Meal Effects Confound Attempts to Counteract Rabeprazole-Induced Hypochlorhydria Decreases in Atazanavir Absorption.

PURPOSE: Clinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically-induced hypochlorhydria. METHODS: In this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100 mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20 mg twice daily), and with 1500 mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule. RESULTS: Pretreatment with rabeprazole resulted in significant reductions in atazanavir Cmax (p < 0.01) and AUC0-last (p < 0.001) (71 and 70%, respectively), and modest decreases in ritonavir Cmax and AUClast (p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV Cmax and 12% of AUClast lost due to rabeprazole. CONCLUSIONS: The co-administration of rabeprazole with atazanavir resulted in significant decreases in atazanavir exposure. The addition of betaine HCl did not sufficiently mitigate the loss of ATV exposure observed during RAB-induced hypochlorhydria. Meal effects lead to a marked difference in the outcome of betaine HCl on atazanavir exposure than we previously reported for dasatanib under fasting conditions.

Clinical commissioning and use of the Novalis Tx linear accelerator for SRS and SBRT.

The purpose of this study was to perform comprehensive measurements and testing of a Novalis Tx linear accelerator, and to develop technical guidelines for com-missioning from the time of acceptance testing to the first clinical treatment. The Novalis Tx (NTX) linear accelerator is equipped with, among other features, a high-definition MLC (HD120 MLC) with 2.5 mm central leaves, a 6D robotic couch, an optical guidance positioning system, as well as X-ray-based image guidance tools to provide high accuracy radiation delivery for stereotactic radiosurgery and stereotactic body radiation therapy procedures. We have performed extensive tests for each of the components, and analyzed the clinical data collected in our clinic. We present technical guidelines in this report focusing on methods for: (1) efficient and accurate beam data collection for commissioning treatment planning systems, including small field output measurements conducted using a wide range of detectors; (2) commissioning tests for the HD120 MLC; (3) data collection for the baseline characteristics of the on-board imager (OBI) and ExacTrac X-ray (ETX) image guidance systems in conjunction with the 6D robotic couch; and (4) end-to-end testing of the entire clinical process. Established from our clinical experience thus far, recommendations are provided for accurate and efficient use of the OBI and ETX localization systems for intra- and extracranial treatment sites. Four results are presented. (1) Basic beam data measurements: Our measurements confirmed the necessity of using small detectors for small fields. Total scatter factors varied significantly (30% to approximately 62%) for small field measurements among detectors. Unshielded stereotactic field diode (SFD) overestimated dose by ~ 2% for large field sizes. Ion chambers with active diameters of 6 mm suffered from significant volume averaging. The sharpest profile penumbra was observed for the SFD because of its small active diameter (0.6 mm). (2) MLC commissioning: Winston Lutz test, light/radiation field congruence, and Picket Fence tests were performed and were within criteria established by the relevant task group reports. The measured mean MLC transmission and dynamic leaf gap of 6 MV SRS beam were 1.17% and 0.36 mm, respectively. (3) Baseline characteristics of OBI and ETX: The isocenter localization errors in the left/right, posterior/anterior, and superior/inferior directions were, respectively, -0.2 ± 0.2 mm, -0.8 ± 0.2 mm, and -0.8 ± 0.4 mm for ETX, and 0.5 ± 0.7 mm, 0.6 ± 0.5 mm, and 0.0 ± 0.5 mm for OBI cone-beam computed tomography. The registration angular discrepancy was 0.1 ± 0.2°, and the maximum robotic couch error was 0.2°. (4) End-to-end tests: The measured isocenter dose differences from the planned values were 0.8% and 0.4%, measured respectively by an ion chamber and film. The gamma pass rate, measured by EBT2 film, was 95% (3% DD and 1 mm DTA). Through a systematic series of quantitative commissioning experiments and end-to-end tests and our initial clinical experience, described in this report, we demonstrate that the NTX is a robust system, with the image guidance and MLC requirements to treat a wide variety of sites - in particular for highly accurate delivery of SRS and SBRT-based treatments.

Synthesis of 4-substituted chlorophthalazines, dihydrobenzoazepinediones, 2-pyrazolylbenzoic acid, and 2-pyrazolylbenzohydrazide via 3-substituted 3-hydroxyisoindolin-1-ones.

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, N,N-dimethylaminophthalimide (8a) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones 9b, 9i-9am. Many of these hydroxyisoindolinones are converted to chlorophthalazines 1b-1v via reaction with hydrazine, followed by chlorination with POCl(3). We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to N,N-dimethylaminophthalimide (8a) provided dihydrobenzoazepinediones 15a-15c via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids 16a-16d and 2-pyrazolyl benzohydrazides 17a-17g rather than the expected alkynyl phthalazinones.

Evaluation of residual patient position variation for spinal radiosurgery using the Novalis image guided system.

PURPOSE: The Novalis system has been demonstrated to achieve accurate target localization on anthropomorphic phantoms. However, other factors, such as rotational deviation, patient intrafraction motion, and image fusion uncertainty due to patient body deformation, could contribute additional position uncertainty for actual patients. This study evaluates such position uncertainty for spinal radiosurgery patients. MATERIALS AND METHODS: Fifty-two consecutive spinal radiosurgery patients were included in the study. Rotational deviation was evaluated from 6-deg of freedom (6D) fusion results for all patients. The combined uncertainty of patient motion and image fusion was determined from fusion results of additional kV x-ray images acquired before, during, and after treatment for 25 of the 52 patients. The uncertainty of image fusion was also evaluated by performing 6D fusion ten different times with various regions of interest in the images selected for fusion. This was performed for two patients with L3 and T2 lesions, respectively, for comparison. RESULTS: The mean rotational deviation was 0.7 +/- 1.8, 0.7 +/- 1.5, and 0.7 +/- 1.6 deg along the yaw, roll, and pitch directions, respectively. The combined uncertainty from patient motion and image fusion was 0.1 +/- 0.9, 0.2 +/- 1.2, and 0.2 +/- 1.0 mm in the anteroposterior (AP), longitudinal, and lateral directions, respectively. The uncertainty (standard deviation) due to image fusion was less than 0.28 mm in any direction for the L3 lesion and 0.8 mm in the AP direction for the T2 lesion. CONCLUSION: Overall position uncertainty for spinal radiosurgery patients has been evaluated. Rotational deviation and patient motion were the main factors contributed to position uncertainty for actual patient treatment.

2D/3D image fusion for accurate target localization and evaluation of a mask based stereotactic system in fractionated stereotactic radiotherapy of cranial lesions.

The purpose of this study was to evaluate the accuracy of a two-dimensional (2D) to three-dimensional (3D) image-fusion-guided target localization system and a mask based stereotactic system for fractionated stereotactic radiotherapy (FSRT) of cranial lesions. A commercial x-ray image guidance system originally developed for extracranial radiosurgery was used for FSRT of cranial lesions. The localization accuracy was quantitatively evaluated with an anthropomorphic head phantom implanted with eight small radiopaque markers (BBs) in different locations. The accuracy and its clinical reliability were also qualitatively evaluated for a total of 127 fractions in 12 patients with both kV x-ray images and MV portal films. The image-guided system was then used as a standard to evaluate the overall uncertainty and reproducibility of the head mask based stereotactic system in these patients. The phantom study demonstrated that the maximal random error of the image-guided target localization was +/-0.6 mm in each direction in terms of the 95% confidence interval (CI). The systematic error varied with measurement methods. It was approximately 0.4 mm, mainly in the longitudinal direction, for the kV x-ray method. There was a 0.5 mm systematic difference, primarily in the lateral direction, between the kV x-ray and the MV portal methods. The patient study suggested that the accuracy of the image-guided system in patients was comparable to that in the phantom. The overall uncertainty of the mask system was +/-4 mm, and the reproducibility was +/-2.9 mm in terms of 95% CI. The study demonstrated that the image guidance system provides accurate and precise target positioning.

A technique of intensity-modulated radiosurgery (IMRS) for spinal tumors.

This study is to demonstrate the feasibility of spinal radiosurgery using an image-guided intensity-modulated radiosurgical (IMRS) procedure. A dedicated Novalis shaped beam surgery unit equipped with a built-in micro-multileaf collimator (mMLC) with a single 6 MV photon beam was used. Each patient was simulated in the supine position using an AcQsim CT simulator with infrared sensitive markers for localization. A variety of different treatment plans were developed, but the most common plan was the use of seven coplanar intensity-modulated beams to minimize radiation to critical organs such as the spinal cord and kidneys. An automatic localization device based on infrared and video cameras was used to guide the initial patient setup. Two keV x-ray imaging systems were used to identify potential deviations from the planned isocenter. A total of 25 patients with spinal tumors have been treated using this procedure with a single prescription dose ranging from 6 to 12 Gy. The final verification images indicated that the average isocenter deviation from the planned isocenter was within 2 mm. The phantom verification of isocenter doses indicated that the average deviation of measured isocenter doses from the planned isocenter doses for all patients treated with intensity-modulated beams was less than 2%. Film dose measurement in a phantom study demonstrated good agreement of above 50% isodose lines between the planned and measured results. Preliminary experience shows that precision delivery of high dose radiation could be administered to the planned target volume while the dose to the critical organs is kept within tolerable limits.