Dynamics of target-mediated drug disposition: characteristic profiles and parameter identification

In this paper we present a mathematical analysis of the basic model for target mediated drug disposition (TMDD). Assuming high affinity of ligand to target, we give a qualitative characterisation of ligand versus time graphs for different dosing regimes and derive accurate analytic approximations of different phases in the temporal behaviour of the system. These approximations are used to estimate model parameters, give analytical approximations of such quantities as area under the ligand curve and clearance. We formulate conditions under which a suitably chosen Michaelis-Menten model provides a good approximation of the full TMDD-model over a specified time interval.     

No association of psychosis in Alzheimer disease with neurodegenerative pathway genes

Psychotic symptoms occur in approximately 40% of subjects with Alzheimer disease (AD with psychosis; AD + P) and identify a subgroup with more rapid cognitive decline. We evaluated in 867 AD subjects the association of AD + P with genes which may modify the pathological process via effects on the accumulation of amyloid beta (Aβ) protein and/or hyperphosphorylated microtubule-associated protein tau (MAPT): amyloid precursor protein (APP), beta-site amyloid precursor protein cleaving enzyme (BACE1), sortilin-related receptor (SORL1), and MAPT. Each gene was thoroughly interrogated with tag single-nucleotide polymorphisms (SNPs), and gene-based tests were used to enhance power. We found no association of these genes with AD + P.     

A single institution experience with biochemical recurrence after radical prostatectomy for tumors that on pathology are of small volume or "insignificant"

ObjectiveSmall volume prostate cancers (<0.5 cc, svPC), and insignificant prostate cancers (<0.5 cc and Gleason scores <7, InsigPC) are considered clinically insignificant by some investigators. The aim of this study is to determine the biochemical recurrence rate (BCR) of svPC and InsigPC in prostatectomy specimens.MethodsIn total, 502 patients with prostate cancer, treated with radical prostatectomy (RP) between 1992 and 2005 and with detailed pathological classification, were included in the present study. Patients were postoperatively followed for a median period of 39.5 months (0.6–150). A total of 82 specimens (16.3%) with svPC including 64 (12.8%) with InsigPC were identified. BCR was defined as 2 consecutive PSA levels >0.10 ng/ml.ResultsIn the total group, the median age at the time of surgery was 62.7 years (42.4–73.4) and the median preoperative PSA level was 8.0 ng/ml. Patients with InsigPC had Gleason scores of 4 in 7%, 5 in 37%, and 6 in 56%. Positive surgical margins were identified in 13 (15.9%) svPC and in 8 (12.7%) InsigPC specimens. The 5-year risk of BCR for the svPC group and the insigPC group was 10% (95% CI 2–18%, 7 and 5 patients, respectively) vs. 35% (95% CI 29–41%) in the rest of the cohort (log rank P = 0.001).ConclusionPatients with svPC and patients with InsigPC have a significantly lower risk of BCR. However, even in this seemingly very favorable patient group, 1 in 10 patients will develop a BCR after RP. Therefore, new studies are needed to examine what the prognostic relevance is of small-volume tumors.     

Better survival in patients with metastasised kidney cancer after nephrectomy: a population-based study in the Netherlands

Aim

Cytoreductive nephrectomy is considered beneficial in patients with metastasised kidney cancer but only a minority of these patients undergo cytoreductive surgery. Factors associated with nephrectomy and the independent effect of nephrectomy on survival were evaluated in this study.

Methods

Patients were selected from the population-based cancer registry and detailed data were retrieved from clinical files. Factors associated with nephrectomy were evaluated by logistic regression analyses. Cox proportional hazard regression analysis was performed to evaluate factors associated with survival; a propensity score reflecting the probability of being treated surgically was included in order to adjust for confounding by indication.

Results

37.5% of 328 patients diagnosed with metastatic kidney cancer between 1999 and 2005 underwent nephrectomy. Patients with a low performance score, high age, ?2 comorbid conditions, ?2 metastases, low or high BMI, weight loss, elevated lactate dehydrogenase, elevated alkaline phosphatase, female gender and liver or bone metastases were less likely to be treated surgically. Three year survival was 25% and 4% for patients with and without nephrectomy, respectively (p < 0.001). After adjustment for other prognostic factors including the propensity score, nephrectomy remained significantly associated with better survival (Hazard ratio: 0.52, 95% Confidence interval: 0.37-0.73).

Conclusions

Even after accounting for prognostic profile, patients still benefit from a nephrectomy; an approximately 50% reduction in mortality was observed. It is, therefore, recommended that patients with metastasised disease receive cytoreductive surgery when there is no contraindication. Trial results on cytoreductive surgery combined with targeted molecular therapeutics are awaited for.     

Prognostic value of p53 for high risk superficial bladder cancer with long-term followup

PURPOSE: The risk of muscle invasive disease in a high risk patient with superficial bladder cancer is up to 50%. Identifying patients at risk for progression remains an unsolved problem. A suggested prognosticator is mutations in the p53 tumor suppressor gene. We determined the value of p53 mutation, as demonstrated by mutation analysis, in a clinically selected group of high risk patients with superficial bladder cancer. MATERIALS AND METHODS: p53 Mutation analysis was performed by automated sequencing of bladder wash samples of 105 patients with high risk superficial bladder cancer. The mutation and WT groups were subsequently compared with regard to mortality, progression, disease worsening and the recurrence-free period. RESULTS: A total of 29 patients had a mutation and 76 had WT. Median followup was 58.3 months (range 3 to 161). A total of 13 patients died of bladder cancer, including 6 of 29 with a mutation and 7 of 76 patients in the WT group. p53 Mutation had no significant prognostic value for decreased survival, progression or disease worsening. Recurrence-free survival was significantly lower in the WT group. CONCLUSIONS: We observed a trend toward a worse clinical outcome in high risk patients with a p53 mutation in the bladder wash. However, no significant differences were seen in clinical outcome parameters. Based on these data we conclude that the prognostic value of a p53 mutation is insufficient for individual policy making.     

The relationship between lower urinary tract symptoms and health status: the UREPIK study

OBJECTIVES: To assess the hypothesis that as lower urinary tract symptoms (LUTS) increase in severity, the impact as measured by the BPH impact index (BII) would also increase. SUBJECTS AND METHODS: The UREPIK survey collected information on this relationship from men and their partners in the Netherlands, Korea, France and the UK. Culturally and linguistically validated versions of three standard questionnaires, the SF-12, the BII and the International Prostate Symptom Score (IPSS) were used to assess the distribution of symptoms and the impact on health status. Stratified random samples of men aged 40-79 years in each community were recruited. Response rates were 72% in Boxmeer, 28% in Auxerre, 60% in Birmingham and 68% in Seoul. Regression analyses were undertaken on total SF-12, BII and IPSS. RESULTS: In all, 4800 index men and 3674 women responded; the BII increased with increasing IPSS. The correlation coefficients were; Boxmeer 0.69, Auxerre 0.56, Birmingham 0.60 and Seoul 0.68. For women, the correlations were slightly lower except in Birmingham, at 0.65 (Boxmeer), 0.44 (Auxerre), 0.71 (Birmingham), 0.57 (Korea). BII scores were higher in women than in men with the same level of IPSS. Adjusting for IPSS there was no association between age and BII. There was an association between IPSS quality-of-life (QoL) score and BII; for men the correlation was 0.62 and for women 0.60. Men and women with the same score on the IPSS QoL reported the same bother. Among those with an IPSS of 20-35 women expressed significantly more bother (P < 0.001). The SF-12 scores decreased as the IPSS and the BII increased in both men and women. Furthermore, the SF-12 mental score decreased with increasing symptoms in the partner. CONCLUSIONS: The relationship between the severity of LUTS and BII was similar in all centres. There is a clear association between the BII and the IPSS QoL question in men and women. The BII discriminates between people who are unhappy about their urinary condition compared with those who are pleased. Although designed for use in men with benign prostatic hyperplasia, the index also appears to be a useful among women. The severity of symptoms of LUTS has an adverse effect on the health status of the individual and his/her partner.     

Attention to Color: An Analysis of Selection, Controlled Search, and Motor Activation, Using Event-Related Potentials

In this study the organization of information processing in a selective search task was examined by analyzing event-related potentials. This task consisted of searching for target letters in a relevant (attended) color. The ERPs revealed two different effects of attention: an early occipital negativity (+/- 150 ms) reflecting feature-specific attention, and a later, central N2b component (+/- 240 ms) reflecting covert orienting of attention. A later, prolonged negativity (search-related negativity) (+/- 300 ms), maximal at Cz, was related to controlled search to letters in the attended color. Detection of relevant targets resulted in a parietal P3b component. Depending on stimulus presentation conditions an earlier response to both attended and unattended targets was found: an N2 component (+/- 250 ms). In these same conditions, C'3-C'4 asymmetries (Corrected Motor Asymmetries--CMA) suggested motor activation at +/- 300 ms, in the same time range as search-related negativity. It was argued that N2 and CMA suggest the existence of a preattentive target detection system, operating in parallel with a slower serial attentive system, as reflected by N2b and search negativity.     

A germline homozygote deletion of the glutathione-S-transferase Mu1 gene predisposes to bladder cancer

INTRODUCTION AND OBJECTIVES: Numerous studies have shown smoking and specific occupational exposures to be risk factors for bladder cancer. The risk of bladder cancer may be modified by the activity of carcinogen metabolizing enzymes. The glutathione-S-transferase Mu1 enzyme (GSTM1) detoxifies arylepoxides which are formed after exposure to certain polycyclic aromatic hydrocarbons and possibly aromatic amines. Approximately 40% of Caucasians lack GSTM1 activity due to a homozygous deletion of the GSTM1 locus on chromosome 1p13 (GSTM1 0/0 genotype). The aim of this study was to evaluate the combined effect of smoking and GSTM1 genotype on the risk of bladder cancer. MATERIALS AND METHODS: Sixty-one patients with transitional cell carcinoma of the bladder and 69 controls matched for age and sex were enrolled from the outpatient clinic. Lifestyle information was collected with a standardized questionnaire. DNA was extracted from white blood cells. The GSTM1 genotype was determined by a PCR-based method. RESULTS: 92% of the 61 patients had a history of smoking compared with 81% of the controls. There was a significant dose-response relationship for pack-years of smoking (trend test: p = 0.003). The proportion of GSTM1 0/0 genotype among patients was 62% compared with 43% among controls (odds ratio = 2.1; 95% CI 1.1-4. 3). The expected interaction between smoking and GSTM1 genotype was not observed. CONCLUSIONS: This study confirms the findings that a germline homozygous deletion of the GSTM1 gene predisposes to bladder cancer. An interaction with smoking was not found.     

Erectile dysfunction: prevalence and effect on the quality of life; Boxmeer study

OBJECTIVE: To assess the prevalence of erectile dysfunction (ED), and its influence on both the quality of life, and health care seeking behaviour. METHOD: An age-stratified random sample was drawn from men aged 40-79 years in Boxmeer, the Netherlands (n = 1771), together with their partners. A questionnaire was mailed to the study population to collect data on ED, and the quality of life, both general and disorder related. The prevalence of ED was measured with the direct question 'Do you have problems getting an erection?'. The influence of ED on sexual function was measured with the Dutch version of the Sexual Function Inventory questionnaire. RESULTS: Seventy percent of all men (n = 1233) and 73% of their partners (n = 1071) responded to the questionnaire. The prevalence of ED increased with age class. To the question regarding problems to get an erection, 13% (95% confidence interval: 11-15%) of all men answered affirmatively (40-49 years: 6%; 50-59: 9%; 60-69: 22%; 70-79: 38%). All men aged 40-49 years of age with ED and 16% of men aged 70-79 with ED considered their ED as bothersome. Amongst 40 to 49 year old men with ED, 64% considered their ED as a big or rather a big problem. Amongst older men this percentage was much smaller: 50-59 years: 38%; 60-69: 37%, and 70-79: 27%. Thirty-four percent of all men with ED and 16% of their spouses were dissatisfied with their sex life. Twenty-five percent of men with ED consulted a doctor, with a mean delay of 13 months. ED bore a strong correlation with the general quality of life and comorbidity. CONCLUSION: ED was a common disorder within the population. Its prevalence was higher among older age groups, but they regarded ED as less of a problem than the younger age groups. Only a quarter of all men with ED consulted a physician.     

Feedback modeling of non-esterified fatty acids in obese Zucker rats after nicotinic acid infusions

This study investigates the impact of disease on nicotinic acid (NiAc)-induced changes in plasma concentrations of non-esterified fatty acids (NEFA). NiAc was given by constant intravenous infusion to normal Sprague–Dawley and obese Zucker rats, and arterial blood samples were taken for analysis of NiAc, NEFA, insulin and glucose plasma concentrations. The intravenous route was intentionally selected to avoid confounding processes, such as absorption, following extravascular administration. Data were analyzed using nonlinear mixed effects modeling (NONMEM, version VI). The disposition of NiAc in the normal rats was described by a two-compartment model with endogenous synthesis of NiAc and two parallel capacity-limited elimination processes. In the obese rats disposition was described by a one-compartment model with endogenous synthesis of NiAc and one capacity-limited elimination process. The plasma concentration of NiAc drove NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M ₁ ) inhibited the formation of R and the last compartment (M _N ) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. Differences in the pharmacodynamic response of the two strains included, in the obese animals, an increased NEFA baseline, diminished rebound and post-rebound oscillation, and a more pronounced slowly developing tolerance during the period of constant drug exposure. The feedback model captured the NiAc-induced changes in NEFA response in both the normal and obese rats. Differences in the parameter estimates between the obese and normal rats included, in the former group, increases in R ₀ , k _in and p by 44, 41 and 78 %, respectively, and decreases in k _out and γ by 64 and 84 %, respectively. The estimates of k _tol and IC ₅₀ were similar in both groups. The NiAc–NEFA concentration–response relationship at equilibrium was substantially different in the two groups, being shifted upwards and to the right, and being shallower in the obese rats. The extent of such shifts is important, as they demonstrate the impact of disease at equilibrium and, if ignored, will lead to erroneous dose predictions and, in consequence, poorly designed studies. The proposed models are primarily aimed at screening and selecting candidates with the highest potential of becoming a viable drug in man.