515 research outputs found
Towards real-time 6D pose estimation of objects in single-view cone-beam X-ray
Deep learning-based pose estimation algorithms can successfully estimate the
pose of objects in an image, especially in the field of color images. 6D Object
pose estimation based on deep learning models for X-ray images often use custom
architectures that employ extensive CAD models and simulated data for training
purposes. Recent RGB-based methods opt to solve pose estimation problems using
small datasets, making them more attractive for the X-ray domain where medical
data is scarcely available. We refine an existing RGB-based model
(SingleShotPose) to estimate the 6D pose of a marked cube from grayscale X-ray
images by creating a generic solution trained on only real X-ray data and
adjusted for X-ray acquisition geometry. The model regresses 2D control points
and calculates the pose through 2D/3D correspondences using
Perspective-n-Point(PnP), allowing a single trained model to be used across all
supporting cone-beam-based X-ray geometries. Since modern X-ray systems
continuously adjust acquisition parameters during a procedure, it is essential
for such a pose estimation network to consider these parameters in order to be
deployed successfully and find a real use case. With a 5-cm/5-degree accuracy
of 93% and an average 3D rotation error of 2.2 degrees, the results of the
proposed approach are comparable with state-of-the-art alternatives, while
requiring significantly less real training examples and being applicable in
real-time applications.Comment: Published at SPIE Medical Imaging 202
Inhibition of OATP1B1 by tyrosine kinase inhibitors: In vitro-in vivo correlations
Background:Several tyrosine kinase inhibitors (TKIs) can decrease docetaxel clearance in patients by an unknown mechanism. We hypothesised that these interactions are mediated by the hepatic uptake transporter OATP1B1.Methods:The influence of 16 approved TKIs on transport was studied in vitro using HEK293 cells expressing OATP1B1 or its mouse equivalent Oatp1b2. Pharmacokinetic studies were performed with Oatp1b2-knockout and OATP1B1-transgenic mice.Results:All docetaxel-interacting TKIs, including sorafenib, were identified as potent inhibitors of OATP1B1 in vitro. Although Oatp1b2 deficiency in vivo was associated with increased docetaxel exposure, single- or multiple-dose sorafenib did not influence docetaxel pharmacokinetics.Conclusion: These findings highlight the importance of identifying proper preclinical models for verifying and predicting TKI-chemotherapy interactions involving transporters
Factors involved in prolongation of the terminal disposition phase of SN-38: clinical and experimental studies
The active metabolite of irinotecan (CPT-11),
7-ethyl-10-hydroxycamptothecin (SN-38), is either formed through enzymatic
cleavage of CPT-11 by carboxyl esterases (CEs) or through cytochrome P-450
3A-mediated oxidation to 7-ethyl-10-[4-(1-piperidino)-1-amino]
carbonyloxycamptothecin (NPC) and a subsequent conversion by CE. In the
liver, SN-38 is glucuronidated (SN-38G) by UGT1A1, which also conjugates
bilirubin. Fourteen patients were treated with 350 mg/m2 CPT-11, and we
performed pharmacokinetic analysis during a 500-h collection period. The
half-life and area under the plasma concentration-time curve of SN-38 were
47+/-7.9 h and 2.0+/-0.79 microM x h, respectively, both representing a
2-fold increase as compared with earlier reported estimates (A. Sparreboom
et al, Clin. Cancer Res., 4: 2747-2754, 1998). As an explanation for this
phenomenon, we noted substantial formation of SN-38 from CPT-11 and NPC by
plasma CE, consistent with the low circulating levels of NPC observed. In
addition, transport studies in Caco-2 monolayers indicated that
nonglucuronidated SN-38 could cross the membrane from apical to
basolateral, indicating the potential for recirculation processes that can
prolong circulation times. Interestingly, individual levels of fecal
beta-glucuronidase, which is known to mediate SN-38G hydrolysis, were not
related to any of the SN-38 kinetic parameters (r = 0.09; P = 0.26),
suggesting that interindividual variation in this enzyme is unimportant in
explaining SN-38 pharmacokinetic variability. We have also found, in
contrast to earlier data, that SN-38G/SN-38 plasma concentration ratios
decrease over time from approximately 7 (up to 50 h) to approximately 1
(at 500 h). This decrease could be explained by the fact that
glucuronidation of SN-38 and bilirubin is increasingly competitive at
lower drug levels. In addition, no evidence was found for SN-38G transport
through the Caco-2 cells. Our findings indicate that until now the
circulation time of SN-38 has been underestimated. This is of crucial
importance to our understanding of the clinical action of CPT-11 and for
future pharmacokinetic/pharmacodynamic relationships
Effects of St. John's wort on irinotecan metabolism
St. John's wort (SJW), a widely used herbal product, has been implicated
in drug interactions resulting from the induced expression of the
cytochrome P450 CYP3A4 isoform. In this study, we determined the effect of
SJW on the metabolism of irinotecan, a pro-drug of SN-38 and a known
substrate for CYP3A4. Five cancer patients were treated with irinotecan
(350 mg/m(2), intravenously) in the presence and absence of SJW (900 mg
daily, orally for 18 days) in an unblinded, randomized crossover study
design. The plasma levels of the active metabolite SN-38 decreased by 42%
(95% confidence interval [CI] = 14% to 70%) following SJW cotreatment with
1.0 micro M x h (95% CI = 0.34 micro M x h to 1.7 micro M x h) versus 1.7
micro M x h (95% CI = 0.83 micro M x h to 2.6 micro M x h) (P =.033,
two-sided paired Student's t test). Consequently, the degree of
myelosuppression was substantially worse in the absence of SJW. These
findings indicate that patients on irinotecan treatment should refrain
from taking SJW because plasma levels of SN-38 were dramatically reduced,
which may have a deleterious impact on treatment outcome
Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients
This study was designed to evaluate irinotecan (CPT-11) disposition and
pharmacodynamics in the presence and absence of the broad-spectrum
antibiotic neomycin. Seven evaluable cancer patients experiencing diarrhea
graded > or =2 after receiving CPT-11 alone (350 mg/m(2) i.v. once every 3
weeks) received the same dose combined with oral neomycin at 1000 mg three
times per day (days -2 to 5) in the second course. Neomycin had no effect
on the systemic exposure of CPT-11 and its major metabolites (P > or =
0.22). However, it changed fecal beta-glucuronidase activity from 7.03 +/-
1.76 microg/h/mg (phenolphthalein assay) to undetectable levels and
decreased fecal concentrations of the pharmacologically active metabolite
SN-38. Although neomycin had no significant effect on hematological
toxicity (P > 0.05), diarrhea ameliorated in six of seven patients (P =
0.033). Our findings indicate that bacterial beta-glucuronidase plays a
crucial role in CPT-11-induced diarrhea without affecting enterocycling
and systemic SN-38 levels
- …