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1.  Glial–Neuronal Interactions—Implications for Plasticity and Drug Addiction 
The AAPS Journal  2009;11(1):123-132.
Among neuroscientists, astrocytes have for long played Cinderella to their neuron stepsisters. While the importance of glia in regulating brain activity was predicted by Ramon y Cajal more than a century ago (Garcia-Marin et al., Trends. Neurosci. 30:479–787, 2007), these cells, until recently, have been thought to play mainly a passive part in synaptic signaling. Results obtained over the last decade have begun to suggest otherwise. Experiments carried out in a number of labs have shown that glial cells, especially astrocytes, directly participate in synaptic signaling and potentially regulate synaptic plasticity and network excitability. The presence of signaling pathways on astrocytes that are analogous to those at presynaptic terminals suggests a role for these cells in network plasticity. Findings that the same signaling pathways can be activated by receptors for drugs of abuse present on astrocytes suggest a role for these cells in the addictive process. In this review, we summarize current understanding of astrocytic role in synaptic signaling and suggest that a complete understanding of the process of addiction requires a better understanding of the functional role of these cells.
doi:10.1208/s12248-009-9085-4
PMCID: PMC2664886  PMID: 19238557
astrocyte; calcium; gliotransmission; nicotinic; synapse; tripartite synapse
2.  Glial–Neuronal Interactions—Implications for Plasticity and Drug Addiction 
The AAPS journal  2009;11(1):123-132.
Among neuroscientists, astrocytes have for long played Cinderella to their neuron stepsisters. While the importance of glia in regulating brain activity was predicted by Ramon y Cajal more than a century ago (Garcia-Marin et al., Trends. Neurosci. 30:479–787, 2007), these cells, until recently, have been thought to play mainly a passive part in synaptic signaling. Results obtained over the last decade have begun to suggest otherwise. Experiments carried out in a number of labs have shown that glial cells, especially astrocytes, directly participate in synaptic signaling and potentially regulate synaptic plasticity and network excitability. The presence of signaling pathways on astrocytes that are analogous to those at presynaptic terminals suggests a role for these cells in network plasticity. Findings that the same signaling pathways can be activated by receptors for drugs of abuse present on astrocytes suggest a role for these cells in the addictive process. In this review, we summarize current understanding of astrocytic role in synaptic signaling and suggest that a complete understanding of the process of addiction requires a better understanding of the functional role of these cells.
doi:10.1208/s12248-009-9085-4
PMCID: PMC2664886  PMID: 19238557
astrocyte; calcium; gliotransmission; nicotinic; synapse; tripartite synapse
4.  Prevalence and Isotypic Complexity of the Anti-Chinese Hamster Ovary Host Cell Protein Antibodies in Normal Human Serum 
The AAPS Journal  2009;12(1):98-106.
Host cell-derived protein impurities may be present at low levels in biopharmaceutical products. Antibodies to host cell proteins are present in individuals with no known exposure to these products. In this study, antibodies to drug process-specific Chinese hamster ovary host cell-derived proteins (CHO-HCP) were measured in unexposed individuals using a validated enzyme-linked immunosorbent assay. Samples that tested positive for anti-CHO-HCP reactivity were further characterized to determine the isotypes and IgG subclasses expressed in each positive individual. The specificity of the detected anti-CHO-HCP antibody isotypes was confirmed by the competitive inhibition assay and the uncoated plate specificity testing. These antibody characterization experiments revealed that the prevalent anti-CHO-HCP antibody subclasses were predominantly IgG1 (present in 66.6% of individuals) and IgG2 (60%), with 33.3% positive for IgG3 while IgG4 was detected in low abundance. Forty percent (40%) of the individuals with IgG type reactivity were also identified as IgM-positive. Anti-CHO-HCP-specific IgE was not detected in the assays used in this study. Some individuals exhibited single isotype anti-CHO-HCP reactivity; others contained a combination of multiple antibody isotypes. Data presented in this study demonstrate the isotypic complexity and the high prevalence of anti-CHO-HCP antibodies in human serum with no known exposure to CHO cell-derived therapeutic biologics.
doi:10.1208/s12248-009-9165-5
PMCID: PMC2811637  PMID: 20013082
antibody isotypes; Chinese hamster ovary cells; host cell protein; immunogenicity response characterization; specificity
5.  Molecular Targets of Dietary Phenethyl Isothiocyanate and Sulforaphane for Cancer Chemoprevention 
The AAPS Journal  2009;12(1):87-97.
Development of cancer is a long-term and multistep process which comprises initiation, progression, and promotion stages of carcinogenesis. Conceivably, it can be targeted and interrupted along these different stages. In this context, many naturally occurring dietary compounds from our daily consumption of fruits and vegetables have been shown to possess cancer preventive effects. Phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) are two of the most widely investigated isothiocyanates from the crucifers. Both have been found to be very potent chemopreventive agents in numerous animal carcinogenesis models as well as cell culture models. They exert their chemopreventive effects through regulation of diverse molecular mechanisms. In this review, we will discuss the molecular targets of PEITC and SFN potentially involved in cancer chemoprevention. These include the regulation of drug-metabolizing enzymes phase I cytochrome P450s and phase II metabolizing enzymes. In addition, the signaling pathways including Nrf2–Keap 1, anti-inflammatory NFκB, apoptosis, and cell cycle arrest as well as some receptors will also be discussed. Furthermore, we will also discuss the similarities and their potential differences in the regulation of these molecular targets by PEITC and SFN.
doi:10.1208/s12248-009-9162-8
PMCID: PMC2811646  PMID: 20013083
dietary cancer chemoprevention; NF-kB; Nrf2; phenethyl isothiocyanate; sulforaphane
6.  Comparing Exponentially Weighted Moving Average and Run Rules in Process Control of Semiquantitative Immunogenicity Immunoassays 
The AAPS Journal  2009;12(1):79-86.
The immunogenicity immunoassay validation process ensures development of a robust, reproducible method. However, no matter how well developed, validated, and maintained a method is, in the course of running a large number of samples over time, it is not uncommon to see bad reagents, poorly calibrated equipment, personnel errors, or other unknown and unpredictable factors that have an impact in the performance of the method and quality of the sample results. The immunogenicity immunoassay thus needs to be closely monitored with an internal statistical quality control process overtime to ensure a consistent and reliable output. The statistical process control has been widely applied to monitor manufacturing processes and in clinical laboratories. Its application to immunogenicity immunoassays is relatively novel. Limited guidance is available to implement the process to monitor semiquantitative immunogenicity immunoassay performance. Here, we have performed a suitability evaluation for process control charts with actual laboratory data from three immunogenicity immunoassay methods each utilizing a different technology platform. Additionally, a panel of prepared samples designed to assess long-term method performance were periodically evaluated for over a year. Finally, we make recommendations for an internal quality control process based on the results of these evaluations.
doi:10.1208/s12248-009-9166-4
PMCID: PMC2811647  PMID: 20012239
control chart; EWMA; immunoassay; OOT
7.  How Minimally Invasive is Microdialysis Sampling? A Cautionary Note for Cytokine Collection in Human Skin and other Clinical Studies 
The AAPS Journal  2009;12(1):73-78.
It is common to refer to microdialysis as a minimally invasive procedure, likening it to insertion of an artificial capillary. While a comparison of this type allows the process to be easily visualized by those outside the field, it tends to provide a false impression of the localized perturbation of the tissue space that is caused by catheter insertion. With the increased acceptance of microdialysis sampling as a viable in vivo sampling method, many researchers have begun to use the technique to explore inflammatory and immune-mediated diseases in the skin and other organs. Unfortunately, many of the molecules of interest, particularly chemokines and cytokines, are known to be generated during the inflammatory response to wounding and the subsequent cellular events leading to wound repair. With more than 11,000 reports citing the use of microdialysis sampling, only a few researchers have sought to assess the tissue damage that is incurred by probe insertion. For this reason, caution is warranted when collecting these molecules and inferring a role for them in clinical disease states. This commentary seeks to remind the research community of the confounding effects that signaling molecules related to the wounding response will have on clinical studies. Proper controls must be incorporated into all studies in order to assess whether or not particular molecules are truly related to the disease state under investigation or have been generated as part of the tissue response to the wound incurred by microdialysis catheter implantation.
doi:10.1208/s12248-009-9163-7
PMCID: PMC2811639  PMID: 19950008
biocompatability; cytokines; microdialysis; wound healing and repair
8.  Small Molecule Modifiers of the microRNA and RNA Interference Pathway 
The AAPS Journal  2009;12(1):51-60.
Recently, the RNA interference (RNAi) pathway has become the target of small molecule inhibitors and activators. RNAi has been well established as a research tool in the sequence-specific silencing of genes in eukaryotic cells and organisms by using exogenous, small, double-stranded RNA molecules of approximately 20 nucleotides. Moreover, a recently discovered post-transcriptional gene regulatory mechanism employs microRNAs (miRNAs), a class of endogenously expressed small RNA molecules, which are processed via the RNAi pathway. The chemical modulation of RNAi has important therapeutic relevance, because a wide range of miRNAs has been linked to a variety of human diseases, especially cancer. Thus, the activation of tumor-suppressive miRNAs and the inhibition of oncogenic miRNAs by small molecules have the potential to provide a fundamentally new approach for the development of cancer therapeutics.
doi:10.1208/s12248-009-9159-3
PMCID: PMC2811638  PMID: 19937410
cancer; microRNA; RNA; RNA interference; small molecule
9.  Compartmental Analysis and its Manifold Applications to Pharmacokinetics 
The AAPS Journal  2009;12(1):61-72.
In this paper, I show how the concept of compartment evolved from the simple dilution of a substance in a physiological volume to its distribution in a network of interconnected spaces. The differential equations describing the fate of a substance in a living being can be solved, qualitatively and quantitatively, with the help of a number of mathematical techniques. A number of parameters of pharmacokinetic interest can be computed from the experimental data; often, the data available are not sufficient to determine some parameters, but it is possible to determine their range.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-009-9160-x) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-009-9160-x
PMCID: PMC2811643  PMID: 19937409
exit time; flow graphs; permanence time; residence time; tracer kinetics; transfer function; turnover time
10.  A History of Biopharmaceutics in the Food and Drug Administration 1968–1993 
The AAPS Journal  2009;12(1):44-50.
The history of biopharmaceutics is reviewed, beginning with its origin out of the Division of Clinical Research in The Bureau of Medicine. The reason for the creation of the Division of Biopharmaceutics, the certification of Food and Drug Administration authority over the functions it was to have, and the implementation of that authority are described. The determination of bioequivalence, the bioavailability decision rules, pharmacokinetics, and drug metabolism are explained. The reason for the development of the Scale-Up and Post Approval Regulations and how they were developed are also explained.
doi:10.1208/s12248-009-9154-8
PMCID: PMC2811644  PMID: 19936940
bioavailability; bioequivalence; biopharmaceutics; FDA; pharmacokinetics; SUPAC
11.  Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease 
The AAPS Journal  2009;12(1):33-43.
The monoclonal antibody market continues to witness an impressive rate of growth and has become the leading source of expansion in the biologic segment within the pharmaceutical industry. Currently marketed monoclonal antibodies target a diverse array of antigens. These antigens are distributed in a variety of tissues such as tumors, lungs, synovial fluid, psoriatic plaques, and lymph nodes. As the concentration of drug at the proximity of the biological receptor determines the magnitude of the observed pharmacological responses, a significant consideration in effective therapeutic application of monoclonal antibodies is a thorough understanding of the processes that regulate antibody biodistribution. Monoclonal antibody distribution is affected by factors such as molecular weight, blood flow, tissue and tumor heterogeneity, structure and porosity, target antigen density, turnover rate, and the target antigen expression profile.
doi:10.1208/s12248-009-9157-5
PMCID: PMC2811642  PMID: 19924542
biodistribution; monoclonal antibodies; pharmacokinetics and pharmacodynamics; tumor penetration
13.  Points to Consider when Establishing Drug Product Specifications for Parenteral Microspheres 
The AAPS Journal  2009;12(1):27-32.
Drug product specifications are a critical element of a good control strategy. Parenteral microsphere products are complex dosage forms, requiring careful development of test methods and acceptance criteria for the specifications. In particular, the in vitro release test method and acceptance criteria require rigorous scientific consideration and should be developed with an eye toward understanding the mechanisms of drug release. The final specifications need to ensure the safety, identity, strength, performance, and quality of the drug product at release and during storage through the end of its shelf-life. The specification limits are typically established based upon regulatory guidance, available data from the manufacturing process (process capability), from non-clinical, clinical, and stability studies.
doi:10.1208/s12248-009-9156-6
PMCID: PMC2811640  PMID: 19921439
control strategy; in vitro mechanism of release; microsphere drug product attribute; microsphere specification; parenteral microspheres
14.  Autoradiography, MALDI-MS, and SIMS-MS Imaging in Pharmaceutical Discovery and Development 
The AAPS Journal  2009;12(1):11-26.
Whole-body autoradiography ((WBA) or quantitative WBA (QWBA)), microautoradiography (MARG), matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI), and secondary ion mass spectrometric imaging (SIMS-MSI) are high-resolution, molecular imaging techniques used to study the tissue distribution of radiolabeled and nonlabeled compounds in ex vivo, in situ biological samples. WBA, which is the imaging of the whole-body of lab animals, and/or their organ systems; and MARG, which provides information on the localization of radioactivity in histological preparations and at the cellular level, are used to support drug discovery and development efforts. These studies enable the conduct of human radiolabeled metabolite studies and have provided pharmaceutical scientists with a high resolution and quantitative method of accessing tissue distribution. MALDI-MSI is a mass spectrometric imaging technique capable of label-free and simultaneous determination of the identity and distribution of xenobiotics and their metabolites as well as endogenous substances in biological samples. This makes it an interesting extension to WBA and MARG, eliminating the need for radiochemistry and providing molecular specific information. SIMS-MSI offers a complementary method to MALDI-MSI for the acquisition of images with higher spatial resolution directly from biological specimens. Although traditionally used for the analysis of surface films and polymers, SIMS has been used successfully for the study of biological tissues and cell types, thus enabling the acquisition of images at submicrometer resolution with a minimum of samples preparation.
doi:10.1208/s12248-009-9158-4
PMCID: PMC2811645  PMID: 19921438
MALDI-MSI; microautoradiography; SIMS-MSI; whole-body autoradiography
15.  Solid Lipid Budesonide Microparticles for Controlled Release Inhalation Therapy 
The AAPS Journal  2009;11(4):771-778.
A solid lipid microparticle system containing budesonide was prepared by oil in water emulsification followed by spray drying. The solid lipid system was studied in terms of morphology, particle size distribution, crystallinity, thermal properties, aerosol performance, and dissolution/diffusion release. The microparticle system was also compared to conventional spray-dried crystalline and amorphous budesonide samples. The particle size distributions of the crystalline, amorphous, and solid lipid microparticles, measured by laser diffraction, were similar; however, the microparticle morphology was more irregular than the spray-dried drug samples. The thermal response of the solid lipid microparticles suggested polymorphic transition and melting of the lipid, glycerol behenate (at ~48°C and ~72°C). No budesonide melting or crystallisation peaks were observed, suggesting that the budesonide was integrated into the matrix. X-ray powder diffraction patterns of the crystalline and amorphous budesonide were consistent with previous studies while the solid lipid microparticles showed two peaks, at approximately 21.3 and 23.5 2θ suggesting the metastable sub-α and primarily β′ form. Analysis of the in vitro diffusion/dissolution of the formulations was studied using a flow through model and curves analysed using difference/similarity factors and fitted using the Higuchi model. Regression analysis of this data set indicated differences in the t0.5, where values of 49.7, 35.3, and 136.9 min were observed for crystalline, amorphous, and the solid lipid microparticles, respectively. The aerosol performance (<5 μm), measured by multistage liquid impinger, was 29.5%, 27.3%, and 21.1 ± 0.6% for the crystalline, amorphous, and the solid lipid microparticles, respectively. This study has shown that solid lipid microparticles may provide a useful approach to controlled release respiratory therapy.
doi:10.1208/s12248-009-9148-6
PMCID: PMC2782082  PMID: 19908147
controlled release; dry powder inhalation; solid lipid microparticles
16.  Comparison of Two Pharmacodynamic Transduction Models for the Analysis of Tumor Therapeutic Responses in Model Systems 
The AAPS Journal  2009;12(1):1-10.
Semi-mechanistic pharmacodynamic (PD) models that capture tumor responses to anticancer agents with fidelity can provide valuable insights that could aid in the optimization of dosing regimens and the development of drug delivery strategies. This study evaluated the utility and potential interchangeability of two transduction-type PD models: a cell distribution model (CDM) and a signal distribution model (SDM). The evaluation was performed by simulating dense and sparse tumor response data with one model and analyzing it using the other. Performance was scored by visual inspection and precision of parameter estimation. Capture of tumor response data was also evaluated for a liposomal formulation of paclitaxel in the paclitaxel-resistant murine Colon-26 model. A suitable PK model was developed by simultaneous fitting of literature data for paclitaxel formulations in mice. Analysis of the simulated tumor response data revealed that the SDM was more flexible in describing delayed drug effects upon tumor volume progression. Dense and sparse data simulated using the CDM were fit very well by the SDM, but under some conditions, data simulated using the SDM were fitted poorly by the CDM. Although both models described the dose-dependent therapeutic responses of Colon-26 tumors, the fit by the SDM contained less bias. The CDM and SDM are both useful transduction models that recapitulate, with fidelity, delayed drug effects upon tumor growth. However, they are mechanistically distinct and not interchangeable. Both fit some types of tumor growth data well, but the SDM appeared more robust, particularly where experimental data are sparse.
doi:10.1208/s12248-009-9155-7
PMCID: PMC2811636  PMID: 19902363
cancer; drug delivery; paclitaxel; pharmacodynamics; pharmacokinetics; transduction models
17.  Critical Factors Influencing the In Vivo Performance of Long-acting Lipophilic Solutions—Impact on In Vitro Release Method Design 
The AAPS Journal  2009;11(4):762-770.
Parenteral long-acting lipophilic solutions have been used for decades and might in the future be used in the design of depots with tailored delivery characteristics. The present review highlights major factors influencing the in vivo performance of lipophilic solutions. Furthermore, an account is given of the characteristics of employed in vitro release methods with a focus on the “state” of sink condition, the stirring conditions, and the oil–water interfacial area. Finally, the capability of in vitro release data to predict the in vivo performance of drug substances administrated in the form of lipophilic solutions is discussed. It is suggested that as long as the major rate-limiting in vivo release mechanism is governed by the drug partitioning between the oil vehicle and the tissue fluid, the use of in vitro release testing in quality control appears to be realistic. With increasing lipophilicity of the drug substances and longer duration of action, the in vivo drug release process may become more complex. As discussed, practical analytical problems together with the inability of release methods to mimic two or more concomitant in vivo events may constitute severe impediments for establishment of in vitro in vivo correlations.
doi:10.1208/s12248-009-9153-9
PMCID: PMC2782087  PMID: 19894123
depot effect; lipophilic solutions; in vitro in vivo correlations; in vitro release methods; parenteral administration
18.  Prediction of Solubility and Permeability Class Membership: Provisional BCS Classification of the World’s Top Oral Drugs 
The AAPS Journal  2009;11(4):740-746.
The Biopharmaceutics Classification System (BCS) categorizes drugs into one of four biopharmaceutical classes according to their water solubility and membrane permeability characteristics and broadly allows the prediction of the rate-limiting step in the intestinal absorption process following oral administration. Since its introduction in 1995, the BCS has generated remarkable impact on the global pharmaceutical sciences arena, in drug discovery, development, and regulation, and extensive validation/discussion/extension of the BCS is continuously published in the literature. The BCS has been effectively implanted by drug regulatory agencies around the world in setting bioavailability/bioequivalence standards for immediate-release (IR) oral drug product approval. In this review, we describe the BCS scientific framework and impact on regulatory practice of oral drug products and review the provisional BCS classification of the top drugs on the global market. The Biopharmaceutical Drug Disposition Classification System and its association with the BCS are discussed as well. One notable finding of the provisional BCS classification is that the clinical performance of the majority of approved IR oral drug products essential for human health can be assured with an in vitro dissolution test, rather than empirical in vivo human studies.
doi:10.1208/s12248-009-9144-x
PMCID: PMC2782078  PMID: 19876745
BA/BE; biopharmaceutics classification system; biowaiver; intestinal absorption; molecular biopharmaceutics; oral drug product
19.  Characterization of Nanoporous Surfaces as Templates for Drug Delivery Devices 
The AAPS Journal  2009;11(4):758-761.
doi:10.1208/s12248-009-9152-x
PMCID: PMC2782086  PMID: 19876743
cyanoacrylate; drug delivery; methyl orange; nanopores; volume calculation
20.  Therapeutic MicroRNA Strategies in Human Cancer 
The AAPS Journal  2009;11(4):747-757.
MicroRNAs (miRNAs) are ~22 nucleotide long, noncoding, endogenous RNA molecules which exert their functions by base pairing with messenger RNAs (mRNAs), thereby regulate protein-coding gene expression. In eukaryotic cells, miRNAs play important roles in regulating biological processes such as proliferation, differentiation, apoptosis, and stem cell self-renewal. The human genome may contain as many as 1,000 miRNAs, and more than 700 of them have been identified. miRNAs are predicted to target up to one third of mRNAs. Each miRNA can target hundreds of transcripts directly or indirectly, while more than one miRNA can converge on a single transcript target. Therefore, the potential regulatory circuitry afforded by miRNA is enormous. Recently, mounting evidence implicates miRNAs as a new class of modulator for human tumor initiation and progression. Therefore, it has been proposed that manipulating miRNA activity and miRNA biogenesis may be a novel avenue for developing efficient therapies against cancer.
doi:10.1208/s12248-009-9145-9
PMCID: PMC2782079  PMID: 19876744
cancer; microRNA; noncoding RNA; therapy
21.  In Vitro Cutaneous Application of ISCOMs on Human Skin Enhances Delivery of Hydrophobic Model Compounds Through the Stratum Corneum 
The AAPS Journal  2009;11(4):728-739.
This study aimed to investigate the effect of a novel kind of immune-stimulating complexes (ISCOMs) on human skin penetration of model compounds in vitro to evaluate their potential as a delivery system, ultimately for transcutaneous vaccination. Special focus was on elucidating the mechanisms of penetration. Preparation of ISCOMs was done by dialysis and subsequent purification in a sucrose density gradient. The penetration pathways of acridine-labeled ISCOMs were visualized using confocal laser scanning microscopy (CLSM). Transmission electron microscopy (TEM) was used to evaluate the ultrastructural changes in the skin after application of the ISCOMs with or without hydration. Transcutaneous permeation of the model compound, methyl nicotinate, was evaluated in diffusion cells. The prepared ISCOMs were 42–52 nm in diameter as evaluated by dynamic light scattering with zeta potentials of −33 to −26.1 mV. TEM investigations verified the presence of ISCOM structures. Penetration of acridine into skin was greatly increased by incorporation into ISCOMs as visualized by CLSM. Permeation of methyl nicotinate was enhanced in the presence of ISCOMs. Ultrastructural changes of the intercellular space in the stratum corneum after exposure of ISCOMs were observed on micrographs, especially for hydrated skin. In conclusion, cutaneous application of ISCOMs leads to increased penetration of hydrophobic model compounds through human stratum corneum and thus shows potential as a transcutaneous delivery system. The increased penetration seems to be reflected by a change in the intercellular space between the corneocytes, and the effect is most likely caused by the components of the ISCOMs rather than intact ISCOMs.
doi:10.1208/s12248-009-9149-5
PMCID: PMC2782083  PMID: 19862629
CLSM; penetration; Posintro™; TEM; vaccine
22.  Herb–Drug Interactions with St John’s Wort (Hypericum perforatum): an Update on Clinical Observations 
The AAPS Journal  2009;11(4):710-727.
St John’s wort (SJW) extracts, prepared from the aerial parts of Hypericum perforatum, contain numerous pharmacologically active ingredients, including naphthodianthrones (e.g., hypericin and its derivatives), phloroglucinols derivatives (e.g., hyperforin, which inhibits the reuptake of a number of neurotransmitters, including serotonin), and flavonoids. Such extracts are widely used for the treatment of mild-to-moderate depression. As a monotherapy, SJW has an encouraging safety profile. However, relevant and, in some case, life-threatening interactions have been reported, particularly with drugs which are substrate of cytochrome P450 and/or P-glycoprotein. Well-documented SJW interactions include (1) reduced blood cyclosporin concentration, as suggested by multiple case reports as well as by clinical trials, (2) serotonin syndrome or lethargy when SJW was given with serotonin reuptake inhibitors, (3) unwanted pregnancies in women while using oral contraceptives and SJW, and (4) reduced plasma drug concentration of antiretroviral (e.g., indinavir, nevirapine) and anticancer (i.e., irinotecan, imatinib) drugs. Hyperforin, which is believed to contribute to the antidepressant action of St John’s wort, is also strongly suspected to be responsible of most of the described interactions.
doi:10.1208/s12248-009-9146-8
PMCID: PMC2782080  PMID: 19859815
cytochrome P450 enzymes; herb–drug interactions; herbal products; P-glycoprotein; St John’s wort
23.  Pharmacokinetic and Pharmacodynamic Modeling of a Monoclonal Antibody Antagonist of Glucagon Receptor in Male ob/ob Mice 
The AAPS Journal  2009;11(4):700-709.
Elevated basal concentrations of glucagon and reduced postprandial glucagon suppression are partly responsible for the increased hepatic glucose production seen in type 2 diabetic patients. Recently, it was demonstrated that an antagonistic human monoclonal antibody (mAb) blocking glucagon receptor (GCGR) has profound glucose-lowering effects in various animal models. To further understand the effects on glucose homeostasis mediated by such an antibody, a pharmacokinetic-pharmacodynamic (PK-PD) study was conducted in a diabetic ob/ob mouse model. Four groups of ob/ob mice were randomized to receive single intraperitoneal administration of placebo, 0.6, 1, or 3 mg/kg of mAb GCGR, a fully human mAb against GCGR. The concentration-time data were used for noncompartmental and compartmental analysis. A semi-mechanistic PK-PD model incorporating the glucose-glucagon inter-regulation and the hypothesized inhibitory effect of mAb GCGR on GCGR signaling pathway via competitive inhibition was included to describe the disposition of glucose and glucagon over time. The pharmacokinetics of mAb GCGR was well characterized by a two-compartment model with parallel linear and nonlinear saturable eliminations. Single injection of mAb GCGR caused a rapid glucose-lowering effect with blood glucose concentrations returning to baseline by 4 to 18 days with increasing dose from 0.6 to 3 mg/kg. Elevation of glucagon concentrations was also observed in a dose-dependent manner. The results illustrated that the feedback relationship between glucose and glucagon in the presence of mAb GCGR could be quantitatively described by the developed model. The model may provide additional understanding in the underlying mechanism of GCGR antagonism by mAb.
doi:10.1208/s12248-009-9150-z
PMCID: PMC2782084  PMID: 19851873
anti-GCGR antibody; glucagon; hepatic glucose production; type 2 diabetes
24.  MicroRNA Regulation of Cancer Stem Cells and Therapeutic Implications 
The AAPS Journal  2009;11(4):682-692.
MicroRNAs (miRNAs) are a class of endogenous non-protein-coding RNAs that function as important regulatory molecules by negatively regulating gene and protein expression via the RNA interference (RNAi) machinery. MiRNAs have been implicated to control a variety of cellular, physiological, and developmental processes. Aberrant expressions of miRNAs are connected to human diseases such as cancer. Cancer stem cells are a small subpopulation of cells identified in a variety of tumors that are capable of self-renewal and differentiation. Dysregulation of stem cell self-renewal is a likely requirement for the initiation and formation of cancer. Furthermore, cancer stem cells are a very likely cause of resistance to current cancer treatments, as well as relapse in cancer patients. Understanding the biology and pathways involved with cancer stem cells offers great promise for developing better cancer therapies, and might one day even provide a cure for cancer. Emerging evidence demonstrates that miRNAs are involved in cancer stem cell dysregulation. Recent studies also suggest that miRNAs play a critical role in carcinogenesis and oncogenesis by regulating cell proliferation and apoptosis as oncogenes or tumor suppressors, respectively. Therefore, molecularly targeted miRNA therapy could be a powerful tool to correct the cancer stem cell dysregulation.
doi:10.1208/s12248-009-9147-7
PMCID: PMC2782081  PMID: 19842044
cancer stem cells; microRNAs; oncogenes; tumor suppressors
25.  Gum Arabic-Coated Magnetic Nanoparticles for Potential Application in Simultaneous Magnetic Targeting and Tumor Imaging 
The AAPS Journal  2009;11(4):693-699.
Magnetic iron oxide nanoparticles (MNP) coated with gum arabic (GA), a biocompatible phytochemical glycoprotein widely used in the food industry, were successfully synthesized and characterized. GA-coated MNP (GA-MNP) displayed a narrow hydrodynamic particle size distribution averaging about 100 nm; a GA content of 15.6% by dry weight; a saturation magnetization of 93.1 emu/g Fe; and a superparamagnetic behavior essential for most magnetic-mediated applications. The GA coating offers two major benefits: it both enhances colloidal stability and provides reactive functional groups suitable for coupling of bioactive compounds. In vitro results showed that GA-MNP possessed a superior stability upon storage in aqueous media when compared to commercial MNP products currently used in magnetic resonance imaging (MRI). In addition, significant cellular uptake of GA-MNP was evaluated in 9L glioma cells by electron spin resonance (ESR) spectroscopy, fluorescence microscopy, and MRI analyses. Based on these findings, it was hypothesized that GA-MNP might be utilized as a MRI-visible drug carrier in achieving both magnetic tumor targeting and intracellular drug delivery. Indeed, preliminary in vivo investigations validate this clinical potential. MRI visually confirmed the accumulation of GA-MNP at the tumor site following intravenous administration to rats harboring 9L glioma tumors under the application of an external magnetic field. ESR spectroscopy quantitatively revealed a 12-fold increase in GA-MNP accumulation in excised tumors when compared to contralateral normal brain. Overall, the results presented show promise that GA-MNP could potentially be employed to achieve simultaneous tumor imaging and targeted intra-tumoral drug delivery.
doi:10.1208/s12248-009-9151-y
PMCID: PMC2782085  PMID: 19842043
brain tumor; drug delivery; gum arabic; magnetic nanoparticle; magnetic targeting

Results 1-25 (98)