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PubMed2000

Conformal irradiation of concave-shaped PTVs in the treatment of prostate cancer by simple 1D intensity-modulated beams.

BACKGROUND: In the case of concave-shaped PTVs including prostate (P) and seminal vesicles (SV), intensity-modulated radiation therapy (IMRT) should improve the therapeutic ratio of the treatment of prostate cancer. PURPOSE: Comparing IMRT by simple 1D modulations with conventional 3D conformal therapy (i.e. non-IMRT) in the treatment of concave-shaped PTVs including P+SV. MATERIALS AND METHODS: For five patients having a concave-shaped PTV (P+SV) previously treated at our Institute with conformal radiotherapy, conventional 3- and 4-fields conformal plans were compared with IMRT plans in terms of biological indices. IMRT plans were generated by using five equi-spaced beams with a partial shielding of the rectum obtainable with our single-absorber modulation technique (Fiorino C, Lev A, Fusca M, Cattaneo GM, Rudello F, Calandrino R. Dynamic beam modulation by using a single dynamic absorber. Phys. Med. Biol. 1995;40:221-240). The modulation was one-dimensional and the shape of the beams was at single minimum in correspondence with the 'core' of the rectum; the beam intensity in the minimum was set equal to 20 or 40% of the open beam intensity. All plans were simulated on the CADPLAN TPS using a pencil-beam based algorithm (with 18 MV X-rays). Tumour control probability (TCP) and normal tissue complication probabilities (NTCPs) (for rectum, bladder and femoral head) were calculated for all situations when varying the isocentre dose from 60 to 90 Gy. Dose distributions were corrected taking dose fractionation into account through the linear-quadratic model; for the TCP/NTCP estimations the Webb-Nahum and the Lyman-Kutcher models were respectively applied. Three different scores were considered: (a) increase of TCP while keeping rectum NTCP equal to 5% (TCP(5%)); (b) increase of the uncomplicated tumour control probability (P+); (c) increase of the biological-based scoring function (S+), developed by Mohan et al. (Mohan R, Mageras GS, Baldwin B, Clinically relevant optimization of 3D conformal treatments. Med. Phys. 1992;19:933-944). The impact of the uncertainty in the knowledge of the parameters of the biological models was investigated for TCP(5%). RESULTS: (a) The average gain in TCP(5%) when considering IMRT against non-IMRT conformal plans was 7.3% (range 5.0-13.5%); (b) the average increase of P+ was 3.4% (range: 1. 0-8.5%); and (c) the average increase of S+ was 5.4% (range 2.9-12. 4%). The largest gain was found for one patient (patient 5) showing a significantly larger overlapping between PTV and rectum. CONCLUSIONS: Simple 1D-IMRT may clearly improve the therapeutic ratio in the treatment of concave-shaped PTVs including P and SV. In the range of clinically suitable values, the impact of the uncertainty of the parameters n and sigma(alpha) does not significantly alter the main results concerning the gain in TCP(5%). The reported gain in terms of P+ and S+ should be considered with great caution because of the intrinsic uncertainties of the model's parameters and, for bladder, because the 'true' DVH (considering variations of the shape and dimension due to variable filling) may be very different from the DVH calculated on a single CT scan. Further investigations should consider inversely-optimised 1D and 2D-IMRT plan in order to compare them in terms of cost-benefit.

Algorithms↗
PubMed1987

Inter-tumor heterogeneity and radiation dose-control curves.

This communication presents a theoretical analysis of the influence of inter-tumor heterogeneity on clinical radiation dose-response curves. Any clinically defined group of tumors consists of individuals each having a unique individual dose-control relation (I-TCP/D). This I-TCP/D relation is steep and is based on Poisson statistics. The population as a whole possesses a heterogeneous dose-control relation (H-TCP/D relation) that is a resultant of the weighted summation of the I-TCP/D curves, each weighted according to its relative frequency in the population. This summation leads to an H-TCP/D curve that is considerably flatter than the steep portion of any I-TCP/D curve. For any specified radiation regimen, three subclasses of tumors exist in any population: the stochastic fraction, which consists of those tumors whose individual tumor control probability lies between 99% and 1% and individual outcome is probabilistic; the refractory fraction, which consists of those tumors each of which has no prospect for control with the specified treatment; and the sensitive fraction, which consists of tumors each of which is absolutely controllable with the specific treatment. Based on plausible parameters, it is estimated that, for tumors associated with an overall tumor control probability of approximately 50%, some 70-85% of failures come from a predictably radioresistant fraction. To optimize and improve the radiation therapy of tumors with unsatisfactory local control, it is necessary to predictably identify the location of each individual in one of the three subclasses.

Dose-Response Relationship, Radiation↗
PubMed2001

Radiation response and cure rate of human colon adenocarcinoma spheroids of different size: the significance of hypoxia on tumor control modelling.

PURPOSE: To evaluate the adequacy of a Poisson tumor control probability (tcp) model and the impact of hypoxia on tumor cure. METHODS AND MATERIALS: A human colon adenocarcinoma cell line, WiDr, was grown as multicellular spheroids of different diameters. Measurements were made of cell survival and spheroid cure following 300-kV X-ray external beam irradiation in air and nitrogen. Cell survival data were fitted using a two-compartment and an oxygen diffusion model. Spheroid cure data were fitted using the tcp model. RESULTS: Hypoxia was seen only for spheroids greater than 500 microm in diameter. For small spheroids tcp estimates of radiosensitivity and clonogenic number showed excellent agreement with experimentally derived values. For large spheroids, although tcp estimates of radiosensitivity were comparable with measurements, estimates of the clonogenic number were considerably lower than the experimental count. Reoxygenation of large spheroids before irradiation resulted in the tcp estimates of the number of clonogenic cells agreeing with measured values. CONCLUSIONS: When hypoxia was absent, the tcp model accurately predicted cure from measured radiosensitivity and clonogen number. When hypoxia was present, the number of cells capable of regrowth in situ was considerably lower than the number of clonogenic cells that initially survived irradiation. As this counteracted the decreased radiosensitivity, hypoxia was less important for cure than predicted from cell survival assays. This finding suggests that chronic hypoxia may not limit directly the success of radiation therapy.

Adenocarcinoma↗
PubMedDate not supplied

An evaluation of nitrous oxide analgesia during transcutaneous pacing.

Transcutaneous cardiac pacing (TCP) is a promising prehospital intervention, but there are little data available regarding protocols to improve patient tolerance to TCP. A 50:50 nitrous oxide:oxygen analgesic mixture also is a commonly employed prehospital intervention. In this randomized, prospective study, we compared the discomfort experienced by 18 healthy subjects when paced in two trials at the capture threshold: one following breathing of a 50:50 nitrous oxide:oxygen mixture; and the second only breathing room air. Discomfort was rated on an analog scale from 1 (minimal discomfort) to 10 (severe pain). Of the 18 subjects, 15 (83%) reported that nitrous oxide improved the tolerance to pacing at capture threshold. The median pain scores at capture threshold in the nitrous oxide and room air group were 3.8 and 5.0 respectively (P less than .05). Nine of the subjects tolerated TCP for the maximum allotted time of 30 seconds in each trial; six tolerated TCP for a longer time period in the nitrous oxide trial; three tolerated TCP longer in the room air trial. These data suggest that inhalation of 50:50 nitrous oxide:oxygen mixture may improve tolerance to TCP in the conscious patient.

Analgesia↗
PubMed2002

Method for the gas chromatographic assay with mass selective detection of trichloro compounds in corks and wines applied to elucidate the potential cause of cork taint.

To investigate the role of trichloro compounds as a potential cause of "cork taint" in wine, an assay for trichloroanisole (TCA) and trichlorophenol (TCP) in corks and wine was developed utilizing solid phase extraction on a C(18) cartridge followed by gas chromatography with mass selective detection. Recovery and imprecision for TCA were 86-102 and 1.6-5.8%, respectively, and for TCP 82-103% and 1.7-3.9%, respectively. Limits of detection and quantitation were 0.1 and 2 ng/L, respectively, for TCA, and 0.7 and 4 ng/L, respectively for TCP. A survey of 2400 commercial wines revealed a higher incidence of cork taint in white wine than in red and in wines utilizing composite cork closures; wines from central Europe and Spain had higher overall rates of contamination and those from Canada and Italy the lowest. Significant but modest associations were found between the TCA and TCP contents of the wines and corks, but many wines exhibiting cork taint had low or undetectable concentrations of TCA. Over a 12-month period, experimentally bottled wines exhibited a slow increase in TCA and TCP content while cork closures manifested a decrease; most bottles showing cork taint contained low levels of TCA, and TCP concentrations were well below the sensory threshold. Neither compound was cytotoxic to human cell lines in culture up to final concentrations of 500 ng/mL. It was concluded that these two trichloro compounds are, at most, minor components of cork taint in commercial wines.

Analysis of Variance↗
PubMed2004

Relationship between bioceramics sintering and micro-particles-induced cellular damages.

We performed experimental studies to confirm the hypothesis that cellular damages occurring around implanted biphasic bioceramics could be related to a micro-particles release because of an insufficient sintering. First, an in vitro cytotoxicity study was performed on four biphasic ceramic (BCP) samples. Without treatment of the extraction medium, a cytotoxicity was observed, although after centrifugation this cytotoxicity disappeared in all samples. Second, micro-particles of hydroxyapatite (HA), beta-tricalcium phosphate (beta-TCP) and 40% beta-TCP/60%HA mixture were used for a cell inhibition study. A decrease of cell viability was observed with the increase in particles concentration. At 10000 particles per cell, the viability and proliferation were completely inhibited. Third, HA, beta-TCP and BCP ceramic granules were implanted in rabbit femoral cavities for 12 weeks. No degradation of HA granules was observed. The degradation was higher for beta-TCP (40%) than for BCP (5%). On the other hand, new bone formation was significantly higher for beta-TCP (21%) and HA (18%) than for BCP (12%). More micro-particles were formed around BCP granules than around beta-TCP, and phagocytised by macrophages. The release of ceramic micro-particles could be related to the sintering process. BCP ceramic have to be sintered at only 1160 degrees C. Consequently, HA micro-particles of BCP ceramic are incompletely sintered and easily released after immersion or implantation. The microparticles could be at the origin of local inflammation and cell damage and could perhaps modify osteogenesis. Attention must be paid to this problem especially with BCP ceramics because of the sintering difficulties of this bioceramic.

Animals↗
PubMed2003

Transverse coloplasty pouch and colonic J-pouch for rectal cancer--a comparative study.

OBJECTIVES: The introduction of the colonic J-pouch has markedly improved the functional outcome of restorative rectal cancer surgery. However colonic J-pouch surgery can be problematic and may present some late evacuatory problems. To overcome these limitations a novel pouch has been proposed: the transverse coloplasty pouch. The purpose of our study was to compare the functional outcomes of these two different types of pouches--the transverse coloplasty pouch (TCP) and the colonic J-pouch (CJP)--during the first 12 months postoperatively. PATIENTS AND METHODS: A prospective randomized trial was conducted in which a total of 30 patients with mid and low rectal cancer were submitted either to a transverse coloplasty pouch or a colonic J-pouch. Clinical defaecatory function was assessed and anorectal physiological assessment was carried out, pre-operatively and at 3, 6 and 12 months postoperatively, by means of a standard clinical questionnaire and by anorectal manometry. RESULTS: No statistically significant differences were found between the two groups regarding bowel function. The postoperative frequency of daily bowel movements was lower in the TCP group in all the phases of the study (3.9 vs. 4.1 at 3 months; 3.1 vs. 3.4 at 6 months; 2.1 vs. 2.8 at 12 months), the same occurring with fragmentation (33% vs. 40% at 3 months; 26.6%vs. 33.3% at 6 months; 7.1%vs. 14.3% at 12 months). Less urgency was also seen in the TCP group during the first 6 months (20%vs. 26.7%), with identical values at 12 months (14.3% vs. 14.3%). No significant differences were also found concerning incontinence grading and scoring, with TCP patients having less nocturnal leaks. At one year two CJP patients (14.3%) needed the use of enemas to evacuate the pouch and provoke defaecation, a problem never seen in TCP patients. The anorectal manometry data was similar in both types of pouches. The local complication rates were also identical in the two groups (20%); more anastomotic leaks were seen in TCP patients (13.2% vs. 6.6%), without reaching a statistical significance. CONCLUSION: The transverse coloplasty pouch has similar functional results but fewer evacuation problems than the J-Pouch, making it a safe and reliable alternative to the colonic J-pouch.

Adult↗
PubMed1999

The merit of sintered PDLLA/TCP composites in management of bone fracture internal fixation.

Polyesters based on lactic acid have been reported in terms of safety and biodegradation in human beings for 2 decades. The greatest advantage of such material is its degradation conducted only by hydrolysis, whereby the ester backbones are supposed to be unchained in the aqueous condition. The final degradable products are carbon dioxide and water which can be metabolized and digested in the physiological environment. The goal of this study was aimed at developing a composite sintered with poly-DL-lactide (PDLLA) and tricalcium phosphate (TCP) ceramic particles for orthopedic application. The TCP particles in a range of 30-60 wt% with 5 wt% increments were doped into the PDLLA matrix which was prepared by melting and hot pressing techniques for the reinforcement. The basic mechanical strength, biodegradable behavior, and biological response of the composites were investigated in the study. Various techniques such as pH meter, UV, Fourier-transform infrared, and x-ray diffractometer were used to examine and record the degradable process of the composites soaked in saline for 1-16 weeks. The rabbit femur condyle fracture fixation test was used to evaluate tissue compatibility and the effects of bone fracture fixation on the composites. Histological observation and x-ray photography were used for investigating assistance. The mechanical strength of the composites initially increased with TCP additions up to 50wt%, but thereafter they showed no significant difference (p < 0.05). The composite with 50 wt% TCP addition showed greater mechanical strength and had good agreement with cortical bone in terms of its elastic modulus of 30-40 GPa. The weight loss of the pure PDLLA soaked in the saline started at 4 weeks and reached 95% after 16 weeks. The composites compared with pure PDLLA, however, showed no apparent evidence of degradation after soaked for 12 weeks. The possible mechanisms for the delayed degradation of the composites in saline might have been solution penetration retardation by the ceramic particles and chemical bonds formed between the interface of the TCP particles and the PDLLA matrix. In the histological evaluation of the rabbit femur condyle fracture fixation test, the surface of the composite with 50 wt% TCP addition was attached by the newly generated bone without fibrous tissue around 8 weeks after implantation. The fractured bone was gradually healed and the composite firmly and properly fixed on the fracture area during the implanted period, which provided a breeding environment for normal bone remodeling. The developed composite was thought to be an alternative material for orthopedic application in the future, especially for bone screws and bone plates.

Absorption↗
PubMed2001

Posterior cruciate-sacrificing versus posterior cruciate-substituting total knee arthroplasty: a study of clinical and functional outcomes in matched patients.

Since the introduction of the Total Condylar Prosthesis (TCP) in 1974, concomitant improvements in surgical technique and prosthetic design have occurred. The individual effects of each of these variables have not been investigated, however. This study evaluates 2 different knee designs using the same operative technique by a single surgeon. All primary total knee arthroplasties performed between 1986 and 1989 were entered into a database of 2 cohorts, TCP and Press Fit Condylar (PFC) knees, matched for age, gender, body weight, and diagnosis. Follow-up data within 12 months of each other were used, evaluating patients clinically and using a self-administered questionnaire. In each cohort, 74 knees were matched by these criteria. Follow-up time was 4.04 and 4.45 years for the TCP and PFC cohorts. Range of motion averaged 107 degrees and 112 degrees for the TCP and PFC cohorts. This difference was statistically significant. Total knee score and functional score improved significantly. Anterior knee pain was present in 9 TCP and 3 PFC knees. Lateral release was performed in 30 TCP and 18 PFC knees. The PFC showed an advantage in ROM, stair function, anterior knee pain, and use of lateral release. Both designs showed comparable pain relief and walking ability.

Adult↗
PubMed2003

Local treatment of Dacron patch graft contaminated with Staphylococcus aureus with antibiotic-releasing porous apatite ceramic: an experimental study in the rabbit.

OBJECTIVE: The purpose of this study was to investigate whether or not infection of prosthetic vascular graft could be prevented with the placement of antibiotic-loaded porous apatite ceramic on the graft with bacterial contamination. METHODS: Teicoplanin as an antibiotic was loaded into a beta-tricalcium phosphate (TCP) block of porous apatite ceramic. The activity of teicoplanin released from teicoplanin-loaded TCP was examined for 40 days at 2-day intervals. In an in vivo study, the graft was patched in the abdominal aorta of a rabbit. Two different doses of Staphylococcus aureus were applied (n = 13). Teicoplanin-loaded TCP was placed around the graft infected with S aureus (n = 6). The graft, the tissue around it, and the arterial blood were collected and cultivated 4 weeks after operation. RESULTS: The activity of teicoplanin in the replaced saline solution was maintained for at least 40 days. Because graft infection was established in all rabbits with a dose of 2 x 10(7) colony forming units, this dose was used as the dose of S aureus in this study. Fifty-seven percent of the subjects died from the infection. When teicoplanin-loaded TCP was placed around the graft contaminated with S aureus, no rabbits died. Bacterial cultures of the graft and of tissues around it were negative in all rabbits killed 4 weeks after operation. This infection was prevented with teicoplanin-loaded TCP in all rabbits. CONCLUSION: Teicoplanin-loaded TCP may be useful in avoiding Dacron graft infection with S aureus in rabbits.

Animals↗
PubMed1980

Evidence for unequal crossing over within the mouse T/t complex.

The Tcp-1 gene located within the T/t complex on chromosome 17 of the mouse codes for a major cell surface-associated protein p63/6.9. Previously, we identified two structural alleles of this gene which specify alternate forms of the p63/6.9 protein. The Tcp-1b allele is associated with all wild-type chromosome 17; the Tcp-1a allele is found only with chromosome 17 carrying a complete t haplotype. Normal recombination along a major length of chromosome 17 is suppressed in mice that are heterozygous for any complete t haplotype. Suppression is not complete, however, and rare crossing over between wild-type and t haplotype chromatin does occur. In this report, 15 rare recombinant chromosomes have been analyzed for Tcp-1 alleles. The results indicate that in four independent events the Tcp-1b and Tcp-1a alleles have become associated in cis position in a single DNA molecule. Further genetic analysis provides support for the hypothesis that a significant nonhomology exists between the arrangement of DNA sequences on wild-type and t-carrying chromosome 17. This could account for both the suppression of normal recombination along the stretch of t chromatin and the frequent unequal crossing over when rare recombinational events do take place.

Alleles↗
PubMed2004

Effect of heterogeneity in radiosensitivity on LQ based isoeffect formalism for low alpha/beta cancers.

Change of fractionation for external beam radiation therapy based on linear-quadratic (LQ) formalism assumes that a single alpha/beta is sufficient to characterize tumour response to dose fractionation. In reality, both inter-patient and intra-tumour heterogeneity might affect the applicability of isoeffectiveness formalism. The impact of heterogeneity on recently proposed hypofractionation schemes for the prostate has been analysed. The alpha/beta ratio was assumed to be Gaussian distributed with a mean value of 1.5 Gy. Gaussian and lognormal distributions for alpha were modelled. TCP model parameters were adjusted to lead to TCP = 0.80 for 70 Gy at 2 Gy per fraction. TCP loss from heterogeneity and doses required to restore TCP = 0.80 were calculated. The effect of heterogeneity was moderate. Doses to restore TCP = 0.80 in most cases were less than 1 Gy. The largest TCP loss was 4%. The difference between predictions of single alpha/beta and heterogeneity models is too small to be detected in a clinical trial.

Dose Fractionation, Radiation↗
PubMed1998

Predicting the radiation control probability of heterogeneous tumour ensembles: data analysis and parameter estimation using a closed-form expression.

A closed-form formula describing the tumour control probability (tcp) of a heterogeneous collection of tumours has been obtained by analytically averaging the homogeneous double-exponential tcp formula over inter-tumour distributions of clonogen radiosensitivity, density and repopulation rate, tumour volume and dose. The formula can be straightforwardly and relatively quickly fitted to clinical data, yielding radiobiological parameter values for use in tcp modelling. The formula was fitted to published tcp data which catalogued tumour control records grouped by dose and tumour volume, and treatment duration. Fitted parameter values, confidence intervals and goodness-of-fit statistics were determined. The sets of parameter values obtained are unique only to within a scaling factor. The formula provides non-rejectable fits to data which grouped tcp by dose and volume when radiosensitivity parameters take values close to laboratory estimates, the fitted volume dependence parameter, however, taking rather high values. Good fits are obtainable with the intuitively reasonable volume parameter value of one, but with radiosensitivity values around one-third of their laboratory estimates. Non-rejectable fits to data which grouped tcp by dose and treatment duration may be obtained with radiosensitivity and repopulation rate parameters lying close to laboratory estimates.

Breast Neoplasms↗
PubMed2000

Monte Carlo dose calculations and radiobiological modelling: analysis of the effect of the statistical noise of the dose distribution on the probability of tumour control.

The aim of this work is to investigate the influence of the statistical fluctuations of Monte Carlo (MC) dose distributions on the dose volume histograms (DVHs) and radiobiological models, in particular the Poisson model for tumour control probability (tcp). The MC matrix is characterized by a mean dose in each scoring voxel, d, and a statistical error on the mean dose, sigma(d); whilst the quantities d and sigma(d) depend on many statistical and physical parameters, here we consider only their dependence on the phantom voxel size and the number of histories from the radiation source. Dose distributions from high-energy photon beams have been analysed. It has been found that the DVH broadens when increasing the statistical noise of the dose distribution, and the tcp calculation systematically underestimates the real tumour control value, defined here as the value of tumour control when the statistical error of the dose distribution tends to zero. When increasing the number of energy deposition events, either by increasing the voxel dimensions or increasing the number of histories from the source, the DVH broadening decreases and tcp converges to the 'correct' value. It is shown that the underestimation of the tcp due to the noise in the dose distribution depends on the degree of heterogeneity of the radiobiological parameters over the population; in particular this error decreases with increasing the biological heterogeneity, whereas it becomes significant in the hypothesis of a radiosensitivity assay for single patients, or for subgroups of patients. It has been found, for example, that when the voxel dimension is changed from a cube with sides of 0.5 cm to a cube with sides of 0.25 cm (with a fixed number of histories of 10(8) from the source), the systematic error in the tcp calculation is about 75% in the homogeneous hypothesis, and it decreases to a minimum value of about 15% in a case of high radiobiological heterogeneity. The possibility of using the error on the tcp to decide how many histories to run for a given voxel size is also discussed.

Computer Simulation↗
PubMed1995

DNA adduct formation in B6C3F1 mice and Fischer-344 rats exposed to 1,2,3-trichloropropane.

1,2,3-Trichloropropane (TCP) is a multispecies, multisite carcinogen which has been found to be an environmental contaminant. In this study, we have characterized and measured DNA adducts formed in vivo following exposure to TCP. [14C]TCP was administered to male B6C3F1 mice and Fischer-344 rats by gavage at doses used in the NTP carcinogenesis bioassay. Both target and nontarget organs were examined for the formation of DNA adducts. Adducts were hydrolyzed from DNA by neutral thermal or mild acid hydrolysis, isolated by HPLC, and detected and quantitated by measurement of radioactivity. The HPLC elution profile of radioactivity suggested that one major DNA adduct was formed. To characterize this adduct, larger yields were induced in rats by intraperitoneal administration of TCP (300 mg/kg). The DNA adduct was isolated by HPLC based on coelution with the radiolabeled adduct, and compared to previously identified adducts. The isolated adduct coeluted with S-[1-(hydroxymethyl)-2-(N7-guanyl)-ethyl]glutathione, an adduct derived from the structurally related carcinogen 1,2-dibromo-3-chloropropane (DBCP). Analysis by electrospray mass spectrometry suggested that the TCP-induced adduct and the DBCP-derived adduct were identical. The 14C-labeled DNA adduct was distributed widely among the organs examined. Adduct levels varied depending on species, organ, and dose. In rat organs, adduct concentrations for the low dose ranged from 0.8 to 6.6 mumol per mol guanine and from 7.1 to 47.6 mumol per mol guanine for the high dose. In the mouse, adduct yields ranged from 0.32 to 28.1 mumol per mol guanine for the low dose and from 12.2 to 208.1 mumol per mol guanine for the high dose. The relationship between DNA adduct formation and organ-specific tumorigenesis was unclear. Although relatively high concentrations of DNA adducts were detected in target organs, several nontarget sites also contained high adduct levels. Our data suggest that factors in addition to adduct formation may be important in TCP-induced carcinogenesis.

Animals↗
PubMed2003

In vitro rat hepatic and intestinal metabolism of the organophosphate pesticides chlorpyrifos and diazinon.

Chlorpyrifos (CPF) and diazinon (DZN) are thionophosphorus organophosphate (OP) insecticides; their toxicity is mediated through CYP metabolism to CPF-oxon and DZN-oxon, respectively. Conversely, CYPs also detoxify these OPs to trichloropyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), respectively. In addition, A-esterase (PON1) metabolism of CPF- and DZN-oxon also forms TCP and IMHP. This study evaluated the role intestinal and hepatic metabolism may play in both the activation and detoxification of CPF and DZN in Sprague-Dawley rats. Similar CYP- and PON1-mediated metabolic profiles were demonstrated in microsomes from liver or isolated intestinal enterocytes. The metabolic efficiency was estimated by calculating the psuedo-1st order rate constant from the metabolic constants by dividing Vmax/Km. In enterocyte microsomes, the CYP metabolic efficiency for metabolism to the oxon metabolites was approximately 28-fold greater for CPF than DZN. Compared on a per nmol P450 basis, the Vmax for CPF in enterocytes was approximately 2-3 times higher than in liver microsomes for the production of CPF-oxon and TCP. The Michaelis-Menten rate constant (Km) for the metabolism of CPF to CPF-oxon was comparable in liver and enterocyte microsomes; however, the enterocyte Km for TCP production was higher (indicating a lower affinity). The smaller volume of intestine, lower amount of CYP, and higher Km for TCP in the enterocyte microsomes, resulted in a lower catalytic efficiency (2 and 62 times) than in liver for oxon and TCP. PON1-mediated metabolism of CPF- and DZN-oxon was also demonstrated in liver and enterocyte microsomes. Although PON1 affinity for the substrates was comparable in hepatic and enterocytic microsomes, the Vmax were 48- to 275-fold higher, in the liver. These results suggest that intestinal metabolism may impact the metabolism of CPF and DZN, especially following low-dose oral exposures.

Animals↗
PubMed1985

Sequential changes in circulating total protein and albumin masses after abdominal vascular surgery.

Sequential changes in total circulating protein (TCP) and total circulating albumin (TCA) masses after different blood replacement regimens were investigated in a prospective study involving 40 patients undergoing reconstructive abdominal aortic surgery. Group I (13 patients) had 80 gm of albumin during operation and 60 gm of albumin during the following 3 days. Blood loss was replaced milliliter for milliliter by whole blood. Group II (14 patients) had the same blood substitution but no albumin. In group III (13 patients), 800 ml of blood loss was replaced by salt water. Maximum decrease in TCP (group II: 17%, group III: 29%) was found 4 hours after the operation. On postoperative day 1, protein mobilization to plasma equalling 10% of TCP had occurred. On day 4, TCP and plasma colloid osmotic pressure had not changed in group I, indicating an unchanged TCA/TCP ratio. In groups II and III, a significant decrease in TCP was followed by complete recovery of TCP. This also entailed a decrease in the TCA/TCP ratio, indicating an enhanced synthesis of acute-phase proteins. Based on these findings, a depression of globulin synthesis by supplemental albumin administration is proposed.

Aorta, Abdominal↗