioxidative defense. We show that tyrosine-induced melanogenesis in cultured normal human melanocytes (NHM) is accompanied by increased production of ROS and decreased concentration of intracellular glutathione. Clinical atypical (dysplastic) nevi (DN) regularly contain more melanin than do normal melanocytes (MC). We also show that in these cultured DN cells three out of four exhibit elevated synthesis of pheomelanin and this is accompanied by their early senescence. By using various redox-sensitive molecular probes, we demonstrate that cultured DN cells produce significantly more ROS than do normal MC from the same donor. Our experiments employing single-cell gel electrophoresis (comet assay) usually reveal higher fragmentation of DNA in DN cells than in normal MC. Even if in some cases the normal alkaline comet assay shows no differences in DNA fragmentation between DN cells and normal MC, the use of the comet assay with formamidopyrimidine DNA glycosylase can disclose that the DNA of the cultured DN cells harbor more oxidative damage than the DNA of normal MC from the same person.

Lack of value of routine analysis of cerebrospinal fluid for prediction and diagnosis of external drainage-related bacterial meningitis.

OBJECT: Routine microbiological and chemical analysis of cerebrospinal fluid (CSF) is often performed to diagnose external drainage-related bacterial meningitis (ED-BM) at an early stage. A cohort study was performed to investigate the value of several commonly used CSF parameters for the prediction and diagnosis of ED-BM. METHODS: In a cohort of 230 consecutive patients in whom external drains had been placed, CSF samples were collected daily, prospectively evaluated for the presence of bacteria using Gram stain and microbiological culture, and analyzed for leukocyte count, protein concentration, glucose concentration, and ratio of CSF glucose to blood glucose. In addition, the CSF concentration of interleukin-6 (IL-6) was determined. The definition of ED-BM was based on positive culture results in combination with clinical symptoms. A matched case-control study was performed to evaluate the cohort longitudinally and to control for biasing factors such as duration of external drainage. External drainage-related bacterial meningitis developed in 22 patients (9.6%). Results from analyses of 1516 CSF samples showed no significant differences between the patients in whom ED-BM developed and a control group without ED-BM during the first 3 days of infection or during the 3 days preceding the infection with regard to leukocyte count, protein concentration, glucose concentration, and CSF/blood glucose ratio. No significant difference between groups was found for the CSF IL-6 concentration during the 3 days preceding the infection. In the matched case-control study, none of the parameters had significant predictive or diagnostic value for ED-BM in analyses using absolute values, ratios, and differences between the current and previous day's values. A comparison of the results from Gram stains and CSF cultures showed that the Gram staining had a very high specificity (99.9%) but a low sensitivity (18% [four of 22 patients] on the 1st day of infection and 60% [nine of 15 patients] on the 2nd day). CONCLUSIONS: Severe disturbances in the CSF of patients with external drains limit the value of routine CSF analysis for prediction or diagnosis of ED-BM. Routine Gram stain of CSF has also limited predictive or diagnostic value due to its low sensitivity in screening for ED-BM.