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Systemic Bioavailability (systemic + bioavailability)
Selected AbstractsIntroduction of lipidization,cationization motifs affords systemically bioavailable neuropeptide Y and neurotensin analogs with anticonvulsant activitiesJOURNAL OF PEPTIDE SCIENCE, Issue 9 2010Brad R. Green Abstract The neuropeptides galanin (GAL), neuropeptide Y (NPY) or neurotensin (NT) exhibit anticonvulsant activities mediated by their respective receptors in the brain. To transform these peptides into potential neurotherapeutics, their systemic bioavailability and metabolic stability must be improved. Our recent studies with GAL analogs suggested that an introduction of lipoamino acids in the context of oligo-Lys residues (lipidization,cationization motif) significantly increases their penetration into the brain, yielding potent antiepileptic compounds. Here, we describe an extension of this strategy to NPY and NT. Rationally designed analogs of NPY and NT containing the lipidization,cationization motif were chemically synthesized and their physicochemical and pharmacological properties were characterized. The analogs NPY-BBB2 and NT-BBB1 exhibited increased serum stability, possessed log D > 1.1, retained high affinities toward their native receptors and produced potent antiseizure activities in animal models of epilepsy following intraperitoneal administration. Our results suggest that the combination of lipidization and cationization may be an effective strategy for improving systemic bioavailability and metabolic stability of various neuroactive peptides. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. [source] Role of adult living donor liver transplantation in patients with hepatitis CLIVER TRANSPLANTATION, Issue 10C 2003Gregory T. Everson Key points 1. Living donor liver transplantation (LDLT) is an option for patients with end-stage liver disease or hepatoma caused by chronic hepatitis C. 2. Reports from some, but not all, transplant centers indicate that hepatitis C may recur earlier, recurrence may be more severe, and graft loss caused by recurrent hepatitis C may be more frequent in LDLT compared with cadaveric transplantation. 3. Several unique characteristics of LDLT (versus cadaveric transplantation) may favor severe recurrence of hepatitis C. These include an increase in genetic similarity between donor and recipient, higher degree of HLA matching, greater systemic bioavailability of immunosuppressive agent, and hepatic regeneration. 4. Hepatic regeneration may promote the acceleration and severity of recurrent hepatitis C by enhancement of hepatitis C viral uptake by hepatocytes through stimulation of the low-density lipoprotein receptor and increase in activity of the internal ribosomal entry site. [source] The limitations of corticosteroid therapy in Crohn's diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2001P. J. Rutgeerts Corticosteroids are highly effective in inducing clinical remission in patients with active Crohn's disease. However, the role of corticosteroids in the treatment of this disease is primarily ameliorative because they are ineffective in maintaining remission or healing mucosal lesions. Nearly half of the patients who initially respond to corticosteroid therapy develop a dependency on corticosteroids or have a relapse within 1 year. In addition, use of these agents is often limited by a relatively high risk of serious adverse effects that can involve nearly every major body system. These effects include: bone loss, which can develop with even short-term and low-dose corticosteroid therapy; metabolic complications such as glucose intolerance and diabetes mellitus; increased intraocular pressure and glaucoma; and potentially lethal infections. To minimize the risk of toxicity, corticosteroids are increasingly recommended for short-term use only at the lowest effective dose to induce remission in patients with moderately to severely active Crohn's disease. Corticosteroid formulations with low systemic bioavailability, such as controlled-release budesonide, may be associated with a lower rate of dermatologic adverse effects but appear to be somewhat less effective than conventional corticosteroids in inducing remission in patients with active Crohn's disease. Immunosuppressive agents such as azathioprine, 6-mercaptopurine, and methotrexate have demon- strated corticosteroid-sparing effects, facilitating the withdrawal of corticosteroids when initiated as maintenance therapy. Infliximab can be used as an alternative to corticosteroids. [source] Molecular targets for the cancer preventive activity of tea polyphenolsMOLECULAR CARCINOGENESIS, Issue 6 2006Chung S. Yang Abstract Inhibition of carcinogenesis by tea and tea polyphenols has been demonstrated in many animal models. The mechanisms of action have been extensively investigated mostly in cell culture systems with (-)-epigallocatechin-3-gallate (EGCG), the most active and major polyphenolic compound from green tea. However, the mechanisms of cancer preventive activity by tea and tea polyphenols are not clearly understood. This article discusses some of the reported mechanisms and possible targets for the action of EGCG. The difficulties and major issues in extrapolating data from studies in cancer cell lines to cancer prevention mechanisms are discussed. Activities observed in cell culture with high concentrations of EGCG may not be relevant because of the limited systemic bioavailability of EGCG. In addition, possible artifacts due to the auto-oxidation of EGCG may complicate this issue. Some recent studies revealed high-affinity EGCG binding proteins as possible direct targets for the action of EGCG. Validating the related cancer preventive mechanisms found in in vitro studies in animal models and human samples would be exciting. © 2006 Wiley-Liss, Inc. [source] Curcumin in Cancer Chemoprevention: Molecular Targets, Pharmacokinetics, Bioavailability, and Clinical TrialsARCHIV DER PHARMAZIE, Issue 9 2010Adeeb Shehzad Abstract Curcumin (diferuloylmethane), a derivative of turmeric is one of the most commonly used and highly researched phytochemicals. Abundant sources provide interesting insights into the multiple mechanisms by which curcumin may mediate chemotherapy and chemopreventive effects on cancer. The pleiotropic role of this dietary compound includes the inhibition of several cell signaling pathways at multiple levels, such as transcription factors (NF-,B and AP-1), enzymes (COX-2, MMPs), cell cycle arrest (cyclin D1), proliferation (EGFR and Akt), survival pathways (,-catenin and adhesion molecules), and TNF. Curcumin up-regulates caspase family proteins and down-regulates anti-apoptotic genes (Bcl-2 and Bcl-XL). In addition, cDNA microarrays analysis adds a new dimension for molecular responses of cancer cells to curcumin at the genomic level. Although, curcumin's poor absorption and low systemic bioavailability limits the access of adequate concentrations for pharmacological effects in certain tissues, active levels in the gastrointestinal tract have been found in animal and human pharmacokinetic studies. Currently, sufficient data has been shown to advocate phase II and phase III clinical trials of curcumin for a variety of cancer conditions including multiple myeloma, pancreatic, and colon cancer. [source] Relative lung and systemic bioavailability of sodium cromoglycate inhaled products using urinary drug excretion post inhalationBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2002Osama Aswania Abstract The relative lung and systemic bioavailability of sodium cromoglycate following inhalation by different methods have been determined using a urinary excretion pharmacokinetic method. On three separate randomised study days, 7 days apart, subjects inhaled (i) 4×5 mg from an Intal® metered dose inhaler (MDI), (ii) 4×5 mg from an MDI attached to a large volume spacer (MDI+SP) and (iii) 20 mg from an Intal Spinhaler® (DPI). Urine samples were provided at 0, 0.5, 1, 2, 5 and 24 h post dose. The mean (S.D.) amount of sodium cromoglycate excreted in the urine during the first 30 min post inhalation was 38.1 (27.5), 222.3 (120.3) and 133.1 (92.2) ,g following MDI, MDI+SP and DPI, respectively. The mean ratio (90% confidence interval) of these amounts excreted in the urine over the first 30 min for MDI+SP vs MDI, DPI vs MDI and MDI+SP vs DPI was 801.0 (358.0, 1244; p<0.002)%, 457.0 (244.0, 670.0; p<0.02)% and 262.4 (110.2, 414.5)%, respectively. Similarly for the 24 h cumulative amount of sodium cromoglycate excreted over the 24 h post inhalation the ratios were 375.4 (232.9, 517.9; p<0.005)%, 287.5 (183.4, 391.6; p<0.02)% and 211.4 (88.3, 334.5)%, respectively. The results highlight better lung deposition of sodium cromoglycate from a metered dose inhaler attached to a large volume spacer. Copyright © 2002 John Wiley & Sons, Ltd. [source] In vivo comparison of the relative systemic bioavailability of fluticasone propionate from three anti-static spacers and a metered dose inhalerBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2009Arun Nair WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Conventional spacers help overcome problems with co-ordination and may improve lung deposition and decrease oropharyngeal impaction. , Antistatic spacers eliminate electrostatic charge and may hence improve respirable dose delivery. , The systemic bioavailability of inhaled fluticasone propionate is primarily dependent on delivery by the pulmonary route and hence the performance of antistatic spacers can be evaluated using adrenal suppression as a sensitive surrogate for relative bioavailability to the lung after an inhalation. WHAT THIS STUDY ADDS , This study compares the relative bioavailability to the lung of inhaled fluticasone delivered via conventional pressurized metered dose inhalers (pMDI) and three antistatic spacers (plastic Zerostat-V, plastic Aerochamber Max, and metal Nebuchamber) in patients with asthma. , All three antistatic spacers when compared with pMDI significantly increased the relative bioavailability to the lungs of inhaled fluticasone in terms of relative adrenal suppression, and there were no significant differences between the plastic and metal antistatic spacers. AIMS The systemic bioavailability of inhaled fluticasone propionate (FP) depends primarily on lung absorption and can be quantified by measuring suppression of overnight and early morning urinary cortisol/creatinine (OUCC and EMUCC, respectively). The aim of the study was to determine the relative bioavailability of hydrofluoroalkane (HFA) FP to the lungs via anti-static plastic (Zerostat-V and Aerochamber Max), metal (Nebuchamber) anti-static spacers and metered dose inhaler [Flixotide Evohaler (EH) (pMDI)]. METHODS A randomized, double-blind, double-dummy, four-way crossover design was used. Eighteen mild to moderate asthmatics received single doses of placebo/HFA-FP 2 mg via the 280-ml Zerostat-V (ZS); 250-ml Nebuchamber (NC); 197-ml Aerochamber Max (AC); and pMDI (EH). Measurements of OUCC and EMUCC were made at baseline and 10 h after each dose. RESULTS Significant suppression of OUCC and EMUCC occurred from baseline with all three spacers, but not Evohaler (geometric mean fold suppression, 95% confidence interval): ZS, 2.74 (1.75, 4.30), P < 0.001; NC, 3.31 (1.81, 6.06), P < 0.001; AC, 4.98 (3.39, 7.31), P < 0.001; and for EH this was 1.42 (0.92, 2.21), P= 0.169 (equating to a 64, 70, 80 and 30% fall in OUCC via the ZS, NC, AC and EH devices, respectively). There were significant differences between all three spacers vs. EH. When compared with the Evohaler, the Zerostat V resulted in 48% greater suppression (P= 0.009); the Nebuchamber 57% greater suppression (P= 0.001); and the Aerochamber Max 71% greater suppression of OUCC (P < 0.001). CONCLUSION All three antistatic spacers significantly increased the relative systemic bioavailability of HFA-FP compared with the standard pMDI. [source] | |||||||||||||