Permanent CD8(+) T cell depletion prevents proteinuria in active Heymann nephritis.

Active Heymann nephritis (HN) is a rat model of human idiopathic membranous nephropathy in which injury is thought to be mediated by membrane attack complex of complement (MAC) activated by antibody (Ab) to glomerular epithelial cells. Recent work has shown that HN develops in C6-deficient rats which cannot assemble MAC, and that infiltration of activated cytotoxic CD8(+) T cells and macrophages into glomeruli coincides with proteinuria. This study examined the role of CD8(+) T cells in mediating glomerular injury in HN by permanent CD8(+) cytotoxic T cell depletion via adult thymectomy (ATx) and anti-CD8 mAb. Groups of rats were depleted of CD8(+) T cells either before immunization for HN or 6 wk after immunization when Ab responses and glomerular IgG deposition were well established. These were compared with groups of HN, ATx/HN, and complete Freund's adjuvant (CFA) controls. Neither group of CD8(+) T cell-depleted rats developed proteinuria, although there was normal development and deposition of Ab. CD8(+) T cell-depleted rats developed neither T cell or macrophage infiltrates nor their effector cytokines, which are present in glomeruli of rats with HN. Examination of lymph node (LN) draining sites of immunization showed these findings were not explained by altered immune events within these LNs. It was concluded that CD8(+) cytotoxic T cells are essential to the mediation of glomerular injury in HN and may be relevant to the pathogenesis and treatment of membranous nephropathy.

Nontraditional approaches to first-in-human studies to increase efficiency of drug development: will microdose studies make a significant impact?

Much has been written recently about low productivity in the pharmaceutical industry and the high cost of drug development. Over a 10-year period ending in 2000, only approximately 11% of compounds tested in humans across 10 large pharmaceutical companies were eventually approved for marketing in the United States and/or Europe. Attrition was highest during phase II (62%) but still significant in phase III (45%) and at the time of registration (23%). Clearly, given the high cost and time required for clinical development, these late-stage failures are unsustainable.

Direct Oral Anticoagulants Vs. Enoxaparin for Prevention of Venous Thromboembolism Following Orthopedic Surgery: A Dose-Response Meta-analysis.

We carried out a dose-response model-based meta-analysis to assess venous thromboembolism (VTE) and bleeding with factor Xa (FXa) inhibitors (apixaban, edoxaban, rivaroxaban) and a thrombin inhibitor (dabigatran) compared with European (EU) (40 mg q.d.) and North American (NA) (30 mg Q12H) dose regimens of a low molecular weight heparin (enoxaparin) following orthopedic surgery. Statistically significant differences in both VTE and bleeding outcomes were found between the NA and EU doses of enoxaparin, with odds ratios (95% confidence interval) for the NA vs. EU dose of 0.73 (0.71-0.76) and 1.20 (1.14-1.29) for total VTE and major bleeding, respectively. At approved doses, estimated odds ratios vs. both doses of enoxaparin for the three FXa inhibitors (range: 0.35-0.75 for VTE; 0.76-1.09 for bleeding) compared with those for dabigatran (range: 0.66-1.21 for VTE; 1.10-1.38 for bleeding) suggested generally greater efficacy and less bleeding for the FXa inhibitors.

Population Pharmacokinetics, Pharmacodynamics, and Exploratory Exposure-Response Analyses of Apixaban in Subjects Treated for Venous Thromboembolism.

Apixaban is approved for treatment of venous thromboembolism (VTE) and prevention of recurrence. Population pharmacokinetics, pharmacokinetics-pharmacodynamics (anti-FXa activity), and exposure-response (binary bleeding and thromboembolic endpoints) of apixaban in VTE treatment subjects were characterized using data from phase I-III studies. Apixaban pharmacokinetics were adequately characterized by a two-compartment model with first-order absorption and elimination. Age, sex, and Asian race had less than 25% impact on exposure, while subjects with severe renal impairment were predicted to have 56% higher exposure than the reference subject (60-year-old non-Asian male weighing 85 kg with creatinine clearance of 100 mL/min). The relationship between apixaban concentration and anti-FXa activity was described by a linear model with a slope estimate of 0.0159 IU/ng. The number of subjects with either a bleeding or thromboembolic event was small, and no statistically significant relationship between apixaban exposure and clinical endpoints could be discerned with a logistic regression analysis.

Phase I and pharmacokinetic study of the novel platinum analogue CI-973 on a 5-daily dose schedule.

CI-973, a platinum(II) derivative with a 2-methyl-1,4-butanediamine carrier ligand, has activity in cisplatin-resistant tumor models in vitro and in vivo. In a Phase I pharmacokinetic study, 31 patients were treated with CI-973 (24 to 50 mg/m2/day for 5 days; 28-day cycles) given i.v. over 30 min without routine antiemetic prophylaxis or hydration. Of the 29 patients evaluable for maximum tolerated dose determination, most had a performance status of 0 or 1, and most had received prior chemotherapy. Neutropenia was dose limiting at 40 and 50 mg/m2/day. Recovery from neutropenia was generally rapid with nadir counts and recovery usually occurring by Days 15 and 22, respectively. Drug-associated thrombocytopenia was uncommon and never severe, even in patients with Grade 4 neutropenia. Anemia was common, but did not appear dose related. Drug-related nausea and vomiting and changes in renal function were relatively infrequent and mild. No clinically evident ototoxicity was reported, although changes in audiograms were noted in several patients. CI-973 concentrations were measured in plasma ultrafiltrate and urine by high-pressure liquid chromatography. The harmonic mean terminal half-life was 2.0 h. The mean CI-973 renal and nonrenal clearance values were 42.3 and 37.4 ml/min/m2, respectively. The mean recovery of CI-973 in urine was 53% of the administered dose. The mean ratio of CI-973 renal clearance to creatinine clearance was 0.92. Total clearance correlated with creatinine clearance (r2 = 0.63). A relationship between toxicity, expressed as the percentage of reduction in absolute granulocyte count, and area under the CI-973 plasma concentration-time curve was found in a subgroup of "good-risk" patients. This relationship, described well by a sigmoidal Emax pharmacodynamic model, did not hold for patients with extensive prior therapy or poor performance status. A model for toxicity prediction based on dose and creatinine clearance has been derived and will be validated in future studies. The recommended Phase II dose of CI-973 is 30 mg/m2/day for 5 days.

The pharmacokinetics of the enantiomers of atenolol.

A number of studies have demonstrated that lipophilic beta-adrenoceptor blocking agents, eliminated almost exclusively by hepatic metabolism, are stereoselectively metabolized in human beings. Previous studies in our laboratory have demonstrated that pindolol, a beta-adrenoceptor blocking agent of intermediate lipophilicity that is eliminated by both hepatic metabolism and renal excretion, is eliminated stereoselectively in the kidney. In the present study we examined the pharmacokinetics of the enantiomers of atenolol, a hydrophilic cardioselective beta-adrenoceptor blocking agent that is eliminated almost exclusively by the kidney. A single 100 mg oral dose of racemic atenolol was administered to six healthy adult men. Concentrations of d- and l-atenolol in plasma and urine were measured by a stereospecific HPLC analytic procedure. In each subject the peak concentration of d-atenolol was greater than the peak concentration of l-atenolol (mean +/- SD of 420 +/- 81 ng/ml vs 366 +/- 61 ng/ml; p less than 0.05). The peak concentration of both enantiomers was reached at the same time in each subject (between 2 and 3 hours). The renal clearances of d- and l-atenolol were not significantly different (109.7 +/- 33.5 ml/min vs 112.5 +/- 36.7 ml/min), probably because the major route of renal elimination is glomerular filtration. The half-lives of d- and l-atenolol were not significantly different (mean +/- SD of 4.6 +/- 1.1 hours vs 5.2 +/- 0.9 hours). However, both the AUC and the amount excreted unchanged in the urine in 24 hours Ae [0-24]) were significantly greater for d-atenolol than for l-atenolol (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of probenecid on the renal elimination of cimetidine.

It is generally assumed that the systems involved in the transport of organic cations and organic anions in the renal proximal tubule are substrate selective (i.e., organic anions do not inhibit organic cation transport and vice versa). However, recent data obtained in vitro have suggested that the organic anion probenecid inhibits the renal transport of the organic cation cimetidine. We addressed the question of whether this interaction is biologically relevant in human beings. The study involved a two-treatment, randomized crossover design. Six healthy male subjects were given an intravenous infusion of 300 mg cimetidine alone as one treatment and, as the other treatment, received multiple oral doses of probenecid before receiving the cimetidine infusion. The renal clearance of cimetidine and inulin was determined in each period. There were no significant differences between treatments in cimetidine plasma concentrations, apparent volume of distribution, systemic clearance, half-life, amount of drug excreted unchanged in the urine, or nonrenal clearance. Probenecid significantly decreased the renal clearance of cimetidine by decreasing both the filtration clearance and the net secretory clearance. These effects were most evident in the first 1/2 to 1 hour after cimetidine administration, when probenecid levels in plasma and renal tissue would have been the highest. Because there was no effect of probenecid on cimetidine plasma concentrations, this interaction is not clinically relevant to the therapeutic use of these two compounds. However, the study demonstrates that renal interactions between organic cations and organic anions can occur in human beings. The mechanism of this interaction and the implications to other drug combinations are being explored.

The pharmacokinetics and pharmacodynamics of diltiazem and its metabolites in healthy adults after a single oral dose.

A potential complicating factor in the characterization of the pharmacokinetics and pharmacodynamics of diltiazem after an oral dose in the presence of two metabolites, N-demethyldiltiazem and desacetyldiltiazem, in plasma. Both N-demethyldiltiazem and desacetylditiazem have been shown to have pharmacologic activity in animal tissues. It is therefore possible that these metabolites contribute to the pharmacologic effect of diltiazem, but this possibility has not been explored. The purpose of this study was to investigate the pharmacokinetics and pharmacodynamics of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem. Particular attention was paid to the effect of diltiazem on atrioventricular conduction. Six healthy men received a 120 mg oral dose of diltiazem. Concentrations of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem in plasma and urine were measured by a sensitive HPLC method. Measures of pharmacologic response (heart rate, blood pressure, and PR interval) were obtained at each blood sampling time. Mean (+/- SD) peak plasma concentrations of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem were 174.3 +/- 72.7, 42.6 +/- 10.0, and 14.9 +/- 3.3 ng/ml, respectively. The apparent half-lives of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem were 6.5 +/- 1.4 hours, 9.4 +/- 2.2 hours, and 18 +/- 6.2 hours, respectively. Both N-demethyldiltiazem and diltiazem were eliminated by net secretion, whereas the renal clearance of desacetyldiltiazem did not exceed clearance by filtration. Both N-demethyldiltiazem and desacetyldiltiazem are bound to plasma proteins, with unbound fractions of 0.323 +/- 0.035 and 0.230 +/- 0.021. These values are similar to the unbound fraction of diltiazem (0.254 +/- 0.027). No significant effect of diltiazem on blood pressure or heart rate was noted. However, a prolongation of the PR interval was observed in all six subjects. Furthermore, an apparent clockwise hysteresis in the concentration-effect relationship was found in four of the six subjects. These findings suggest that some form of acute tolerance to the electrophysiologic effect of diltiazem develops, but the results of pharmacodynamic modeling suggest that this is not caused by the antagonistic effects the metabolites.

The cellular basis of cardiac allograft rejection: VIII. Mechanisms underlying delayed allograft rejection in PVG C6-deficient rats.

BACKGROUND: The delayed allograft rejection in C6-deficient PVG C6- rats compared with normal PVG rats has been attributed to the lack of alloantibody activation of the membrane attack complex of complement. As T cells alone have been shown to effect graft rejection, we examined T-cell responses in PVG C6- rats. METHODS: The cellular infiltrate and its mRNA for cytokines and effector molecules in DA heart allografts to PVG and PVG C6- rats was compared by immunoperoxidase staining and semiquantitative reverse transcriptase polymerase chain reaction. The ability of pure populations of T cells or alloantibody to mediate DA heart graft rejection in irradiated (750 rads) PVG and PVG C6- rats was also compared. RESULTS: The median rejection time of DA heart allografts was 8 days in PVG rats and 17.5 days in PVG C6-. PVG C6- rats sensitized to DA by two skin grafts rejected DA heart grafts in 5-6 days. CD3+, CD4+, CD8+, interleukin-2 receptor-positive T cell, macrophage, and natural killer cell infiltration, as well as class II major histocompatibility complex and intercellular adhesion molecule-1 up-regulation, in grafts was similar in naive PVG and PVG C6- rats. mRNA for T helper 1 cytokine interleukin-2, interferon-gamma, tumor necrosis factor-beta, macrophage molecules tumor necrosis factor-alpha, and inducible nitric oxide synthase, as well as cytotoxic T-cell effector molecules perforin and granzyme A and B, were found to be the same in the grafts from both naive PVG and naive PVG C6- rats. Thus, there appeared to be no difference in the T-cell effector response between the PVG and PVG C6- groups. There were higher alloantibody titers in PVG C6- rats than in PVG hosts. Irradiation ablated rejection and alloantibody responses and reconstitution with naive T cells alone restored rejection in both PVG and PVG C6- rats. Irradiated rats given serum from PVG rats that had rejected DA grafts did not effect rejection of DA grafts even if given naive T cells. Sensitized T cells restored second set. CONCLUSIONS: PVG C6- rats have normal T-cell responses and can mediate allograft rejection in the absence of alloantibody. The failure of PVG C6- to reject allografts rapidly may be a result of the poor clearance of alloantisera leading to enhancement of graft survival rather than a critical role for complement and membrane attack complex in acute rejection.

Impact of population pharmacokinetic-pharmacodynamic analyses on the drug development process: experience at Parke-Davis.

BACKGROUND: Continued scepticism about the benefits of population pharmacokinetics and/or population pharmacodynamics, here referred to collectively as the population approach, hampers its widespread application in drug development. At the same time the sources of this scepticism have not been clearly defined. In an attempt to capture and clearly define these concerns and to help communicate the value of the population approach in drug development at Parke-Davis we conducted a survey of customers within the company. The results of this survey are presented here. METHODS: All drug development programmes conducted over the past 10 years that included a population approach in data analysis and interpretation were identified. A brief description of the population analysis was prepared together with a brief description of how the resulting information was used in each drug development programme. These synopses were forwarded to relevant members of each drug development team together with a survey designed to solicit opinions as to the relevance and impact of these analyses. RESULTS: The most frequent use of information derived from population-based analysis was in labelling. In all cases of drugs making to New Drug Application (NDA) submission the analyses resulted in information that was included in approved or proposed labelling. In almost half of the cases summarised here (5 of 12), population-based analysis was perceived to have resulted in information that influenced the direction of individual development programmes. In many of these cases the information was serendipitous. It is also noted that most of these analyses were not the result of clearly defined objectives and prospective analysis plans. CONCLUSIONS: Use of the population approach, even when applied retrospectively, may have value in complementing or supporting interpretation of other data collected during the course of a trial. Atypical systemic exposure is quickly and easily assessed for correlation with adverse events or exceptional efficacy in retrospective or ad hoc evaluation. Although we know of no direct evidence, it is possible that such use of population pharmacokinetic data has facilitated NDA review and approval by providing insight into the role of atypical systemic drug exposure in otherwise spurious events.

Efficacy and local tolerance of a low-dose, 7-day matrix estradiol transdermal system in the treatment of menopausal vasomotor symptoms.

OBJECTIVE: To determine the efficacy and local tolerance of a new matrix transdermal drug-delivery system that delivers 0.02 mg of 17 beta-estradiol (E2) daily for 7 days for the relief of vasomotor symptoms. METHODS: A total of 324 surgically or naturally menopausal women, all with prior hysterectomy and moderate to severe vasomotor symptoms (56-140 hot flushes per week, with episodes of sweating, during a baseline observation period), participated in two independent, 12-week, randomized, double-blind, placebo-controlled studies. After a 4-week, treatment-free period, each woman received a continuous regimen of either one E2 transdermal system, two E2 transdermal systems, or placebo transdermal system(s) applied every week for 12 weeks. Efficacy was measured as reduction in hot flush frequency, determined from subject diaries. To measure local tolerance, skin irritation (erythema and edema) was objectively and systematically evaluated under blue light after removal of the transdermal system(s). Serum E2 and estrone concentrations were determined in one of the studies during baseline and on days 1, 9, 30, 58, 79, and 84. RESULTS: Mean hot flush frequency decreased from 80 hot flushes per week at baseline to approximately 13 hot flushes per week (84% decrease) after 12 weeks of transdermal E2 treatment. Compared with placebo, the decrease in hot flush frequency was significant as early as weeks 2 and 3, and was maintained through the end of the study. Few clinically significant skin reactions occurred, and only nine (3%) of the subjects withdrew because of a skin effect. After initial increase, serum E2 concentrations remained stable throughout the study, achieving values of approximately 20 and 40 pg/mL above baseline for one and two E2 transdermal systems, respectively. CONCLUSION: The E2 transdermal system effectively reduced the frequency of moderate to severe vasomotor symptoms as early as the second week of therapy and was very well tolerated. The decrease in hot flush frequency was similar to that reported for oral and other transdermal estrogens, but at lower serum E2 concentrations. This result may be due to the stable E2 blood level achieved with this transdermal system.

Effect of probenecid on the pharmacokinetics and pharmacodynamics of procainamide.

Renal tubular transport of organic anions and cations is assumed to be mutually exclusive. However, results of a number of in vitro and in vivo studies suggest an interaction between the organic anion, probenecid, and various organic cations in the proximal renal tubule. To evaluate the clinical importance of such an interaction, the authors investigated the pharmacokinetics and pharmacodynamics of procainamide, an organic cation with a low therapeutic index that is excreted in part by active secretion in the proximal tubule, in the presence and absence of probenecid. In a randomized crossover study, six healthy subjects received a single 750-mg IV dose of procainamide, with and without prior probenecid administration (2 g orally). Blood and urine samples were obtained and pharmacokinetic parameters of procainamide were determined in each treatment period. QT intervals were measured from ECG recordings that were obtained at blood collection times for pharmacodynamic evaluation. Coadministration of probenecid did not result in any significant change in the overall disposition of procainamide. In particular, renal clearance was not significantly different (488 +/- 95 mL/min without probenecid vs. 478 +/- 69 mL/min in the presence of probenecid). Our data suggest an interaction between probenecid and procainamide in the proximal renal tubule does not exit. Reasons for this lack of interaction are discussed.

Pharmacokinetics of a 7-day 17 beta-estradiol transdermal delivery system: effect of application site and repeated applications on serum concentrations of estradiol and estrone.

FemPatch (Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI), a new 7-day 17 beta-estradiol transdermal delivery system (TDS), has been developed for treatment of menopausal vasomotor symptoms. This two-period crossover study was conducted to determine the effects of TDS application site (buttocks versus abdomen) and early TDS replacement on estradiol and estrone concentrations, and to quantify intersubject and intrasubject pharmacokinetic variability. Eighteen healthy, postmenopausal female volunteers received a single 7-day TDS application to the abdomen and repeated TDS applications to the buttocks (regular replacement on days 7 and 14, intentional early replacement on day 17, and removal on day 21). Serial serum samples were assayed for estradiol and estrone by validated radioimmunoassay methods. The 7-day TDS delivers estradiol at a constant, near zero-order rate for the duration of application, independent of application site. Mean serum estradiol concentrations were higher after application to the buttocks than after application to the abdomen (19 and 15 pg/mL above baseline, respectively), making the buttocks the preferred site for TDS application. Mean serum concentration of estradiol was slightly higher (23 pg/mL above baseline) for the treatment week with early TDS replacement due to the transient increase in concentration over the first 24 hours after replacement. Parallel but smaller increases in concentrations of estrone were observed. Serum estradiol and estrone concentrations are reproducible within an individual from application to application (coefficient of variation, 25%). Variability between individuals was higher (coefficient of variation, 40-50%).

Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion.

The effect of atovarstatin on digoxin pharmacokinetics was assessed in 24 healthy volunteers in two studies. Subjects received 0.25 mg digoxin daily for 20 days, administered alone for the first 10 days and concomitantly with 10 mg or 80 mg atorvastatin for the last 10 days. Mean steady-state plasma digoxin concentrations were unchanged by administration of 10 mg atorvastatin. Mean steady-state plasma digoxin concentrations following administration of digoxin with 80 mg atorvastatin were slightly higher than concentrations following administration of digoxin alone, resulting in 20% and 15% higher Cmax and AUC(0-24) values, respectively. Since tmax and renal clearance were not significantly affected, the results are consistent with an increase in the extent of digoxin absorption in the presence of atorvastatin. Digoxin is known to undergo intestinal secretion mediated by P-glycoprotein. Since atorvastatin is a CYP3A4 substrate and many CYP3A4 substrates are also substrates for P-glycoprotein transport, the influence of atorvastatin and its metabolites on P-glycoprotein-mediated digoxin transport in monolayers of the human colon carcinoma (Caco-2) cell line was investigated. In this model system, atorvastatin exhibited efflux or secretion kinetics with a K(m) of 110 microM. Atorvastatin (100 microM) inhibited digoxin secretion (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the extent of inhibition observed with verapamil, a known inhibitor of P-glycoprotein transport. Thus, the increase in steady-state digoxin concentrations produced by 80 mg atorvastatin coadministration may result from inhibition of digoxin secretion into the intestinal lumen.

Electron pencil-beam redefinition algorithm dose calculations in the presence of heterogeneities.

The electron pencil-beam redefinition algorithm (PBRA) is currently being refined and evaluated for clinical use. The purpose of this work was to evaluate the accuracy of PBRA-calculated dose in the presence of heterogeneities and to benchmark PBRA dose accuracy for future improvements to the algorithm. The PBRA was evaluated using a measured electron beam dose algorithm verification data set developed at The University of Texas M. D. Anderson Cancer Center. The data set consists of measurements made using 9 and 20 MeV beams in a water phantom with air gaps, internal air and bone heterogeneities, and irregular surfaces. Refinements to the PBRA have enhanced the speed of the dose calculations by a factor of approximately 7 compared to speeds previously reported in published data; a 20 MeV, 15 x 15 cm2 field electron-beam dose distribution took approximately 10 minutes to calculate. The PBRA showed better than 4% accuracy in most experiments. However, experiments involving the low-energy (9 MeV) electron beam and irregular surfaces showed dose differences as great as 22%, in albeit a small fractional region. The geometries used in this study, particularly those in the irregular surface experiments, were extreme in the sense that they are not seen clinically. A more appropriate clinical evaluation in the future will involve comparisons to Monte Carlo generated patient dose distributions using actual computed tomography scan data. The present data also serve as a benchmark against which future enhancements to the PBRA can be evaluated.

Effect of using an initial polyenergetic spectrum with the pencil-beam redefinition algorithm for electron-dose calculations in water.

This work compares the accuracy of dose distributions computed using an incident polyenergetic (PE) spectrum and a monoenergetic (ME) spectrum in the electron pencil-beam redefinition algorithm (PBRA). It also compares the times required to compute PE and ME dose distributions. This has been accomplished by comparing PBRA calculated dose distributions with measured dose distributions in water from the National Cancer Institute electron collaborative working group (ECWG) data set. Comparisons are made at 9 and 20 MeV for the 15 x 15 cm2 and 6 x 6 cm2 fields at 100- and 110-cm SSD. The incident PE spectrum is determined by a process that best matches the weighted sum of monoenergetic PBRA calculated central-axis depth doses, each calculated with the energy correction factor, C(E), equal to unity, to the ECWG measured depth dose for the 15 x 15 cm2 field at 100-cm SSD. C(E) is determined by a least square fit to central-axis depth dose for the PE PBRA. Results show that both the PE and ME PBRA accurately calculate central-axis depth dose at 100-cm SSD for the 6 x 6 cm2 and 15 x 15 cm2 field sizes and also at 110-cm SSD for the 15 x 15 cm2 field size. In the penumbral region, the PE PBRA calculation is significantly more accurate than the ME PBRA for all measurement conditions. Both the PE and ME PBRA exhibit significant dose errors (> 4%) outside the penumbra at shallow depths for the 6 x 6 cm2 and 15 x 15 cm2 fields at 100-cm SSD and inside the penumbra at shallow depths for the 6 x 6 cm2 field size at 110-cm SSD. These errors are attributed to the fact that the PBRA does not model collimator scatter in the incident beam. Calculation times for the PE PBRA are approximately 70%-140% greater than those for the ME PBRA. We conclude that the PE PBRA is significantly more accurate than the ME PBRA, and we believe that the increase in time for the PE PBRA will not significantly impact the clinical utility of the PBRA.

A measured data set for evaluating electron-beam dose algorithms.

The purpose of this work was to develop an electron-beam dose algorithm verification data set of high precision and accuracy. Phantom geometries and treatment-beam configurations used in this study were similar to those in a subset of the verification data set produced by the Electron Collaborative Working Group (ECWG). Measurement techniques and quality-control measures were utilized in developing the data set to minimize systematic errors inherent in the ECWG data set. All measurements were made in water with p-type diode detectors and using a Wellhöfer dosimetry system. The 9 and 20 MeV, 15 x 15 cm2 beams from a single linear accelerator composed the treatment beams. Measurements were made in water at 100 and 110 cm source-to-surface distances. Irregular surface measurements included a "stepped surface" and a "nose-shaped surface." Internal heterogeneity measurements were made for bone and air cavities in differing orientations. Confidence in the accuracy of the measured data set was reinforced by a comparison with Monte Carlo (MC)-calculated dose distributions. The MC-calculated dose distributions were generated using the OMEGA/BEAM code to explicitly model the accelerator and phantom geometries of the measured data set. The precision of the measured data, estimated from multiple measurements, was better than 0.5% in regions of low-dose gradients. In general, the agreement between the measured data and the MC-calculated data was within 2%. The quality of the data set was superior to that of the ECWG data set, and should allow for a more accurate evaluation of an electron beam dose algorithm. The data set will be made publicly available from the Department of Radiation Physics at The University of Texas M. D. Anderson Cancer Center.

Modelling pencil-beam divergence with the electron pencil-beam redefinition algorithm.

The electron pencil-beam redefinition algorithm (PBRA), which is used to calculate electron beam dose distributions, assumes that the virtual source of each pencil beam is identical to that of the broad beam incident on the patient. In the present work, a virtual source specific for each pencil beam is modelled by including the source distance as a pencil-beam parameter to be redefined with depth. To incorporate a variable pencil-beam source distance parameter, the transport equation was reformulated to explicitly model divergence resulting in the algorithm divPBRA. Allowing the virtual source position to vary with individual pencil beams is expected to better model the effects of heterogeneities on local electron fluence divergence (or convergence). Selected experiments from a measured data set developed at The University of Texas M D Anderson Cancer Center were used to evaluate the accuracy of the dose calculated using divPBRA. Results of the calculation showed that the theory accurately predicted the virtual source position in regions of side-scatter equilibrium and predicted reasonable virtual source positions in regions lacking side-scatter equilibrium (i.e. penumbra and in the vicinity and shadow of internal heterogeneities). Results of the evaluation showed the dose accuracy of divPBRA to be marginally better to that of PBRA, except in regions of extremely sharp dose perturbations, where the divPBRA calculations were significantly greater than the measured data. Dose calculations using divPBRA took 45% longer than those using PBRA. Therefore, we concluded that divPBRA offers no significant advantage over PBRA for the purposes of clinical treatment planning. However, the results were promising and divPBRA might prove useful if further modelling were to include large-angle scattering, low-energy delta rays and brehmsstrahlung.

Minimal androgenic activity of a new oral contraceptive containing norethindrone acetate and graduated doses of ethinyl estradiol.

The pharmacokinetics and androgenic activity of Estrostep, a new oral contraceptive providing low-dose estrogen in a graduated sequence with a constant dose of progestin, were characterized in an open-label, nonrandomized study in 17 normally cycling women treated for three cycles with Estrostep. Women received 1 mg of norethindrone acetate daily combined with 20 microg of ethinyl estradiol daily for the first 5 days (1/20), 30 microg of ethinyl estradiol daily for the next 7 days (1/30), and 35 microg of ethinyl estradiol daily for 9 days (1/35). No medication was given for 7 days in each cycle to allow for withdrawal bleeding. Serial blood samples for the measurement of ethinyl estradiol and norethindrone concentrations were collected on days 5, 12, and 21 of the third treatment cycle for the 1/20, 1/30, and 1/35 dose, respectively. Sex hormone-binding globulin (SHBG) and free testosterone were measured at baseline, on day 1 of cycles 2 and 3 (SHBG only), and on days 5, 12, and 21 of cycle 3. Mean steady-state plasma ethinyl estradiol and norethindrone concentrations increased over cycle 3. The increases in ethinyl estradiol concentrations were proportional to dose. The increases in norethindrone concentrations were related to ethinyl estradiol-dependent increases in SHBG concentrations, which were 218%, 253%, and 296% of baseline values on days 5, 12, and 21, respectively. Mean plasma free testosterone concentrations decreased 47%, 60%, and 64% below baseline on days 5, 12, and 21 of cycle 3, respectively. Graduated ethinyl estradiol doses combined with a constant norethindrone acetate dose progressively increase SHBG and decrease free testosterone, which overrides any theoretic concerns of androgenic activity of norethindrone acetate. Although true androgenic activity can be determined only by assessing endpoints such as acne, hirsutism, and lipids in large controlled trials, the observed changes in circulating SHBG and free testosterone concentrations indicate that Estrostep has little, if any, intrinsic androgenic activity.

Herbicides and herbicide degradates in shallow groundwater and the Cedar River near a municipal well field, Cedar Rapids, Iowa.

Water samples were collected near a Cedar Rapids, Iowa municipal well field from June 1998 to August 1998 and analyzed for selected triazine and acetanilide herbicides and degradates. The purpose of the study was to evaluate the occurrence of herbicides and herbicide degradates in the well field during a period following springtime application of herbicides to upstream cropland. The well field is in an alluvial aquifer adjacent to the Cedar River. Parent herbicide concentrations generally were greatest in June, and decreased in July and August. Atrazine was most frequently detected and occurred at the greatest concentrations; acetochlor, cyanazine and metolachlor also were detected, but at lesser concentrations than atrazine. Triazine degradate concentrations were relatively small (< 0.50 microg/l) and generally decreased from June to August. Although the rate of groundwater movement is relatively fast (approx. 1 m per day) in the alluvial aquifer near the Cedar River, deethylatrazine (DEA) to atrazine ratios in groundwater samples collected near the Cedar River indicate that atrazine and DEA probably are gradually transported into the alluvial aquifer from the Cedar River. Deisopropylatrazine (DIA) to DEA ratios in water samples indicate most DIA in the Cedar River and alluvial aquifer is produced by atrazine degradation, although some could be from cyanazine degradation. Acetanilide degradates were detected more frequently and at greater concentrations than their corresponding parent herbicides. Ethanesulfonic-acid (ESA) degradates comprised at least 80% of the total acetanilide-degradate concentrations in samples collected from the Cedar River and alluvial aquifer in June, July and August; oxanilic acid degradates comprised less than 20% of the total concentrations. ESA-degradate concentrations generally were smallest in June and greater in July and August. Acetanilide degradate concentrations in groundwater adjacent to the Cedar River indicate acetanilide degradates are transported into the alluvial aquifer in a manner similar to that indicated for atrazine and DEA.