Home About us Contact
|
Home About us Contact | ||
|
|
||
Drug Penetration (drug + penetration)
Selected AbstractsCytotoxicity of doxorubicin-loaded Con A-liposomesDRUG DEVELOPMENT RESEARCH, Issue 5 2006Hercília Maria Lins Rolim Santos Abstract The present study investigated the potential of Concanavalin A lectin (Con A) conjugated to liposomes (Con A-liposomes) for targeting doxorubicin (DOX) to cells. The physicochemical properties and the cytotoxicity of DOX-loaded Con A-liposomes were evaluated. DOX-loaded Con A-liposomes were prepared by incubation of DOX-loaded liposomes with a Con A-SATA derivative. Lectin biological activity was monitored before and after conjugation by a hemagglutinating assay. The cytotoxicity of DOX-loaded Con A-liposomes was evaluated in terms of the inhibition of NCI-H299 and HEp-2 cell proliferation using the MTT method. The affinity of lectinized liposomes with these cells was thus assessed by evaluating the cytotoxic effect of the DOX released into cells. Stable DOX-loaded Con A-liposomes were obtained and their high affinity for cells was corroborated. The encapsulation of DOX into Con A-liposomes produced an inhibition of roughly 70% of Hep-2 cell proliferation and 50% of cell inhibition was verified on HCI-H292. DOX in solution was able to inhibit only 20% of cell proliferation for both cell lines. Unloaded Con A-liposomes were not cytotoxic. The encapsulation of DOX into Con A-liposomes improves drug penetration into cells, thereby enhancing its cytotoxicity, especially in Hep-2 cells. Drug Dev. Res. 67:430,437, 2006. © 2006 Wiley-Liss, Inc. [source] Rapidly profiling blood,brain barrier penetration with liposome EKCELECTROPHORESIS, Issue 14 2007Yongjun Wang Abstract This report intended to study the potential of liposome EKC (LEKC) as a convenient and high-throughput screening tool to assess drug penetration across the blood,brain barrier (BBB). The retention factors (k) of 24 structurally diverse compounds were determined with LEKC and vesicle EKC (VEKC), respectively. Principal component analysis of the steady-state concentrations ratio of compounds in the brain and in the blood expressed as log,BB, log,kLEKC, log,kVEKC, and other lipophilic descriptors including octanol/water partition coefficient (Clog,P), octanol/water distribution coefficients (log,D7.4), and polar surface area (PSA), showed the maximum similarity of partitioning processes in LEKC to drug penetration across the BBB. Furthermore, the log,BB were correlated with the above five lipophilic descriptors, and the results showed that log,kLEKC gave the better correlation coefficient (r2,=,0.811, p <0.0001) than those of log,D7.4, Clog,P, PSA, and log,kVEKC (r2,=,0.730, 0.672, 0.627, and 0.620, p <0.0001). This is the first report of the use of LEKC as a promising rapid tool to profile drug penetration across the BBB. [source] Blood,brain barrier damage and brain penetration of antiepileptic drugs: Role of serum proteins and brain edemaEPILEPSIA, Issue 4 2009Nicola Marchi Summary Purpose:, Increased blood,brain barrier (BBB) permeability is radiologically detectable in regions affected by drug-resistant epileptogenic lesions. Brain penetration of antiepileptic drugs (AEDs) may be affected by BBB damage. We studied the effects of BBB damage on brain distribution of hydrophilic [deoxy-glucose (DOG) and sucrose] and lipophilic (phenytoin and diazepam) molecules. We tested the hypothesis that lipophilic and hydrophilic drug distribution is differentially affected by BBB damage. Methods:, In vivo BBB disruption (BBBD) was performed in rats by intracarotid injection of hyperosmotic mannitol. Drugs (H3-sucrose, 3H-deoxy-glucose, 14C-phenytoin, and C14-diazepam) or unlabeled phenytoin was measured and correlated to brain water content and protein extravasation. In vitro hippocampal slices were exposed to different osmolarities; drug penetration and water content were assessed by analytic and densitometric methods, respectively. Results:, BBBD resulted in extravasation of serum protein and radiolabeled drugs, but was associated with no significant change in brain water. Large shifts in water content in brain slices in vitro caused a small effect on drug penetration. In both cases, total drug permeability increase was greater for lipophilic than hydrophilic compounds. BBBD reduced the amount of free phenytoin in the brain. Discussion:, After BBBD, drug binding to protein is the main controller of total brain drug accumulation. Osmotic BBBD increased serum protein extravasation and reduced free phenytoin brain levels. These results underlie the importance of brain environment and BBB integrity in determining drug distribution to the brain. If confirmed in drug-resistant models, these mechanisms could contribute to drug brain distribution in refractory epilepsies. [source] Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humansFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2004M. Molimard Abstract Absorption, distribution, metabolism and excretion of desloratadine, fexofenadine, levocetirizine, and mizolastine in humans have been compared. The time required to reach peak plasma levels (tmax) is shortest for levocetirizine (0.9 h) and longest for desloratadine (,3 h). Steady-state plasma levels are attained after about 6 days for desloratadine, 3 days for fexofenadine, 2,3 days for mizolastine and by the second day for levocetirizine. The apparent volume of distribution is limited for levocetirizine (0.4 L/kg) and mizolastine (1,1.2 L/kg), larger for fexofenadine (5.4,5.8 L/kg) and particularly large for desloratadine (, 49 l/kg). Fexofenadine and levocetirizine appear to be very poorly metabolized (, 5 and 14% of the total oral dose, respectively). Desloratadine and mizolastine are extensively metabolized. After administration of 14C-levocetirizine to healthy volunteers, 85 and 13% of the radioactivity are recovered in urine and faeces, respectively. In contrast, faeces are the preferential route of excretion for 14C-fexofenadine (80% vs. 11% of the radioactive dose in urine). The corresponding values are 41% (urine) and 47% (faeces) for 14C-desloratadine, 84,95% (faeces) and 8,15% (urine) for 14C-mizolastine. The absolute bioavailability is 50,65% for mizolastine; it is high for levocetirizine as the percentage of the drug eliminated unchanged in the 48 h urine is 77% of the oral dose; the estimation for fexofenadine is at least 33%; no estimation was found for desloratadine. Fexofenadine is a P-glycoprotein (P-gp) substrate and P-gp is certainly involved both in the poor brain penetration by the compound and, at least partially, in a number of observed drug interactions. An interaction of desloratadine with P-gp has been suggested in mice, whereas the information on mizolastine is very poor. The fact that levocetirizine is a substrate of P-gp, although weak in an in vitro model, could contribute to prevent drug penetration into the brain, whereas it is unlikely to be of any clinical relevance for P-gp-mediated drug interactions. [source] PLGA nanospheres for the ocular delivery of flurbiprofen: Drug release and interactionsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2008E. Vega Abstract Poly(D,L -lactide- co -glycolide) nanospheres incorporating flurbiprofen were prepared by the solvent displacement technique for purposes of assessing (i) drug,polymer physicochemical interactions, (ii) flurbiprofen release from the polymer matrix and (iii) eye permeation of the drug formulated in the colloidal system. The resulting nanospheres were on average 200,300 nm in size and bore a negative charge (,-potential around ,25 mV). They were shown by atomic force microscopy and transmission electron microscopy to be spherical and regular in shape. Thermal methods, infrared spectroscopy and X-ray diffraction showed that the drug was dispersed inside the particles. These tests evidenced an eutectic mixture meaning more widespread dispersion of the drug in the polymer system. Entrapped flurbiprofen was released in vitro from the polymer system by dissolution and diffusion in high drug loaded nanospheres, whereas those with a lesser load showed only diffusion. The ex vivo corneal permeation study showed that flurbiprofen-loaded nanospheres enhanced drug penetration by about twofold over commercial eye drops containing poly(vinyl alcohol) and by about fourfold over flurbiprofen in pH 7.4 phosphate buffer. The corneal hydration level of each cornea was determined to evaluate potential corneal damage. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5306,5317, 2008 [source] Development of a PCR-based diagnostic test detecting a nt230(del4) MDR1 mutation in dogs: verification in a moxidectin-sensitive Australian ShepherdJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2005J. GEYER A subpopulation of dogs of the Collie and Australian Shepherd breeds show increased sensitivity to central nervous actions of ivermectin, doramectin, loperamide, and probably several other drugs. The molecular background for this greater sensitivity is a nonsense mutation in the MDR1 efflux pump, which is part of the functional blood,brain barrier and normally limits drug penetration into the brain. This report describes a rapid PCR-based method for detection of this nt230(del4) MDR1 mutation using a small amount of genomic DNA from blood cells. Thereby, homozygous intact, homozygous mutated, and heterozygous mutated MDR1 genotypes can be clearly differentiated by high resolution polyacrylamide gel electrophoresis. Using this diagnostic test two Collies and one Australian Shepherd were screened for the nt230(del4) MDR1 mutation. The Collies had no history of altered drug sensitivity and showed homozygous intact and heterozygous mutated MDR1 alleles, respectively. However, the Australian Shepherd developed clear signs of neurotoxicity including ataxia, crawling, acoustic and tactile hyperexcitability, and miosis after a single dose of moxidectin (400 ,g/kg). For this dog two mutated MDR1 alleles were detected. This report describes for the first time moxidectin neurotoxicosis in a dog with a homozygous MDR1 mutation. [source] Matrix-assisted laser desorption/ionization imaging mass spectrometry of oxaliplatin derivatives in heated intraoperative chemotherapy (HIPEC)-like treated rat kidneyRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 4 2010Amina Bouslimani Oxaliplatin [1,2-diaminocyclohexane (dach)-Pt complex] is a platinum anticancer drug which is mainly used in the treatment of advanced colorectal cancer, particularly in Heated Intraoperative Chemotherapy (HIPEC) for the treatment of colorectal peritoneal carcinomatosis. In order to better understand the penetration of oxaliplatin in treated tissues we performed a direct imaging of tissue sections from HIPEC-like treated rat kidney using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. This procedure allowed the detection and localization of oxaliplatin and its metabolites, the monocysteine and monomethionine complexes, in kidney sections. Specifically, oxaliplatin and its metabolites were localized exclusively in the kidney cortex, suggesting that it did not penetrate deeply into the organ. Based on these results, an imaging analysis of human tumors collected after HIPEC is currently in progress to assess the distribution of oxaliplatin and/or metabolites with the aim of defining clinical conditions to improve drug penetration. Copyright © 2010 John Wiley & Sons, Ltd. [source] Antibiotic therapy , rationale and evidence for optimal drug concentrations in prostatic and seminal fluid and in prostatic tissueANDROLOGIA, Issue 5 2003Kurt G. Naber Summary. The theoretical background of drug penetration into the prostate is outlined, emphasizing the phenomenon of ion-trapping and the role of nonionic diffusion of weak acids, bases and amphoteric drugs across biological membranes with a pH gradient. Determination of drug concentrations in human prostatic secretion are problematic because of possible urinary contamination. Studies have been carried out mainly in healthy volunteers. The results have to be interpreted with caution, if not care was taken to rule out or at least identify urinary contamination. Analysing the concentrations of various fluoroquinolones in prostatic and seminal fluid as well as in prostatic tissue, it becomes obvious that the fluoroquinolones differ not only in plasma concentrations but also in their penetration ability to these sites. In spite of intensive investigations, our knowledge is still limited concerning the mechanisms that govern the transport of antibiotic drugs into and their activity in the various prostatic compartments and how the findings can be applied clinically. Nevertheless, overall the concentrations at the site of infection of most of the fluoroquinolones should be sufficient for the treatment of chronic bacterial prostatitis and vesiculitis caused by susceptible pathogens. [source] Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosingCANCER, Issue 6 2002A surrogate marker of brain penetration Abstract BACKGROUND Vincristine (VCR) is used widely in oncology practice, and regular dosing is commonly associated with the development of sensorimotor or autonomic neuropathies. However, the incidence of VCR-related central nervous system (CNS) toxicity is comparatively low, suggesting that the blood-brain barrier may limit drug penetration into the brain parenchyma. This study determined whether measurable concentrations of VCR could be detected in the cerebrospinal fluid (CSF), as a surrogate marker of brain parenchyma penetration, after bolus intravenous injection in children without primary CNS pathology. METHODS The authors studied 17 pediatric patients ages 2.5,14.1 years (median, 6.8 years) with acute lymphoblastic leukemia or non-Hodgkin lymphoma without evidence of leptomeningeal disease. Patients received VCR 1.5 mg/m2 by intravenous bolus injection followed at varying intervals by lumbar puncture for scheduled intrathecal methotrexate administration under general anesthesia. Paired VCR concentrations in both plasma and CSF were measured in each patient simultaneously at times ranging from 8 minutes to 146 minutes after the VCR injection. Three patients were studied twice. The paired samples were stored at ,40 °C until analysis using a high performance liquid chromatography assay with a sensitivity of 0.1 ,g/L in CSF and 0.4 ,g/L in plasma. RESULTS Plasma VCR concentrations ranged from 2.2 ,g/L to 91.2 ,g/L. No measurable VCR concentrations were detected in the CSF samples. CONCLUSIONS Measurable concentrations of VCR in CSF are not achieved after the administration of standard intravenous bolus doses of VCR. The current observations are consistent with the relative rarity of VCR-related CNS neurotoxicity compared with the commonly observed sensorimotor and autonomic neuropathies. These findings suggest that the penetration of VCR into the brain parenchyma of patients with a relatively intact blood-brain barrier is low and that VCR may have a limited role in the CNS-directed therapy of these patients. Cancer 2002;94:1815,20. © 2002 American Cancer Society. DOI 10.1002/cncr.10397 [source] A mathematical model of the impact of infused targeted cytotoxic agents on brain tumours: implications for detection, design and deliveryCELL PROLIFERATION, Issue 6 2002Lawrence M. Wein Motivated by the recent development of highly specific agents for brain tumours, we develop a mathematical model of the spatio-temporal dynamics of a brain tumour that receives an infusion of a highly specific cytotoxic agent (e.g. IL-4-PE, a cytotoxin comprised of IL-4 and a mutated form of Pseudomonas exotoxin). We derive an approximate but accurate mathematical formula for the tumour cure probability in terms of the tumour characteristics (size at time of detection, proliferation rate, diffusion coefficient), drug design (killing rate, loss rate and convection constants for tumour and tissue), and drug delivery (infusion rate, infusion duration). Our results suggest that high specificity is necessary but not sufficient to cure malignant gliomas; a nondispersed spatial profile of pretreatment tumour cells and/or good drug penetration are also required. The most important levers to improve tumour cure appear to be earlier detection, higher infusion rate, lower drug clearance rate and better convection into tumour, but not tissue. In contrast, the tumour cure probability is less sensitive to a longer infusion duration and enhancements in drug potency and drug specificity. [source] | ||||||||||||||||