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PubMed2004

A genome scan for quantitative trait loci and imprinted regions affecting reproduction in pigs.

Quantitative trait loci for reproductive traits in a three-generation resource population of a cross between low-indexing pigs from a control line and high-indexing pigs from a line selected 10 generations for increased index of ovulation rate and embryonic survival are reported. Phenotypic data were collected in F2 females for birth weight (BWT, n = 428), weaning weight (WWT, n = 405), age at puberty (AP, n = 295), ovulation rate (OR, n = 423), number of fully formed pigs (FF, n = 370), number of pigs born alive (NBA, n = 370), number of mummified pigs (MUM, n = 370), and number of stillborn pigs (NSB, n = 370). Grandparent, F1, and F2 animals were genotyped for 151 microsatellite markers. Sixteen putative QTL (P < 0.10) for reproductive traits were identified in previous analyses of these data with single QTL line-cross models. Data were reanalyzed with multiple QTL models, including imprinting effects. Data also were analyzed with half-sib models. Permutation was used to establish genome-wide significance levels ( = 0.01, 0.05, and 0.10). Thirty-one putative QTL for reproductive traits and two QTL for birth weight were identified (P < 0.10). One Mendelian QTL for FF (P < 0.05), one for NBA (P < 0.05), three for NSB (P < 0.05), three for NN (P < 0.05), seven for AP (P < 0.10), five for MUM (P < 0.10), and one for BWT (P < 0.10) were found. Partial imprinting of QTL affecting OR (P < 0.01), BWT (P < 0.05), and MUM (P < 0.05) was detected. There were four paternally expressed QTL for NN (P < 0.10) and one each for AP (P < 0.05) and MUM (P < 0.10). Maternally expressed QTL affecting NSB (P < 0.10), NN (P < 0.10), and MUM (P < 0.10) were detected. No QTL were detected with half-sib analyses. Multiple QTL models with imprinting effects are more appropriate for analyzing F2 data than single Mendelian QTL line-cross models.

Animals↗

PubMedDate not supplied

Prognostic variables associated with implant failure: a retrospective effectiveness study.

The purpose of this study was to determine implant survival rates by means of life table analyses for a cohort of patients not part of a prospective efficacy trial and treated by practitioners at varying experience levels. Prognostic variables associated with implant failure were identified by means of proportional hazards models and advanced statistical methods that account for patient effects. Ninety-nine consecutive patients treated from 1987 to 1991 with follow-up to 1994 were included in this retrospective study. A total of 384 dental implants (79.7% Brånemark, 19.3% IMZ plasma-sprayed, 1% IMZ hydroxyapatite-coated) were placed and subsequently supported 108 prostheses. Survival and proportional hazards modeling were used to generate Kaplan-Meier survival curves and to identify variables associated with implant failure. Survey data analysis was used to adjust for any patient effects for variables identified as significant through the proportional hazards models. Thirty-four implants failed over the follow-up period (median follow-up time 3.6 years), resulting in an overall failure rate of 8.9%. Seventeen of 99 patients experienced an implant failure. When prosthesis type was excluded from the modeling process, survey data analysis identified posterior location and an implant width of less than 4.0 mm as being associated with implant failure (all P < .05).

Adult↗

PubMed2003

Developmental typology of trajectories to nighttime bladder control: epidemiologic application of longitudinal latent class analysis.

The authors aimed to characterize developmental trajectories to nighttime continence by applying two latent class models-longitudinal latent class analysis (LLCA) and latent class growth analysis (LCGA)-to data on nighttime bed-wetting from a population-based birth cohort, the Medical Research Council 1946 National Survey of Health and Development cohort. Data on a binary outcome (wetting in the past month vs. not wetting) were available for children at six ages (4, 6, 8, 9, 11, and 15 years) assessed in 1950, 1952, 1954, 1955, 1957, and 1961. For 3,272 children with complete data (62.5% of the cohort), results of sequential model comparisons (T classes vs. T + 1 classes) and chi-square goodness-of-fit tests were evaluated using parametric bootstrapping. At least four trajectory classes (LLCA and LCGA) were identified. Associations between class membership and the prevalence of related measures were examined using a confirmatory latent class analysis approach. Inclusion of 1,483 children with partially incomplete data (n = 4,755; 90.9% of the cohort) enabled the authors to refine trajectories further: normal development (prevalence = 84.0%); delayed acquisition of bladder control ("transient" (8.7%) and "persistent" (1.8%)), capturing primary enuresis; chronic bed-wetting (2.6%), or experiencing night wetting until age 15 years; and a final trajectory (relapse = 2.9%) capturing secondary or onset enuresis. This empirically based, typologic approach to analysis of extensive longitudinal data in a general population sample provides an alternative perspective to that offered by traditional diagnostic criteria.

Adolescent↗

PubMed2003

Comparison of polymorphisms in the alpha7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects.

The hypothesis that the 15q13-15 region of chromosome 15 contains a gene that contributes to the etiology of schizophrenia is supported by multiple genetic linkage studies. The alpha7 neuronal nicotinic acetylcholine receptor (CHRNA7) gene was selected as the best candidate gene in this region for molecular investigation, based on these linkage findings and biological evidence in both human and rodent models. CHRNA7 receptors are decreased in expression in postmortem brain of schizophrenic subjects. A dinucleotide marker, D15S1360, in intron two of the CHRNA7 gene is genetically linked to an auditory gating deficit found in schizophrenics and half of the first-degree relatives of patients. Single strand conformation polymorphism (SSCP) and sequence analyses of DNA from schizophrenic and control individuals identified 33 variants in the coding region and intron/exon borders of the CHRNA7 gene and its partial duplication, dupCHRNA7; common polymorphisms were mapped. Twenty-one variants were found in the exons, but non-synonymous changes were rare. Although the expression of CHRNA7 is decreased in schizophrenia, the general structure of the remaining receptors is likely to be normal.

Base Sequence↗

PubMed1999

A novel labeling approach supports the five-transmembrane model of subunit a of the Escherichia coli ATP synthase.

Cysteine mutagenesis and surface labeling has been used to define more precisely the transmembrane spans of subunit a of the Escherichia coli ATP synthase. Regions of subunit a that are exposed to the periplasmic space have been identified by a new procedure, in which cells are incubated with polymyxin B nonapeptide (PMBN), an antibiotic derivative that partially permeabilizes the outer membrane of E. coli, along with a sulfhydryl reagent, 3-(N-maleimidylpropionyl) biocytin (MPB). This procedure permits reaction of sulfhydryl groups in the periplasmic space with MPB, but residues in the cytoplasm are not labeled. Using this procedure, residues 8, 27, 37, 127, 131, 230, 231, and 232 were labeled and so are thought to be exposed in the periplasm. Using inside-out membrane vesicles, residues near the end of transmembrane spans 1, 64, 67, 68, 69, and 70 and residues near the end of transmembrane spans 5, 260, 263, and 265 were labeled. Residues 62 and 257 were not labeled. None of these residues were labeled in PMBN-permeabilized cells. These results provide a more detailed view of the transmembrane spans of subunit a and also provide a simple and reliable technique for detection of periplasmic regions of inner membrane proteins in E. coli.

Amino Acid Sequence↗

PubMed2005

In vitro peripheral blood mononuclear cell proliferation in a crossbred cattle population.

Immune function measured by Staphylococcus aureus- and phytohemagglutinin- (PHA-) induced cell proliferation was assessed in a population of 445 genetically defined, F2 and backcross Charolais-Holstein crossbred cattle when the animals were approximately 5 mo of age. Variation in Staph. aureus-induced, PHA-induced, and control proliferation [peripheral blood mononuclear cell (PBMC) and media only] was observed at d 2, 3, 4, 5, 9, and 10 of in vitro culture. The levels of Staph. aureus-induced, PHA-induced, and control proliferation were strongly positively correlated between days of culture within-assay (e.g., between d 2 and d 3 or between d 4 and d 5). Responses were also positively correlated when the same individuals were resampled and the assay repeated within 3 mo. Analyses fitting linear mixed models using REML showed that Staph. aureus-induced and PHA-induced proliferation was significantly associated with control proliferation and the year of birth. The age of the animal at sampling influenced only Staph. aureus-induced proliferation, with Staph. aureus-induced proliferation increasing with the age of the animal. Control proliferation was influenced by a sex x cross interaction, although in this study, sex was confounded by management, as female cattle were housed and reared differently from male cattle. All 3 measures of immune function were influenced by sire, demonstrating that these traits are partially under genetic control, and indicating that it may ultimately be possible to identify quantitative trait loci for these measures of immunity.

Animals↗

PubMed2000

A neurobehavioral treatment for unilateral complex partial seizure disorders: a comparison of right- and left-hemisphere patients.

This study looked at the efficacy of a multi-disciplinary neurobehavioral approach for treating patients with complex partial seizure disorders. Patients with a seizure focus in either the left or right hemisphere were compared for overall effectiveness of this approach in achieving control of complex partial seizures. Patients in this study received short-term treatment based on a model of self-control developed by the Andrews/Reiter Epilepsy Research Program. This research selected all patients who met the lateralization criterion from among cases receiving short-term treatment between 1992 and 1996. Forty-four patients were identified, a group of 21 right-hemisphere subjects and a second group of 23 left-hemisphere subjects. These patients were treated in a short-term (5 consecutive days) treatment protocol and then released, with weekly phone contact for 6 months following treatment. They were then followed for an additional 19 months through the continued submission of their seizure logs and journals. Subjects in both groups kept seizure records throughout the study starting with a two-month baseline period. Other data collected allowed study of the interaction of emotional states with seizure occurrence. This project produced valuable and relevant information regarding neurobehavioral management interventions as an effective adjunctive or alternative treatment for obtaining seizure control in epilepsy patients. Overall, 79% of patients treated achieved seizure control. More than 64% identified a recognizable emotional state that triggered seizures. The emotional trigger was specific for either the right or left hemisphere.

Adult↗

PubMed2001

Probing the mechanism of insulin fibril formation with insulin mutants.

The molecular basis of insulin fibril formation was investigated by studying the structural properties and kinetics of fibril formation of 20 different human insulin mutants at both low pH (conditions favoring monomer/dimer) and at pH 7.4 (conditions favoring tetramer/hexamer). Small-angle X-ray scattering showed insulin to be monomeric in 20% acetic acid, 0.1 M NaCl, pH 2. The secondary structure of the mutants was assessed using far-UV circular dichroism, and the tertiary structure was determined using near-UV circular dichroism, quenching of intrinsic fluorescence by acrylamide and interactions with the hydrophobic probe 1-anilino-8-naphthalene-sulfonic acid (ANS). The kinetics of fibril formation were monitored with the fluorescent dye, Thioflavin T. The results indicate that the monomer is the state from which fibrils arise, thus under some conditions dissociation of hexamers may be rate limiting or partially rate limiting. The insulin mutants were found to retain substantial nativelike secondary and tertiary structure under all conditions studied. The results suggest that fibril formation of the insulin mutants is controlled by specific molecular interactions that are sensitive to variations in the primary structure. The observed effects of several mutations on the rate of fibril formation are inconsistent with a previously suggested model for fibrillation [Brange, J., Whittingham, J., Edwards, D., Youshang, Z., Wollmer, A., Brandenburg, D., Dodson, G., and Finch, J. (1997) Curr. Sci. 72, 470-476]. Two surfaces on the insulin monomer are identified as potential interacting sites in insulin fibrils, one consisting of the residues B10, B16, and B17 and the other consisting of at least the residues A8 and B25. The marked increase in the lag time for fibril formation with mutations to more polar residues, as well as mutations to charged residues, demonstrates the importance of both hydrophobic and electrostatic interactions in the initial stages of fibrillation. A model for insulin fibril formation is proposed in which the formation of a partially folded intermediate is the precursor for associated species on the pathway to fibril formation.

Amino Acid Sequence↗

PubMed1992

Field distributions in the rat tibia with and without a porous implant during electrical stimulation: a parametric modeling.

Expeditious post-operative ingrowth of bone is necessary for clinically successful fixation of porous joint prostheses. Electrical or electromagnetic fields to stimulate bone growth into porous implants have been used; however, they produced nonconvincing data. This was partially attributable to the lack of quantification of the localized electric fields produced in the pores of the implants. Therefore, this study set out: i) to quantify the local electric field values induced into the surface pores of nonconducting implants by "capacitive" coupling and to determine the magnitude of the macroscopically applied capacitively coupled electrical currents to induce specific electric field amplitudes in the pores, ii) to identify the important dielectric properties of the implant-tissue interface, and iii) to create the basis for successfully applying electrical fields in an animal model to stimulate bone ingrowth. A finite element method was used to calculate the electric field gradients and current densities present in a rat tibia modeled with a porous intramedullary implant when capacitively stimulated. Results indicated that while the current density in the pores are reduced in comparison to the region just outside the pore by about one order of magnitude, a significant current density still exists in the pore region. Furthermore, the presence of the implant increases the current densities in the trabecular bone while decreasing these values in the cortical bone. Replacing the trabecular bone in the pore by saline increases the current density in the pore by three-fold, but decreases the voltage gradient by a similar factor.

Animals↗

PubMed1984

Molecular mechanisms of recombination in Saccharomyces cerevisiae: testing mitotic and meiotic models by analysis of hypo-rec and hyper-rec mutations.

Recombination in the yeast Saccharomyces cerevisiae has been the subject of extensive genetic studies documenting the general properties of intragenic and intergenic recombination and the differences between mitotic and meiotic gene conversion and reciprocal exchange. Spontaneous mitotic and meiotic events differ in the time of onset of recombination relative to chromosomal replication, symmetry versus asymmetry of putative heteroduplex DNA regions, polarity of conversion of intragenic markers, and the lengths of DNA segments that undergo coincident conversion. The differences observed and the properties of yeast rec mutations provide evidence for multiple modes or pathways of mitotic and meiotic recombination. Several molecular models of recombination have been proposed to account for the basic parameters of genetic recombination and the differences between mitotic and meiotic recombination. Since the models differ with respect to the partial reactions comprising recombination they predict the isolation of different classes of hypo-recombination and hyper-recombination rec mutants. We have isolated a broad spectrum of yeast REC gene mutations that includes both hyper-rec and hypo-rec mutants. Five phenotypic classes of rec variants have been identified based upon their effects on spontaneous mitotic gene conversion and intergenic recombination. Their characteristics demonstrate that mitotic gene conversion and intergenic recombination are under independent as well as coordinate genetic control. Four gene mutations affecting recombination rad50, rad52, rem1 and spo11 have been extensively examined in several laboratories and illustrate the information that can be obtained by characterization of double mutant strains, detailed genotypic analysis of recombinants, and studies of meiotic recombination in cells in which the reductional division of meiosis has been bypassed by the spo13 mutation.

DNA↗

PubMed1994

Applications of physiologic pharmacokinetic modeling in carcinogenic risk assessment.

The use of physiologically based pharmacokinetic (PBPK) models has been proposed as a means of estimating the dose of the reactive metabolites of carcinogenic xenobiotics reaching target tissues, thereby affording an opportunity to base estimates of potential cancer risk on tissue dose rather than external levels of exposure. In this article, we demonstrate how a PBPK model can be constructed by specifying mass-balance equations for each physiological compartment included in the model. In general, this leads to a system of nonlinear partial differential equations with which to characterize the compartment system. These equations then can be solved numerically to determine the concentration of metabolites in each compartment as functions of time. In the special case of a linear pharmacokinetic system, we present simple closed-form expressions for the area under the concentration-time curves (AUC) in individual tissue compartments. A general relationship between the AUC in blood and other tissue compartments is also established. These results are of use in identifying those parameters in the models that characterize the integrated tissue dose, and which should therefore be the primary focus of sensitivity analyses. Applications of PBPK modeling for purposes of tissue dosimetry are reviewed, including models developed for methylene chloride, ethylene oxide, 1,4-dioxane, 1-nitropyrene, as well as polychlorinated biphenyls, dioxins, and furans. Special considerations in PBPK modeling related to aging, topical absorption, pregnancy, and mixed exposures are discussed. The linkage between pharmacokinetic models used for tissue dosimetry and pharmacodynamic models for neoplastic transformation of stem cells in the target tissue is explored.

Animals↗

PubMed1996

Non-T cell-derived IL-4 plays an important role in IgE production induced by antigen resensitization and is resistant to FK506.

The present study investigates the role of non-T cell-derived IL-4 in IgE production. It is well known that IL-4 is generally produced by T cells and induces IgE production. We have demonstrated that non-T cells also produce IL-4 in vivo by injection with Ag following passive sensitization of mice with IgE. In contrast to its known potent immunosuppressive effects on T cells, FK506 only partially inhibited IL-4 produced by non-T cells; therefore, FK506 was found to be a useful tool for identifying a cell source of IL-4 production. We used this observation to examine the role of non-T cell-derived IL-4 in IgE production. The production of a high titer of IgE was induced by priming BALB/c mice with Ascaris suum extract and further enhanced by secondary immunization. The IgE production in this model was dependent on IL-4, since both primary and secondary IgE production were completely suppressed by injection with anti-IL-4 Ab. Although primary IgE production was completely inhibited by FK506, secondary IgE production was not inhibited. Furthermore, IL-4 induction in plasma was only partially inhibited by FK506 when the A. suum extract-primed mice were resensitized with Ag. These results indicate that IL-4 produced by non-T cells plays a crucial role in secondary IgE production.

Animals↗

PubMed1991

Gum arabic glycoprotein is a twisted hairy rope : a new model based on o-galactosylhydroxyproline as the polysaccharide attachment site.

Separation of the wound exudate from Acacia senegal (L.) Willd., "gum arabic," on a preparative Superose-6 column gave two major fractions: a high molecular weight gum arabic glycoprotein (GAGP) containing about 90% carbohydrate and a lower molecular weight heterogenous gum arabic polysaccharide fraction. Hydrogen fluoride-deglycosylation of GAGP gave a large ( approximately 400 residue) hydroxyproline-rich polypeptide backbone (dGAGP). Alkaline hydrolysis of GAGP showed that most of the carbohydrate was attached to the polypeptide backbone as small ( approximately 30 residue) hydroxyproline (Hyp)-polysaccharide substituents. After partial acid hydrolysis of the Hyp-polysaccharide fraction we identified O-galactosylhydroxyproline as the glycopeptide linkage, identical with that of hydroxyproline-rich arabinogalactan-proteins (AGPs). However, unlike the acidic alanine-rich AGPs, GAGP is basic and notably deficient in alanine. Thus, while the GAGP polypeptide backbone more closely resembles that of the Hyp-rich cell wall protein extensin, the GAGP polysaccharide sidechains resemble AGPs. Possibly all three proteins comprise a phylogenetically related extensin superfamily of extended rod-like macromolecules. The "wattle-blossom" model for AGP and gum arabic predicts a few large polysaccharide substituents along the polypeptide backbone of a spheroidal macromolecule. On the contrary, our data imply a rodlike molecule with numerous small polysaccharide substituents (attached to 24% of the Hyp residues), regularly arranged along a highly periodic polypeptide backbone based, hypothetically, on a 10 to 12 residue repetitive peptide motif. Thus, a simple statistical model of the gum arabic glycoprotein predicts a repeating polysaccharide-peptide subunit of about 7 kilodaltons. The small polysaccharide substituents will maximize intramolecular hydrogen bonding if aligned along the long axis of the molecule, forming in effect a twisted hairy rope. Electron micrographs of rotary shadowed GAGP molecules support that prediction and may also explain how such apparently large molecules can exit the cell by endwise reptation through the small pores of the primary cell wall.

Journal Article↗

PubMed1999

Dramatic inhibition of retinal and choroidal neovascularization by oral administration of a kinase inhibitor.

The most common cause of new blindness in young patients is retinal neovascularization, and in the elderly is choroidal neovascularization. Therefore, there has been a great deal of attention focused on the development of new treatments for these disease processes. Previous studies have demonstrated partial inhibition of retinal neovascularization in animal models using antagonists of vascular endothelial growth factor or other signaling molecules implicated in the angiogenesis cascade. These studies have indicated potential for drug treatment, but have left many questions unanswered. Is it possible to completely inhibit retinal neovascularization using drug treatment with a mode of administration that is feasible to use in patients? Do agents that inhibit retinal neovascularization have any effect on choroidal neovascularization? In this study, we demonstrate complete inhibition of retinal neovascularization in mice with oxygen-induced ischemic retinopathy by oral administration of a partially selective kinase inhibitor that blocks several members of the protein kinase C family, along with vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases. The drug also blocks normal vascularization of the retina during development but has no identifiable adverse effects on mature retinal vessels. In addition, the kinase inhibitor causes dramatic inhibition of choroidal neovascularization in a laser-induced murine model. These data provide proof of concept that pharmacological treatment is a viable approach for therapy of both retinal and choroidal neovascularization.

Administration, Oral↗

PubMed2004

Efficient prediction of alternative splice forms using protein domain homology.

Alternative splicing can yield manifold different mature mRNAs from one precursor. New findings indicate that alternative splicing occurs much more often than previously assumed. A major goal of functional genomics lies in elucidating and characterizing the entire spectrum of alternative splice forms. Existing approaches such as EST-alignments focus only on the mRNA sequence to detect alternative splice forms. They do not consider function and characteristics of the resulting proteins. One important example of such functional characterization is homology to a known protein domain family. A powerful description of protein domains are profile Hidden Markov models (HMM) as stored in the Pfam database. In this paper we address the problem of identifying the splice form with the highest similarity to a protein domain family. Therefore, we take into consideration all possible splice forms. As demonstrated here for a number of genes, this homology based approach can be used successfully for predicting partial gene structures. Furthermore, we present some novel splice form predictions with high-scoring protein domain homology and point out that the detection of splice form specific protein domains helps to answer questions concerning hereditary diseases. Simple approaches based on a BLASTP search cannot be applied here, since the number of possible splice forms increases exponentially with the number of exons. To this end, we have developed an efficient polynomial-time algorithm, called ASFPred (Alternative Splice Form Prediction). This algorithm needs only a set of exons as input.

Algorithms↗

PubMed2004

The mortality index for neonatal transportation score: a new mortality prediction model for retrieved neonates.

OBJECTIVE: To develop a mortality prediction score for retrieved neonates based on the information given at the first telephone contact with a retrieval service. METHODS: Data from the New South Wales Newborn and Pediatric Emergency Transport Service database were examined. Analysis was performed with the results for 2504 infants (median gestational age: 36 weeks; range: 24-43 weeks) who were <72 hours of age at the time of referral and whose outcome (neonatal death or survival) was known. The study population was divided randomly into 2 halves, the derivation and validation cohorts. Univariate analysis was performed to identify variables in the derivation cohort related to neonatal death. The variables were entered into a multivariate logistic regression analysis with neonatal death as the outcome. Receiver operator characteristic (ROC) curves were constructed with the regression model and data from the derivation cohort and then the validation cohort. The results were used to generate an integer-based score, the Mortality Index for Neonatal Transportation (MINT) score. ROC curves were constructed to assess the ability of the MINT score to predict perinatal and neonatal death. RESULTS: A 7-variable (Apgar score at 1 minute, birth weight, presence of a congenital anomaly, and infant's age, pH, arterial partial pressure of oxygen, and heart rate at the time of the call) model was constructed that generated areas under ROC curves of 0.82 and 0.83 for the derivation and validation cohorts, respectively. The 7 variables were then used to generate the MINT score, which gave areas under ROC curves of 0.80 for both neonatal and perinatal death. CONCLUSION: Data collected at the first telephone contact by the referring hospital with a regionalized transport service can identify neonates at the greatest risk of dying.

Analysis of Variance↗

PubMed1994

Hypoglycemia caused by selegiline, an antiparkinsonian drug: can such side effects be predicted?

Treatment with selegiline produced profound hypoglycemia in a 70-year-old man with Parkinson's disease. The hypoglycemia was accompanied by hyperinsulinemia and persisted for 1 week after selegiline was discontinued. Although this side effect of antidepressant monoamine oxidase inhibitors was well documented in 1959-1968 publications, it was not known to the manufacturer of selegiline. Effects of drugs on glucose metabolism may be predictable through a novel molecular modeling technique developed in our laboratories, which shows that glucose exhibits stereochemical complementarity to a specific site in partially unwound DNA. Selegiline and other molecules affecting glucose metabolism fit into the same DNA base sequence. It therefore should be possible to employ this technique to identify pharmaceutical agents that possess hypoglycemic or hyperglycemic effects in vivo.

Aged↗

PubMed2004

Polymer-drug compatibility: a guide to the development of delivery systems for the anticancer agent, ellipticine.

To establish a method for predicting polymer-drug compatibility as a means to guide formulation development, we carried out physicochemical analyses of polymer-drug pairs and compared the difference in total and partial solubility parameters of polymer and drug. For these studies, we employed a range of biodegradable polymers and the anticancer agent Ellipticine as the model drug. The partial and total solubility parameters for the polymer and drug were calculated using the group contribution method. Drug-polymer pairs with different enthalpy of mixing values were analyzed by physicochemical techniques including X-ray diffraction and Fourier transform infrared. Polymers identified to be compatible [i.e., polycaprolactone (PCL) and poly-beta-benzyl-L-aspartate (PBLA)] and incompatible [i.e., poly (d,l-lactide (PLA)], by the above mentioned methods, were used to formulate Ellipticine. Specifically, Ellipticine was loaded into PBLA, PCL, and PLA films using a solvent casting method to produce a local drug formulation; while, polyethylene oxide (PEO)-b-polycaprolactone (PCL) and PEO-b-poly (d,l-lactide) (PLA) copolymer micelles were prepared by both dialysis and dry down methods resulting in a formulation for systemic administration. The drug release profiles for all formulations and the drug loading efficiency for the micelle formulations were also measured. In this way, we compared formulation characteristics with predictions from physicochemical analyses and comparison of total and partial solubility parameters. Overall, a good correlation was obtained between drug formulation characteristics and findings from our polymer-drug compatibility studies. Further optimization of the PEO-b-PCL micelle formulation for Ellipticine was also performed.

Antineoplastic Agents↗