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1.  Pharmacodynamic Model of Parathyroid Hormone Modulation by a Negative Allosteric Modulator of the Calcium-Sensing Receptor 
The AAPS Journal  2011;13(2):265-273.
In this study, a pharmacodynamic model is developed, based on calcium–parathyroid hormone (PTH) homeostasis, which describes the concentration–effect relationship of a negative allosteric modulator of the calcium-sensing receptor (CaR) in rats. Plasma concentrations of drug and PTH were determined from plasma samples obtained via serial jugular vein sampling following single subcutaneous doses of 1, 5, 45, and 150 mg/kg to male Sprague–Dawley rats (n = 5/dose). Drug pharmacokinetics was described by a one-compartment model with first-order absorption and linear elimination. Concentration-time profiles of PTH were characterized using a model in which the compound allosterically modulates Ca+2 binding to the CaR that, in turn, modulates PTH through a precursor-pool indirect response model. Additionally, negative feedback was incorporated to account for tolerance observed at higher dose levels. Model fitting and parameter estimation were conducted using the maximum likelihood algorithm. The proposed model well characterized the data and provided compound specific estimates of the Ki and cooperativity constant (α) of 1.47 ng/mL and 0.406, respectively. In addition, the estimated model parameters for PTH turnover were comparable to that previously reported. The final generalized model is capable of characterizing both PTH–Ca+2 homeostasis and the pharmacokinetics and pharmacodynamics associated with the negative allosteric CaR modulator. As such, the model provides a simple platform for analysis of drugs targeting the PTH–Ca+2 system.
doi:10.1208/s12248-011-9266-9
PMCID: PMC3085713  PMID: 21437757
allosteric; bone; calcium sensing receptor; ionized calcium; osteoporosis; parathyroid hormone; pharmacodynamics; pharmacokinetics
2.  Nonviral Gene Delivery: Principle, Limitations, and Recent Progress 
The AAPS Journal  2009;11(4):671-681.
Gene therapy is becoming a promising therapeutic modality for the treatment of genetic and acquired disorders. Nonviral approaches as alternative gene transfer vehicles to the popular viral vectors have received significant attention because of their favorable properties, including lack of immunogenicity, low toxicity, and potential for tissue specificity. Such approaches have been tested in preclinical studies and human clinical trials over the last decade. Although therapeutic benefit has been demonstrated in animal models, gene delivery efficiency of the nonviral approaches remains to be a key obstacle for clinical applications. This review focuses on existing and emerging concepts of chemical and physical methods for delivery of therapeutic nucleic acid molecules in vivo. The emphasis is placed on discussion about problems associated with current nonviral methods and recent efforts toward refinement of nonviral approaches.
doi:10.1208/s12248-009-9143-y
PMCID: PMC2782077  PMID: 19834816
gene delivery; gene therapy; lipoplex; nonviral vectors; polyplex; transfection
3.  Targeted Delivery of Nucleic Acid-Based Therapeutics to the Pulmonary Circulation 
The AAPS Journal  2009;11(1):23-30.
Targeted delivery of functional nucleic acids (genes and oligonucleotides) to pulmonary endothelium may become a novel therapy for the treatment of various types of lung diseases. It may also provide a new research tool to study the functions and regulation of novel genes in pulmonary endothelium. Its success is largely dependent on the development of a vehicle that is capable of efficient pulmonary delivery with minimal toxicity. This review summarizes the recent progress that has been made in our laboratory along these research directions. Factors that affect pulmonary nucleic acids delivery are also discussed.
doi:10.1208/s12248-008-9073-0
PMCID: PMC2664874  PMID: 19132538
delivery; endothelial cells; genes; lung; oligonucleotides; pulmonary circulation; siRNA; targeting
4.  Nonviral gene delivery: What we know and what is next 
The AAPS Journal  2007;9(1):E92-E104.
Gene delivery using nonviral approaches has been extensively studied as a basic tool for intracellular gene transfer and gene therapy. In the past, the primary focus has been on application of physical, chemical, and biological principles to development of a safe and efficient method that delivers a transgene into target cells for appropriate expression. This review summarizes the current status of the most commonly used nonviral methods, with an emphasis on their mechanism of action for gene delivery, and their advantages and limitations for gene therapy applications. The technical aspects of each delivery system are also reviewed, with a focus on how to achieve optimal delivery efficiency. A brief discussion of future development and further improvement of the current systems is intended to stimulate new ideas and encourage rapid advancement in this new and promising field.
doi:10.1208/aapsj0901009
PMCID: PMC2751307  PMID: 17408239
Gene delivery; gene therapy; nonviral vectors; transfection

Results 1-4 (4)