Abstract:
:The aim of the present study was to investigate the mechanism of aqueous degradation of Salinosporamide A (NPI-0052; 1), a potent proteasome inhibitor that is currently in Phase I clinical trials for the treatment of cancer and is characterized by a unique beta-lactone-gamma-lactam bicyclic ring structure. The degradation of 1 was monitored by HPLC and by both low- and high-resolution mass spectral analyses. Apparent first-order rate constants for the degradation at 25 degrees C were determined in aqueous buffer solutions (ionic strength 0.15 M adjusted with NaCl) at various pH values in the range of 1 to 9. Degradation kinetics in water and in deuterium oxide were compared as a mechanistic probe. The studies were performed at pH (pD) 4.5 at 25 degrees C. To further confirm the reaction mechanism, the degradation was also performed in (18)O-enriched water and the degradation products subjected to HPLC separation prior to mass spectral analysis. Solubility and stability in (SBE)(7m)-beta-cyclodextrin (Captisol) solutions were also determined. The hydrolytic degradation of 1, followed by both HPLC and LC/MS, showed that the drug in aqueous solutions gives a species with a molecular ion consistent with the beta-lactone hydrolysis product (NPI-2054; 2). This initial degradant further rearranges to a cyclic ether (NPI-2055; 3) via an intramolecular nucleophilic displacement reaction. The kinetic results showed that the degradation of 1 was moderately buffer catalyzed (general base) and the rate constants were pH independent in the range of 1-5 and base dependent above pH 6.5. No acid catalysis was observed. The kinetic deuterium solvent isotope effect (KSIE) was 3.1 (kH/kD) and a linear proton inventory plot showed that the rate-determining step involved only a single proton transfer. This suggested that a neighboring hydroxyl group (as opposed to a second water molecule) facilitated water attack at pD 4.5. Mass spectral analysis from the (18)O-labeling studies proved that the mechanism involves acyl-oxygen bond cleavage and not a carbonium ion mechanism. 1 is unstable in water (t(90%) journal_name journal_title authors doi subject pub_date pages issue eissn issn pii journal_volume pub_type
abstract::The blood-brain barrier (BBB) limits the distribution of systemically administered therapeutics to the central nervous system (CNS). Intranasal delivery is a noninvasive method that targets drugs to the brain and spinal cord along olfactory and trigeminal neural pathways, bypassing the BBB and minimizing systemic expo...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.21604
更新日期:2009-07-01 00:00:00
abstract::In recent years, biotechnologically derived peptide and protein-based drugs have developed into mainstream therapeutic agents. Peptide and protein drugs now constitute a substantial portion of the compounds under preclinical and clinical development in the global pharmaceutical industry. Pharmacokinetic and exposure/r...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章,评审
doi:10.1002/jps.20125
更新日期:2004-09-01 00:00:00
abstract::The interaction between four different microparticulate drug carriers and macrophages was investigated in vitro. The microparticles, consisting of crosslinked starch (1,4-alpha-D-glucan with 1,6-alpha-branches), dextran (1,6-alpha-D-glucan with 1,3-alpha-branches), lichenan (1,3-beta-D-glucan), or mannan (1,6-alpha-D-...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600760209
更新日期:1987-02-01 00:00:00
abstract::To study if electrostatic charge initially present in mannitol powder plays a role in the generation of aerosols, mannitol was unipolarly charged to varying magnitudes by tumbling the powder inside containers of different materials. The resulting charge in the powder was consistent with predictions from the triboelect...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.21996
更新日期:2010-05-01 00:00:00
abstract::Surfactants stabilize proteins through two major mechanisms: (1) their preferential location at nearby interfaces, in this way precluding protein adsorption; and/or (2) their association with protein into "complexes" that prevent proteins from interacting with surfaces as well as each other. However, selection of surf...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.23908
更新日期:2014-05-01 00:00:00
abstract::A series of unrelated steroids were tested for antimineralocorticoid activity by Kagawa's test in male rats and by modified test in female rats. Adrenalectomized male rats given 12 mcg desoxycorticosterone (DOC) and 2.5 ml normal saline received 1 mg of the test steroid, and their urine was analyzed for sodium and po...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600590532
更新日期:1970-05-01 00:00:00
abstract::A tetrazole ring is often used in drug discovery as a replacement for the carboxylic acid group. Previous work indicates that compounds containing a tetrazole moiety show asymmetric permeability in Caco-2 cells characteristic of an efflux transporter substrate. The aim of this study is to determine which transporters ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.20526
更新日期:2006-04-01 00:00:00
abstract::The structural integrity and conformational stability of various IgG1-Fc proteins produced from the yeast Pichia pastoris with different glycosylation site occupancy (di-, mono-, and nonglycosylated) were determined. In addition, the physical stability profiles of three different forms of nonglycosylated Fc molecules ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.23975
更新日期:2014-06-01 00:00:00
abstract::The location and conformation of fosinopril sodium (FS) in a lamellar liquid crystal of water, sodium dodecyl sulfate, and decanol was studied by low-angle X-ray diffraction. The result showed the FS molecule to be located within the amphiphilic part of the liquid crystalline structure with the polar parts anchored at...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600830517
更新日期:1994-05-01 00:00:00
abstract::DB844 (CPD-594-12), N-methoxy-6-{5-[4-(N-methoxyamidino)phenyl]-furan-2-yl}-nicotinamidine, is an oral prodrug that has shown promising efficacy in both mouse and monkey models of second stage human African trypanosomiasis. However, gastrointestinal (GI) toxicity was observed with high doses in a vervet monkey safety ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.23765
更新日期:2014-01-01 00:00:00
abstract::The pneumococcal histidine triad protein D (PhtD) is believed to play a central role in pneumococcal metal ion homeostasis and has been proposed as a promising vaccine candidate against pneumococcal disease. To investigate for potential stabilizers, a panel of physiologically relevant metals was screened using the the...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2017.06.003
更新日期:2017-10-01 00:00:00
abstract::Lysosomes are acidic intracellular organelles that can extensively sequester basic lipophilic drugs due to pH and membrane partitioning, and therefore may significantly influence subcellular drug concentrations. Current in vitro methods for lysosomal drug sequestration evaluation typically lack the ability to accurate...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2020.05.026
更新日期:2020-09-01 00:00:00
abstract::The period of time after administration over which blood level measurements are required to obtain a reliable bioavailability comparison of two or more formulations of the same drug was considered by the analysis of bioavailability data taken from the literature. The drugs examined, selected to represent a range of ab...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600640921
更新日期:1975-09-01 00:00:00
abstract::Targeted echogenic liposome dispersions for ultrasonic enhancement of vasoactive and pathological components of endothelium and atherosclerosis have recently been developed. The component lipids required for acoustic and targeting properties include phosphatidylcholine, phosphatidylethanolamine phosphatidylglycerol (P...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.1142
更新日期:2001-12-01 00:00:00
abstract::The pharmacologically active compound (33% reduction in rabbit intraocular pressure recovery rate assay) 1-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoline (MC4), which showed ocular hypotensive action and had optimum physicochemical properties, was characterized for its ocular absorption and distribution properties to bett...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.22720
更新日期:2011-12-01 00:00:00
abstract::A multichannel continuous-flow apparatus for dissolution rate measurements is described. Typical data are presented to demonstrate its utility for studies with bulk drug powders as well as with tablets and capsules without any change of setup. Procedures are given for the preparation of powder samples for dissolution ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600641024
更新日期:1975-10-01 00:00:00
abstract::Corneal penetration studies were conducted in unanesthetized albino rabbits using various organic compounds representing both polar and nonpolar species. Very low molecular weight compounds demonstrate rapid uptake into the aqueous humor despite the lipid-like barrier imposed by the corneal epithelium. Evidence that t...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600770103
更新日期:1988-01-01 00:00:00
abstract::Simple assays for extraction and determination of the concentrations of the antibiotics oxytetracycline, oxolinic acid, and flumequine in a drug dosage form for farmed fish are described. HPLC with UV detection was used in the analyses. The recovery of all three drugs was approximately 100%, and the precision varied f...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600820517
更新日期:1993-05-01 00:00:00
abstract::Eight analogs of the fentanyl-type analgesics, in which the piperidine ring is restricted into a boat conformation, were evaluated for analgesic activity. All analogs were less active than fentanyl, but interesting conformational and structural relationships were observed. Results of the study are discussed. ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600690934
更新日期:1980-09-01 00:00:00
abstract::Poor dissolution performance is one of the challenges encountered in dosage form design of amorphous solid dispersions (ASDs). This study was aimed to investigate the effect of solid-liquid interactions of an encapsulated ASD on drug release. Drug release profiles of a molecularly interacting amorphous celecoxib solid...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.22462
更新日期:2011-06-01 00:00:00
abstract::Synthetic peptides corresponding to the variable tandem repeat domain of the cancer-associated antigen MUC1 mucin are candidates for cancer vaccines. In our investigation mice were immunized via subcutaneous injection with poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres containing a MUC1 mucin peptide. It was hy...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1021/js980070s
更新日期:1998-11-01 00:00:00
abstract::A physically based method for arriving at topological indexes is described. The derived indexes correlate with molecular surface areas and with the molecular connectivity index. The newly derived index seems to account better for the expected distinctions among primary, secondary, and tertiary alcohol aqueous solubili...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600680713
更新日期:1979-07-01 00:00:00
abstract::To evaluate the potential of cell-penetrating peptide-based delivery of apoptosis-inducer gene in cancer therapy, a modified HIV-1 TAT peptide (dimerized TAT peptide, dTAT) was studied. The dTAT and plasmid DNA (pDNA) complexes (dTAT-pDNA) were condensed using calcium chloride (dTAT-pDNA-Ca2+). This simple nonviral fo...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2016.08.023
更新日期:2017-01-01 00:00:00
abstract::In vitro iontophoretic administration of drugs through a microporous polyolefin membrane with hydrophilic urethane polymerfilled pores was done for the ionized drugs dexamethasone sodium phosphate, hydrocortisone sodium phosphate, and prednisolone sodium succinate, and for a nonionizable drug cortisone acetate. Curren...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600780308
更新日期:1989-03-01 00:00:00
abstract::In recent years, computational methods have garnered much attention in protein engineering. A large number of computational methods have been developed to analyze the sequences and structures of proteins and have been used to predict the various properties. Antibodies are one of the emergent protein therapeutics, and ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章,评审
doi:10.1016/j.xphs.2020.01.011
更新日期:2020-05-01 00:00:00
abstract::The melt from the usual monoclinic phase (Phase I) of biclotymol (T(fusI) = 400.5 +/- 1.0 K, Delta(fus)H(I) = 36.6 +/- 0.9 kJ mol(-1)) recrystallizes into another phase, Phase II, that melts at T(fusII) = 373.8 +/- 0.2 K (Delta(fus)H(II) = 28.8 +/- 1.0 kJ mol(-1)). The transformation of Phase II into Phase I is found ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.21285
更新日期:2008-09-01 00:00:00
abstract::Sustained-release formulations such as hydroxypropyl methylcellulose (HPMC)-based hydrophilic matrix tablets of poorly water-soluble drugs often result in incomplete release because of the poor solubility and dissolution rate of the drug in the hydrophilic matrix. Sulfobutylether-beta-cyclodextrins ((SBE)(7M)-beta-CDs...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.1034
更新日期:2001-07-01 00:00:00
abstract::An assay is described for the determination of the H2-receptor antagonist, cimetidine, in human plasma and urine. Alkalinized plasma or urine was extracted with methylene chloride, the organic phase was evaporated, and the reconstituted residue was analysed by high-pressure liquid chromatography (HPLC) using a reverse...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600710528
更新日期:1982-05-01 00:00:00
abstract::A three-way crossover bioavailability study was performed using nine adult male volunteers with three different commercial prednisone tablets. Plasma samples were assayed for prednisolone, the active metabolite of prednisone, by a radioimmunoassay method. Statistical analysis showed significant differences in the rate...
journal_title:Journal of pharmaceutical sciences
pub_type: 临床试验,杂志文章
doi:10.1002/jps.2600641035
更新日期:1975-10-01 00:00:00
abstract::Co-amorphous drug-amino acid systems have gained growing interest as an alternative to common amorphous formulations which contain polymers as stabilizers. Several preparation methods have recently been investigated, including vibrational ball milling on a laboratory scale or spray drying in a larger scale. In this st...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2016.09.027
更新日期:2017-01-01 00:00:00