Evaluation of the In-vitro Digestion Profiles of Long and Medium Chain Glycerides and the Phase Behaviour of Their Lipolytic Products

The Journal of Pharmacy and Pharmacology. Jan, 2002  |  Pubmed ID: 11833493

An evaluation of the in-vitro digestion profile and phase behaviour of the common formulation lipids Miglyol 812 (medium chain triglyceride, MCT), Capmul MCM (C8/C10 monoglyceride/ diglyceride mixture), soybean oil (long chain triglyceride, LCT) and Maisine 35-1 (C18 monoglyceride/diglyceride mixture), is described. Experiments were conducted using titrimetric, high-performance thin-layer chromatographic (HPTLC) and ultracentrifugational techniques under model fasted and post-prandial intestinal conditions. The rate and extent of digestion of the medium chain lipids was greater than the corresponding long chain lipids, and independent of bile salt concentration, with complete conversion to monoglyceride and fatty acid occurring after 30 min digestion. The long chain lipid digests separated into an oily phase (containing undigested triglyceride and diglyceride), an aqueous phase (containing bile salt, fatty acid and monoglyceride) and a pellet phase (containing approximately 5 mm of fatty acid, presumably as an insoluble soap) after ultracentrifugation. Higher proportions of long chain fatty acid and monoglyceride were dispersed into the aqueous phase with increasing bile salt concentrations. In contrast, medium chain lipolytic products separated only into an aqueous phase and a pellet fraction in a bile-salt-independent manner. The digestion of both the C8/C10 and C18 monoglyceride/diglyceride lipid mixtures was more rapid than the corresponding triglyceride, especially at early time points. This investigation provides insight into the relative digestion kinetics of medium chain and long chain lipids and provides information regarding the phase behaviour of their lipolytic products under conditions modelled on those expected after oral administration. The data also provide a background for improved understanding of the potential utility of long chain and medium chain lipid-based formulations.

Cutaneous Leiomyosarcoma

Plastic and Reconstructive Surgery. Mar, 2002  |  Pubmed ID: 11884817

Cutaneous leiomyosarcoma is a rare soft-tissue sarcoma with negligible metastatic potential, but local recurrence rates after surgical excision have ranged from 14 percent to 42 percent. Unlike other sarcomas, guidelines for the optimal surgical excision margin of cutaneous leiomyosarcoma are not clearly defined in the existing literature. A review of local experience with this condition revealed eight patients over 12 years, none of whom developed local recurrence or distant metastases. This is despite poor prognostic factors in seven patients and excision margins ranging from 1 to 27 mm. These findings are compared with previously published data, and conclusions are drawn based on analysis of the collective results. Complete surgical excision with a narrow margin is recommended, and patients should be observed for a minimum of 5 years after surgery.

A Physicochemical Basis for the Extensive Intestinal Lymphatic Transport of a Poorly Lipid Soluble Antimalarial, Halofantrine Hydrochloride, After Postprandial Administration to Dogs

Journal of Pharmaceutical Sciences. Mar, 2002  |  Pubmed ID: 11920750

The highly lipid soluble, free-base form of halofantrine (Hf base; approximately 50 mg/mL in triglyceride lipids), a highly lipophilic (calculated log P approximately 8.5) antimalarial, has recently been shown to undergo significant intestinal lymphatic transport (54% of administered dose) after postprandial administration to dogs. In contrast, the clinically available hydrochloride salt of Hf (Hf small middle dot HCl), was not considered to be a likely substrate for lymphatic transport because its solubility in long-chain triglyceride lipids is low (< 1 mg/mL). This paper reports the lymphatic transport of Hf after postprandial administration of Hf.HCl, which was surprisingly high at 47% of the administered dose, and not significantly different from that of Hf base. It was postulated that partial conversion of solubilized Hf.HCl to the highly lipid soluble Hf base within the intestinal lumen might account for the extensive lymphatic transport. However, as Hf is a tertiary amine with an expected pK(a) of > 10, at gastrointestinal pH, the fraction of Hf present as the free base form is likely to be extremely low. Physicochemical studies exploring the solubility and pK(a) of Hf suggest that Hf.HCl was extensively solubilized following fed administration. When solubilized in representative fed state mixed micellar solutions, its apparent pK(a) was 6.92 and considerably lower than anticipated for a tertiary amine. It appears that the extensive lymphatic transport of Hf observed after postprandial administration of Hf.HCl was likely to be due to the conversion of solubilized Hf.HCl to the free base. Therefore, in addition to indicators such as log P and triglyceride solubility, factors such as drug solubilization in representative fed state intestinal conditions and the possible conversion to the un-ionized form should be considered when predicting the potential lymphatic transport of salts of poorly water soluble acids and bases.

Systematic Evaluation of Map Quality: Human Chromosome 22

American Journal of Human Genetics. Jun, 2002  |  Pubmed ID: 11992248

Marker positions on nine genetic linkage, radiation hybrid, and integrated maps of human chromosome 22 were compared with their corresponding positions in the completed DNA sequence. The proportion of markers whose map position is <250 kb from their respective sequence positions ranges from 100% to 35%. Several discordant markers were identified, as well as four regions that show common inconsistencies across multiple maps. These shared discordant regions surround duplicated DNA segments and may indicate mapping or assembly errors due to sequence homology. Recombination-rate distributions along the chromosome were also evaluated, with male and female meioses showing significantly different patterns of recombination, including an 8-Mb male recombination desert. The distributions of radiation-induced chromosome breakage for the GB4 and the G3 radiation hybrid panels were also evaluated. Both panels show fluctuations in breakage intensity, with different regions of significantly elevated rates of breakage. These results provide support for the common assumption that radiation-induced breaks are generally randomly distributed. The present studies detail the limitations of these important map resources and should prove useful for clarifying potential problems in the human maps and sequence assemblies, as well as for mapping and sequencing projects in and across other species.

Arab Genetic Disease Database (AGDDB): a Population-specific Clinical and Mutation Database

Human Mutation. Jun, 2002  |  Pubmed ID: 12007218

Here we present the Arab Genetic Disease Database (AGDDB), a curated catalog of genetic disorders found in Arab populations. The first release of the database is populated primarily with information from the textbook Genetic Disorders Among Arab Populations [Teebi and Farag, 1997]. AGDDB is composed of data elements revolving around disorder reports. Other reports cover clinical, genomic, reference, and population frequency elements and their important attributes. The Arab Genetic Disease Consortium (30 investigators, 18 countries) is responsible for editing and reviewing AGDDB data. After initial indexing, AGDDB contains over 1,000 unique disorder entries. Entries are linked to their counterparts in the Online Mendelian Inheritance in Man (OMIM) database; similar associations with relevant locus-specific and central mutation databases are planned. The database can be queried by keyword across all its fields, with more focused searches allowed. The database is freely available and may be accessed at www.agddb.org. The database serves as a robust prototype for cataloging variation and disorder information within a specific population.

Structural Contingency Theory and Individual Differences: Examination of External and Internal Person-team Fit

The Journal of Applied Psychology. Jun, 2002  |  Pubmed ID: 12090618

This article develops and tests a structurally based, integrated theory of person-team fit. The theory developed is an extension of structural contingency theory and considers issues of external fit simultaneously with its examination of internal fit at the team level. Results from 80 teams working on an interdependent team task indicate that divisional structures demand high levels of cognitive ability on the part of teammembers. However, the advantages of high cognitive ability in divisional structures are neutralized when there is poor external fit between the structure and the environment. Instead, emotional stability becomes a critical factor among teammembers when a divisional structure is out of alignment with its environment. Individual differences seem to play little or no role in functional structures, regardless of the degree of external fit.

Structured Triglyceride Vehicles for Oral Delivery of Halofantrine: Examination of Intestinal Lymphatic Transport and Bioavailability in Conscious Rats

Pharmaceutical Research. Sep, 2002  |  Pubmed ID: 12403073

To compare the influence of triglyceride vehicle intramolecular structure on the intestinal lymphatic transport and systemic absorption of halofantrine in conscious rats.

Predicting the Outcome of Prostate Biopsy in a Racially Diverse Population: a Prospective Study

Urology. Nov, 2002  |  Pubmed ID: 12429310

To develop a mathematical model to predict prostate biopsy outcome using readily available clinical variables.

Role of Advanced 2 and 3-dimensional Ultrasound for Detecting Prostate Cancer

The Journal of Urology. Dec, 2002  |  Pubmed ID: 12441931

We explored the clinical usefulness of spectrum analysis and neural networks for classifying prostate tissue and identifying prostate cancer in patients undergoing transrectal ultrasound for diagnostic or therapeutic reasons.

An in Vitro Examination of the Impact of Polyethylene Glycol 400, Pluronic P85, and Vitamin E D-alpha-tocopheryl Polyethylene Glycol 1000 Succinate on P-glycoprotein Efflux and Enterocyte-based Metabolism in Excised Rat Intestine

AAPS PharmSci. 2002  |  Pubmed ID: 12646011

The potential inhibitory effects of 3 excipients (polyethylene glycol [PEG] 400, Pluronic P85, and vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate [TPGS]) on the P-glycoprotein (P-gp) -mediated efflux of digoxin (DIG) and cytochrome P450 3A (CYP3A) -mediated metabolism of verapamil (VRP) have been examined in an in vitro permeability model. Experiments were conducted utilizing rat jejunal tissue mounted in diffusion chambers and included assessment of the serosal to mucosal (s to m) transport of DIG and the formation of norverapamil (NOR) during the mucosal to serosal transport of VRP, as measures of P-gp efflux and CYP3A metabolism, respectively. The presence of PEG at 1%, 5%, and 20% (wt/vol) reduced both the s to m flux of DIG (by 47%, 57%, and 64%, respectively, when compared to control) and the metabolism of VRP (by 54%, 78%, and 100%) in a concentration-dependent manner. P85 (0.1% wt/vol) significantly reduced s to m DIG flux by 47% and inhibited VRP metabolism by 42%. TPGS had insignificant effects on both metabolism and efflux at a concentration of 0.01% (wt/vol). The P-gp inhibitory effects of PEG and P85 were evident regardless of whether the excipient was added to the mucosal side, the serosal side, or both sides of the tissue. The current data suggest that inclusion of PEG and P85 as solubilizing agents during in vitro permeability assessment may have a significant impact on both drug metabolism and efflux processes. These compounds appear to exert their effects on P-gp primarily via direct transporter inhibition - or indirectly, through effects on buffer osmolarity, membrane fluidity, and/or mitochondrial toxicity and subsequent adenosine triphosphate (ATP) depletion.

Urothelial Neoplasms of the Kidney and Ureter. An Epidemiologic, Pathologic, and Clinical Review

American Journal of Clinical Pathology. Jun, 2002  |  Pubmed ID: 14569801

Urothelial neoplasms occur with varying frequency at different sites along the urothelial tract. Approximately 5% of urothelial neoplasms occur in the kidneys and ureters, while the majority of these tumors occur in the urinary bladder. Consequently, urothelial disease of the bladder has been evaluated to a greater extent than urothelial tumors elsewhere, and many of the features of bladder urothelial neoplasms have been applied to these tumors at other sites. While the classification of urothelial neoplasms is the same for tumors in the bladder, kidney, and ureter, there are some features of urothelial neoplasms of the kidney and ureter that are unique to these sites. An epidemiologic, pathologic, and clinical review of urothelial neoplasms of the kidney and ureter is presented.

Ultrasonic Spectrum-analysis and Neural-network Classification As a Basis for Ultrasonic Imaging to Target Brachytherapy of Prostate Cancer

Brachytherapy. 2002  |  Pubmed ID: 15062187

Conventional B-mode ultrasound is the standard means of imaging the prostate for guiding prostate biopsies and planning brachytherapy of prostate cancer. Yet B-mode images do not allow adequate visualization of cancerous lesions of the prostate. Ultrasonic tissue-typing imaging based on spectrum analysis of radiofrequency echo signals has shown promise for overcoming the limitations of B-mode imaging for visualizing prostate tumors. Tissue typing based on radiofrequency spectrum analysis uses nonlinear methods, such as neural networks, to classify tissue by using spectral-parameter and clinical-variable values. Two- and three-dimensional images based on these methods show potential for improving the guidance of prostate biopsies and the targeting of radiotherapy of prostate cancer. Two-dimensional images have been imported into instrumentation for real-time biopsy guidance and into commercial dose-planning software for brachytherapy planning. Three-dimensional renderings seem to be capable of depicting locations and volumes of cancer foci.

Combining Artificial Neural Networks and Transrectal Ultrasound in the Diagnosis of Prostate Cancer

Oncology (Williston Park, N.Y.). Oct, 2003  |  Pubmed ID: 14606364

Arguably the most important step in the prognosis of prostate cancer is early diagnosis. More than 1 million transrectal ultrasound (TRUS)-guided prostate needle biopsies are performed annually in the United States, resulting in the detection of 200,000 new cases per year. Unfortunately, the urologist's ability to diagnose prostate cancer has not kept pace with therapeutic advances; currently, many men are facing the need for prostate biopsy with the likelihood that the result will be inconclusive. This paper will focus on the tools available to assist the clinician in predicting the outcome of the prostate needle biopsy. We will examine the use of "machine learning" models (artificial intelligence), in the form of artificial neural networks (ANNs), to predict prostate biopsy outcomes using prebiopsy variables. Currently, six validated predictive models are available. Of these, five are machine learning models, and one is based on logistic regression. The role of ANNs in providing valuable predictive models to be used in conjunction with TRUS appears promising. In the few studies that have compared machine learning to traditional statistical methods, ANN and logistic regression appear to function equivalently when predicting biopsy outcome. With the introduction of more complex prebiopsy variables, ANNs are in a commanding position for use in predictive models. Easy and immediate physician access to these models will be imperative if their full potential is to be realized.

A Kinetic Evaluation of the Absorption, Efflux, and Metabolism of Verapamil in the Autoperfused Rat Jejunum

The Journal of Pharmacology and Experimental Therapeutics. Apr, 2003  |  Pubmed ID: 12649363

P-glycoprotein (P-gp)-mediated drug efflux from the apical membrane of enterocytes is believed to modulate intestinal cytochrome P450 3A (CYP3A) metabolism by altering substrate access to the CYP3A enzyme. This interplay between P-gp and CYP3A was investigated in a rat in situ model of intestinal permeation, where a recirculating luminal perfusion of the jejunum was coupled with mesenteric vein blood collection to simultaneously monitor the uptake, transport, and metabolism of the P-gp and CYP3A substrate, verapamil. Transport of intact verapamil into the venous blood was increased by 160, 84, and 160%, and the intestinal extraction ratio on passage across the jejunum was reduced by 15, 24, and 97% by inhibitors of P-gp [PSC833 ([3'-keto-Me-Bmt(1)]-[Val(2)]-cyclosporin)], CYP3A (midazolam), or P-gp and CYP3A (ketoconazole), respectively, when present in the luminal perfusate and compared with control experiments. Compartmental kinetic analysis of the data revealed that inhibition of P-gp did not affect the rate constant describing verapamil metabolism but, rather, increased the intestinal uptake of verapamil and stimulated a disproportionate increase in verapamil transport into the venous blood. The increase in verapamil transport, in the absence of changes to metabolism, reduced the intestinal extraction ratio. This finding may be explained by saturation of intracellular verapamil binding sites within the intestinal tissue in response to increased verapamil uptake resulting from P-gp inhibition. The current findings confirm previous in vitro and theoretical approaches which suggest that P-gp can modulate the extent of intestinal extraction of P-gp/CYP3A substrates.

Does Stereoselective Lymphatic Absorption Contribute to the Enantioselective Pharmacokinetics of Halofantrine In Vivo?

Biopharmaceutics & Drug Disposition. May, 2003  |  Pubmed ID: 12698498

Halofantrine (Hf) is a chiral, lipophilic phenanthrene methanol antimalarial which exhibits both enantioselective plasma pharmacokinetics and extensive lymphatic absorption when administered postprandially. In order to determine whether enantioselective lymphatic absorption contributes to the previously reported enantioselective pharmacokinetics of Hf, lymph samples collected from thoracic duct-cannulated dogs dosed with racemic Hf (100 mg, administered postprandially) were assayed with a chiral HPLC method capable of quantifying the relative amounts of (+)- and (-)-Hf. During the period when the majority (>95%) of Hf transport into lymph occurred (0-5 h post dose), essentially equal amounts of the two enantiomers were present in the intestinal lymph. At later times (e.g. 5-12 h post dose), there was a steady increase in the fraction of (+)-Hf present in lymph. The trends evident at later time points most likely reflect an increase in the proportion of (+)-Hf present in systemic blood, (resulting from enantioselective systemic metabolism) and a corresponding increase in (+)-Hf in the thoracic lymph by equilibration of drug across blood and lymphatic capillaries, as opposed to enantioselective lymphatic transport per se. This study was the first to examine the possibility of stereoselectivity in lymphatic transport, however, the data suggest that drug absorption (at least in the case of halofantrine) via the intestinal lymphatics is not enantioselective.

Using the Polymer Partitioning Method to Probe the Thermodynamic Activity of Poorly Water-soluble Drugs Solubilized in Model Lipid Digestion Products

Journal of Pharmaceutical Sciences. Jun, 2003  |  Pubmed ID: 12761815

The thermodynamic activity of solubilized drug is an important determinant of the extent of absorption of lipophilic drugs from the gastrointestinal tract. In this study, the polymer partitioning method was evaluated for its use in the determination of the thermodynamic activity of lipophilic drugs when solubilized in colloidal digestion products, using drug in dilute solution as a reference ideal solution. The lipophilic drugs griseofulvin, diazepam, and danazol partitioned into a polymeric receiver phase from non-micellar solution as a function of drug lipophilicity. The concentration of drug that partitioned into the polymer was linearly proportional to the concentration of free drug in solution, and this allowed the measured partition coefficient to be utilized as an indicator of the drug activity coefficient. The addition of a solubilizing species such as bile salt micelles caused a reduction in drug activity of a similar magnitude to that predicted from micelle equilibrium solubility data in the identical micellar solutions. The addition of micelle swelling lipids such as lecithin and fatty acids resulted in further reductions in activity coefficient. The ability to measure drug activity in model digestive systems has potential for application in the rational development of improved lipid-based formulations of poorly water-soluble drugs for oral administration.

Contribution of Lymphatically Transported Testosterone Undecanoate to the Systemic Exposure of Testosterone After Oral Administration of Two Andriol Formulations in Conscious Lymph Duct-cannulated Dogs

The Journal of Pharmacology and Experimental Therapeutics. Sep, 2003  |  Pubmed ID: 12807999

Orally administered testosterone (T) is ineffective in the treatment of male androgen deficiency syndromes due to extensive presystemic first-pass metabolism. In contrast, the lipophilic long-chain ester testosterone undecanoate (TU) exhibits androgenic activity that has been attributed to formation of T via systemic hydrolysis of lymphatically transported TU. However, there are no definitive data regarding the oral bioavailability of TU or the extent to which lymphatically transported TU contributes to the systemic availability of T after oral TU administration. This report describes the application of stable isotope methodology in a thoracic lymph duct-cannulated dog model to study the oral bioavailability and lymphatic transport of TU after postprandial administration. When administered as either Andriol or Andriol Testocaps, the mean (+/-S.E., n = 4) absolute bioavailability of TU was 3.25 +/- 0.48 and 2.88 +/- 0.88%, respectively, and lymphatically transported TU accounted for between 91.5 and 99.7% of the systemically available ester. Model-independent pharmacokinetic analysis indicated that 83.6 +/- 1.6 and 84.1 +/- 8.2% of the systemically available T, resulting from Andriol or Andriol Testocaps, respectively, was due to systemic hydrolysis of lymphatically transported TU. These data demonstrate that intestinal lymphatic transport of TU produces increased systemic exposure of T by avoiding the extensive first-pass effect responsible for the inactivation of T after oral administration.

Backing Up Behaviors in Teams: the Role of Personality and Legitimacy of Need

The Journal of Applied Psychology. Jun, 2003  |  Pubmed ID: 12814289

In this article, the authors developed several hypotheses regarding both the main and interactive effects of 2 types of team inputs on backing up behaviors in teams: (a) team composition characteristics in terms of the personality of the members of the team and (b) team task characteristics in terms of the extent to which the nature of the task is one that legitimately calls for some members of the team to back up other members of the team. Results from a study of 71 4-person teams performing a computerized tactical decision-making task suggest that the legitimacy of the need for back up has an important main effect on the extent to which team members provide assistance to and receive assistance from each other. In addition, the legitimacy of the need for back up also has important interactive effects with both the personality of the back up recipient and the personality of the back up providers on backing up behaviors in teams.

Application of Compartmental Modeling to an Examination of in Vitro Intestinal Permeability Data: Assessing the Impact of Tissue Uptake, P-glycoprotein, and CYP3A

Drug Metabolism and Disposition: the Biological Fate of Chemicals. Sep, 2003  |  Pubmed ID: 12920171

P-glycoprotein (P-gp)-mediated drug efflux and cytochrome p450 3A (CYP3A) metabolism within the enterocyte have been implicated as potential biochemical barriers to intestinal drug permeability. The current studies examined the in vitro intestinal permeability of verapamil, a common P-gp and CYP3A substrate, using both disappearance and appearance measurements, and investigated the possible impact of P-gp efflux on the intestinal extraction of verapamil. Bidirectional permeability and metabolism studies were conducted across rat jejunal tissue in side-by-side diffusion chambers and data were modeled using compartmental kinetics. Substantial tissue uptake of verapamil was evident in the in vitro model and resulted in a disappearance permeability coefficient that was approximately 10-fold greater than that determined from verapamil appearance in the receptor chamber. Polarization of the bidirectional transport of verapamil was evident due to P-gp efflux (efflux ratio of 2.5), and significant intestinal extraction of verapamil on passage across the tissue was observed (mucosal to serosal extraction ratio of 0.31 +/- 0.04). Surprisingly, the selective P-gp inhibitor, valspodar (PSC833), had an insignificant impact on P-gp-mediated efflux of verapamil; however, selective CYP3A inhibition (afforded by midazolam) increased mucosal to serosal verapamil transport 1.6-fold, presumably through a reduction in intestinal metabolism. Using a four-compartment model, simulations of the impact of P-gp on the intestinal extraction ratio of verapamil demonstrated that for efflux to increase intestinal extraction, a nonlinear relationship must exist between the extent of drug metabolism and the extent of drug transport; the origin of this "nonlinearity" may include saturable drug metabolism, accumulation, and/or distribution.

Pharmacokinetic Model to Describe the Lymphatic Absorption of R-metHu-leptin After Subcutaneous Injection to Sheep

Pharmaceutical Research. Aug, 2003  |  Pubmed ID: 12948012

The purpose of this work was to develop a pharmacokinetic model to describe the contribution of the lymphatics to the absorption and bioavailability of r-metHu-Leptin administered by subcutaneous (SC) injection to sheep.

Examination of Oral Absorption and Lymphatic Transport of Halofantrine in a Triple-cannulated Canine Model After Administration in Self-microemulsifying Drug Delivery Systems (SMEDDS) Containing Structured Triglycerides

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences. Sep, 2003  |  Pubmed ID: 13678797

The potential for lipidic self-microemulsifying drug delivery systems (SMEDDS) containing triglycerides with a defined structure, where the different fatty acids on the glycerol backbone exhibit different metabolic fate, to improve the lymphatic transport and the portal absorption of a poorly water-soluble drug, halofantrine, were investigated in fasted lymph cannulated canines. Two different structured triglycerides were incorporated into the SMEDDS; 1,3-dioctanoyl-2-linoleyl-sn-glycerol (C8:0-C18:2-C8:0) (MLM) and 1,3-dilinoyl-2-octanoyl-sn-glycerol (C18:2-C8:0-C18:2) (LML). A previously optimised SMEDDS formulation for halofantrine, comprising of triglyceride, Cremophor EL, Maisine 35-1 and ethanol was selected for bioavailability assessment. The extent of lymphatic transport via the thoracic duct was 17.9% of the dose for the animals dosed with the MLM SMEDDS and 27.4% for LML. Also the plasma availability was affected by the triglyceride incorporated into the multi-component delivery system and availabilities of 56.9% (MLM) and 37.2% (LML) were found. These data indicate that the pharmaceutical scientist can use the structure of the lipid to affect the relative contribution of the two absorption pathways. The MLM formulation produced a total bioavailability of 74.9%, which is higher than the total absorption previously observed after post-prandial administration. This could indicate the utility of disperse lipid-base formulations based on structured triglycerides for the oral delivery of halofantrine, and potentially other lipophilic drugs.

Team Learning: Collectively Connecting the Dots

The Journal of Applied Psychology. Oct, 2003  |  Pubmed ID: 14516247

This article tests the degree to which personal and situational variables impact the acquisition of knowledge and skill within interactive project teams. On the basis of the literature regarding attentional capacity, constructive controversy, and truth-supported wins, the authors examined the effects of cognitive ability, workload distribution, Agreeableness, Openness to Experience, and structure on team learning. Results from 109 four-person project teams working on an interdependent command and control simulator indicated that teams learned more when composed of individuals who were high in cognitive ability and when the workload was distributed evenly. Conversely, team learning was negatively affected when teams were composed of individuals who were high in Agreeableness. Finally, teams using a paired structure learned more than teams structured either functionally or divisionally. Theoretical and practical implications are discussed, as well as possible limitations and directions for future research.

Conscientiousness, Autonomy Fit, and Development: a Longitudinal Study

The Journal of Applied Psychology. Oct, 2003  |  Pubmed ID: 14516255

The authors examined employee development and its relationship with Conscientiousness and person-environment fit (in terms of needs and supplies of autonomy). They hypothesized that Conscientiousness would be positively associated with development but only when employees felt that the autonomy supplied by the organization did not fit their needs. In other words, whereas Conscientiousness could supply the dispositional resources for development, misfit was needed to create the need for development. The results supported the authors' predictions. Conscientiousness was positively related to development but only when employees were misfits with respect to autonomy. Employee involvement in development activities was then linked to subsequent fit.

Intestinal Lymphatic Transport of Halofantrine Occurs After Oral Administration of a Unit-dose Lipid-based Formulation to Fasted Dogs

Pharmaceutical Research. Sep, 2003  |  Pubmed ID: 14567642

To examine whether the small quantities of lipid present in unit-dose microemulsion formulations comprising medium- (C8-10) or long-chain (C18) glyceride lipids can stimulate the intestinal lymphatic transport of halofantrine (Hf), a model lymphatically transported drug.

Influenza Immunization Practices Among Pediatric Oncologists

Journal of Pediatric Hematology/oncology. Feb, 2003  |  Pubmed ID: 12571465

To describe the opinions of pediatric oncologists regarding the use of influenza vaccine in children with cancer and to identify factors that influence practitioners' recommendations about influenza vaccine.

Separation and Characterization of the Colloidal Phases Produced on Digestion of Common Formulation Lipids and Assessment of Their Impact on the Apparent Solubility of Selected Poorly Water-soluble Drugs

Journal of Pharmaceutical Sciences. Mar, 2003  |  Pubmed ID: 12587125

Colloidal mixtures containing bile salts (BS), phosphatidylcholine (PC), and medium and long-chain monoglycerides and fatty acids were prepared as model systems to represent typical intestinal contents after digestion of formulation derived lipids under both low (5 mM BS/1.25 mM PC) and high (20 mM BS/5 mM PC) BS and PC conditions. Size-exclusion chromatography of the colloidal species that formed in the medium-chain digests indicated the presence of vesicles, mixed micelles, and simple micelles, whereas the long-chain digests contained only vesicles and mixed micelles. In the long-chain digests the mixed micellar phase was the predominant drug solubilizing species for griseofulvin, danazol, and halofantrine, although for increasingly lipophilic drugs, the vesicular phase contributed an increasing proportion of the solubilization capacity. In contrast, the solubilization capacity of the vesicular phase was predominant in the medium-chain digests, and no clear trends were evident in the relationship between drug lipophilicity and proportional solubilization. These data highlight the need to consider the colloidal species that form in the small intestine during the digestion of common formulation lipids and the coincident enhancement in drug solubilization provided under these circumstances.

Desbutylhalofantrine: Evaluation of QT Prolongation and Other Cardiovascular Effects After Intravenous Administration in Vivo

Journal of Cardiovascular Pharmacology. Mar, 2003  |  Pubmed ID: 12605019

Desbutylhalofantrine (Hfm) is an active and equipotent metabolite of halofantrine (Hf). Both compounds are effective in the treatment of sensitive and multidrug-resistant and In vitro data and interpretation of some clinical studies of Hf have suggested that, unlike Hf, Hfm may be devoid of adverse cardiac effects. The aim of these investigations was to provide the first in vivo examination of the intrinsic capacity of Hfm to affect repolarization in the heart, using an anesthetized rabbit model. Using a dose-rising regimen, Hfm was administered IV at doses of 1, 1, 2, 4, and 8 mg/kg and the baseline rate-corrected QT interval (QTc) value of 377 +/- 13 ms rose to 394 +/- 16, 396 +/- 12, 429 +/- 18, 433 +/- 16, and 489 +/- 15 ms, respectively. There were no significant changes in blood pressure, heart rate, or PR or QRS intervals. The Hfm plasma concentrations were quantitated after high-performance liquid chromatographic analysis, the results indicating a significant correlation between Hfm plasma concentration and QT(c) prolongation. The study also identified a concentration-dependent hemolysis of erythrocytes after administration of Hfm. The conclusions from this study are that IV administration of Hfm does cause a significant prolongation of the QT(c) interval in a rabbit model.

Probing Drug Solubilization Patterns in the Gastrointestinal Tract After Administration of Lipid-based Delivery Systems: a Phase Diagram Approach

Journal of Pharmaceutical Sciences. Feb, 2004  |  Pubmed ID: 14705191

The formation of lyotropic phases resulting from the digestion of formulation lipids has a pronounced impact on the intestinal solubilization and resultant bioavailability of poorly water-soluble drugs. In this study, phase diagrams were produced to determine the phase behavior of the digestion products of common formulation lipids (C8:0, C12:0, and C18:1) under model physiological conditions. Pseudoternary phase diagrams were constructed using varying proportions of SEIF (Simulated Endogenous Intestinal Fluid) and fatty acid (FA) and monoglyceride (MG) (as representative exogenous lipid digestion products). A change from liquid crystal to colloidal liquid (containing mixed micelles and vesicles) was observed with decreasing FA/MG concentrations. The solubilization enhancement ratio (SER) afforded by these phases for a series of poorly water-soluble compounds (hydrocortisone and hydrocortisone esters, clogP = 1.4 to 5.2) was measured relative to the intrinsic solubility in buffer. Large increases in SER were observed in both lamellar (10-2000 fold) and cubic (10-30,000 fold) liquid crystal phases. Positive correlations were observed between the solubilization benefit provided by each phase and drug lipophilicity (r(2) > or = 0.9). These phase/solubility trends assist in our understanding of the mechanism by which poorly water-soluble drugs are trafficked across the intestinal colloidal species that form during the digestion of lipid-based drug delivery systems.

Low AUA Symptom Score Independently Predicts Positive Prostate Needle Biopsy: Results from a Racially Diverse Series of 411 Patients

Urology. Jan, 2004  |  Pubmed ID: 14751356

To evaluate the prebiopsy parameters, including the American Urological Association symptom score (AUASS), that may be predictive of positive biopsy. Transrectal ultrasound (TRUS) biopsy of the prostate represents the reference standard in the diagnosis of prostate cancer.

Immune Responses to Influenza Immunization in Children Receiving Maintenance Chemotherapy for Acute Lymphoblastic Leukemia

Pediatric Blood & Cancer. Jan, 2004  |  Pubmed ID: 14752792

To compare the immune responses to influenza vaccine in children with acute lymphoblastic leukemia (ALL) receiving maintenance chemotherapy with those in healthy children.

Pharmacokinetics of Recombinant Human Leukemia Inhibitory Factor in Sheep

The Journal of Pharmacology and Experimental Therapeutics. Jun, 2004  |  Pubmed ID: 14872093

The pharmacokinetics of recombinant human leukemia inhibitory factor (rhLIF) were investigated following i.v. and s.c. administration of a wide range of dose levels. Parallel studies were conducted where single i.v. bolus doses of 12.5, 25, 100, 250, 500, or 750 microg/kg rhLIF (n = 2) or s.c. doses of 10, 20, or 50 microg/kg rhLIF (n = 4) were administered to sheep. Blood samples were collected for up to 24 h postdosing, and the plasma concentrations of rhLIF were analyzed by enzyme-linked immunosorbent assay. Noncompartmental analysis demonstrated an increase in the terminal elimination half-life (from 0.27 to 2.29 h) and a decrease in systemic clearance (from 5.18 to 1.09 ml/min/kg) with increasing i.v. doses of rhLIF, suggesting nonlinear pharmacokinetic behavior. A greater than proportional increase in the area under the plasma concentration-time curve with dose also indicated significantly nonlinear pharmacokinetics after s.c. administration. A mechanistic compartmental model was developed to characterize the pharmacokinetics of rhLIF. The key feature of the model accounting for the nonlinear pharmacokinetic behavior of rhLIF was high-affinity, saturable receptor binding and subsequent cellular internalization and degradation. The apparent total density of LIF cell surface receptors and receptor turnover dynamics were included in the model, along with nonspecific binding and linear elimination from the systemic circulation. The absorption of rhLIF from the s.c. injection site into the systemic circulation was characterized by a first-order absorption process via a delay compartment. The proposed model satisfactorily captured the complex pharmacokinetic profiles of rhLIF following both i.v. and s.c. administration.

Evaluation of the Impact of Altered Lipoprotein Binding Conditions on Halofantrine Induced QTc Interval Prolongation in an Anaesthetized Rabbit Model

The Journal of Pharmacy and Pharmacology. Jan, 2004  |  Pubmed ID: 14980003

Halofantrine has been observed to cause QT interval prolongation in susceptible patients and the effect has most commonly been observed after post-prandial administration. Halofantrine-induced QT prolongation occurs in conjunction with a significant increase in plasma halofantrine concentrations and an increase in halofantrine association with post-prandial plasma lipoproteins. The increased association of halofantrine with post-prandial lipoproteins is accompanied by a marked change in drug distribution between the different plasma lipoprotein fractions. This study was designed to evaluate the putative role of myocardium-based lipoprotein receptor-mediated uptake of lipoproteins as a possible contributing factor to the observed effect of halofantrine on QT intervals. The extent of QT interval prolongation following intravenous halofantrine administration (10 mg kg(-1)) to normolipidaemic (fasted) or hyperlipidaemic (induced with Intralipid infusion) anaesthetized New Zealand White rabbits (n = 6) was determined, as was the distribution of halofantrine between the plasma lipoprotein classes. The results, however, were in contrast to the suggested hypothesis since the QT interval was reduced (and not increased) after halofantrine administration to hyperlipidaemic rabbits relative to fasted rabbits. Therefore, it is unlikely that lipoprotein-based uptake of halofantrine into the myocardium is a major contributor to the previously observed increase in QT prolongation after post-prandial administration of halofantrine.

Influence of Physicochemical Properties on the Patterns of Association of a Series of Aliphatic Esters of Halofantrine with Plasma Lipoproteins

Journal of Controlled Release : Official Journal of the Controlled Release Society. Mar, 2004  |  Pubmed ID: 14980776

Although the association of lipophilic drugs with plasma lipoproteins has not been fully characterized, there are several reports of lipoprotein association being influential in pharmacokinetic and pharmacodynamic profiles of important therapeutic agents. The current studies utilized a series of aliphatic esters of halofantrine to evaluate the role of several physicochemical properties on the interaction of the different compounds with plasma lipoproteins. Density gradient ultracentrifugation techniques were employed to determine drug association in triglyceride rich (TRL), low-density (LDL) and high-density lipoproteins (HDL), under both fasted and post-prandial conditions. Compound solubility in medium or long chain triglycerides was a useful indicator of the extent of drug-lipoprotein association, particularly for the triglyceride rich lipoproteins (chylomicrons and very low-density lipoproteins). This is likely a function of the compounds being solubilized within the apolar (triglyceride and cholesterol ester) lipid core. However, molecular size also played an important role in determining lipoprotein distribution, particularly for association with the more protein abundant lipoproteins, such as HDL. Lipoprotein association of Hf analogues containing longer unsaturated esters was best correlated with total lipoprotein surface area rather than with lipoprotein core lipid volumes.

Drug Solubilization Behavior During in Vitro Digestion of Simple Triglyceride Lipid Solution Formulations

Pharmaceutical Research. Feb, 2004  |  Pubmed ID: 15032305

The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during digestion of either long-chain or medium-chain triglyceride (TG) lipid formulations.

Drug Solubilization Behavior During in Vitro Digestion of Suspension Formulations of Poorly Water-soluble Drugs in Triglyceride Lipids

Pharmaceutical Research. Feb, 2004  |  Pubmed ID: 15032306

The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during the in vitro digestion of long-chain or medium-chain triglyceride (TG) lipid suspension formulations.

Use of in Vitro Lipid Digestion Data to Explain the in Vivo Performance of Triglyceride-based Oral Lipid Formulations of Poorly Water-soluble Drugs: Studies with Halofantrine

Journal of Pharmaceutical Sciences. May, 2004  |  Pubmed ID: 15067688

The relative oral bioavailability (BA) of halofantrine base (Hf) was assessed in male beagle dogs after administration of a medium chain triglyceride (MCT), a long chain triglyceride (LCT), and a blended LCT/MCT lipid solution formulation of Hf (Study 1) and after administration of suspensions of Hf base and Hf. HCl in LCT (Study 2). A series of in vitro lipid digestion experiments were also performed in an attempt to clarify the data obtained. In vitro drug solubilization profiles were markedly dependent on the mass of lipid employed in lipid digestion experiments. At high lipid masses ( approximately 25 mg triglyceride/mL), MCT formulations gave maximal benefit, whereas at low lipid concentrations ( approximately 5 mg triglyceride/mL), LCT formulations provided improved solubilization capacity. The in vitro digestion and solubilization data at lower lipid masses were consistent with the in vivo data where the BA of Hf after oral administration of the LCT solution > LCT/MCT blend > MCT solution. The second BA study showed similar, albeit variable, exposure after oral administration of a suspension of Hf base or Hf. HCl in LCT and this trend was broadly consistent with in vitro results. This study demonstrates the potential utility of in vitro digestion models to assess and rank order the in vivo performance of lipid solution and suspension formulations of poorly water-soluble drugs such as Hf.

Susceptibility to Lipase-mediated Digestion Reduces the Oral Bioavailability of Danazol After Administration As a Medium-chain Lipid-based Microemulsion Formulation

Pharmaceutical Research. Aug, 2004  |  Pubmed ID: 15359575

To investigate the impact of lipidic formulation type on in vitro dispersion and digestion properties and the relationship to oral bioavailability, using danazol as a model lipophilic poorly water-soluble drug.

A Novel Cubic Phase of Medium Chain Lipid Origin for the Delivery of Poorly Water Soluble Drugs

Journal of Controlled Release : Official Journal of the Controlled Release Society. Sep, 2004  |  Pubmed ID: 15380632

The existence of a novel cubic liquid crystalline phase is described within the pseudo-ternary system comprising lauric acid, monolaurin, and simulated endogenous intestinal fluid (SEIF). This phase behaviour has been characterized using cross-polarizing light microscopy (CPLM), and the structure of the cubic phase identified by small angle X-ray scattering (SAXS). The presence of the cubic phase was found to be temperature sensitive within the 20-37 degrees C range making it putative material for in situ gelation purposes. The cubic phase was shown to have a high capacity to solubilise a model poorly water-soluble drug, cinnarizine, and initial in vitro release data highlight the potential of this phase to provide sustained release. Absorption of cinnarizine from the cubic phase was studied in an unconscious rat model via duodenal administration and blood sampling via the carotid artery. The rate of absorption was significantly reduced when compared to a simple suspension formulation, a likely combination of retarded erosion of the cubic phase together with hindered drug release from the cubic matrix. The results of this study suggest that this cubic phase may potentially be of benefit in the delivery of poorly water-soluble compounds due to its high loading capacity and potential for sustained release. The ability to manipulate this system using temperature may warrant further interest in delivery applications via other routes of administration.

Recent Developments in Tissue-type Imaging (TTI) for Planning and Monitoring Treatment of Prostate Cancer

Ultrasonic Imaging. Jul, 2004  |  Pubmed ID: 15754797

Because current methods of imaging prostate cancer are inadequate, biopsies cannot be effectively guided and treatment cannot be effectively planned and targeted. Therefore, our research is aimed at ultrasonically characterizing cancerous prostate tissue so that we can image it more effectively and thereby provide improved means of detecting, treating and monitoring prostate cancer. We base our characterization methods on spectrum analysis of radiofrequency (rf) echo signals combined with clinical variables such as prostate-specific antigen (PSA). Tissue typing using these parameters is performed by artificial neural networks. We employed and evaluated different approaches to data partitioning into training, validation, and test sets and different neural network configuration options. In this manner, we sought to determine what neural network configuration is optimal for these data and also to assess possible bias that might exist due to correlations among different data entries among the data for a given patient. The classification efficacy of each neural network configuration and data-partitioning method was measured using relative-operating-characteristic (ROC) methods. Neural network classification based on spectral parameters combined with clinical data generally produced ROC-curve areas of 0.80 compared to curve areas of 0.64 for conventional transrectal ultrasound imaging combined with clinical data. We then used the optimal neural network configuration to generate lookup tables that translate local spectral parameter values and global clinical-variable values into pixel values in tissue-type images (TTIs). TTIs continue to show cancerous regions successfully, and may prove to be particularly useful clinically in combination with other ultrasonic and nonultrasonic methods, e.g., magnetic-resonance spectroscopy.

Study of Stem Cell Function Using Microarray Experiments

FEBS Letters. Mar, 2005  |  Pubmed ID: 15763554

DNA Microarrays are used to simultaneously measure the levels of thousands of mRNAs in a sample. We illustrate here that a collection of such measurements in different cell types and states is a sound source of functional predictions, provided the microarray experiments are analogous and the cell samples are appropriately diverse. We have used this approach to study stem cells, whose identity and mechanisms of control are not well understood, generating Affymetrix microarray data from more than 200 samples, including stem cells and their derivatives, from human and mouse. The data can be accessed online (StemBase; http://www.scgp.ca:8080/StemBase/).

Congenital Auricular Anomalies: Topographic Anatomy, Embryology, Classification, and Treatment Strategies

Plastic and Reconstructive Surgery. May, 2005  |  Pubmed ID: 15861078

Congenital auricular anomalies are heterogeneous, with various descriptive and eponymous terms being used. Current classification systems are useful in guiding surgical treatment of severe anomalies. However, they do not generally account for the less severe anomalies, which form the majority of congenital auricular anomalies, nor their contemporary treatment. In this article, the authors review the anatomy and embryology of the external ear and propose a simple classification of congenital auricular anomalies that encompasses all forms of congenital auricular anomalies, facilitates proper diagnosis, and guides treatment. Congenital auricular anomalies should be classified as malformational or deformational anomalies. Malformational auricular anomalies are caused by embryologic maldevelopment that occurs between the fifth and ninth week of gestation resulting in deficient and/or supernumerary auricular components. Deformational auricular anomalies result from in utero or ex utero deformational forces, including those caused by an aberrant insertion of the intrinsic or extrinsic auricular muscles. Malformational auricular anomalies generally require surgical correction during childhood or adolescence. For practical purposes, deformational auricular anomalies have a full complement of chondrocutaneous components that can be digitally manipulated to a normal shape. These anomalies are best treated by auricular molding, which is effective if it is initiated within the first 3 months of life. Deformational auricular anomalies are best regarded as a pediatric public health issue and are best managed nonsurgically. Education of neonatal pediatricians, obstetricians, family doctors, and midwives will allow proper early diagnosis of all congenital auricular anomalies, which is vital to appropriate treatment. These practitioners should be encouraged to manage deformational auricular anomalies early in life so that surgery can be largely avoided in these patients.

Model to Predict Prostate Biopsy Outcome in Large Screening Population with Independent Validation in Referral Setting

Urology. May, 2005  |  Pubmed ID: 15882727

To develop a model capable of predicting prostate biopsy outcomes in a large screening population, with independent validation in the referral setting.

An Improved Method for the Purification of Rat Liver-type Fatty Acid Binding Protein from Escherichia Coli

Protein Expression and Purification. Nov, 2005  |  Pubmed ID: 15914028

Rat liver fatty acid binding protein (L-FABP) was efficiently expressed in Escherichia coli and purified to homogeneity. The cDNA encoding L-FABP was ligated into the pTrc99A expression vector and expressed by induction with isopropyl-beta-d-thiogalactopyranoside under the control of the P(trc) promoter. Following an 18 h induction period, L-FABP constituted approximately 3% of the cytosolic protein. The protein could be purified to electrophoretic homogeneity (silver-stained polyacrylamide gel detection) by ammonium sulfate fractionation (65% saturation) of the soluble bacterial lysate followed by the chromatographic sequence of anion-exchange-->hydrophobic interaction-->anion-exchange chromatography. The recombinant protein displayed an isoelectric point of 7.0 and cross-reactivity with rabbit anti-(human L-FABP) polyclonal antibody. The ligand binding properties of the delipidated L-FABP were examined by titration with the fluorescent probe 1-anilino-8-naphthalene sulfonic acid and isothermal titration calorimetric analysis of oleic acid binding. The purified rat L-FABP displayed a binding stoichiometry of 2:1 (ANS:L-FABP) with dissociation constants (K(d)) of 1.7 and 15.5 microM for the high and low affinity binding sites, respectively. The K(d) values determined by ITC for oleic acid binding were 0.155 and 4.04 microM with a binding stoichiometry of approximately 2 mol of fatty acid/mol of protein. These physicochemical and binding properties are in agreement with those of L-FABP isolated from rat liver tissue.

Absence of Lower Urinary Tract Symptoms is an Independent Predictor for Cancer at Prostate Biopsy, but Prostate-specific Antigen is Not: Results from a Prospective Series of 569 Patients

Clinical Prostate Cancer. Jun, 2005  |  Pubmed ID: 15992462

Prostate needle biopsy (PNB) is the definitive method for the diagnosis of prostate cancer. Our objective was to evaluate prebiopsy parameters, including lower urinary tract symptoms, that may be predictive of positive biopsy.

Increasing the Number of Biopsy Cores Improves the Concordance of Biopsy Gleason Score to Prostatectomy Gleason Score

BJU International. Aug, 2005  |  Pubmed ID: 16042723

To evaluate taking more biopsy cores for predicting the radical prostatectomy (RP) Gleason score compared with the biopsy Gleason score, as although random sextant biopsies are the standard for a tissue diagnosis of prostate cancer, and taking more biopsies increases the detection rate, it is uncertain whether taking more cores improves the prediction of the RP Gleason score.

Goal Orientation: Effects on Backing Up Behavior, Performance, Efficacy, and Commitment in Teams

The Journal of Applied Psychology. Jul, 2005  |  Pubmed ID: 16060798

The author examined the predictive validity of goal orientation in teams on both team process and outcome variables. Results indicate that when mean goal orientation scores were used as a way of describing team members' inputs, learning orientation was related to backing up behavior, efficacy, and commitment. The relationships between performance orientation and efficacy and commitment, however, were more complex and were clarified when task performance was also taken into account. Performance orientation had a negative effect on efficacy when task performance was low and a positive effect on commitment when task performance was high. The implications of these findings for theory and research on goal orientation in teams and team staffing are discussed.

Bile Increases Intestinal Lymphatic Drug Transport in the Fasted Rat

Pharmaceutical Research. Nov, 2005  |  Pubmed ID: 16132351

This study was conducted to determine the influence of (1) the source of recruited endogenous fatty acid (FA), and (2) bile on intestinal lymphatic transport of halofantrine (Hf) in fasted rats.

Impaired DNA Replication Within Progenitor Cell Pools Promotes Leukemogenesis

PLoS Biology. Dec, 2005  |  Pubmed ID: 16277552

Impaired cell cycle progression can be paradoxically associated with increased rates of malignancies. Using retroviral transduction of bone marrow progenitors followed by transplantation into mice, we demonstrate that inhibition of hematopoietic progenitor cell proliferation impairs competition, promoting the expansion of progenitors that acquire oncogenic mutations which restore cell cycle progression. Conditions that impair DNA replication dramatically enhance the proliferative advantage provided by the expression of Bcr-Abl or mutant p53, which provide no apparent competitive advantage under conditions of healthy replication. Furthermore, for the Bcr-Abl oncogene the competitive advantage in contexts of impaired DNA replication dramatically increases leukemogenesis. Impaired replication within hematopoietic progenitor cell pools can select for oncogenic events and thereby promote leukemia, demonstrating the importance of replicative competence in the prevention of tumorigenesis. The demonstration that replication-impaired, poorly competitive progenitor cell pools can promote tumorigenesis provides a new rationale for links between tumorigenesis and common human conditions of impaired DNA replication such as dietary folate deficiency, chemotherapeutics targeting dNTP synthesis, and polymorphisms in genes important for DNA metabolism.

Lymphatic Absorption is the Primary Contributor to the Systemic Availability of Epoetin Alfa Following Subcutaneous Administration to Sheep

The Journal of Pharmacology and Experimental Therapeutics. Apr, 2005  |  Pubmed ID: 15579493

The contribution of the lymphatics to the absorption and systemic availability of recombinant human epoetin alfa (rHuEPO) following s.c. injection was examined using a cannulated sheep model. Parallel studies were conducted in sheep where a single bolus dose was administered either by i.v. (10, 100, or 1000 IU/kg) or s.c. (400 IU/kg) injection. The first s.c. group served as a control for the calculation of absolute bioavailability. In the second group, the efferent popliteal lymphatic duct was cannulated and peripheral lymph draining the injection site was continuously collected. In the third group, the thoracic duct was cannulated to allow collection of central lymph just prior to entry into the systemic circulation. Blood was periodically sampled from all animals, and concentrations in serum and lymph were determined by enzyme-linked immunosorbent assay. The cumulative amount of rHuEPO recovered in peripheral and central lymph was 83.9 +/- 6.6% and 75.3 +/- 3.9% of the administered dose, respectively, indicating almost complete absorption from the s.c. injection site and minimal clearance during transit through the lymphatic system. After i.v. administration, the systemic clearance of rHuEPO decreased with increasing dose, reflecting capacity-limited elimination kinetics. A pharmacokinetic model was developed to simultaneously fit experimental data for all treatment groups and estimate bioavailability. The direct measurement of >75% of the dose in peripheral and central lymph independently verifies the calculated bioavailability of 87% and demonstrates the major role of the lymphatic route in the overall s.c. bioavailability of rHuEPO after s.c. administration with this animal model.

Influence of the Intermediate Digestion Phases of Common Formulation Lipids on the Absorption of a Poorly Water-soluble Drug

Journal of Pharmaceutical Sciences. Mar, 2005  |  Pubmed ID: 15619248

The influence of different model intestinal phases (modelled on those likely to be produced in vivo after the digestion of commonly used formulation lipids) on the absorption profile of cinnarizine has been studied. Combinations of C8, C12, or C18:1 fatty acid and monoglyceride and simulated endogenous intestinal fluid were formulated to provide examples of liquid (L1), lamellar (L(alpha)), and cubic (C) liquid crystalline phases. Phases containing cinnarizine were dosed intraduodenally and absorption was assessed in an anesthetized rat model. Bile duct ligation was performed to inhibit the effects of digestion/dilution on the phase structure. Absorption from the L(alpha) phases (C8 and C12 lipids) was statistically higher (p < 0.05) than a cinnarizine suspension: however, a statistically significant difference was not observed from the L1 and C phases. The rigid C18:1 C phase showed evidence of providing for sustained drug absorption. Experiments in bile intact rats with the C8 L(alpha) and C18:1 C phase highlighted that the absorption-modifying properties of these phases were influenced by dilution in the endogenous bile milieu, with absorption from L(alpha) phase reducing (possibly through precipitation of solubilized drug) and increasing in the case of the C18:1 C phase, possibly through the coexistence of L1 and C upon dilution permitting more efficient transfer of solubilized drug.

Necrotising Fasciitis and Cellulitis After Traditional Samoan Tattooing: Case Reports

The Journal of Infection. Feb, 2005  |  Pubmed ID: 15667917

Traditional Samoan tattooing, ta tatau, is a vital part of Samoan culture. It is being performed with greater frequency on New Zealand resident Samoans. Unfortunately, ta tatau has recently been the causal factor in two significant infectious cases, in one of which death resulted. The two cases were clinically reviewed. An investigation into the history and practice of ta tatau was made in an attempt to identify causal factors that could be addressed. The two cases had similar causal themes. These included improper sanitary techniques, ta tatau being performed in unlicensed premises by temporary tattooists, patients that were unwilling to access medical services due to the expectations of tradition, lack of follow-up and lack of infection advice by the tattooist. Life threatening infectious complications has not previously been described for traditional Samoan tattooing. Improper sanitary conditions in combination with late presentation to medical services have been suggested as the cause of these cases. The technique, tools, culture and trends are discussed and recommendations are made for reducing infectious complications.

The Interaction of Lipophilic Drugs with Intestinal Fatty Acid-binding Protein

The Journal of Biological Chemistry. May, 2005  |  Pubmed ID: 15722357

Intestinal fatty acid-binding protein (I-FABP) is a small protein that binds long-chain dietary fatty acids in the cytosol of the columnar absorptive epithelial cells (enterocytes) of the intestine. The binding cavity of I-FABP is much larger than is necessary to bind a fatty acid molecule, which suggests that the protein may be able to bind other hydrophobic and amphipathic ligands such as lipophilic drugs. Herein we describe the binding of three structurally diverse lipophilic drugs, bezafibrate, ibuprofen (both R- and S-isomers) and nitrazepam to I-FABP. The rank order of affinity for I-FABP determined for these compounds was found to be R-ibuprofen approximately bezafibrate > S-ibuprofen > nitrazepam. The binding affinities were not directly related to aqueous solubility or partition coefficient of the compounds; however, the freely water-soluble drug diltiazem showed no affinity for I-FABP. Drug-I-FABP interaction interfaces were defined by analysis of chemical shift perturbations in NMR spectra, which revealed that the drugs bound within the central fatty acid binding cavity. Each drug participated in a different set of interactions within the cavity; however, a number of common contacts were observed with residues also involved in fatty acid binding. These data suggest that the binding of non-fatty acid lipophilic drugs to I-FABP may increase the cytosolic solubility of these compounds and thereby facilitate drug transport from the intestinal lumen across the enterocyte to sites of distribution and metabolism.

An Examination of the Interplay Between Enterocyte-based Metabolism and Lymphatic Drug Transport in the Rat

Drug Metabolism and Disposition: the Biological Fate of Chemicals. May, 2006  |  Pubmed ID: 16467133

The current study has examined whether drugs that are transported to the systemic circulation via the intestinal lymph (and therefore associate with lipoproteins within the enterocyte) are accessible to enterocyte-based metabolic processes. The impact of changes to the mass of lipid present within the enterocyte-based lymph lipid precursor pool (LLPP) on the extent of enterocyte-based drug metabolism has also been addressed. Low (5 mg oleic acid/h) or high [20 mg oleic acid/5.2 mg lyso-phosphatidylcholine/h] lipid dose formulations containing halofantrine (which is lymphatically transported and metabolized) or dichlorodiphenyltrichloroethane (DDT) (which is lymphatically transported and relatively metabolically inert) and radiolabeled oleic acid were infused into the duodenum of lymph duct-cannulated rats. After 5 h, drug and radiolabeled oleic acid were removed from the infusions, allowing calculation of the first order turnover rate constants describing drug and oleic acid transport from the LLPP into lymph from the washout profiles. In one group of animals, bolus doses of ketoconazole were also administered to inhibit cytochrome P450-based metabolism. The rate constant describing halofantrine transport from the LLPP into the lymph was lower than that of oleic acid, whereas these differences were abolished in the presence of ketoconazole. DDT and oleic acid exhibited similar turnover rate constants. The data therefore suggest that enterocyte-based metabolism removes halofantrine from the LLPP before transport into the lymph. Furthermore, enhancing the lymphatic transport of halofantrine by coadministration of larger quantities of lipid reduced the difference between the turnover rate constant for halofantrine and oleic acid and seemed to reduce the extent of enterocyte-based metabolism.

Prostate Specific Antigen Remains an Independent Predictor of Cancer at Prostate Biopsy in Black American Men but Not in White Men: Results from a Consecutive Series of 914 Men

The Journal of Urology. Mar, 2006  |  Pubmed ID: 16469578

Black American men may be at increased risk for prostate cancer but differences in prebiopsy parameters between black and white men have not been fully examined. Therefore, we identified the prebiopsy parameters that may be predictive of prostate cancer in black and white men.

Examination of the Impact of a Range of Pluronic Surfactants on the In-vitro Solubilisation Behaviour and Oral Bioavailability of Lipidic Formulations of Atovaquone

The Journal of Pharmacy and Pharmacology. Jun, 2006  |  Pubmed ID: 16734982

Exogenous surfactants are increasingly used to enhance the dispersion properties of lipid-based formulations of poorly water-soluble drugs, yet their possible effects on formulation digestion and oral bioavailability in-vivo are not well documented. In this study, in-vitro dispersion and digestion experiments were conducted using formulations comprising a blend of long-chain glycerides, ethanol, a model poorly water-soluble drug (atovaquone), and a series of surfactants including Cremophor EL and a range of Pluronic surfactants (Pluronics L121, L61, L72, L43 and F68). Inclusion of Cremophor EL, a surfactant with a high hydrophilic-lipophilic balance (HLB), promoted complete digestion of the formulation and effective dispersion and solubilisation of the lipolytic products and co-administered drug. Surprisingly, formulations containing the Pluronic (L121) with the lowest HLB (0.5) equally effectively promoted digestion and drug solubilisation and a trend towards decreased digestion and drug solubilisation was observed with Pluronics of increasing HLB values. All formulations effectively prevented drug precipitation, suggesting possible utility in-vivo, and no correlation was evident between the ability of the formulations to self-emulsify on dispersion and to promote drug solubilisation on digestion. Subsequent assessment of the oral bioavailability of atovaquone after administration of formulations containing Cremophor EL or Pluronic L121 or a simple solution of atovaquone in long-chain glycerides confirmed the utility of lipid-based formulations for enhancing the oral bioavailability of poorly water-soluble drugs such as atovaquone, but also indicated that in some cases microemulsion preconcentrate formulations may not provide additional bioavailability benefits beyond that achievable using simple lipid solutions.

An Abnormal Mitochondrial-hypoxia Inducible Factor-1alpha-Kv Channel Pathway Disrupts Oxygen Sensing and Triggers Pulmonary Arterial Hypertension in Fawn Hooded Rats: Similarities to Human Pulmonary Arterial Hypertension

Circulation. Jun, 2006  |  Pubmed ID: 16735674

The cause of pulmonary arterial hypertension (PAH) was investigated in humans and fawn hooded rats (FHR), a spontaneously pulmonary hypertensive strain.

25-year Prostate Cancer Control and Survival Outcomes: a 40-year Radical Prostatectomy Single Institution Series

The Journal of Urology. Aug, 2006  |  Pubmed ID: 16813891

We report on 25-year cancer control and survival outcomes after radical prostatectomy in a single center series of patients treated during a 40-year period.

An Acute and Coincident Increase in FABP Expression and Lymphatic Lipid and Drug Transport Occurs During Intestinal Infusion of Lipid-based Drug Formulations to Rats

Pharmaceutical Research. Aug, 2006  |  Pubmed ID: 16858652

To determine a) whether administration of lipid-based formulations can acutely up-regulate the intestinal expression of I-FABP and L-FABP and b) whether this occurs coincidentally with an increase in intestinal lymphatic lipid and drug transport.

Permeability Assessment of Poorly Water-soluble Compounds Under Solubilizing Conditions: the Reciprocal Permeability Approach

Journal of Pharmaceutical Sciences. Oct, 2006  |  Pubmed ID: 16883557

The objective of this study was to develop a general method to assess the intestinal permeability of poorly water-soluble drugs where low-aqueous drug solubility requires conduct of experiments under solubilizing experimental conditions. The permeability (Papp) of diazepam (DIA) was assessed across excised rat jejunum in the absence (Pappcontrol) and presence (Pappuncorr) of polysorbate-80 (PS-80). The micellar association constant (Ka) of DIA, estimated via equilibrium solubility studies, was used to correct Pappuncorr data and obtain an estimate of the true permeability coefficient (Pappcorr). An alternate approach was also developed (the reciprocal permeability approach) to allow direct estimation of Pappcorr without the need for independent estimation of Ka. The approach was further examined experimentally using a range of model drugs. DIA Pappcorr values obtained using the Ka from equilibrium solubility studies deviated from Papp(control) values, especially at PS-80 concentrations above 0.1% w/v. In contrast, data obtained using the reciprocal permeability method were consistent with Pappcontrol across the PS-80 concentration range. Similar trends were observed with propranolol (PRO), antipyrine (ANT), naproxen (NAP), and cinnarizine (CIN). The reciprocal permeability approach therefore provides a simple and accurate method by which the permeability of poorly water-soluble compounds may be estimated under solubilizing conditions.

Distortion-product Otoacoustic Emission Suppression Growth in Normal and Noise-exposed Rabbits

The Journal of the Acoustical Society of America. Aug, 2006  |  Pubmed ID: 16938977

This study investigated noise-induced changes in suppression growth (SG) of distortion product otoacoustic emissions (DPOAEs). Detailed measurements of SG were obtained in rabbits as a function of f2 frequencies at four primary-tone levels. SG measures were produced by using suppressor tones (STs) presented at two fixed distances from f2. The magnitude of suppression was calculated for each ST level and depicted as contour plots showing the amount of suppression as a function of the f2 frequency. At each f2, SG indices included slope, suppression threshold, and an estimate of the tip-to-tail value. All suppression measures were obtained before and after producing a cochlear dysfunction using a monaural exposure to a 2-h, 110-dB SPL octave-band noise centered at 2 kHz. The noise exposure produced varying amounts of cochlear damage as revealed by changes in DP-grams and auditory brainstem responses. However, average measures of SG slopes, suppression thresholds, and tip-to-tail values failed to mirror the mean DP-gram loss patterns. When suppression-based parameters were correlated with the amount of DPOAE loss, small but significant correlations were observed for some measures. Overall, the findings suggest that measures derived from DPOAE SG are limited in their ability to detect noise-induced cochlear damage.

The Absorption of Darbepoetin Alfa Occurs Predominantly Via the Lymphatics Following Subcutaneous Administration to Sheep

Pharmaceutical Research. Sep, 2006  |  Pubmed ID: 16951999

To determine the contribution of the lymphatics to the systemic availability of darbepoetin alfa (DA) using an established sheep model.

Cationic Poly-L-lysine Dendrimers: Pharmacokinetics, Biodistribution, and Evidence for Metabolism and Bioresorption After Intravenous Administration to Rats

Molecular Pharmaceutics. Sep-Oct, 2006  |  Pubmed ID: 17009860

Cationic poly-L-lysine 3H-dendrimers with either 16 or 32 surface amine groups (BHALys [Lys]4 [3H-Lys]8 [NH2]16 and BHALys [Lys]8 [3H-Lys]16 [NH2]32, generation 3 and 4, respectively) have been synthesized and their pharmacokinetics and biodistribution investigated after intravenous administration to rats. The species in plasma with which radiolabel was associated was also investigated by size exclusion chromatography (SEC). Rapid initial removal of radiolabel from plasma was evident for both dendrimers (t(1/2) < 5 min). Approximately 1 h postdose, however, radiolabel reappeared in plasma in the form of free lysine and larger (but nondendrimer) species that coeluted with albumin by SEC. Plasma and whole blood pharmacokinetics were similar, precluding interaction with blood components as a causative factor in either the rapid removal or reappearance of radioactivity in plasma. Administration of monomeric 3H L-lysine also resulted in the appearance in plasma of a radiolabeled macromolecular species that coeluted with albumin by SEC, suggesting that biodegradation of the dendrimer to L-lysine and subsequent bioresorption may explain the pharmacokinetic profiles. Capping the Lys8 dendrimer with D-lysine to form BHALys [Lys]4 [3H-Lys]8 [D-Lys]16 [NH2]32 resulted in similar, and very rapid, initial disappearance kinetics from plasma when compared to the L-lysine capped dendrimer. Since significant extravasation of these large hydrophilic molecules seems unlikely, this most likely reflects both elimination and extensive binding to vascular surfaces. Capping with "non-natural" D-lysine also appeared to render the dendrimer essentially inert to the biodegradation process. For the L-lysine capped dendrimers, radiolabel was widely distributed throughout the major organs, with no apparent selectivity for organs of the reticuloendothelial system. In contrast, a greater proportion of the administered radiolabel was recovered in the organs of the reticuloendothelial system for the D-lysine capped system, as might be expected for a nondegrading circulating foreign colloid. To our knowledge this is the first data to demonstrate the biodegradation/bioresorption of poly-L-lysine dendrimers and has significant implications for the utility of these systems as drugs or drug delivery systems.

Tissue Uptake of DDT is Independent of Chylomicron Metabolism

Archives of Toxicology. Apr, 2006  |  Pubmed ID: 16180009

To determine whether DDT uptake from chylomicrons (CM) into tissues is coincident with CM core lipid uptake.

The Lymph Lipid Precursor Pool is a Key Determinant of Intestinal Lymphatic Drug Transport

The Journal of Pharmacology and Experimental Therapeutics. Feb, 2006  |  Pubmed ID: 16249368

The influence of the size and turnover kinetics of the enterocyte-based lymph lipid precursor pool (LLPP) on intestinal lymphatic drug transport has been examined. Mesenteric lymph duct-cannulated rats were infused intraduodenally with low (2-5 mg/h) or high (20 mg/h) lipid-dose formulations containing 100 microg/h halofantrine (Hf, a model drug) and 1 microCi/h (14)C-oleic acid (OA) (as a marker for lipid transport) until steady-state rates of lipid(dX(L)/dt)(ss) and drug (dD(L)/dt)(ss) transport in lymph were obtained. After 5 h, the infusion was changed to formulations of the same composition but excluding (14)C-OA and Hf, allowing calculation of the first order rate constants describing turnover of lipid (K(X)) and drug (K(D)) from the LLPP into the lymph from the washout kinetics. The mass of lipid (X(LP)) and drug (D(LP)) in the LLPP was also determined. Biliary-lipid output was determined in a separate group of rats that had been infused with the same formulations. The results indicate that after administration of high lipid doses, lymphatic drug transport is dependent on the mass of exogenous lipid available in the LLPP and the rate of lipid pool turnover into the lymph. In contrast, after administration of low lipid doses, biliary-derived endogenous lipids are most likely to be the primary drivers of drug incorporation into the LLPP and lymph. Therefore, the LLPP size and composition seem to be major determinants of lymphatic drug transport, and formulation components, which increase lipid pool size, may therefore enhance lymphatic drug transport.

Treatment of Upper Tract Urothelial Carcinoma: a Review of Surgical and Adjuvant Therapy

Reviews in Urology. 2006  |  Pubmed ID: 17021628

Upper tract urothelial carcinoma is a disease entity that has not been as extensively studied and reviewed as carcinoma of the bladder. Recent advances in technology and adjuvant therapy have changed the treatment armamentarium of oncologists and urologists. A literature review was conducted that focused on newer surgical techniques, including laparoscopy and endoscopic management of upper tract disease. Adjuvant therapy including immunotherapy, chemotherapy, and radiation is also reviewed. Nephroureterectomy with removal of a bladder cuff still remains the gold standard of treatment. However, laparoscopic nephroureterectomy is quickly becoming popular, with equivalent recurrence rates. Because of the relatively recent introduction of laparoscopy into the urologic field, long-term data with respect to recurrence rates and survival rates are not yet available. Immunotherapy has also shown promise, but with higher recurrence rates than surgery. Chemotherapy and radiation also show some improvement in recurrence rates, but there have been no randomized, prospective trials. Endoscopic management is acceptable in patients with severe medical comorbidities or solitary kidneys but requires rigorous and close follow-up. Adjuvant therapy with either chemotherapy or radiation is still debated but does offer some improvement in disease-specific survival. Randomized, prospective, placebo-controlled studies are required but are difficult to perform because of the relatively low incidence and prevalence of this disease.

Impact of Cremophor-EL and Polysorbate-80 on Digoxin Permeability Across Rat Jejunum: Delineation of Thermodynamic and Transporter Related Events Using the Reciprocal Permeability Approach

Journal of Pharmaceutical Sciences. Feb, 2007  |  Pubmed ID: 17051595

The effect of Cremophor-EL (Cr-EL) and polysorbate-80 (PS-80) on the transepithelial permeability of digoxin (DIG) has been evaluated using the reciprocal permeability approach to delineate thermodynamic and transporter related events. Permeability data were corrected for solubilization using the micellar association constant (Ka) obtained from Papp data generated in the presence of the nonspecific ATPase inhibitor sodium orthovanadate. In the presence of mucosal Cr-EL, a concentration dependent decrease in serosal-mucosal (S-M) and increase in M-S transport was observed. Whilst serosal Cr-EL resulted in a reduction in S-M DIG transport, no impact on M-S transport was apparent. For PS-80, the presence of either serosal or mucosal surfactant led to a decrease in secretory (S-M) DIG transport, however no effect on absorptive transport was evident. The data confirm the potential P-gp inhibitory effects of Cr-EL, but suggest that in contrast to Cr-EL, PS-80 is not a potent inhibitor of P-gp and is incapable of increasing absorptive drug transport, at least in excised rat intestinal tissue and at the concentrations tested. The data are also consistent with the involvement of additional transporters (both apical and basolateral) in the intestinal permeability of DIG, although more definitive data is required to confirm this possibility.

Prostate Cancer-specific Survival in Men Treated with Hormonal Therapy After Failure of Radical Prostatectomy

European Urology. Aug, 2007  |  Pubmed ID: 17140724

We hypothesized that prostate cancer-specific survival (PCaSS) could be accurately predicted in men in whom radical prostatectomy (RP) failed and who received hormonal therapy (HT) after RP failure.

An Abnormal Digital Rectal Examination is an Independent Predictor of Gleason > or =7 Prostate Cancer in Men Undergoing Initial Prostate Biopsy: a Prospective Study of 790 Men

BJU International. Mar, 2007  |  Pubmed ID: 17155976

To evaluate our experience with a referral population of 790 patients undergoing initial prostate biopsy in the prostate-specific antigen (PSA) era, to assess the role of a digital rectal examination (DRE) in predicting the outcome of prostate needle biopsy (PNB) and to evaluate if DRE findings were associated with cancer grade.

Development and External Validation of an Extended Repeat Biopsy Nomogram

The Journal of Urology. Feb, 2007  |  Pubmed ID: 17222622

We hypothesized that the outcome of repeat biopsy could be accurately predicted. We tested this hypothesis in a contemporary cohort from 3 centers.

A Mitochondria-K+ Channel Axis is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth

Cancer Cell. Jan, 2007  |  Pubmed ID: 17222789

The unique metabolic profile of cancer (aerobic glycolysis) might confer apoptosis resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential (DeltaPsim) and low expression of the K+ channel Kv1.5, both contributing to apoptosis resistance. Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases DeltaPsim, increases mitochondrial H2O2, and activates Kv channels in all cancer, but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a promising selective anticancer agent.

Posttransplant Hodgkin Lymphoma Preceded by Polymorphic Posttransplant Lymphoproliferative Disorder: Report of a Pediatric Case and Review of the Literature

Journal of Pediatric Hematology/oncology. Feb, 2007  |  Pubmed ID: 17279008

Epstein-Barr virus-mediated posttransplant lymphoproliferative disorder (PTLD) is a well-recognized complication of immunosuppression in transplant patients and has broad clinical manifestations and pathologic features ranging from reactive lymphoid proliferation to malignant lymphoma. The category of Hodgkin lymphoma and Hodgkin lymphomalike PTLD is an uncommon variant of PTLD. Development of Hodgkin lymphoma subsequent to other subtypes of PTLD in the same patient is even more unusual, especially in pediatric patients. In this report, we describe a pediatric case of Epstein-Barr virus-associated posttransplant Hodgkin lymphoma developing several years after the patient was diagnosed with polymorphic PTLD and review the literature of the previously reported cases in children to further help characterize the clinical features, histopathologic appearances, biology, and treatment strategies of this uncommon entity.

Does the Number of Prostate Biopsies Performed Affect the Nature of the Cancer Identified?

Nature Clinical Practice. Urology. Mar, 2007  |  Pubmed ID: 17290246

Experience Improves Staging Accuracy of Endorectal Magnetic Resonance Imaging in Prostate Cancer: What is the Learning Curve?

The Canadian Journal of Urology. Feb, 2007  |  Pubmed ID: 17324322

Accurate clinical staging is critical in guiding treatment for patients with prostate adenocarcinoma. Endorectal magnetic resonance imaging (MRI) has been advocated to improve staging accuracy. In order to assess the learning curve for endorectal MRI interpretation, we compared two cohorts of patients with high-risk prostate who underwent endorectal MRI at a center with limited prior exposure to this imaging modality.

Lipids and Lipid-based Formulations: Optimizing the Oral Delivery of Lipophilic Drugs

Nature Reviews. Drug Discovery. Mar, 2007  |  Pubmed ID: 17330072

Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development - most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.

Increasing the Proportional Content of Surfactant (Cremophor EL) Relative to Lipid in Self-emulsifying Lipid-based Formulations of Danazol Reduces Oral Bioavailability in Beagle Dogs

Pharmaceutical Research. Apr, 2007  |  Pubmed ID: 17372700

To investigate the impact of a change in the proportions of lipid, surfactant and co-solvent on the solubilisation capacity of self-emulsifying formulations of danazol during in vitro dispersion and digestion studies and correlation with in vivo bioavailability in beagle dogs.

Gene Function in Early Mouse Embryonic Stem Cell Differentiation

BMC Genomics. 2007  |  Pubmed ID: 17394647

Little is known about the genes that drive embryonic stem cell differentiation. However, such knowledge is necessary if we are to exploit the therapeutic potential of stem cells. To uncover the genetic determinants of mouse embryonic stem cell (mESC) differentiation, we have generated and analyzed 11-point time-series of DNA microarray data for three biologically equivalent but genetically distinct mESC lines (R1, J1, and V6.5) undergoing undirected differentiation into embryoid bodies (EBs) over a period of two weeks.

Examination of the Role of Intestinal Fatty Acid-binding Protein in Drug Absorption Using a Parallel Artificial Membrane Permeability Assay

Chemistry & Biology. Apr, 2007  |  Pubmed ID: 17462580

Transcellular diffusion across the absorptive epithelial cells (enterocytes) of the small intestine is the main route of absorption for most orally administered drugs. The process by which lipophilic compounds transverse the aqueous environment of the cytoplasm, however, remains poorly defined. In the present study, we have identified a structurally diverse group of lipophilic drugs that display low micromolar binding affinities for a cytosolic lipid-binding protein - intestinal fatty acid-binding protein (I-FABP). Binding to I-FABP significantly enhanced the transport of lipophilic drug molecules across a model membrane, and the degree of transport enhancement was related to both drug lipophilicity and I-FABP binding affinity. These data suggest that intracellular lipid-binding proteins such as I-FABP may enhance the membrane transport of lipophilic xenobiotics and facilitate drug access to the enterocyte cytoplasm and cytoplasmic organelles.

Mechanical Failure Rate of Da Vinci Robotic System

The Canadian Journal of Urology. Apr, 2007  |  Pubmed ID: 17466155

Robotic-assisted laparoscopic radical prostatectomy (RLRP) is playing an increasing role in the surgical management of prostate cancer. The benefits of minimally invasive surgery, enhanced surgeon familiarity with the instrumentation, and increased patient demand has led to the popularity of this surgical technique. There are, however, shortcomings specifically associated with this technology. Notably, instrumentation failure associated with robotic procedures represents a new and unique problem in urological surgery. We examine the rate of mechanical failure of the da Vinci robotic system and its impact on our prostate cancer program.

A Lipid-based Liquid Crystalline Matrix That Provides Sustained Release and Enhanced Oral Bioavailability for a Model Poorly Water Soluble Drug in Rats

International Journal of Pharmaceutics. Aug, 2007  |  Pubmed ID: 17467935

Liquid crystalline phases that are stable in excess water, formed using lipids such as glyceryl monooleate (GMO) and oleyl glycerate (OG), are known to provide a sustained release matrix for poorly water soluble drugs in vitro, yet there has been no report of the use of these materials to impart oral sustained release behaviour in vivo. In the first part of this study, in vitro lipolysis experiments were used to compare the digestibility of GMO with a second structurally related lipid, oleyl glycerate, which was found to be less susceptible to hydrolysis by pancreatic lipase than GMO. Subsequent oral bioavailability studies were conducted in rats, in which a model poorly water soluble drug, cinnarizine (CIN), was administered orally as an aqueous suspension, or as a solution in GMO or OG. In the first bioavailability study, plasma samples were taken over a 30 h period and CIN concentrations determined by HPLC. Plasma CIN concentrations after administration in the GMO formulation were only sustained for a few hours after administration while for the OG formulation, the plasma concentration of cinnarizine was at its highest level 30 h after dosing, and appeared to be increasing. A second study in which CIN was again administered in OG, and plasma samples taken for 120 h, revealed a Tmax for CIN in rats of 36 h and a relative oral bioavailability of 344% when compared to the GMO formulation (117%) and the aqueous suspension formulation (assigned a nominal bioavailability of 100%). The results indicate that lipids that form liquid crystalline structures in excess water, may have application as an oral sustained release delivery system, providing they are not digested rapidly on administration.

Clinical Benefits and Economic Analysis of Pegylated Liposomal Doxorubicin/vincristine/dexamethasone Versus Doxorubicin/vincristine/dexamethasone in Patients with Newly Diagnosed Multiple Myeloma

Clinical Lymphoma & Myeloma. Apr, 2007  |  Pubmed ID: 17562253

Pegylated liposomal doxorubicin has reduced toxicity compared with conventional doxorubicin. In a noninferiority trial randomizing patients to receive pegylated liposomal doxorubicin 40 mg/m(2) and vincristine 1.4 mg/m(2) (maximum, 2 mg) intravenously on day 1 plus reduced-dose dexamethasone 40 mg orally on days 1-4 (DVd; n = 97) or conventional doxorubicin 9 mg/m(2) per day and vincristine 0.4 mg per day continuous intravenous infusion on days 1-4 plus reduced-dose dexamethasone (VAd; n = 95) for >/= 4 cycles. Treatment was repeated every 4 weeks until maximal response, disease progression, unacceptable toxicity, or until patients underwent transplantation. Treatment cost was estimated by applying standard US costs in 2004 to recorded health-care resource utilization units. Outcome measures included response, toxicity, and treatment cost. Objective response rates (DVd, 44%; VAd, 41%), progression-free survival (hazard ratio, 1.11; P = 0.69), and overall survival (hazard ratio, 0.88; P = 0.67) were similar between treatment groups. DVd was associated with significantly less grade 3/4 neutropenia or neutropenic fever (10% vs. 24%; P = 0.01), less sepsis, antibiotic use, growth factor support, and alopecia, but more hand-foot syndrome. Study drug costs were significantly higher for DVd versus VAd; however, lower costs for drug administration and supportive care more than offset this difference, resulting in nominally lower overall study drug treatment costs for DVd (DVd, $34,442; VAd, $35,846; P = 0.76). The DVd regimen demonstrated similar efficacy and cost with less toxicity and supportive care compared with VAd. This should improve clinical utility and optimize the opportunity for transplantation.

Development and External Validation of an Extended 10-core Biopsy Nomogram

European Urology. Aug, 2007  |  Pubmed ID: 17010505

To test the accuracy of a previously externally validated sextant biopsy nomogram in referred men exposed to > or =10 or more biopsy cores. Moreover, we explored the hypothesis that a more accurate predictive tool could be developed.

Low Dose Lipid Formulations: Effects on Gastric Emptying and Biliary Secretion

Pharmaceutical Research. Nov, 2007  |  Pubmed ID: 17657595

Food stimulates changes to gastrointestinal secretion and motility patterns, however, the effect of smaller quantities of lipid, such as that contained in a lipid-based drug formulation, has not been detailed. This study aimed to examine the effects of small quantities of lipid on gastric emptying and biliary secretion.

How Useful is PSA Velocity As a Screening Tool for Prostate Cancer Detection?

Nature Clinical Practice. Urology. Sep, 2007  |  Pubmed ID: 17684505

ChIP on SNP-chip for Genome-wide Analysis of Human Histone H4 Hyperacetylation

BMC Genomics. 2007  |  Pubmed ID: 17868463

SNP microarrays are designed to genotype Single Nucleotide Polymorphisms (SNPs). These microarrays report hybridization of DNA fragments and therefore can be used for the purpose of detecting genomic fragments.

Lymphatic Absorption of Subcutaneously Administered Proteins: Influence of Different Injection Sites on the Absorption of Darbepoetin Alfa Using a Sheep Model

Drug Metabolism and Disposition: the Biological Fate of Chemicals. Dec, 2007  |  Pubmed ID: 17875672

The relative contribution of the lymph and blood in the absorption of darbepoetin alfa (DA) from different s.c. injection sites was determined using a central lymph-cannulated sheep model. DA was administered to parallel groups either as a bolus i.v. injection (0.5 mug/kg) into the jugular vein or as a bolus s.c. injection (2 mug/kg) into the interdigital space, the abdomen, or the shoulder. In the lymph-cannulated groups, the thoracic lymph duct was cannulated for continuous collection of central lymph, and blood samples were periodically collected via the jugular vein in all the groups. The concentration of DA in serum and lymph was determined by enzyme-linked immunosorbent assay. The total fraction of the dose reaching the systemic circulation and the fractions absorbed via the lymph and the blood were determined. A pharmacokinetic model was constructed to simultaneously fit the data from all the treatment groups. Absorption was essentially complete for all three injection sites in non-lymph-cannulated s.c. groups, but the rates of absorption differed significantly. Based on the modeling results for the lymph-cannulated groups, the lymphatics represented the predominant absorption route for both the interdigital (90 +/- 1%) and the abdomen (67 +/- 9%) injection sites. Fluorescein isothiocyanate dextran visualization studies revealed that the lymph draining the shoulder injection site entered the thoracic lymph duct distal to the point of cannulation, effectively precluding collection of thoracic lymph from this site. For that reason, the contribution of the lymphatics following injection in the shoulder could not be determined using these cannulation procedures.

Impact of Surface Derivatization of Poly-L-lysine Dendrimers with Anionic Arylsulfonate or Succinate Groups on Intravenous Pharmacokinetics and Disposition

Molecular Pharmaceutics. Nov-Dec, 2007  |  Pubmed ID: 17953445

Tritium-labeled poly- l-lysine dendrimers displaying 8 or 16 surface lysines have been capped with benzene sulfonate (BS), benzene disulfonate (BDS), or succinate (Succ) groups, and the intravenous pharmacokinetics and disposition profiles of the resulting dendrimers (Lys(8)(BS)(16), Lys(16)(BS)(32), Lys(16)(BDS)(32), Lys(16)(Succ)(32)) have been evaluated. Lys(16)(Succ)(32) was rapidly removed from the plasma primarily via renal elimination. Lys(16)(BS)(32) and Lys(16)(BDS)(32) were opsonized, resulting in more prolonged plasma elimination kinetics and increased uptake by the liver. Data obtained at higher doses suggested some evidence of nonlinear pharmacokinetics. Lys(8)(BS)(16) had reduced affinity for plasma proteins and was cleared more rapidly than the larger Lys(16)(BS)(32) or Lys(16)(BDS)(32) dendrimers. Lys(8)(BS)(16) and Lys(16)(BS)(32) were metabolized in vivo, resulting in the production of a low molecular weight species (possibly the cleavage product Lys(BS) (2)) that was extensively renally eliminated and accounted for almost all of the radioactivity recovered in urine ( approximately 20-45% of administered (3)H). In contrast, only 3-5% of the administered (3)H was recovered in the urine of rats administered Lys(16)(BDS)(32), suggesting increased resistance to in vivo degradation. The plasma clearance, distribution, and metabolic profiles of lysine dendrimers are therefore significantly influenced by the structure and charge of the capping groups. In particular, larger arylsulfonate-capped lysine dendrimers are rapidly opsonized and initially cleared from the plasma by the reticuloendothelial organs. The degree of metabolism is subsequently dictated by the nature of the surface capping group with BDS surfaces seemingly more resistant to breakdown. In contrast, smaller arylsulfonate-capped dendrimers are less readily opsonized and phagocytozed but are metabolically labile, and succinate-capped dendrimers are rapidly eliminated by the kidneys.

StemBase: a Resource for the Analysis of Stem Cell Gene Expression Data

Methods in Molecular Biology (Clifton, N.J.). 2007  |  Pubmed ID: 18453254

StemBase is a database of gene expression data obtained from stem cells and derivatives mainly from mouse and human using DNA microarrays and Serial Analysis of Gene Expression. Here, we describe this database and indicate ways to use it for the study the expression of particular genes in stem cells or to search for genes with particular expression profiles in stem cells, which could be associated to stem cell function or used as stem cell markers.

Characterization of the Drug Binding Specificity of Rat Liver Fatty Acid Binding Protein

Journal of Medicinal Chemistry. Jul, 2008  |  Pubmed ID: 18533710

Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in the cytosolic solubilization of fatty acids during fat absorption. In the current studies, the interaction of L-FABP with a range of lipophilic drugs has been evaluated to explore the potential for L-FABP to provide an analogous function during the absorption of lipophilic drugs. Binding affinity for L-FABP was assessed by displacement of a fluorescent marker, 1-anilinonaphthalene-8-sulfonic acid (ANS), and the binding site location was determined via nuclear magnetic resonance chemical shift perturbation studies. It was found that the majority of drugs bound to L-FABP at two sites, with the internal site generally having a higher affinity for the compounds tested. Furthermore, in contrast to the interaction of L-FABP with fatty acids, it was demonstrated that a terminal carboxylate is not required for specific binding of lipophilic drugs at the internal site of L-FABP.

Interfering RNA-mediated Purine Analog Resistance for in Vitro and in Vivo Cell Selection

Blood. Dec, 2008  |  Pubmed ID: 18587011

The advancement of gene therapy has been slowed, in part, by inefficient transduction of targeted cells and poor long-term engraftment of genetically modified cells. Thus, the ability to select for a desired population of cells within a recipient would be of great benefit for improving gene therapy. Proposed strategies for in vivo cell selection using drug resistance genes have had disappointing outcomes and/or require highly genotoxic medications to be effective. We hypothesized that resistance to purine analogs, a well-tolerated, relatively low-toxicity class of medications, could be provided to cells using interfering RNA against hypoxanthine phosphoribosyl transferase. Using a lentiviral vector, we found that interfering RNA-mediated purine analog resistance (iPAR) provided relative resistance to 6-thioguanine (6TG) in murine hematopoietic cells compared with control- and untransduced cells. iPAR attenuated 6TG-induced G(2)/M checkpoint activation, cell-cycle arrest, and apoptosis. Furthermore, in recipients of transplanted bone marrow cells with iPAR, treatment with 6TG resulted in increased percentages of transduced peripheral blood cells and hematopoietic progenitor cells in the bone marrow. Secondary transplantations resulted in higher hematopoietic contributions from 6TG-treated primary recipients relative to phosphate-buffered saline-treated recipients. These findings indicate that iPAR/6TG can be used for in vivo hematopoietic progenitor cell selection.

A Nomogram Predicting Metastatic Progression After Radical Prostatectomy

International Journal of Urology : Official Journal of the Japanese Urological Association. Oct, 2008  |  Pubmed ID: 18662174

To develop and internally validate a nomogram predicting the individual probability of metastatic progression after radical prostatectomy according to the length of disease-free interval.

BCL6 Expression Correlates with Monomorphic Histology in Children with Posttransplantation Lymphoproliferative Disease

Journal of Pediatric Hematology/oncology. Sep, 2008  |  Pubmed ID: 18776761

Posttransplantation lymphoproliferative disease (PTLD) is a complication of organ transplantation with high mortality. Predicting response to first-line therapy, reduction of immune suppression, is difficult because of the heterogeneity of lesions and disease behavior. We sought to determine if BCL6 protein expression in PTLD cells is associated with poor outcome. In a cohort of 25 children with PTLD, 9 of the patients' tumor specimens were positive for BCL6 protein expression. Eight of 13 monomorphic lesions were BCL6 positive, compared with 1 of 11 evaluable polymorphic lesions (P=0.01). Only 1 of the patients with BCL6 expression responded to reduced immune suppression (P=0.19). Recipients of heart transplants who developed PTLD had reduced overall survival rates compared with recipients of other organ transplants who developed PTLD (P=0.04).

An Evaluation of the Relative Roles of the Unstirred Water Layer and Receptor Sink in Limiting the In-vitro Intestinal Permeability of Drug Compounds of Varying Lipophilicity

The Journal of Pharmacy and Pharmacology. Oct, 2008  |  Pubmed ID: 18812024

The roles of the unstirred water layer (UWL) and receptor sink on the in-vitro transmembrane permeability of an increasingly lipophilic series of compounds (mannitol (MAN), diazepam (DIA) and cinnarizine (CIN)) have been assessed. Altered carbogen bubbling rates were used as a means to change the UWL thickness and polysorbate-80 (PS-80), bovine serum albumin (BSA) and alpha-1-acid glycoprotein (AAG) were employed to alter sink conditions. After correction for solubilisation, Papp data for MAN, DIA and CIN were consistent across varying donor PS-80 concentrations suggesting that for the drugs examined here, the donor UWL did not limit in-vitro permeability. Similarly, altered bubbling rates and receptor sink conditions had no impact on the permeability of MAN. In contrast, decreasing the size of the receptor UWL or adding solubilising agents to the receptor sink resulted in modest enhancements to the permeability of the more lipophilic probe DIA. For the most lipophilic compound, CIN, very significant changes to measured permeability (>30 fold) were possible, but were most evident only after concomitant changes to both the UWL and sink conditions, suggesting that the effectiveness of enhanced sink conditions were dependent on a decrease in the width of the UWL.

Evaluation of the Impact of Surfactant Digestion on the Bioavailability of Danazol After Oral Administration of Lipidic Self-emulsifying Formulations to Dogs

Journal of Pharmaceutical Sciences. Feb, 2008  |  Pubmed ID: 18064698

Lipid-based formulations of danazol with varying quantities of included surfactant have been examined in vitro and in vivo. Formulations comprising fatty acid ester surfactants were readily hydrolysed during in vitro digestion, although Cremophor RH40 (CrRH) was less effectively hydrolysed than Cremophor EL (CrEL). Formulations comprising high quantities of digestible surfactant also appeared to less effectively prevent danazol precipitation during in vitro evaluation. These trends were replicated in vivo where danazol bioavailability in beagle dogs was higher after oral administration of self-emulsifying formulations employing 55% (w/w) CrRH when compared with CrEL. The oral bioavailability of danazol after administration of drug formulated in surfactant alone, however, was poor. Studies using predispersed and encapsulated formulations of CrRH subsequently suggested that the low bioavailability of the single surfactant formulations reflected poor dispersion. Mixtures of surfactants, improved dispersion and good oral bioavailability of danazol was evident after administration of formulations comprising CrRH and either Pluronic L121 or Gelucire 44-14, in spite of evidence of danazol precipitation during in vitro digestion of the Gelucire formulation. These data suggest that effective dispersion and resistance to precipitation during both dispersion and digestion are key design parameters for lipid-based formulations comprising high proportions of surfactant.

Formulation of Lipid-based Delivery Systems for Oral Administration: Materials, Methods and Strategies

Advanced Drug Delivery Reviews. Mar, 2008  |  Pubmed ID: 18068260

Oral lipid-based drug delivery systems may include a broad range of oils, surfactants, and cosolvents. This diversity makes comparison of lipid-based formulations difficult. Although the relationship between formulation and drug absorption is understood at a conceptual level, performance in vivo cannot be predicted with confidence at present. The Lipid Formulation Classification System (LFCS) identifies the factors which are likely to affect performance in vivo. There is now a need to establish performance criteria which will facilitate in vitro-in vivo correlation studies. In this review we discuss the properties of excipients, and identify criteria for selection of excipients for lipid-based formulations. Excipients are discussed in the context of the LFCS, our existing knowledge of the fate of these materials during dispersion and digestion, and the likely consequences of their use in formulations. We outline the formulation strategies that can be used for each type of lipid formulation, and suggest a framework for the in vitro testing of each type. Finally we address the choice of lipid formulations in relation to the physicochemical properties of the drug.

Lipid-based Delivery Systems and Intestinal Lymphatic Drug Transport: a Mechanistic Update

Advanced Drug Delivery Reviews. Mar, 2008  |  Pubmed ID: 18155316

After oral administration, the majority of drug molecules are absorbed across the small intestine and enter the systemic circulation via the portal vein and the liver. For some highly lipophilic drugs (typically log P>5, lipid solubility>50 mg/g), however, association with lymph lipoproteins in the enterocyte leads to transport to the systemic circulation via the intestinal lymph. The attendant delivery benefits associated with lymphatic drug transport include a reduction in first-pass metabolism and lymphatic exposure to drug concentrations orders of magnitude higher than that attained in systemic blood. In the current review we briefly describe the mechanisms by which drug molecules access the lymph and the formulation strategies that may be utilised to enhance lymphatic drug transport. Specific focus is directed toward recent advances in understanding regarding the impact of lipid source (both endogenous and exogenous) and intracellular lipid trafficking pathways on lymphatic drug transport and enterocyte-based first-pass metabolism.

Enhancing Intestinal Drug Solubilisation Using Lipid-based Delivery Systems

Advanced Drug Delivery Reviews. Mar, 2008  |  Pubmed ID: 18155801

Lipid-based delivery systems are finding increasing application in the oral delivery of poorly water-soluble, lipophilic drugs. Whilst lipidic dose forms may improve oral bioavailability via several mechanisms, enhancement of gastrointestinal solubilisation remains argueably the most important method of absorption enhancement. This review firstly describes the mechanistic rationale which underpins the use of lipid-based delivery systems to enhance drug solubilisation and briefly reviews the available literature describing increases in oral bioavailability after the administration of lipid solution, suspension and self-emulsifying formulations. The use of in vitro methods including dispersion tests and more complex models of in vitro lipolysis as indicators of potential in vivo performance are subsequently described, with particular focus on recent data which suggests that the digestion of surfactants present in lipid-based formulations may impact on formulation performance. Finally, a series of seven guiding principles for formulation design of lipid-based delivery systems are suggested based on an analysis of recent data generated in our laboratories and elsewhere.

Lipid-based Systems for the Enhanced Delivery of Poorly Water Soluble Drugs

Advanced Drug Delivery Reviews. Mar, 2008  |  Pubmed ID: 18160174

A Nomogram Predicting Long-term Biochemical Recurrence After Radical Prostatectomy

Cancer. Mar, 2008  |  Pubmed ID: 18286530

Men who undergo radical prostatectomy (RP) are at long-term risk of biochemical recurrence (BCR). In this report, the authors have described a model capable of predicting BCR up to at least 15 years after RP that can adjust predictions according to the disease-free interval.

The Impact of Molecular Weight and PEG Chain Length on the Systemic Pharmacokinetics of PEGylated Poly L-lysine Dendrimers

Molecular Pharmaceutics. May-Jun, 2008  |  Pubmed ID: 18393438

The impact of PEGylation on the pharmacokinetics and biodistribution of (3)H-labeled poly l-lysine dendrimers has been investigated after intravenous administration to rats. The volumes of distribution, clearance and consequently the plasma half-lives of the PEGylated dendrimers were markedly dependent on the total molecular weight of the PEGylated dendrimer, but were not specifically affected by the PEG chain length alone. In general, the larger dendrimer constructs (i.e. >30 kDa) had reduced volumes of distribution, were poorly renally cleared and exhibited extended elimination half-lives ( t 1/2 1-3 days) when compared to the smaller dendrimers (i.e. <20 kDa) which were rapidly cleared from the plasma principally into the urine ( t 1/2 1-10 h). At later time points the larger dendrimers concentrated in the organs of the reticuloendothelial system (liver and spleen); however, the absolute extent of accumulation was low. Size exclusion chromatography of plasma and urine samples revealed that the PEGylated dendrimers were considerably more resistant to biodegradation in vivo than the underivatized poly l-lysine dendrimer cores. The results suggest that the size of PEGylated poly l-lysine dendrimer complexes can be manipulated to optimally dictate their pharmacokinetics, biodegradation and bioresorption behavior.

Seeing is Believing

Cancer Biomarkers : Section A of Disease Markers. 2008  |  Pubmed ID: 18957709

Use of Plasma Proteins As Solubilizing Agents in in Vitro Permeability Experiments: Correction for Unbound Drug Concentration Using the Reciprocal Permeability Approach

Journal of Pharmaceutical Sciences. Jan, 2008  |  Pubmed ID: 17585392

The purpose of the present study was to explore the applicability of the reciprocal permeability approach to correct for changes in thermodynamic activity when in vitro permeability data are generated in the presence of plasma proteins. Diazepam (DIA), digoxin (DIG), and propranolol (PRO) permeability was assessed in the presence of bovine serum albumin (BSA) and bovine alpha-1-acid glycoprotein (AAG). The reciprocal permeability approach was subsequently employed to calculate the true permeability coefficient (Papp(corr)) and the operational protein association constant (nK(a)). For BSA binding, good agreement was observed between the Papp(corr) values and Papp values obtained in the absence of protein. For PRO and AAG, where binding affinity was high, deviation in the reciprocal permeability plots was evident suggesting ligand depletion at low drug/high protein concentrations. Bidirectional DIG permeability data in the presence of either BSA or AAG indicated that neither protein had an effect on the efflux transporters involved in DIG permeability. The data suggest that plasma proteins can be utilized in permeability experiments with no adverse effects on transporter function and that the reciprocal permeability approach can be used to correct permeability data for changes in unbound drug concentration.

Adjuvant Radiotherapy After Radical Prostatectomy Shows No Ability to Improve Rates of Overall and Cancer-specific Survival in a Matched Case-control Study

BJU International. Mar, 2009  |  Pubmed ID: 19021603

To assess the effect of adjuvant radiotherapy (aRT) on the rate of cancer-specific and overall survival after radical prostatectomy (RP) in a group of patients with a long-term follow-up, as there is controversy about the benefit of aRT after RP for prostate cancer when endpoints beyond biochemical and local recurrence are considered.

Phase II Trial of Neoadjuvant Docetaxel and Gefitinib Followed by Radical Prostatectomy in Patients with High-risk, Locally Advanced Prostate Cancer

Cancer. Feb, 2009  |  Pubmed ID: 19130458

Prostate cancer trials investigating neoadjuvant hormonal therapy, followed by surgery, have demonstrated that elimination of all tumor cells from the primary site is rare. The authors report a phase 2 trial assessing the efficacy and toxicity of docetaxel and gefitinib in patients with high-risk localized prostate cancer as neoadjuvant therapy before radical prostatectomy (RP).

Characterization of Lipophilic Drug Binding to Rat Intestinal Fatty Acid Binding Protein

Molecular and Cellular Biochemistry. Jun, 2009  |  Pubmed ID: 19160019

Intestinal fatty acid binding protein (I-FABP) is present at high levels in the absorptive cells of the intestine (enterocytes) where it plays a role in the intracellular solubilization of fatty acids (FA). However, I-FABP has also been shown to bind to a range of non-FA ligands, including some lipophilic drug molecules, albeit with generally lower affinity than FA. The significance of these lower affinity interactions with exogenous compounds is not known. In this manuscript, we describe further characterization of drug-rat I-FABP binding interactions using a thermal-shift assay. A structural explanation of the observed affinity of rat I-FABP for different drugs based on spectroscopic data and modeling experiments is presented. In addition, immunocytochemistry has been used to probe the expression of I-FABP in a cell culture model reflective of the absorptive cells of the small intestine. Taken together, these data suggest a possible role for I-FABP in the disposition of some lipophilic drugs within the enterocyte.

Intestinal Lymphatic Transport Enhances the Post-prandial Oral Bioavailability of a Novel Cannabinoid Receptor Agonist Via Avoidance of First-pass Metabolism

Pharmaceutical Research. Jun, 2009  |  Pubmed ID: 19280324

To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs.

Recent Developments in StemBase: a Tool to Study Gene Expression in Human and Murine Stem Cells

BMC Research Notes. 2009  |  Pubmed ID: 19284540

Currently one of the largest online repositories for human and mouse stem cell gene expression data, StemBase was first designed as a simple web-interface to DNA microarray data generated by the Canadian Stem Cell Network to facilitate the discovery of gene functions relevant to stem cell control and differentiation.

Management of Non-germinal Testicular Tumors

World Journal of Urology. Aug, 2009  |  Pubmed ID: 19322569

Non-germinal tumors account for less than 10% of all testicular tumors and consist of a wide array of benign and malignant lesions. Due to their rarity, little is known about the appropriate management of malignant non-germinal testicular tumors.

Pharmacokinetics and Tumor Disposition of PEGylated, Methotrexate Conjugated Poly-l-lysine Dendrimers

Molecular Pharmaceutics. Jul-Aug, 2009  |  Pubmed ID: 19453158

Dendrimers have potential for delivering chemotherapeutic drugs to solid tumors via the enhanced permeation and retention (EPR) effect. The impact of conjugation of hydrophobic anticancer drugs to hydrophilic PEGylated dendrimer surfaces, however, has not been fully investigated. The current study has therefore characterized the effect on dendrimer disposition of conjugating alpha-carboxyl protected methotrexate (MTX) to a series of PEGylated (3)H-labeled poly-l-lysine dendrimers ranging in size from generation 3 (G3) to 5 (G5) in rats. Dendrimers contained 50% surface PEG and 50% surface MTX. Conjugation of MTX generally increased plasma clearance when compared to conjugation with PEG alone. Conversely, increasing generation reduced clearance, increased metabolic stability and reduced renal elimination of the administered radiolabel. For constructs with molecular weights >20 kDa increasing the molecular weight of conjugated PEG also reduced clearance and enhanced metabolic stability but had only a minimal effect on renal elimination. Tissue distribution studies revealed retention of MTX conjugated smaller (G3-G4) PEG(570) dendrimers (or their metabolic products) in the kidneys. In contrast, the larger G5 dendrimer was concentrated more in the liver and spleen. The G5 PEG(1100) dendrimer was also shown to accumulate in solid Walker 256 and HT1080 tumors, and comparative disposition data in both rats (1 to 2% dose/g in tumor) and mice (11% dose/g in tumor) are presented. The results of this study further illustrate the potential utility of biodegradable PEGylated poly-l-lysine dendrimers as long-circulating vectors for the delivery and tumor-targeting of hydrophobic drugs.

Solution Characterization of the Extracellular Region of CD147 and Its Interaction with Its Enzyme Ligand Cyclophilin A

Journal of Molecular Biology. Aug, 2009  |  Pubmed ID: 19500591

The CD147 receptor plays an integral role in numerous diseases by stimulating the expression of several protein families and serving as the receptor for extracellular cyclophilins; however, neither CD147 nor its interactions with its cyclophilin ligands have been well characterized in solution. CD147 is a unique protein in that it can function both at the cell membrane and after being released from cells where it continues to retain activity. Thus, the CD147 receptor functions through at least two mechanisms that include both cyclophilin-independent and cyclophilin-dependent modes of action. In regard to CD147 cyclophilin-independent activity, CD147 homophilic interactions are thought to underlie its activity. In regard to CD147 cyclophilin-dependent activity, cyclophilin/CD147 interactions may represent a novel means of signaling since cyclophilins are also peptidyl-prolyl isomerases. However, direct evidence of catalysis has not been shown within the cyclophilin/CD147 complex. In this report, we have characterized the solution behavior of the two most prevalent CD147 extracellular isoforms through biochemical methods that include gel-filtration and native gel analysis as well as directly through multiple NMR methods. All methods indicate that the extracellular immunoglobulin-like domains are monomeric in solution and, thus, suggest that CD147 homophilic interactions in vivo are mediated through other partners. Additionally, using multiple NMR techniques, we have identified and characterized the cyclophilin target site on CD147 and have shown for the first time that CD147 is also a substrate of its primary cyclophilin enzyme ligand, cyclophilin A.

Oral Bioavailability Assessment and Intestinal Lymphatic Transport of Org 45697 and Org 46035, Two Highly Lipophilic Novel Immunomodulator Analogues

Current Drug Delivery. Aug, 2009  |  Pubmed ID: 19534711

Org 45697 (MW 600.7, clogP 7.92, soybean oil solubility 50 mg/g) and Org 46035 (MW 601.6, clog P 8.46, soybean oil solubility 40 mg/g) are two poorly water soluble (<0.1 microg/ml), highly lipophilic drug candidates with immunomodulator activity and highly analogous chemical structures. After oral administration to conscious ambulatory rats in an aqueous-based methylcellulose/Tween 80 suspension, the bioavailability of both compounds was low (< 2% of administered dose). However, bioavailability was significantly increased (> 5 fold) after oral administration in a long chain triglyceride lipid (olive oil) formulation. Subsequent studies have explored the potential for solubilising formulations, including lipid-based formulations, to enhance the oral bioavailability of Org 45697 and Org 46035 and secondly to explore the potential contribution of intestinal lymphatic transport to intestinal absorption. The experimental data show that solubilising formulations may provide for significant increases in oral bioavailability for Org 45697 and Org 46035 and that after co-administration with lipid, 35-50% of the absorbed dose may be transported to the systemic circulation via the intestinal lymph. Interestingly, the lymphatic transport of the less lipid soluble analogue, Org 46035 was approximately 40% lower than that of Org 45697 suggesting that relatively subtle differences in lipid solubility can have significant impact on the extent of lymphatic transport.

Probing the Fibrate Binding Specificity of Rat Liver Fatty Acid Binding Protein

Journal of Medicinal Chemistry. Sep, 2009  |  Pubmed ID: 19663428

Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.

PEGylation of Polylysine Dendrimers Improves Absorption and Lymphatic Targeting Following SC Administration in Rats

Journal of Controlled Release : Official Journal of the Controlled Release Society. Dec, 2009  |  Pubmed ID: 19686787

Polylysine dendrimers have potential as highly flexible, biodegradable nanoparticular carriers that may also promote lymphatic transport. The current study was undertaken to determine the impact of PEGylation on the absorption and lymphatic transport of polylysine dendrimers modified by surface derivatisation with PEG (200, 570 or 2000Da) or 4-benzene sulphonate following SC or IV dosing. PEGylation led to the PEG(200) derived dendrimer being rapidly and completely absorbed into the blood after SC administration, however only 3% of the administered dose was recovered in pooled thoracic lymph over 30h. Increasing the PEG chain length led to a systematic decrease in absorption into the blood and an enhancement of the proportion recovered in the lymphatics (up to 29% over 30h). For the PEG(570) and PEG(2000) derived dendrimers, indirect access to the lymph via equilibration across the capillary beds also appeared to play a role in lymphatic targeting after both IV and SC dosing. In contrast, the anionic benzene sulphonate-capped dendrimer was not well absorbed from the SC injection site (26% bioavailability) into either the blood or the lymph. The data suggest that PEGylated poly-L-lysine dendrimers are well absorbed from SC injection sites and that the extent of lymphatic transport may be enhanced by increasing the size of the PEGylated dendrimer complex.

Lymphatic Transport of Methylnortestosterone Undecanoate (MU) and the Bioavailability of Methylnortestosterone Are Highly Sensitive to the Mass of Coadministered Lipid After Oral Administration of MU

The Journal of Pharmacology and Experimental Therapeutics. Nov, 2009  |  Pubmed ID: 19696095

The contribution of lymphatic transport to the oral bioavailability of methylnortestosterone (M) after oral administration of the lipophilic prodrug methylnortestosterone undecanoate (MU) has been evaluated, and the sensitivity of lymphatic MU transport to lymphatic lipid transport has been investigated. M and MU were administered intravenously and orally to greyhound dogs to determine absolute bioavailability after oral dosing of MU. MU was also administered orally with differing quantities of food (lipid) to lymph duct-cannulated greyhound dogs to investigate the relative roles of lymph versus blood transport on M bioavailability and the effect of lipid load on systemic exposure. The relationship between lymphatic lipid and MU transport was further investigated in anesthetized rats. The oral bioavailability of M after administration of MU was found to be highly dependent on coadministration of food, and the bioavailability of M increased approximately 700% in fed versus fasted animals. In both cases, lymph diversion resulted in negligible systemic exposure of M, indicating almost complete dependence on lymphatic transport of MU for systemic exposure of M. Lymphatic transport of MU was even more highly dependent on the quantity of coadministered lipid and increased more than 50-fold with increasing lipid load. Therefore, increasing the quantity of food or lipid coadministered with MU stimulated a significant increase in the lymphatic transport of MU and systemic exposure of M. The lipid sensitivity of lymphatic transport of MU is significantly higher than previously observed for more metabolically stable compounds, suggesting a role for coadministered lipid in promoting avoidance of enterocyte-based cleavage of MU.

Radical Retropubic Cystectomy

BJU International. Dec, 2009  |  Pubmed ID: 20053198

Vincristine Induced Peripheral Neuropathy Potentiated by Voriconazole in a Patient with Previously Undiagnosed CMT1X

Pediatric Blood & Cancer. Feb, 2009  |  Pubmed ID: 18837430

Peripheral neuropathy is a well-known side effect of vincristine, a micro-tubule inhibitor commonly used to treat malignancies. Severe neurologic adverse events can occur in patients with Charcot-Marie-Tooth disease (CMT) treated with vincristine. Voriconazole is an antifungal agent used increasingly in children with malignancy. Because of its metabolism by hepatic p450 enzymes, voriconazole may inhibit the clearance of many medications, including vincristine. We report a case of vincristine related neuropathy that was exacerbated by voriconazole in a patient with previously undiagnosed, X-linked CMT.

MRI After Technically Successful Renal Cryoablation: Early Contrast Enhancement As a Common Finding

AJR. American Journal of Roentgenology. Mar, 2010  |  Pubmed ID: 20173161

The purpose of this study was to assess the MRI appearance and enhancement of renal masses within 36 hours after cryoablation.

Irradiation Selects for P53-deficient Hematopoietic Progenitors

PLoS Biology. Mar, 2010  |  Pubmed ID: 20208998

Identification and characterization of mutations that drive cancer evolution constitute a major focus of cancer research. Consequently, dominant paradigms attribute the tumorigenic effects of carcinogens in general and ionizing radiation in particular to their direct mutagenic action on genetic loci encoding oncogenes and tumor suppressor genes. However, the effects of irradiation are not limited to genetic loci that encode oncogenes and tumor suppressors, as irradiation induces a multitude of other changes both in the cells and their microenvironment which could potentially affect the selective effects of some oncogenic mutations. P53 is a key tumor suppressor, the loss of which can provide resistance to multiple genotoxic stimuli, including irradiation. Given that p53 null animals develop T-cell lymphomas with high penetrance and that irradiation dramatically accelerates lymphoma development in p53 heterozygous mice, we hypothesized that increased selection for p53-deficient cells contributes to the causal link between irradiation and induction of lymphoid malignancies. We sought to determine whether ionizing irradiation selects for p53-deficient hematopoietic progenitors in vivo using mouse models. We found that p53 disruption does not provide a clear selective advantage within an unstressed hematopoietic system or in previously irradiated BM allowed to recover from irradiation. In contrast, upon irradiation p53 disruption confers a dramatic selective advantage, leading to long-term expansion of p53-deficient clones and to increased lymphoma development. Selection for cells with disrupted p53 appears to be attributable to several factors: protection from acute irradiation-induced ablation of progenitor cells, prevention of irradiation-induced loss of clonogenic capacity for stem and progenitor cells, improved long-term maintenance of progenitor cell fitness, and the disabling/elimination of competing p53 wild-type progenitors. These studies indicate that the carcinogenic effect of ionizing irradiation can in part be explained by increased selection for cells with p53 disruption, which protects progenitor cells both from immediate elimination and from long-term reductions in fitness following irradiation.

A Nomogram Predicting Prostate Cancer-specific Mortality After Radical Prostatectomy

Urologia Internationalis. 2010  |  Pubmed ID: 20215815

We describe a model capable of predicting prostate cancer (PCa)-specific mortality up to 20 years after a radical prostatectomy (RP), which can adjust the predictions according to disease-free interval.

The Role of the Intestinal Lymphatics in the Absorption of Two Highly Lipophilic Cholesterol Ester Transfer Protein Inhibitors (CP524,515 and CP532,623)

Pharmaceutical Research. May, 2010  |  Pubmed ID: 20221896

To evaluate the potential role of intestinal lymphatic transport in the absorption and oral bioavailability of members of an emerging class of anti-atherosclerosis drugs (CETP inhibitors). CP524,515 and CP532,623 are structurally related with eLogD(7.4) >5; however, only CP524,515 (and not CP532,623) had sufficient solubility (>50 mg/g) in long-chain triglyceride (LCT) to be considered likely to be lymphatically transported.

The Early-onset Torsion Dystonia-associated Protein, TorsinA, is a Homeostatic Regulator of Endoplasmic Reticulum Stress Response

Human Molecular Genetics. Sep, 2010  |  Pubmed ID: 20584926

Early-onset torsion dystonia is the most severe heritable form of dystonia, a human movement disorder that typically starts during a developmental window in early adolescence. Deletion in the DYT1 gene, encoding the torsinA protein, is responsible for this dominantly inherited disorder, which is non-degenerative and exhibits reduced penetrance among carriers. Here, we explore the hypothesis that deficits in torsinA function result in an increased vulnerability to stress associated with protein folding and processing in the endoplasmic reticulum (ER), where torsinA is located. Using an in vivo quantitative readout for the ER stress response, we evaluated the consequences of torsinA mutations in transgenic nematodes expressing variants of human torsinA. This analysis revealed that, normally, torsinA serves a protective function to maintain a homeostatic threshold against ER stress. Furthermore, we show that the buffering capacity of torsinA is greatly diminished by the DYT1-associated deletion or mutations that prevent its translocation to the ER, block ATPase activity, or increase the levels of torsinA in the nuclear envelope versus ER. Combinations of transgenic Caenorhabditis elegans designed to mimic clinically relevant genetic modifiers of disease susceptibility also exhibit a direct functional correlation to changes in the ER stress response. Furthermore, using mouse embryonic fibroblasts (MEFs) from torsinA knockout mice, we demonstrated that loss of endogenous torsinA results in enhanced sensitivity to ER stress. This study extends our understanding of molecular mechanisms underlying dystonia, and establishes a new functional paradigm to evaluate therapeutic strategies to compensate for reduced torsinA activity in the ER as a means to restore homeostatic balance and neuronal function.

Genomic Predictors of Prostate Cancer Therapy Outcomes

Expert Review of Molecular Diagnostics. Jul, 2010  |  Pubmed ID: 20629511

Although numerous attempts have been made to forecast outcomes for prostate cancer after therapy using clinical and histological variables, the ability to accurately predict an individual's response to a specific treatment remains elusive. Recently, major advances in the field of genomics have made possible the near-comprehensive assessment of the genetic status of tumor genomes, with major concentration on predicting an individual's response to a specific treatment. Genomic approaches to treatment response include, but are not limited to, detection of gene rearrangements, DNA copy-number aberrations, single-nucleotide polymorphisms, epigenetic changes and differential gene-expression patterns. These approaches have been used to predict response to treatment for local and systemic disease in multiple small cohorts. Further study with larger cohorts and longer follow-up should result in more concordance among genomic approaches, and will enable physicians to gain insight into the heterogeneity of supposedly 'similar' cancers and help tailor treatments accordingly.

The Mechanism of Lymphatic Access of Two Cholesteryl Ester Transfer Protein Inhibitors (CP524,515 and CP532,623) and Evaluation of Their Impact on Lymph Lipoprotein Profiles

Pharmaceutical Research. Sep, 2010  |  Pubmed ID: 20635194

To explore the mechanism of lymphatic access of the CETP inhibitors (CETPi) CP524,515 and CP532,623 and probe their potential effect on lymph lipoprotein development.

Phytantriol and Glyceryl Monooleate Cubic Liquid Crystalline Phases As Sustained-release Oral Drug Delivery Systems for Poorly Water Soluble Drugs I. Phase Behaviour in Physiologically-relevant Media

The Journal of Pharmacy and Pharmacology. Jul, 2010  |  Pubmed ID: 20636872

The potential utility of liquid crystalline lipid-based formulations in oral drug delivery is expected to depend critically on their structure formation and stability in gastrointestinal fluids. The phase behaviour of lipid-based liquid crystals formed by phytantriol and glyceryl monooleate, known to form a bicontinuous cubic phase in excess water, was therefore assessed in physiologically-relevant simulated gastrointestinal media.

Phytantriol and Glyceryl Monooleate Cubic Liquid Crystalline Phases As Sustained-release Oral Drug Delivery Systems for Poorly Water-soluble Drugs II. In-vivo Evaluation

The Journal of Pharmacy and Pharmacology. Jul, 2010  |  Pubmed ID: 20636873

Lipid-based liquid crystals formed from phytantriol (PHY) and glyceryl monooleate (GMO) retain their cubic-phase structure on dilution in physiologically relevant simulated gastrointestinal media, suggesting their potential application as sustained-release drug-delivery systems for poorly water-soluble drugs. In this study the potential of PHY and GMO to serve as sustained-release lipid vehicles for a model poorly-water-soluble drug, cinnarizine, was assessed and compared to that of an aqueous suspension formulation.

When Goal Orientations Collide: Effects of Learning and Performance Orientation on Team Adaptability in Response to Workload Imbalance

The Journal of Applied Psychology. Sep, 2010  |  Pubmed ID: 20718514

The authors draw on resource allocation theory (Kanfer & Ackerman, 1989) to develop hypotheses regarding the conditions under which collective learning and performance orientation have interactive effects and the nature of those effects on teams' ability to adapt to a sudden and dramatic change in workload. Consistent with the theory, results of a laboratory study in which teams worked on a computerized, decision-making task over 3 performance trials revealed that learning and performance orientation had independent effects on team adaptability when teams had slack resources available for managing their changed task. Time helped explain the independent effects of performance orientation. Results also revealed that learning and performance orientation had interactive effects when teams did not have slack resources. Finally, the results of this study indicate that teams lacking slack resources were better able to balance high levels of learning and performance orientation over time with practice on the changed task.

Targeted Drug Delivery to Lymphocytes: a Route to Site-specific Immunomodulation?

Molecular Pharmaceutics. Dec, 2010  |  Pubmed ID: 20958081

Lymphocytes are central to the progression of autoimmune disease, transplant rejection, leukemia, lymphoma and lymphocyte-resident viral diseases such as HIV/AIDs. Strategies to target drug treatments to lymphocytes, therefore, represent an opportunity to enhance therapeutic outcomes in disease states where many current treatment regimes are incompletely effective and promote significant toxicities. Here we demonstrate that highly lipophilic drug candidates that preferentially access the intestinal lymphatics after oral administration show significantly enhanced access to lymphocytes leading to improved immunomodulatory activity. When coadministered with such drugs, lipids enhance lymphocyte targeting via a three tiered action: promotion of drug absorption from the gastrointestinal tract, enhancement of lymphatic drug transport and stimulation of lymphocyte recruitment into the lymphatics. This strategy has been exemplified using a highly lipophilic immunosuppressant (JWH015) where coadministration with selected lipids led to significant increases in lymphatic transport, lymphocyte targeting and IL-4 and IL-10 expression in CD4+ and CD8+ lymphocytes after ex vivo mitogen stimulation. In contrast, administration of a 2.5-fold higher dose of JWH015 in a formulation that did not stimulate lymph transport had no effect on antiinflammatory cytokine levels, in spite of equivalent drug exposure in the blood. The current data suggest that complementary drug design and delivery strategies that combine highly lipophilic, lymphotropic drug candidates with lymph-directing formulations provide enhanced selectivity, potency and therapeutic potential for drug candidates with lymphocyte associated targets.

Using Polymeric Precipitation Inhibitors to Improve the Absorption of Poorly Water-soluble Drugs: A Mechanistic Basis for Utility

Journal of Drug Targeting. Dec, 2010  |  Pubmed ID: 20973755

The inclusion of certain polymers within solid dispersion or lipid-based formulations can maintain drug supersaturation after dispersion and/or digestion of the vehicle, leading to improvements in bioavailability and variability in exposure. This review presents an overview of the fundamental principles that underpin drug precipitation mechanisms, describes the mechanisms by which precipitation may be inhibited, discusses the methods that can be used to identify polymeric precipitation inhibitors (PPIs), and summarizes current literature evidence of the most effective PPIs. Preliminary data from our laboratory is also presented, which describes the precipitation inhibition behavior of 53 polymeric materials using supersaturated solutions of danazol as a model, poorly water-soluble drug. These studies identify a group of PPIs with superior precipitation inhibition qualities, the majority of which are cellulose-based. These new results in combination with previous published data indicate that PPIs represent an appealing new technology with the potential to improve drug absorption for poorly water-soluble drugs. The molecular determinants of polymer utility, however, remain relatively poorly understood, although the cellulose derivates appear, in general, to provide the most benefit. More detailed studies are therefore required to define the parameters that most effectively predict and quantify the drug-polymer relationships that control precipitation inhibition.

Does a Perioperative Belladonna and Opium Suppository Improve Postoperative Pain Following Robotic Assisted Laparoscopic Radical Prostatectomy? Results of a Single Institution Randomized Study

The Canadian Journal of Urology. Oct, 2010  |  Pubmed ID: 20974030

Robotic assisted laparoscopic radical prostatectomy (RALP) is a common treatment for localized prostate cancer. Despite a primary advantage of improved postoperative pain, patients undergoing RALP still experience discomfort. Belladonna, containing the muscarinic receptor antagonists atropine and scopolamine, in combination with opium as a rectal suppository (B & O) may improve post-RALP pain. This study evaluates whether a single preoperative B & O results in decreased postoperative patient-reported pain and analgesic requirements.

Capping Methotrexate α-carboxyl Groups Enhances Systemic Exposure and Retains the Cytotoxicity of Drug Conjugated PEGylated Polylysine Dendrimers

Molecular Pharmaceutics. Apr, 2011  |  Pubmed ID: 21171585

A generation 5 PEGylated (PEG 1100) polylysine dendrimer, conjugated via a stable amide linker to OtBu protected methotrexate (MTX), was previously shown to have a circulatory half-life of 2 days and to target solid tumors in both rats and mice. Here, we show that deprotection of MTX and substitution of the stable linker with a matrix metalloproteinase (MMP) 2 and 9 cleavable linker (PVGLIG) dramatically increased plasma clearance and promoted deposition in the liver and spleen (50-80% of the dose recovered in the liver 3 days post dose). Similar rapid clearance was also seen using a scrambled peptide suggesting that clearance was not dependent on the cleavable nature of the linker. Surprisingly, dendrimers where OtBu capped MTX was linked to the dendrimer surface via the hexapeptide linker showed equivalent in vitro cytotoxicity against HT1080 cells when compared to the uncapped dendrimer and also retained the long circulating characteristics of the stable constructs. The OtBu capped MTX conjugated dendrimer was subsequently shown to significantly reduce tumor growth in HT1080 tumor bearing mice compared to control. In contrast the equivalent dendrimer comprising uncapped MTX conjugated to the dendrimer via the same hexapeptide linker did not reduce tumor growth, presumably reflecting very rapid clearance of the construct. The results are consistent with the suggestion that protection of the α-carboxyl group of methotrexate may be used to improve the circulatory half-life and reduce the liver accumulation of similar MTX-conjugated dendrimers, while still retaining antitumor activity in vivo.

Characterisation and Tumour Targeting of PEGylated Polylysine Dendrimers Bearing Doxorubicin Via a PH Labile Linker

Journal of Controlled Release : Official Journal of the Controlled Release Society. Jun, 2011  |  Pubmed ID: 21315119

Polylysine dendrimers have potential as biodegradable vectors for the delivery of cytotoxic drugs to solid tumours. Here, the cytotoxicity, drug release and tumour targeting properties of Generation 5 PEGylated polylysine dendrimers comprising an outer generation of l-lysine or succinimyldipropyldiamine (SPN) and containing doxorubicin (DOX) linked through an acid labile 4-(hydrazinosulfonyl) benzoic acid (HSBA) linker have been characterised. Less than 10% of the DOX load was released from LYS or SPN dendrimers in pH 7.4 buffer over 3 days. In contrast approximately 100% release was evident at pH 5. The DOX-conjugated dendrimers also retained similar cytotoxic properties to free DOX in in vitro cell culture studies (presumably as a result of in situ liberation of free DOX). The clearance patterns of the DOX conjugated SPN and all-lysine dendrimers were similar to the equivalent non-DOX conjugated systems, however the SPN dendrimers showed reduced metabolic lability and increased uptake into RES organs when compared to the equivalent all-lysine dendrimers. In vivo assessment of the DOX-conjugated, PEGylated polylysine dendrimers (both SPN and LYS constructs) in rats bearing Walker 256 tumours revealed higher uptake into tumour tissue when compared with control tissue such as muscle (~8 fold) and heart (~3 fold). The data suggest that polylysine dendrimers containing DOX conjugated via an acid labile HSBA linker may provide a mechanism to target the delivery of DOX to tumours.

Quantitative Ultrasound in Cancer Imaging

Seminars in Oncology. Feb, 2011  |  Pubmed ID: 21362522

Ultrasound is a relatively inexpensive, portable, and versatile imaging modality that has a broad range of clinical uses. It incorporates many imaging modes, such as conventional gray-scale "B-mode" imaging to display echo amplitude in a scanned plane; M-mode imaging to track motion at a given fixed location over time; duplex, color, and power Doppler imaging to display motion in a scanned plane; harmonic imaging to display nonlinear responses to incident ultrasound; elastographic imaging to display relative tissue stiffness; and contrast-agent imaging with simple contrast agents to display blood-filled spaces or with targeted agents to display specific agent-binding tissue types. These imaging modes have been well described in the scientific, engineering, and clinical literature. A less well-known ultrasonic imaging technology is based on quantitative ultrasound (QUS), which analyzes the distribution of power as a function of frequency in the original received echo signals from tissue and exploits the resulting spectral parameters to characterize and distinguish among tissues. This article discusses the attributes of QUS-based methods for imaging cancers and providing improved means of detecting and assessing tumors. The discussion will include applications to imaging primary prostate cancer and metastatic cancer in lymph nodes to illustrate the methods.

Nanostructured Liquid Crystalline Particles Provide Long Duration Sustained-release Effect for a Poorly Water Soluble Drug After Oral Administration

Journal of Controlled Release : Official Journal of the Controlled Release Society. Jul, 2011  |  Pubmed ID: 21497623

This study is the first to demonstrate the ability of nanostructured liquid crystal particles to sustain the absorption of a poorly water soluble drug after oral administration. Cubic (V(2)) liquid crystalline nanostructured particles (cubosomes) formed from phytantriol (PHY) were shown to sustain the absorption of cinnarizine (CZ) beyond 48h after oral administration to rats. Plasma concentrations were sustained within the range of 21.5±1.5ng/mL from 12 to 48h. In stark contrast, cubosomes prepared using glyceryl monooleate (GMO) did not sustain the absorption of CZ and drug concentrations fell below quantifiable levels after 24h. Sustained absorption of CZ from PHY cubosomes lead to a significant enhancement (p<0.05) in oral bioavailability (F%=21%) compared to a CZ suspension (9%) and oleic acid emulsion (12%). Analysis of the nanostructured particles in simulated gastric and intestinal fluids using small angle x-ray scattering (SAXS) revealed that the V(2)Pn3m nanostructure of PHY cubosomes was maintained for extended periods of time, in contrast to GMO cubosomes where the V(2)Im3m nanostructure was lost within 18h after exposure, suggesting that degradation of the LC nanostructure may limit sustained drug release. In addition, PHY cubosomes were shown to be extensively retained in the stomach (>24h) leading to the conclusion that in the case of non-digestible PHY cubosomes, the stomach may act as a non-sink reservoir that facilitates the slow release of poorly water soluble drugs, highlighting the potential use of non-digestible LC nanostructured particles as novel sustained oral drug delivery systems.

Fatty Acid Binding Proteins: Potential Chaperones of Cytosolic Drug Transport in the Enterocyte?

Pharmaceutical Research. Sep, 2011  |  Pubmed ID: 21523511

Several poorly water-soluble drugs have previously been shown to bind to intestinal (I-FABP) and liver fatty acid binding protein (L-FABP) in vitro. The purpose of this study was to examine the potential role of drug binding to FABPs on intestinal permeability and gut wall metabolism in vivo.

Acute Hypertriglyceridemia Promotes Intestinal Lymphatic Lipid and Drug Transport: a Positive Feedback Mechanism in Lipid and Drug Absorption

Molecular Pharmaceutics. Aug, 2011  |  Pubmed ID: 21604764

Elevated systemic levels of triglyceride-rich lipoproteins (TRL) are a risk factor for the development of atherosclerosis. In patients with metabolic syndrome (MetS), intestinal TRL overproduction contributes to high systemic TRL levels, and recent studies suggest that systemic changes in MetS such as increases in plasma fatty acids and insulin resistance stimulate intestinal TRL production. The current study has examined whether increases in systemic TRL influence intestinal lipid transport and lipoprotein assembly pathways and evaluates the impact of these changes on the absorption and lymphatic transport of lipids and a model lipophilic drug (halofantrine). Mesenteric lymph-duct or bile-duct cannulated rats were administered IV saline or (14)C-labeled chylomicron (CM) (to increase systemic TRL) and intraduodenal (3)H lipids and drug. Changes to biliary lipid output and lymphatic lipid and drug transport were subsequently examined. Increasing systemic TRL concentrations stimulated a significant increase in lymphatic lipid and drug transport. The increased lipids in lymph were not derived from bile or the intestinal blood supply (fatty acid or IV infused (14)C-CM). Rather, an increase in lymphatic transport of duodenally sourced lipids was evident. Increasing plasma levels of TRL therefore stimulated lipid absorption and lymphatic transport via a positive feedback process. The data also suggest that the changes to intestinal TRL formation that result from raised systemic TRL levels may impact on the absorption of highly lipophilic drugs and therefore the reproducibility of drug treatments.

Targeting the Lymphatics Using Dendritic Polymers (dendrimers)

Advanced Drug Delivery Reviews. Sep, 2011  |  Pubmed ID: 21683746

Dendrimers are unique biomaterials that are constructed by the stepwise addition of layers (generations) of polymer around a central core. They can be constructed with a range of molecular weights and have a polyfunctional surface that facilitates the attachment of drugs and pharmacokinetic modifiers such PEG or targeting moieties. These properties have led to considerable interest in the development of dendrimers for a range of biomedical applications. After subcutaneous administration, larger dendrimers in particular (> 8 nm), preferentially drain from the injection site into the peripheral lymphatic capillaries and therefore have potential as lymphatic imaging agents for magnetic resonance and optical fluorescence lymphangiography and as vectors for drug-targeting to lymphatic sites of disease progression. In general, lymphatic targeting of dendrimers is enhanced by increasing size although ultimately larger constructs may be incompletely absorbed from the injection site. Increasing hydrophilicity and reducing surface charge enhances drainage from subcutaneous injection sites, but the reverse is true of uptake into lymph nodes where charge and hydrophobicity promote retention. Larger hydrophilic dendrimers are also capable of extravasation from the systemic circulation, absorption into the lymphatic system and recirculation into the blood. Lymphatic recirculation may therefore be a characteristic of PEGylated dendrimers with long systemic circulation times.

Differences in Colloidal Structure of PEGylated Nanomaterials Dictate the Likelihood of Accelerated Blood Clearance

Journal of Pharmaceutical Sciences. Nov, 2011  |  Pubmed ID: 21721002

PEGylated liposomes are known to exhibit accelerated clearance from systemic circulation on repeat administration (the so-called "accelerated blood clearance" or ABC effect); however, little is known about this effect for other PEGylated colloidal drug delivery systems. Furthermore, our understanding of the mechanisms by which the ABC effect is induced is limited. This article further addresses these issues by examining the impact of colloid types [polyethylene glycol (PEG)-liposomes, PEG-micelles] of varying sizes on the appearance of the ABC effect when readministered 7 days after a "priming" dose. Intravenous injection of PEG-liposomes and putative PEG-micelles induced the production of anti-PEG immunoglobulin (Ig) M, although decreasing the average particle size led to reduced IgM titres. The ABC effect was observed for PEGylated phospholipid/cholesterol-based liposomes 7 days after an initial "priming" dose of liposome; however, addition of increasing levels of PEGylated lipid to form micelles reduced the propensity of observation of the ABC effect, correlating with the reduced IgM production. The results suggest that although PEG-micelles may stimulate limited production of anti-PEG IgM, which leads to accelerated clearance of subsequently administered PEG-liposomes, PEGylated micelles themselves are not substrates for IgM binding and do not exhibit a similar ABC.

Incidence of Second Malignancies After External Beam Radiotherapy for Clinical Stage I Testicular Seminoma

BJU International. Aug, 2011  |  Pubmed ID: 21883828

Study Type - Harm (case series) Level of Evidence 4 What's known on the subject? and What does the study add? We know that radiation therapy is associated with an increased risk of second malignancies in patients with testicular cancer. However, we know that radiation is being used very commonly in patients with clinical stage I seminoma, despite evidence that it is not required. Moreover, we have now identified which specific second malignancies occur in these patients after radiotherapy. OBJECTIVES: •  To determine the use of adjuvant external beam radiotherapy (EBRT) for patients with clinical stage I testicular seminoma in the USA. •  To quantify the risk of specific second primary malignancies (SPMs) associated with radiation exposure in these patients. PATIENTS AND METHODS: •  We used the Surveillance, Epidemiology and End Results database to identify patients diagnosed with clinical stage I testicular seminoma between 1973 and 2000. •  We evaluated the use of EBRT in these patients. •  We calculated standardized incidence ratios of specific SPMs in these patients. •  We stratified the incidence of SPMs based on age at seminoma diagnosis and time to SPM from initial seminoma diagnosis. RESULTS: •  Adjuvant EBRT use declined from the first decade of the study period to the last decade of the study period (80.6% vs 70.2%). •  Overall, there was a 19% increase in SPMs in patients exposed to EBRT (observed/expected, O/E, 1.51; 95% CI, 1.08-1.31) compared to the general population. •  Specifically, significantly increased risks were observed for thyroid cancer (O/E, 2.32; 95% CI, 1.16-4.16), pancreatic cancer (O/E, 2.38; 95% CI, 1.43-3.72), non-bladder urothelial malignancies (O/E, 4.27; 95% CI, 1.57-9.29), bladder cancer (O/E, 1.47; 95% CI, 1.01-2.28), all haematological malignancies (O/E, 1.44; 95% CI, 1.08-1.89) and non-Hodgkin's lymphoma (O/E, 1.77; 95% CI, 1.22-2.48). •  Patients had a persistently elevated risk of SPMs 15 years from the time of initial clinical stage I testicular seminoma diagnosis (O/E, 1.29; 95% CI, 1.10-1.49). CONCLUSIONS: •  We confirmed the increased risk of SPMs after EBRT for seminoma, and we identified the specific types of SPMs that develop. •  The risk of EBRT-associated SPM persists for years after the initial seminoma diagnosis, and patients should be informed about these long-term risks.

Ultrasound-guided Thoracic Facet Injections: Description of a Technique

Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine. Mar, 2011  |  Pubmed ID: 21357557

The purpose of this study was to describe a technique using ultrasound guidance to perform thoracic facet joint injections.

Dendrimer Pharmacokinetics: the Effect of Size, Structure and Surface Characteristics on ADME Properties

Nanomedicine (London, England). Aug, 2011  |  Pubmed ID: 21955077

Dendrimers show increasing promise as drug-delivery vectors and can be generated with a wide range of scaffold structures, sizes and surface functionalities. To this point, the majority of studies of dendrimer-based drug-delivery systems have detailed pharmacodynamic outcomes, or have followed the pharmacokinetics of a solubilized or conjugated drug. By contrast, detailed commentary on the in vivo fate of the dendrimer carrier is less evident, even though the pharmacokinetics of the carrier will likely dictate both pharmacodynamic and toxicokinetic outcomes. In the current article, the influence of size, structure and surface functionality on the absorption, distribution, metabolism and elimination (ADME) properties of dendrimers have been examined and the implications of these findings for delivery system design are discussed.

Correction to "targeted Drug Delivery to Lymphocytes: a Route to Site-specific Immunomodulation?"

Molecular Pharmaceutics. Dec, 2011  |  Pubmed ID: 21995681

The History and Anatomy of Urologic Lymphadenectomy

The Urologic Clinics of North America. Nov, 2011  |  Pubmed ID: 22045169

The history of urologic lymphadenectomy is rich and diverse. Our current understanding of its use and benefits is a product of the hard work of numerous physicians and scientists from many nations. Standard dissection templates for the various urologic malignancies are based on a complete understanding of the anatomy of the lymphatic system, which has developed immensely since Hippocrates first described the white blood of the lymphatic system while performing an axillary dissection. It is hoped that the next 100 years will bring even greater comprehension of its value and utility.

Racial/Ethnic Patterns in Prostate Cancer Outcomes in an Active Surveillance Cohort

Prostate Cancer. 2011  |  Pubmed ID: 22096650

Introduction. Concern regarding overtreatment of prostate cancer (CaP) is leading to increased attention on active surveillance (AS). This study examined CaP survivors on AS and compared secondary treatment patterns and overall survival by race/ethnicity. Methods. The study population consisted of CaP patients self-classified as black or white followed on AS in the Center for Prostate Disease Research (CPDR) multicenter national database between 1989 and 2008. Secondary treatment included radical prostatectomy (RP), external beam radiation therapy or brachytherapy (EBRT-Br), and hormone therapy (HT). Secondary treatment patterns and overall survival were compared by race/ethnicity. Results. Among 886 eligible patients, 21% were black. Despite racial differences in risk characteristics and secondary treatment patterns, overall survival was comparable across race. RP following AS was associated with the longest overall survival. Conclusion. Racial disparity in overall survival was not observed in this military health care beneficiary cohort with an equal access to health care.

Doxorubicin-Conjugated PEGylated Dendrimers Show Similar Tumoricidal Activity but Lower Systemic Toxicity When Compared to PEGylated Liposome and Solution Formulations in Mouse and Rat Tumor Models

Molecular Pharmaceutics. Jan, 2012  |  Pubmed ID: 22233281

PEGylated polylysine dendrimers show promise as novel drug delivery systems with the potential to direct site specific deposition patterns and to reduce toxicity at nontarget sites. Here the activity and toxicity profiles of a generation 5 polylysine dendrimer with 50% surface conjugation of PEG1100 and 50% surface conjugation of doxorubicin (via an acid labile 4-hydrazinosulfonyl benzoic acid linker) have been compared in a Walker 256 rat tumor model and a human MDA-MB231 xenograft in mice. A direct comparison was also made to a PEGylated liposomal formulation of doxorubicin and a doxorubicin solution. In both rat and mouse breast cancer models, the dendrimer formulation gave equivalent antitumor efficacy when compared to the liposomal or solution doxorubicin formulations and administration of all three doxorubicin formulations resulted in a significant reduction (>75%) in tumor growth in both models at doses ranging from 2 to 10 mg/kg doxorubicin equivalents. The dendrimer formulation, however, was better tolerated by both rats and mice, and approximately 2-fold higher doses were required to induce similar levels of toxicity (as assessed by organ weight, peripheral white cell counts, body weight and survival curves) when compared to administration of the doxorubicin solution or PEGylated liposomal doxorubicin. In rats the appearance of palmar plantar erythematosis (PPE), or hand foot syndrome, was also less evident after administration of dendrimer doxorubicin when compared to the liposome. Finally, even after administration to mice at 2-fold higher doses, dendrimer-doxorubicin resulted in a reduced incidence of cardiotoxicity when compared with a simple solution formulation of doxorubicin. The data suggest that dendrimer-based doxorubicin formulations may provide advantage over solution and liposomal formulations of doxorubicin via a reduction in systemic toxicity.

Association of Chemotherapeutic Drugs with Dendrimer Nanocarriers: An Assessment of the Merits of Covalent Conjugation Compared to Noncovalent Encapsulation

Molecular Pharmaceutics. Jan, 2012  |  Pubmed ID: 22250750

Cancer is a leading cause of death within developed nations, and part of this morbidity is due to difficulties associated with its treatment. Currently, anticancer therapy relies heavily upon the administration of small molecule cytotoxic drugs that attack both cancerous and noncancerous cells due to limited selectivity of the drugs and widespread distribution of the cytotoxic molecules throughout the body. The antitumor efficacy and systemic toxicity of existing chemotherapeutic drugs can, however, be improved by employing formulation and particle engineering approaches. Thus, drug delivery systems can be developed that more specifically target tumor tissue using both passive (such as the enhanced permeation and retention effect) and active (through the use of cancer targeting ligands) modalities. Dendrimers are one such system that can be developed with high structural monodispersity, long plasma circulation times and precise control over surface structure and biodistribution properties. Chemotherapeutic drugs can be associated with dendrimers via covalent conjugation to the surface, or via encapsulation of drugs within the structure. Each of these approaches has demonstrated therapeutic benefit relative to the administration of free drug. Thus far, however, there has not been a systematic review toward which drug association approach will provide the best outcomes in terms of antitumor efficacy and systemic toxicity. Hence, the current literature is reviewed here and recommendations are proposed as to the suggested approach to develop dendrimers as tumor targeted drug-delivery vectors.

The Long-term Outcomes After Radical Prostatectomy of Patients with Pathologic Gleason 8-10 Disease

Advances in Urology. 2012  |  Pubmed ID: 21941534

Background. We explored the long-term clinical outcomes including metastases-free survival and prostate cancer-specific survival (PCSS) in patients with pathologic Gleason 8-10 disease after radical prostatectomy (RP). Methods. We report on 91 patients with PCSS data with a median followup of 8.2 years after RP performed between 1988 and 1997. Cox regression and Kaplan-Meier analysis were used to evaluate year of surgery, pathologic stage, and surgical margin status as predictors of PCSM. Results. Median age was 65 years (IQR: 61-9), and median PSA was 9.7 ng/ml (IQR: 6.1-13.4). Of all patients, 62 (68.9%) had stage T3 disease or higher, and 48 (52.7%) had a positive surgical margin. On multivariate analysis, none of the predictors were statistically significant. Of all patients, the predicted 10-year BCR-free survival, mets-free survival, and PCSS were 59% (CI: 53%-65%), 88% (CI: 84%-92%), and 94% (CI: 91%-97%), respectively. Conclusions. We have demonstrated that cancer control is durable even 10 years after RP in those with pathologic Gleason 8-10 disease. Although 40% will succumb to BCR, only 6% of patients died of their disease. These results support the use of RP for patients with high-risk localized prostate cancer.

A Comparison of Changes to Doxorubicin Pharmacokinetics, Antitumor Activity, and Toxicity Mediated by PEGylated Dendrimer and PEGylated Liposome Drug Delivery Systems

Nanomedicine : Nanotechnology, Biology, and Medicine. Jan, 2012  |  Pubmed ID: 21704192

The pharmacokinetics, biodistribution, and antitumor efficacy of three doxorubicin formulations (doxorubicin in saline, conjugated to a polylysine dendrimer, and encapsulated within a stealth liposome) were investigated in Walker 256 tumor-bearing rats. Liposomal and dendrimer-based delivery systems resulted in more prolonged plasma exposure of total doxorubicin when compared to administration of doxorubicin in saline, although concentrations of free doxorubicin remained low in both cases. Biodistribution profiles revealed enhanced accumulation of dendrimer- and liposome-associated doxorubicin in tumors when compared to doxorubicin alone, although all three doxorubicin formulations reduced tumor growth to a similar extent. Markers of systemic toxicity (spleen weight, white blood cell counts, body weight, and cardiotoxicity) were more pronounced in rats that received doxorubicin and liposomal doxorubicin when compared to dendrimer-doxorubicin. The data provide preliminary evidence that dendrimer-doxorubicin displays similar antitumor efficacy to PEGylated liposomal doxorubicin, but with lower systemic toxicity (resulting from reduced drug exposure to nontarget organs). FROM THE CLINICAL EDITOR: In this manuscript, three different doxorubicin preparations are compared and preliminary evidence suggests that dendrimer-doxorubicin displays similar antitumor efficacy to PEGylated liposomal doxorubicin, but with lower systemic toxicity.

The Association Between Pre-operative PSA and Prostate Cancer-specific Mortality in Patients with Long-term Follow-up After Radical Prostatectomy

The Prostate. Jan, 2012  |  Pubmed ID: 21520159

The clinical and pathologic predictors of prostate cancer-specific mortality (PCSM) many years after radical prostatectomy (RP) remain to be fully elucidated. We explored the association between pre-operative prostate-specific antigen (PSA) and other pathologic predictors and PCSM in men who have undergone (RP).