AAPS PharmSci最新文献

Numerous genetic variations have been shown to affect disease susceptibility and drug response. Pharmacogenomics aims at improving therapy on the basis of genetic information for each individual patient. Furthermore, sex chromosomes broadly determine biological differences between males and females. Consequently, substantial sex differences exist in phenotypic manifestation of disease and treatment response. This review discusses the role of sex in coronary artery disease, schizophrenia, and depression--complex multigenic disorders with considerable sex differences in frequency and presentation. Moreover, genetic factors underlying disease and drug response appear to differ between male and female patients. This appears to result at least in part from different physiological effects exerted by sex hormones such that polymorphisms in susceptibility genes may have physiological relevance only in males or females. However, few examples have been discovered to play a role in complex multigenic diseases, and the mechanistic basis of genetic variants as sex-dependent susceptibility factors has yet to be explored. Therefore, pharmacogenomic studies must consider sex differences in an effort to optimize individual drug therapy.

Globalization of the pharmaceutical industry has led to a need to harmonize the regulatory requirements governing the marketing of medicinal products. To minimize the barriers impeding global drug product registration, the International Conference on the Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) was established in 1990. The ICH has developed a series of guidelines that reflect agreements reached by participating nations on aspects of the chemistry and clinical technical sections that will fulfill the regulatory requirements of these various jurisdications. Nevertheless, there continue to be points of divergent perspectives and barriers that can impede the use of foreign clinical data. Given the importance of these issues, the Regulatory Science (RS) section of the American Association of Pharmaceutical Scientists (AAPS), in conjunction with the Regulatory Affairs Professional Society (RAPS) and the Canadian Association of Professional Regulatory Affairs (CAPRA) cosponsored a public forum on this topic. This manuscript provides a summary of the speaker presentations and audience discussions regarding the design of clinical trials and the extrapolation of results from these trials to support international drug registration.

The objective of this study was to evaluate amphiphilic star-like macromolecules (ASMs) as a topical drug delivery system. Indomethacin, piroxicam, and ketoprofen were individually encapsulated into the ASMs using coprecipitation. The effects of the ASMs on percutaneous permeation of nonsteroidal anti-inflammatory drugs (NSAIDs) across full thickness, hairless mouse skin were evaluated in vitro using modified Franz diffusion cells. In addition, solubility and in vitro release experiments were performed to characterize ASMs behavior in aqueous media. Poly(ethylene glycol) (PEG) and Pluronic P-85 were used as polymer controls to compare the role of PEG and amphiphilic behavior in the ASMs. In vitro release experiments indicated that ASMs can delay drug release (P <.05), whereas solubility measurements showed that ASMs can increase NSAIDs aqueous solubility (P <.05). Percutaneous permeation studies revealed that ASMs decreased both flux and Q24 of drugs compared with the control (P <.10). Skin pretreatment studies with ASM-containing solution before drug application demonstrated that pretreatment similarly influenced NSAID percutaneous permeation. In conclusion, ASMs likely slow drug permeation through 2 mechanisms, delayed drug diffusion from its core and skin dehydration by its shell. Thus, ASMs may be useful for delayed dermal delivery or prevention of compound permeation through the skin (eg, sunscreens, N,N-diethyl-m-toluamide [DEET]) from aqueous formulations.

The purpose of this study was to identify optimal preservatives for a multidose formulation of a humanized monoclonal antibody using experimental design techniques. The effect of antimicrobial parenteral preservatives (benzyl alcohol, chlorobutanol, methylparaben, propylparaben, phenol, and m-cresol) on protein stability was assessed using size-exclusion chromatography, differential scanning calorimetry, right-angle light scattering, UV spectroscopy, and potency testing using a cell-based fluorescence-activated cell sorting method. A quick, cost-effective preservative screening test was designed. Combinations of preservatives were examined using an I-optimal experimental design. The protein was most stable in the presence of methylparaben and propylparaben, and was compatible with benzyl alcohol and chlorobutanol at low concentrations. Phenol and m-cresol were not compatible with the protein. The I-optimal experimental design indicated that as an individual preservative, benzyl alcohol was promising. The model also indicated several effective combinations of preservatives that satisfied the antimicrobial efficacy and physical stability constraints. The preservative screening test and the experimental design approach were effective in identifying optimal concentrations of antimicrobial preservatives for a multidose protein formulation; (1) benzyl alcohol, and (2) the combination of methylparaben and chlorobutanol were screened as potential candidates to satisfy the regulatory requirements of various preservative efficacy tests.

The purpose of this study was to evaluate the mechanisms of aggregate formation and excipient stabilization in freeze-dried formulations of a recombinant humanized monoclonal antibody. Protein degradation was measured using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) and native size exclusion chromatography, and protein structure was studied using Fourier transform-infrared spectrometry and circular dichroism. The results showed that protein aggregates present following reconstitution were composed of native antibody structure and a reduced amount of free thiol when compared to protein monomer, which implied that intermolecular disulfides were involved in the aggregation mechanism. An excipient-free formulation resulted in reversible solid-state protein structural alteration and increased aggregation during storage. This correlated with dehydration to an extent that the amount of water was less than the estimated number of surface-accessible hydrogen-bonding sites on the protein. Improved native-like solid-state protein structure and reduced aggregation were obtained by formulation with enough carbohydrate to fulfill the hydrogen-bonding sites on the surface of the protein. Carbohydrate in excess of this concentration has less of an influence on protein aggregation. Reduced aggregation during storage was obtained by the addition of sufficient excipient to both stabilize solid-state protein structure and provide an environment that consisted of an amorphous glassy state matrix.

The objective of this study was to determine whether FM-VP4, a novel compound derived from plant sterols, can effectively reduce cholesterol accumulation within rat intestinal epithelial crypt (IEC-6) cells. EC-6 cells were cultured in Dulbecco's minimal essential medium (DMEM) containing 5% fetal bovine serum, 100 U/mL penicillin, 100 micro g/mL streptomycin, and 0.1 units/mL insulin at 37 degrees C under a humidified 5% CO2 atmosphere and seeded at 6.4 x 10(4) cells/well in 48-well plates. Experiments were initiated 14 days postconfluence. IEC-6 cells were exposed to [3H]cholesterol micelles (containing oleic and taurcholic acids), co-incubated with FM-VP4 (0, 10, 50, and 100 micro M) in Hepes Buffered Sterile Saline (HBSS). Cells were also preincubated with FM-VP4 prior to [3H]cholesterol micelle incubation to determine whether its effects are elicited intracellularly. The cellular localization of cholesterol was determined using digitonin. To determine the effects of cholesterol on the extent of FM-VP4 accumulation within IEC-6 cells, [3H]FM-VP4 was incubated with IEC-6 cells in the presence of unlabeled cholesterol micelles (0, 10, and 50 micro M). The extent of [3H]cholesterol or [3H]FM-VP4 associated with cell monolayers was determined after cell lysis using liquid scintillation counting in a Beckman LS6500 Scintillation Counter. Dose-response and time course studies were performed in which control (no FM-VP4 treatment) and FM-VP4 (10-100 micro M) were co-incubated with 50- micro M [3H]cholesterol micelles from 1 minute to 24 hours. Incubation with only 50- micro M FM-VP4 for less than 24 hours resulted in a 50% to 60% reduction (n = 6, P <.05) in [3H]cholesterol associated with the monolayer compared with control (n = 6). Preincubation of FM-VP4 did not elicit a significant reduction in cholesterol accumulation compared with control (n = 6). Approximately 25% of the total [3H]cholesterol associated with the cells was determined to be cytosolic, while 75% was noncytosolic in the presence and/or absence of FM-VP4. [3H]FM-VP4 was also shown to associate with IEC-6 cells at similar concentrations to cholesterol with the most pronounced inhibition of FM-VP4 accumulation occurring at a cholesterol concentration of 50 micro M. However, cholesterol-induced inhibition was detectable only after 1 hour of incubation. FM-VP4 inhibits cholesterol accumulation within IEC-6 cells and is most effective at equimolar concentrations with cholesterol. Our findings further suggest that the action of FM-VP4 is likely at the cell surface and not elicited intracellularly.

Dr Stephen DeFelice coined the term "Nutraceutical" from "Nutrition" and "Pharmaceutical" in 1989. The term nutraceutical is being commonly used in marketing but has no regulatory definition. An attempt to redefine nutraceuticals and functional foods is made in this article. The proposed definitions can help distinguish between functional foods, nutraceuticals, and dietary supplements. The advantages and disadvantages of nutraceuticals are also briefly discussed.

The purposes of this study were (1) to assess the utility of the economic theory of demand for insurance for modeling voluntary Medicare drug benefit enrollment decisions and (2) to explore the degree of adverse selection and crowd-out that might occur under a voluntary enrollment Medicare prescription benefit. Data were collected using a cross-sectional, mail survey of 2,100 community-dwelling adults aged 65 and older in Wisconsin. Respondents were asked to evaluate their likelihood of enrollment in any of 4 hypothetical drug benefit plans under the assumption that they could enroll in one of the hypothetical plans or maintain their current coverage. Data analyses included bivariate comparisons across enrollment likelihood categories and logit analysis of enrollment likelihood as a function of respondent characteristics. 1041 usable survey forms were returned for an adjusted response rate of 51.5%. Older adults with 4 or more chronic conditions were most likely to report that they were "very likely" to enroll in one of the hypothetical drug plans, as were those with the highest out-of-pocket drug spending in the previous 30 days. Respondents with no or self-purchased drug benefits were more likely than those with employer-based plans to express a higher likelihood of enrollment in one of the hypothetical plans. Adverse selection may be problematic for a voluntary enrollment Medicare drug benefit. Given that high out-of-pocket drug spending (secondary to drug coverage source) was a consistent predictor of enrollment likelihood, demand-side factors affecting the crowding out of employer-based drug coverage sources by a voluntary enrollment drug benefit appear minimal. However, the availability of a Medicare prescription benefit may still lead to crowd-out through employer incentives.

An accurate, precise, and sensitive high-performance liquid chromatography (HPLC) assay was developed for the determination of atenolol in human plasma samples to compare the bioavailability of 2 atenolol tablet (50 mg) formulations in 24 volunteers of both sexes. The study had an open, randomized, 2-period crossover design with a 1-week washout period. Plasma samples were obtained over a 24-hour interval. Atenolol concentrations were analyzed by combined reversed phase liquid chromatography and fluorescence detection (lambda(EX) = 258 nm, lambda(EM) = 300 nm). From the atenolol plasma concentration versus time curves, the following pharmacokinetic parameters were obtained: AUC(0-24h), AUC(0- infinity ), and C(max). The geometric mean of test/reference 50-mg tablets individual percent ratio was 102.2% for AUC(0-24h), and 101.6% for C(max). The 90% confidence intervals (CI) were 100.2% to 105.4% and 100.9% to 103.5%, respectively. Since the 90% CI for both C(max) and AUC(0-24h) were within the 80% to 125% interval proposed by the Food and Drug Administration, it was concluded that atenolol (50-mg tablets) test formulation was bioequivalent to the reference formulation, with regard to both the rate and extent of absorption.