Variations In Kinetics Research Articles

A Probabilistic Modeling Approach in Thermal Inactivation: Estimation of Postprocess Bacillus cereus Spore Prevalence and Concentration

The survival of spore-forming bacteria is linked to the safety and stability of refrigerated processed foods of extended durability (REPFEDs). A probabilistic modeling approach was used to assess the prevalence and concentration of Bacillus cereus spores surviving heat treatment for a semiliquid chilled food product. This product received heat treatment to inactivate nonproteolytic Clostridium botulinum during manufacture and was designed to be kept at refrigerator temperature postmanufacture. As key inputs for the modeling, the assessment took into consideration the following factors: (i) contamination frequency (prevalence) and level (concentration) of both psychrotrophic and mesophilic strains of B. cereus, (ii) heat resistance of both types (expressed as decimal reduction times at 90°C), and (iii) intrapouch variability of thermal kinetics during heat processing (expressed as the time spent at 90°C). These three inputs were established as statistical distributions using expert opinion, literature data, and specific modeling, respectively. They were analyzed in a probabilistic model in which the outputs, expressed as distributions as well, were the proportion of the contaminated pouches (the likely prevalence) and the number of spores in the contaminated pouches (the likely concentration). The prevalence after thermal processing was estimated to be 11 and 49% for psychrotrophic and mesophilic strains, respectively. In the positive pouches, the bacterial concentration (considering psychrotrophic and mesophilic strains combined) was estimated to be 30 CFU/g (95th percentile). Such a probabilistic approach seems promising to help in (i) optimizing heat processes, (ii) identifying which key factor(s) to control, and (iii) providing information for subsequent assessment of B. cereus resuscitation and growth.

Mediterranean sea eddy kinetic energy variability from 11 years of altimetric data

The eddy kinetic energy (EKE) variability of the Mediterranean Sea over eleven years (1993–2003) was studied using merged (T/P, Jason, ERS and Envisat) altimetric data. Special efforts were made to improve the data selection and the mapping procedure. The introduction of the Mean Dynamic Topography [Rio M.-H., Poulain P.-M., Pascual A., Mauri E., Larnico G., 2005, “A mean dynamic topography of the Mediterranean Sea computed from altimetric data and in situ measurements”, submitted to J. Mar. Syst. (Liège Colloquium special issue).] made it possible to derive the absolute dynamic topography. Thus, an improved and more complete data set was obtained, which enabled previous studies based on altimetric data ([Iudicone D., Santoreli R., Marullo S., Gerosa P., 1998, “Sea level variability and surface eddy statistics in the Mediterranean Sea from TOPEX/POSEIDON data”, J. Geoph. Res. 103 (C2), 2995–3011.]; [Ayoub N., Le Traon P.-Y., De Mey P., 1998, “A description of the Mediterranean surface circulation from combined ERS-1 and TOPEX/POSEIDON altimetric data”, J. Mar. Syst. 18 (1–3), 3–40.]; [Larnicol G., Le Traon P.-Y., Ayoub N., De Mey P., 1995, “Mean sea level and surface circulation variability of the Mediterranean Sea from 2 years of TOPEX/POSEIDON altimetry ”, J. Geoph. Res. 100 (C12), 25,163–25,177.]; [Larnicol G., Ayoub N., Le Traon P.-Y., 2002, “Major changes in Mediterranean Sea level variability from 7 years of TOPES/Poseidon and ERS-1/2 data”, J. Mar. Syst. 33–34, 63–89.] to be enhanced. In particular, for the first time a relatively accurate description of the mean EKE distribution in the Mediterranean Sea could be provided. The mean EKE structure is the consequence of the superposition of different variability components. As previously described in other studies, mesoscale, seasonal and interannual components play a key role in this variability, but the contribution of long-term decadal signals, as well as sporadic events, are also important. In addition, a specific variability pattern is observed in each sub-basin of the Mediterranean Sea (Western, Ionian and Levantine). The observed permanent/recurrent structures, as well as the transient ones, are subject to annual variations that occurred with different phases: permanent/recurrent structures (such as the Alboran Gyres and the Ierapetra Eddy — IE) are at maximum intensity in late summer (October to January) whereas areas of mesoscale activity (southwest of Sardinia, central Ionian and Mersa-Matruh areas) display maximum intensity in winter (January to April). Both annual and interannual variations are more pronounced in the eastern part of the basin. On the western side, mesoscale activity is relatively stable. The appearance of sporadic energetic structures leads to a positive trend in the Alboran Sea and north of the Tyrrhenian, while a negative trend is observed south of Majorca. The seasonal EKE variations are mainly concentrated southwest of Sardinia. They are found to be modulated by interannual variability, with a weakening of both the mean EKE and the amplitude of the seasonal cycle between 1997 and 2000 and between 2001 and 2003. In the Ionian Sea, the EKE variability is affected by the reversal of the circulation in 1997. This phenomenon suggests that the decadal scale of variability should not be overlooked in this basin. A strong positive EKE trend, coupled with an increase in the seasonal cycle amplitude, is observed in 1997 in the central Ionian. The high correlation of wind stress variations and high-frequency EKE in the Ionian Sea, suggests that the seasonal variations are partly due to wind-induced mesoscale activity. In the Levantine Sea, an even stronger positive EKE trend is observed, partly influenced by strong activity around the IE and in the Mersa-Matruh and Shikmona areas. Seasonal variations are present all over the studied period and are either largely influenced by the IE activity at the beginning and end of the period, or are concentrated at the entrance of the basin and in the Mersa-Matruh area. In the latter, larger amplitude are observed after 1997, as in the Ionian Sea. Also, different processes of variability are observed, confirming that the Mersa-Matruh area must be considered as the site of intense mesoscale activity.

Daily Monitoring of Cyclosporine (Csa) Allows Better Control of Graft vs. Leukaemia Effect (GvL): Single Centre Experience.

The most important consideration in modern SCT practices is the fine balance that is required to achieve adequate immunosuppression and stable engraftment thus allowing the platform to mount an effective GVL response. Though CsA facilitates this objective, it is associated with several adverse clinical manifestations due to its narrow therapeutic index (TI) and wide variability in the absorption kinetics. Weekly monitoring of trough CsA levels are used to adjust the dose. The aim of this study is to determine whether daily monitoring of CsA levels enables better achievement of these goals and yet reduce the serious toxicities.Patients & methods: Twenty three patients (M=15, F=8, median age 46yrs range 19–63) received an allogeneic transplant (sibling-15, MUD-7 mismatched unrelated-1) since March 2004 when we started to monitor daily CsA levels (Biostat TDX analyser using fluorescent immunoassay) from the day of first administration until the time of discharge. The transplants included full intensity (FI=11), reduced intensity (RI=11) or customised (1) for various haematolymphoid malignancies. Patients received uniform GVHD prophylaxis with IV CsA (RI+FI) and methotrexate (FI) as per standard loading doses. The CsA target level was adjusted to 200–220 ng/ml from Day-1 onwards and was later modified according to the treatment strategy. Oral CsA administration was started when patients were able to switch over. Results Nine of 23 (40%) patients developed acute GVH (n=7 grade1–2, n=2 grade 3–4) at a median of 23.5 days (10–28). Two of 9 patients required addition of steroids by Day+30. The median CsA level at the first occurrence of GVH was 247ng/ml (113–333) and the median CsA level during hospitalisation was 207 ng/ml (136–291). Only one patient who received T cell addback required increased dose of IV CsA to manage Grade 4 GVH. Twenty two/22 patients engrafted with a median day to neutrophil recovery being 13 days (8–35). One patient lost his graft due to a low initial cell dose and the inability of the MUD donor to donate any further cells. There was no significant difference in the baseline and Day30 creatinine levels (median highest creatinine 108μmol/l range 58–267) or bilirubin levels (median highest bilirubin 27μmol/l, range15–251). Five/22 patients developed CMV reactivation/infection and 1 developed RSV infection. No patients developed seizures and in one patient pre-existent neuropathy was exacerbated which was directly attributable to CsA. Twenty one/22 patients (95.5%) switched to oral CsA by Day+25. In 8/22 (36.36%) patients, the target CsA levels was around 100–150 ng/ml at the time of discharge. The median duration of hospital stay was 35days (24–130).Conclusions: These observations suggests that daily monitoring of CsA is safe and successful. This allowed successful engraftment and a more liberal management of Grade 1–2 GVH thus allowing us to maximise the GVL effect. Despite concomitant use of other toxic drugs, side effects were minimal and reversible. Close observation of early clinical manifestations enabled us to modify the immunosuppressive strategy at later time periods. This approach also allowed us to better manage patients suffering from CMV and EBV/PTLD (patient number 10 on day+88) by reducing the dose during active infections.

A physiologically based toxicokinetic model of inhalation exposure to xylenes in Caucasian men

Widespread exposure to the volatile aromatic hydrocarbons, ortho-, meta-, and para-xylene occurs in many industries including the manufacture of plastics, pharmaceuticals, and synthetic fibers. This paper describes the development of a physiologically based toxicokinetic model using biomonitoring data to quantify the kinetics of ortho-, meta-, and para-xylenes. Serial blood concentrations of deuterium-labeled xylene isomers were obtained over 4 days after 37 controlled, 2 h inhalation exposures to different concentrations of the isomers. Peak toxicant concentrations in blood occurred in all subjects at the termination of exposure. Systemic clearance averaged 116 L/h ± 34 L/h, 117 L/h ± 23 L/h, and 129 L/h ± 33 L/h for ortho-, para-, and meta-xylene, respectively. The half-life of each toxicant in the terminal phase (>90 h post-exposure) was fit by the model, yielding values of 30.3 ± 10.2 h for para-xylene, 33.0 ± 11.7 h for meta-xylene and 38.5 ± 18.2 h for ortho-xylene. Significant isomeric differences were found ( p < 0.05) for toxicant half-life, clearance and extrahepatic metabolism. Inter-individual variability seen in this study suggests that airborne concentration guidelines may not protect all workers. A Biological Exposure Index is preferred for this purpose since it is integrative and reflective of inter-individual kinetic variability.

Development of a Ct equation taking into consideration the effect of lot variability on the inactivation of Cryptosporidium parvum oocysts with ozone

Cryptosporidium parvum oocysts are prevalent in surface water and ground water under the influence of surface water, and are difficult to inactivate using free chlorine, the most common disinfectant currently used for treating drinking water. In contrast, it has been shown that ozone is a more effective disinfectant than chlorine. US EPA is currently evaluating a treatment rule, which addresses the control of C. parvum oocysts in drinking water. The use of Ct (average disinfectant concentration multiplied by characteristic contact time) values is being considered as one of the options for demonstrating adequate control of this microbial contaminant. The purpose of this study is to incorporate the variability in inactivation kinetics among different lots of oocysts and to develop a statistical model for Ct based on first-order delayed Chick–Watson inactivation kinetics. A Bayesian approach is used to estimate the delayed Chick–Watson kinetic parameters. A log-linear regression analysis is then used to represent the effect of temperature on the resulting kinetic parameters. The overall model developed in this study provides an approach for water utilities and regulatory agencies to decide on the level of safety needed when developing treatment requirements for the inactivation of C. parvum oocysts with ozone as part of broader risk assessment considerations.

Variability Of Gait Parameters In Patients With Multiple Sclerosis

Patients with Multiple Sclerosis (MS) often complain of fluctuation in their symptoms and movement patterns that they frequently attribute to fatigue. In order to determine the ef.cacy of treatments aimed at improving movement coordination, it is necessary to understand the variability of motor function associated with the disease. PURPOSE To determine the within- and between-day variability of gait mechanics in subjects with MS compared to healthy controls. It was hypothesized that the MS subjects would be more variable than the healthy controls and that there would be within- and between-day differences in variability. METHODS Five gait analysis sessions were performed on each of 20 subjects with MS (age 43.0 ± 9.6 yrs, height 166. 6± 9.0cm, mass 79.7 ± 19.3kg) and 8 healthy controls (age 40.9 ± 8.6yrs, height 167.4 ± 14.6cm, mass 72.6 ± 14.2kg). Three data collections took place in the morning and afternoon of one day (AM1, PM Fresh, PM Fatigue) and the final two collections took place one week later in the morning only (AM2 Fresh, AM2 Fatigue). Gait cycles for each condition were time normalized to the stride cycle (100 data points). The standard deviations (SDs) of fifteen stride cycles for kinematic data were calculated for each point and then averaged to determine the measure of variability for the sagittal plane angles at the ankle, knee, and hip. For the kinetic data, the SDs of three gait cycles were calculated and the average during stance was used as the measure of variability for vertical ground reaction forces and sagittal plane moments and powers at the ankle, knee and hip. Two-way ANOVAs (group × condition) with repeated measures were used to assess the differences in variability. RESULTS Kinematic and kinetic gait variability was not different across conditions for the MS group. However, the MS group had significantly more joint angle variability (p < 0.05) than the control group at the hip (1.85 ± 0.45 vs. 1.62 ± 0.32 deg), knee (2.59 ± 0.69 vs. 2.19 ± 0.35 deg), and ankle (1.48 ± 0.35 vs. 1.30 ± 0.21 deg). Kinetic variability was not different between groups. CONCLUSION In general, MS subjects have greater kinematic variability than healthy control subjects. Supported by the University of Delaware Center for Research Development

The Refinement of Uncertainty/Safety Factors in Risk Assessment by the Incorporation of Data on Toxicokinetic Variability in Humans

The derivation of safe levels of exposure in humans for compounds that are assumed to cause threshold toxicity has relied on the application of a 100-fold uncertainty factor to a measure for the threshold, such as the no observed adverse effect level (NOAEL) or the benchmark dose (BMD). This 100-fold safety factor consists of the product of two 10-fold factors allowing for human variability and interspecies differences. The International Programme on Chemical Safety has suggested the subdivision of these 10-fold factors to allow for variability in toxicokinetics and toxicodynamics. This subdivision allows the replacement of the default uncertainty factors with a chemical-specific adjustment factor (CSAF) when suitable data are available. This short review describes potential options to refine safety factors used in risk assessment, with particular emphasis on pathway-related uncertainty factors associated with variability in kinetics. These pathway-related factors were derived from a database that quantified interspecies differences and human variability in phase I metabolism, phase II metabolism, and renal excretion. This approach allows metabolism and pharmacokinetic data in healthy adults and subgroups of the population to be incorporated in the risk-assessment process and constitutes an intermediate approach between simple default factors and chemical-specific adjustment factors.

Genetic polymorphisms in the glucuronosyltransferases 1A1, 1A8 and 1A9 in relation to pharmacokinetics of furosemide

Background/Aims About 30% of the loop diuretic furosemide is eliminated via glucuronidation. According to in vitro data, uridine diphosphate glucuronosyltransferase (UGT) 1A8 may catalyze in this reaction but the quantitatively relevant isoenzyme in humans has not been unambiguously identified. We analyzed whether polymorphisms in UGT1A1, 1A8 and 1A9 are associated with the pharmacokinetics of furosemide. Methods In an open-label single dose study 93 healthy male volunteers got 80 mg furosemide and pharmacokinetics were measured over 24 hours after dosing. Polymorphisms in the UGT1A1, -1A8, and -1A9 genes were analyzed by pyrosequencing. Results Seven polymorphisms distributed over the UGT1A1 gene and 2 polymorphisms in the UGT1A8 and UGT1A9 genes were analyzed in correlation with furosemide total oral clearance. One C/T polymorphism in the intron 3 of the UGT1A1 gene was associated with furosemide clearance (p= 0.024) with a mean of 16.7, 17.2, and 22.3 L/h in CC, CT, and TT carriers, respectively. One A/T polymorphism at position −276 in the UGT1A9 promotor was also associated (p=0.049) with mean clearance of 18.0, 14.1, and 13.0 L/h in A/A, A/T, and T/T carriers. Significant associations with furosemide drug actions were not found. Conclusions There was a large interindividual kinetic and dynamic variability of furosemide in healthy volunteers and genetic polymorphisms in UGT enzymes may partially explain this variability. Clinical Pharmacology & Therapeutics (2005) 77, P34–P34; doi: 10.1016/j.clpt.2004.12.021

Mycophenolic acid pharmacokinetics and related outcomes early after renal transplant

The pharmacokinetics of mycophenolic acid and its glucuronide are complex. This study investigated the pharmacokinetics, pharmacodynamics and protein binding of mycophenolic acid and its glucuronide metabolite, early post-transplant in renal allograft recipients. Forty-two de novo renal transplant recipients receiving mycophenolate mofetil and concomitant cyclosporin (n = 32) or tacrolimus (n = 10) participated in the study. Blood samples were taken on day 5 post-transplant for measurement of free and total concentrations of mycophenolic acid, mycophenolic acid glucuronide and relevant biochemistry. Associations between free fraction and biochemistry were investigated. Free and total 6-h area under the concentration-time curve (AUC0-6) of mycophenolic acid was assessed relative to clinical outcomes in the first month post-transplant. Kinetic variability of free and total mycophenolic acid and its glucuronide was greater in patients on cyclosporin (12- to 18-fold variation) than on tacrolimus (four- to fivefold) cotherapy. Cyclosporin-treated patients also had significantly lower predose total mycophenolic acid concentrations than tacrolimus-treated patients (median 0.8 mg l(-1) and 1.6 mg l(-1), respectively, P = 0.002). Mycophenolic acid glucuronide predose concentration correlated positively with mycophenolic acid glucuronide AUC0-6 (r > 0.95). Mycophenolic acid free fraction varied 11-fold, from 1.6% to 18.3%, whilst the glucuronide free fraction varied threefold, from 17.4% to 54.1%. Urea and creatinine concentrations correlated positively (r > 0.46), whilst albumin correlated negatively (r = -0.54) with free fraction of mycophenolic acid. Similar relationships were found for the free fraction of mycophenolic acid glucuronide. Mycophenolic acid free fraction was on average 70% higher in patients with albumin concentrations below a specified albumin cut-off concentration of 31 g l(-1)[free fraction = 7 +/- 4% for lower albumin and 4 +/- 3% for higher albumin, respectively; P = 0.001; 95% confidence interval (CI) for the difference 1.9, 4.2]. Neither free nor total mycophenolic acid AUC0-6 was related to rejection (P > 0.07). Free AUC0-6 was significantly higher in those patients with thrombocytopenic, leukopenic and/or infectious outcomes than in those without (mean +/- SD 1.9 +/- 0.3 mg h(-1) l(-1) and 1.1 +/- 0.1 mg h(-1) l(-1), P = 0.0043; 95% CI for the difference 0.3, 1.4). The marked variability in mycophenolic acid/glucuronide pharmacokinetics occurring early post-transplant during the current study was greater in cyclosporin (12-18-fold) than in tacrolimus (four- to fivefold) treated patients. Concomitant cyclosporin was associated with total mycophenolic acid concentrations approximately half that of tacrolimus. Patients with marked renal impairment had the highest free fractions reported to date. The exposure to unbound mycophenolic acid was significantly related to infections and haematological toxicity.

Pharmacokinetic Considerations Relating to Tacrolimus Dosing in the Elderly

Relaxation of the upper age limits for solid organ transplantation coupled with improvements in post-transplant survival have resulted in greater numbers of elderly patients receiving immunosuppressant drugs such as tacrolimus. Tacrolimus is a potent agent with a narrow therapeutic window and large inter- and intraindividual pharmacokinetic variability. Numerous physiological changes occur with aging that could potentially affect the pharmacokinetics of tacrolimus and, hence, patient dosage requirements. Tacrolimus is primarily metabolised by cytochrome P450 (CYP) 3A enzymes in the gut wall and liver. It is also a substrate for P-glycoprotein, which counter-transports diffused tacrolimus out of intestinal cells and back into the gut lumen. Age-associated alterations in CYP 3A and P-glycoprotein expression and/or activity, along with liver mass and body composition changes, would be expected to affect the pharmacokinetics of tacrolimus in the elderly. However, interindividual variation in these processes may mask any changes caused by aging. More investigation is needed into the impact aging has on CYP and P-glycoprotein activity and expression. No single-dose, intense blood-sampling study has specifically compared the pharmacokinetics of tacrolimus across different patient age groups. However, five population pharmacokinetic studies, one in kidney, one in bone marrow and three in liver transplant recipients, have investigated age as a co-variate. None found a significant influence for age on tacrolimus bioavailability, volume of distribution or clearance. The number of elderly patients included in each study, however, was not documented and may have been only small. It is likely that inter- and intraindividual pharmacokinetic variability associated with tacrolimus increase in elderly populations. In addition to pharmacokinetic differences, donor organ viability, multiple co-morbidity, polypharmacy and immunological changes need to be considered when using tacrolimus in the elderly. Aging is associated with decreased immunoresponsiveness, a slower body repair process and increased drug adverse effects. Elderly liver and kidney transplant recipients are more likely to develop new-onset diabetes mellitus than younger patients. Elderly transplant recipients exhibit higher mortality from infectious and cardiovascular causes than younger patients but may be less likely to develop acute rejection. Elderly kidney recipients have a higher potential for chronic allograft nephropathy, and a single rejection episode can be more devastating. There is a paucity of information on optimal tacrolimus dosage and target trough concentration in the elderly. The therapeutic window for tacrolimus concentrations may be narrower. Further integrated pharmacokinetic-pharmacodynamic studies of tacrolimus are required. It would appear reasonable, based on current knowledge, to commence tacrolimus at similar doses as those used in younger patients. Maintenance dose requirements over the longer term may be lower in the elderly, but the increased variability in kinetics and the variety of factors that impact on dosage suggest that patient care needs to be based around more frequent monitoring in this age group.

Role of Cytochrome P450 Activity in the Fate of Anticancer Agents and in Drug Resistance

Although activity of cytochrome P450 isoenzymes (CYPs) plays a major role in the fate of anticancer agents in patients, there are relatively few clinical studies that evaluate drug metabolism with therapeutic outcome. Nevertheless, many clinical reports in various non-oncology fields have shown the dramatic importance of CYP activity in therapeutic efficacy, safety and interindividual variability of drug pharmacokinetics. Moreover, variability of drug metabolism in the liver as well as in cancer cells must also be considered as a potential factor mediating cancer resistance. This review underlines the role of drug metabolism mediated by CYPs in pharmacokinetic variability, drug resistance and safety. As examples, biotransformation pathways of tamoxifen, paclitaxel and imatinib are reviewed. This review emphasises the key role of therapeutic drug monitoring as a complementary tool of investigation to in vitro data. For instance, pharmacokinetic data of anticancer agents have not often been published within subpopulations of patients who show ultra-rapid, extensive or poor metabolism (e.g. due to CYP2D6 and CYP2C19 genotypes). Besides kinetic variability in the systemic circulation, induction of CYP activity may participate in creating drug resistance by speeding up the cancer agent degradation specifically in the target cells. For one cancer agent, various mechanisms of resistance are usually identified within different cell clones. This review also tries to emphasise that drug resistance mediated by CYP activity in cancer cells should be taken into consideration to a greater degree. The unequivocal identification of the metabolising enzymes involved in clinical conditions will eventually allow improvement and individualisation of anticancer agent therapy, i.e. drug dosage and selection. In addition, a more complete understanding of the metabolism of anticancer agents will assist in the prediction of drug-drug interactions, as anticancer agent combinations are becoming more prevalent.

Human variability in xenobiotic metabolism and pathway-related uncertainty factors for chemical risk assessment: a review

This review provides an account of recent developments arising from a database that defined human variability in phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferases, glucuronidation, glycine conjugation, sulphation) and renal excretion. This database was used to derive pathway-related uncertainty factors for chemical risk assessment that allow for human variability in toxicokinetics. Probe substrates for each pathway of elimination were selected on the basis that oral absorption was >95% and that the metabolic route was the primary route of elimination of the compound (60–100% of a dose). Intravenous data were used for compounds for which absorption was variable. Human variability in kinetics was quantified for each compound from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups of the population using parameters relating to chronic exposure (metabolic and total clearances, area under the plasma concentration–time curve (AUC)) and acute exposure (Cmax) (data not presented here). The pathway-related uncertainty factors were calculated to cover 95%, 97.5% and 99% of the population of healthy adults and of each subgroup.Pathway-related uncertainty factors allow metabolism data to be incorporated into the derivation of health-based guidance values. They constitute an intermediate approach between the general kinetic default factors (3.16) and a chemical-specific adjustment factor. Applications of pathway-related uncertainty factors for chemical risk assessment and future refinements of the approach are discussed. A knowledge-based framework to predict human variability in kinetics for xenobiotics showing a threshold dose below which toxic effects are not observed, is proposed to move away from default assumptions.

Oral antiarrhythmic drugs in converting recent onset atrial fibrillation.

This article reviews clinical studies on oral antiarrhythmic drugs in converting recent onset atrial fibrillation. An oral loading dose of an antiarrhythmic drug for cardioversion of atrial fibrillation could be an option, due to its simplicity, both for patients admitted to outpatient departments and for episodic treatment by self administration outside the hospital. The latter treatment strategy has recently been pointed out by the American College of Cardiology, the American Heart Association and the European Society of Cardiology as the 'pill in the pocket approach'. Articles were identified by Medline 1966 to November 2001 and Embase 1966 to November 2001. Randomized studies of oral antiarrhythmic drugs versus placebo or comparative treatment, which are written in the English language, were selected. Non-randomized or non-comparative studies were selected if the results of an analysis to identify predictors for successful conversion are described. The review of clinical trials is followed by a description of pharmacokinetic parameters of the antiarrhythmic drugs. Studies meeting the inclusion criteria were on propafenone, flecainide, sotalol, amiodarone, quinidine, digoxin and verapamil. Conversion rates of a single oral loading dose of 600 mg propafenone varied between 37% and 41% at 4 h after ingestion. Propafenone was more effective than quinidine, amiodarone and placebo. A single oral dose of 300 mg flecainide restored sinus rhythm in 59% and 68% of patients at 3 h. Flecainide was more effective than amiodarone and placebo. Oral sotalol, digoxin and verapamil were not effective in converting atrial fibrillation to sinus rhythm. Propafenone and flecainide are effective in converting recent onset atrial fibrillation. No serious ventricular arrhythmia, other serious proarrhythmic effects or serious non cardiac adverse events were observed. Regular supraventricular tachyarrhythmias with 1:1 AV conduction were rare and were also observed in placebo treated patients. Propafenone and flecainide are more effective in patients with atrial fibrillation of less than 24 h. The association between cardioversion and patient characteristics are not consistent between studies. The pharmacokinetics of flecainide, with lower interindividual variability of absorption kinetics, no genetically determined formation of an active metabolite and a more rapid distribution to myocardial tissue, are more favourable for episodic treatment as compared to propafenone. Both flecainide and propafenone are safe in hospitalized patients. Out of hospital self administration of antiarrhythmic drugs, also described as the 'pill in the pocket approach', could be an option for selected patients, after the treatment has proven to be safe in hospital.

An integrated basin modelling study applying asphaltene kinetics from reservoired petroleum in the Snorre Area, northern North Sea

Abstract The evolution of the petroleum systems in the Tampen Spur area, with main focus on the filling directions of the northern part of Snorre field, was addressed through 2D basin modelling (Petromod V. 4.5 and 7.0). The geochemical classification of the petroleum populations in the area represented the framework for considering the different kitchen areas and migration systems. Results from the basin modelling support, in general terms, the previous geochemical classification and petroleum families in the region. However, a separate well-defined main kitchen area for the Snorre Field was deduced opposed to the multiple kitchen areas having contributed to the filling as proposed in the literature. Our conclusions are based on the quantitative evaluation of the different proposed kitchen areas and the timing and extent of petroleum generation. Modelling of petroleum generation was performed using asphaltene kinetics determined on petroleum asphaltenes from Snorre oils. This approach was chosen in order to avoid problems associated with the kinetic variability encountered in the Draupne formation. The petroleum asphaltene kinetics was used to delineate the extent of the kitchen area, which reached the time/temperature conditions necessary for the generation of the analysed oil phase. The results thus differ from conventional oil window approximations as we utilize kinetic source rock parameters in the migrated oil for tracing out the generative basin. Three 2D lines crossing the main kitchen areas were modelled in this study. The models were calibrated to data from eight wells, consisting of measured vitrinite reflectance, corrected well temperatures and pore pressure. Three main kitchen areas were considered; one to the west and northwest of Snorre field, one directly to the north (Møre basin) and one to the east of the field (34/5 kitchen). Modelling suggests that the kitchen area to the west and northwest of Snorre is largely immature and that the volume of potentially generated petroleum is too small to fill the Snorre structure. In the northern kitchen area, the seismic indicated very thin upper Jurassic deposits, which reaches oil window maturities only at a relatively large distance from the structure. The modelling also demonstrated problems related to the filling of the Snorre structure from the Møre Basin. The combined effect of a thin source rock, which implies a regionally large drainage area to fill the structure, and the large distance to the mature kitchen, lead to the conclusion that the Møre Basin did not contribute significant volumes of petroleum to the Snorre field. In contrast, the kitchen area east of Snorre Field (the 34/5 kitchen) proved in the modelling to be mature and volumetrically large enough to account for the entire filling of the Snorre Field.

Kinetic Diversity of Single-Channel Burst Openings Underlying Persistent Na + Current in Entorhinal Cortex Neurons

The kinetic diversity of burst openings responsible for the persistent Na + current ( I NaP) in entorhinal cortex neurons was examined by separately analyzing single bursts. Although remarkable kinetic variability was observed among bursts in terms of intraburst opening probability and mean open and closed times, the values of time constants describing intraburst open times ( τ o(b)s) and closed times ( τ c(b)s) were distributed around well-defined peaks. At −40 mV, τ o(b) peaks were found at ∼0.34 ( τ o(b)1) and 0.77 ( τ o(b)2) ms, and major τ c(b) peaks were found at ∼0.24 ( τ c(b)1) and 0.54 ( τ c(b)2) ms. In ∼80% of the bursts two preferential gating modes were found that consisted of a combination of either τ o(b)1 and τ c(b)2 (“intraburst mode 1”), or τ o(b)2 and τ c(b)1 (“intraburst mode 2”). Individual channels could switch between different gating modalities, but normally tended to maintain a specific gating mode for long periods. Mean burst duration also displayed considerable variability. At least three time constants were found to describe burst duration, and the frequencies at which each of the corresponding “bursting states” occurred varied in different channels. Short-lasting bursting states were preferentially associated with intraburst mode 1, whereas very-long-lasting bursts tended to gate according to mode 2 only or other modes that included considerably longer mean open times. These results show that I NaP channels can generate multiple intraburst open and closed states and bursting states, but these different kinetic states tend to combine in definite ways to produce a limited number of prevalent, well-defined gating modalities. Modulation of distinct gating modalities in individual Na + channels may be a powerful form of plasticity to influence neuronal excitability and function.

Human variability in the renal elimination of foreign compounds and renal excretion-related uncertainty factors for risk assessment

Renal excretion is an important route of elimination for xenobiotics and three processes determine the renal clearance of a compound [glomerular filtration (about 120 ml/min), active renal tubular secretion (>120 ml/min) and passive reabsorption (<120 ml/min)]. Human variability in kinetics has been quantified using a database of 15 compounds excreted extensively by the kidney (>60% of a dose) to develop renal-excretion related uncertainty factors for the risk assessment of environmental contaminants handled via this route. Data were analysed from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups using parameters relating primarily to chronic exposure [renal and total clearances, area under the plasma concentration time-curve (AUC)] and acute exposure (Cmax). Interindividual variability in kinetics was low for both routes of exposure, with coefficients of variation of 21% (oral) and 24% (intravenous) that were largely independent of the renal processes involved. Renal-excretion related uncertainty factors were below the default kinetic uncertainty factor of 3.16 for most subgroups analysed with the exception of the elderly (oral data) and neonates (intravenous data) for whom renal excretion-related factors of 4.2 and 3.2 would be required to cover up to 99% of these subgroups respectively.

Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6.

Bupropion is applied in depression and smoking cessation. Genetic polymorphisms in cytochrome P450 2B6 (CYP2B6) may cause variability in bupropion pharmacokinetics since hydroxylation is known to be mediated by CYP2B6. Bupropion may be a probe drug for CYP2B6 activity in humans. Bupropion pharmacokinetics were studied after a single oral dose of 150 mg in 121 healthy male volunteers. The amino acid polymorphisms R22C, Q172H, S259R, K262R and R487C were analysed by polymerase chain reaction and restriction fragment length polymorphism and plasma concentrations were measured by high-performance liquid chromatography. Pharmacokinetic analysis was performed by non-parametric methods and by population pharmacokinetic modelling. A unimodal distribution of bupropion and hydroxybupropion kinetic parameters was detected with a mean (range) area under the curve (AUC) of 3.64 (0.89-8.14) micromol.h/l for bupropion and 25.5 (6.72-75.3) micromol.h/l for hydroxybupropion. Population kinetic analysis revealed that bupropion total clearance via CYP2B6 alleles *1, *2, *5 and *6 did not differ, but clearance via allele *4 was 1.66-fold higher compared to wild-type allele *1 (P=0.001). Corresponding to the high clearance of bupropion, carriers of the CYP2B6 genotype *1/*4 had significantly higher Cmax of hydroxybupropion compared to all other genotypes (P=0.03). Only a minor fraction of the variability in bupropion and hydroxybupropion kinetics could be explained by the known CYP2B6 amino acid variants, in particular by the CYP2B6*4 allele. The role of this allele should also be studied in other CYP2B6 substrates, including cyclophosphamide, halothane, mianserin, promethazine and propofol.

Endothelin-1 Decreases Gap Junctional Intercellular Communication by Inducing Phosphorylation of Connexin 43 in Human Ovarian Carcinoma Cells

Endothelin-1 (ET-1) is overexpressed in ovarian carcinoma and acts as an autocrine factor selectively through the ETA receptor (ETAR) to promote tumor cell proliferation, survival, neovascularization, and invasiveness. Loss of gap junctional intercellular communication (GJIC) is critical for tumor progression by allowing the cells to escape growth control. Exposure of HEY and OVCA 433 ovarian carcinoma cell lines to ET-1 led to a 50-75% inhibition in intercellular communication and to a decrease in the connexin 43 (Cx43)-based gap junction plaques. To investigate the phosphorylation state of Cx43, ovarian carcinoma cell lysates were immunoprecipitated and transient tyrosine phosphorylation of Cx43 was detected in ET-1-treated cells. BQ 123, a selective ETAR antagonist, blocked the ET-1-induced Cx43 phosphorylation and cellular uncoupling. Gap junction closure was prevented by tyrphostin 25 and by the selective c-Src inhibitor, PP2. Furthermore, the increased Cx43 tyrosine phosphorylation was correlated with ET-1-induced increase of c-Src activity, and PP2 suppressed the ET-1-induced Cx43 tyrosine phosphorylation, indicating that inhibition of Cx43-based GJIC is mainly mediated by the Src tyrosine kinase pathway. In vivo, the inhibition of human ovarian tumor growth in nude mice induced by the potent ETAR antagonist, ABT-627, was associated with a reduction of Cx43 phosphorylation. These findings indicate that the signaling mechanisms involved in GJIC disruption on ovarian carcinoma cells depend on ETAR activation, which leads to the Cx43 tyrosine phosphorylation mediated by c-Src, suggesting that ETAR blockade may contribute to the control of ovarian carcinoma growth and progression also by preventing the loss of GJIC.

Is the renal dosimetry for [90Y-DOTA0,Tyr3]octreotide accurate enough to predict thresholds for individual patients?

The accuracy in the dosimetry for radionuclide therapy shows a great contrast to that obtained in external beam radiotherapy. The dosimetry for [(90)Y-DOTA(0), Tyr(3)] octreotide is evaluated in patients to see whether the accuracy of the dosimetry is high enough to distinguish the probability for radiation nephropathy. The 5% threshold for late end-point nephropathy at 23 Gy with external beam radiotherapy becomes with (90)Y therapy at least 30-35 Gy, when it is given in three or more fractions. More accurate linear-quadratic (LQ) model parameters are, however, needed to predict a more precise threshold for renal damage in this dose rate region. The average MIRD-based dose to the kidneys was 27 +/- 4 Gy (N = 52) with no evidence for renal damage. The variance in the dose is only caused by the high variability in renal uptake kinetics of the compound. Using the actual kidney volumes instead of the phantom values lowered the kidney dose considerably, but the variance in the dose greatly increased. As the peptide specifically localizes in the kidney cortex, the dose to the cortex increased up to a factor 1.5 compared to the MIRD whole kidney dose. Both the sum of uncertainties of ? 40% in the actual dose to the kidneys and the unknown maximum tolerable kidney dose for internal therapy make that a fixed injected activity of 13.32 GBq together with a patient-averaged dosimetry is as good as patient-kinetics specific dosimetry using the MIRD method.

Kinetic variability of AMPA receptors among olfactory bulb neurons in culture.

AMPA receptors, which are composed of four subunits (GluR1-4), help mediate synaptic transmission at most excitatory synapses in the brain. Their subunit composition influences the kinetics of AMPA receptor deactivation and desensitization, thus, the efficacy of synaptic transmission. Immunohistochemical data suggest that AMPA receptor subunit expression in the olfactory bulb (OB) follows a distinct laminar and cellular distribution. However, little is known about the kinetic properties of AMPA receptors on OB neurons. In this study, we used kinetic analysis and pharmacologic methods to demonstrate that the rate and extent of desensitization of OB AMPA receptors vary within and between neuronal subtypes. Such variability suggests that a broad functional diversity of AMPA receptors contributes to olfactory information processing.