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PubMed1982

Plasma progesterone levels after using high dose suppositories. A preliminary report.

Rectal administration of progesterone in relatively high doses is sometimes advocated for a few gynaecological disorders. Two different kinds of suppositories, containing 200 mg of active substance in a fatty base, were administered to six volunteers. The progesterone plasma concentrations, measured at I, 2 and 6 hours after administration, showed large interindividual differences. However, the average concentrations did not differ significantly between the two kinds of suppositories. The concentrations reached are in the order of magnitude of the normal top levels in the second half of the menstrual cycle.

Biopharmaceutics↗
PubMed2003

Synthesis and in vitro properties of prednisolone 21-sulfate sodium as a colon-specific prodrug of prednisolone.

Colon-specific delivery of glucocorticoids is highly desirable for the efficient treatment of inflammatory bowel disease. We synthesized prednisolone 21-sulfate sodium (PDS) as a colon-specific prodrug of prednisolone (PD) and investigated its properties using rats as test animals. We expected that introduction of sulfate ester as a sodium salt might increase the hydrophilicity and restrict the absorption in the GI tract. If PDS is stable and nonabsorbable in the upper intestine, it will be delivered to the colon as an intact form, where it hydrolyze by the sulfatase to release PD. Compared with PD, the solubility of PDS increased and the apparent partition coefficient decreased greatly. PDS was stable on incubation with pH 1.2 and 6.8 buffer solutions and with the contents of the stomach and small intestine. On incubation with the cecal contents, PDS decreased to 9.6% of the dose in 10 h producing PD. The amount of PD increased to give a maximum 54% of the dose and decreased. As a control, when PD was incubated with the cecal contents, it decreased to 29% of the dose in 8 h, which implied that reduction of PD proceeded under such conditions. These results suggested that hydrolysis of PDS took place to produce and accumulate PD, which decreased by reduction as the incubation period extended. Our results suggested that PDS can be a promising colon-specific prodrug of PD, and sulfate ester group might serve as a potential colon-specific promoiety, especially for the drugs which are resistant to reduction in the colon.

Administration, Oral↗
PubMedDate not supplied

The influence of the route of administration on the bioavailability of an endogenous macromolecule: chondroitin sulphate (CSA).

The absorption of chondroitin sulphate (CSA) has been investigated in rabbits after the oral administration of a single dose of 100 mg of CSA per kg of body weight. The oral dose was administered as a lipid suspension or in enteric capsules. No absorption of CSA could be demonstrated. Oral administration did not cause the release of a clearing factor into the bloodstream, a phenomenon that is known to occur in the presence of CSA. The concentration of this factor did not decrease after oral administration of CSA.

Administration, Oral↗
PubMed2005

[Cost reductions and their effects on drug research].

There are numerous reasons for the decline in pharmaceutical R and D in Germany. To mention the most important: inadequate public sponsoring of R and D activities and the late onset of biotechnology support. Cost containment in drug spending is also a major hurdle for R and D investments. An overview for the time span from 1992 to 2001, initiated by the OECD organization, reveals that average price increases for drugs in Germany are at their lowest levels as compared to other markets such as Canada, the USA, Australia and the remaining European markets. In addition, R and D productivity has, in general, decreased. Independent of locations and despite the use of new technologies, it has even worsened. This situation has not changed through the introduction of biotech products. For Germany, it is recommended to increase the investment in R and D, in order to reduce bureaucratic overheads and to better estimate innovation.

Animals↗
PubMed2005

P-glycoprotein induction and tumor cell-kill dynamics in response to differential doxorubicin dosing strategies: a theoretical pharmacodynamic model.

PURPOSE: The objectives of this work were 1) to develop a theoretical pharmacodynamic model that captures dynamic changes resulting from drug/therapy mediated P-glycoprotein (P-gp) induction and 2) to compare the pharmacodynamic outcomes of several doxorubicin (DOX) dosing schemes through simulations. METHODS: We developed a theoretical model that included a pharmacokinetic (PK) model for intracellular DOX-mediated P-gp induction and a pharmacodynamic (PD) model using a threshold trigger function for tumor cell-kill. In this model, both the level of P-gp induction and rate of tumor cell death were modulated by intracellular DOX concentration. Most model parameters were obtained from literature sources, and a few were either fixed or reasonably estimated. RESULTS: Comparative dosing simulations showed that a 10-week constant infusion in which a tumor cell population was continuously exposed to the drug did not produce the best PD profile. On the other hand, dosing schemes where the cell population was initially challenged with a high dose, followed by intermittent dosing, generated the best PD profile. The favorable outcome of the latter dosing schemes was correlated with the lowest expression of P-gp in terms of area under the curve (AUC) during treatment period. CONCLUSIONS: The simulations led us to conclude that drug resistance, particularly resistance caused by P-gp overexpression, induced during chemotherapy may, in part, be circumvented by designing optimal dosing strategies that minimize P-gp induction.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Intracellular delivery of Bak BH3 peptide by microbubble-enhanced ultrasound.

PURPOSE: To investigate the possibility of intracellular delivery of Bak BH3 peptide using sonoporation effect by microbubble-enhanced ultrasound. METHODS: HeLa and BJAB cells were exposed to 1.696-Mhz focused ultrasound with 2% microbubble contrast agents (OPTISON). Cell-impermeable calcein was used as an indicator for successful sonoporation, and propidium iodide staining was used for cell viability assessment. Peptides were also exposed to ultrasound with OPTISON and analyzed with mass spectrometry for evaluation of stability under ultrasound exposure. The effect of transduced Bak BH3 peptide was evaluated by the cell viability of successfully sonoporated cells. RESULTS: Bak BH3 peptides did not undergo mechanical degradation with microbubble-enhanced ultrasound exposure. With the increase of acoustic energy exposure, the sonoporation efficiency saturated both in BJAB and HeLa cells, while direct cell death rate by ultrasound exposure tended to increase. When BJAB cells were treated with 100 microM Bak BH3 peptides, and ultrasound exposure with ultrasound contrast agents (OPTISON), an increased 35% cell death was confirmed. On the other hand, although HeLa cells had a similar trend, they failed to exhibit statistical significance. CONCLUSIONS: Our results suggest that microbubble-enhanced focused ultrasound peptide transduction is possible. Further optimization of ultrasound exposure conditions may be necessary.

Antineoplastic Agents↗
PubMed2005

Experimental and computational studies of epithelial transport of mefenamic acid ester prodrugs.

PURPOSE: A series of ester derivatives of mefenamic acid were synthesized with the aim of suppressing local gastrointestinal toxicity of mefenamic acid. A computational method was used to assist the design of the prodrug and to gain insights into the structure relationship of these compounds as P-glycoprotein (P-gp) substrates. The prodrugs were studied for their enzymatic stability, bidirectional permeability across Caco-2 monolayer, and their potential as transporter modulators METHODS: Bidirectional transport studies were performed using Caco-2 cells. Compounds exhibiting an efflux ratio of > or =2 were further examined for their potential interaction with P-gp and multidrug resistance-associated protein (MRP) using verapamil and indomethacin. Calcein efflux inhibition studies were conducted to investigate the efflux mechanism of these compounds. Geometry optimization of the esters was performed, and the spatial separation of two electron donor groups of each prodrug was measured. RESULTS: Morpholinoethyl ester (3) and pyrrolidinoethyl ester (4) of mefenamic acid showed evidence of efflux mechanism. Inhibition by verapamil had a pronounced effect on the transport of 3 and 4. Indomethacin, however, completely inhibited the apical efflux of 3 but enhanced the efflux ratio of 4. Both compounds increased the ratio of cellular calcein accumulation by 3- to 5-fold over control. Consistent with the experimental data, the computational results suggest the involvement of P-gp or its interaction in 3 and 4 transport. CONCLUSIONS: Apical efflux of 3 is associated with P-gp and MRP, but the efflux of 4 involves P-gp and/or MRP. The computational approach used in this study provided the basis for P-gp substrates of compounds 3 and 4 from their electron donor subunits spatial separation.

Animals↗