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Biomedical subjects

M Mezei

Publications and source records attributed to M Mezei.

At least 37 records · Page 2Linked to original sources
PubMed1997

Comparative topical anaesthesia of EMLA and liposome-encapsulated tetracaine.

BACKGROUND: The eutectic mixture of local anaesthetics (EMLA) provides effective topical anaesthesia after a minimum of 60 to 90 min application. Since liposome-encapsulated tetracaine (LET) can provide rapid dermal penetration, the goal of this study was to compare the local anaesthetic effects of EMLA and LET in human volunteers after 60 min application. METHODS: After obtaining institutional approval and informed consent, healthy volunteers were recruited in a double blind, crossover, randomized trial. The study creams (0.5 ml EMLA and 0.5 ml LET 5%) were applied randomly to opposite arms for 60 min. The discomfort of i.v. catheterization was assessed using a visual analogue pain score (VAS). Cutaneous side effects of the creams were recorded. RESULTS: Sixty-one subjects were studied. Twenty-one were excluded because of technical difficulties. Forty subjects completed the study and were included in the data analysis. The mean ( +/- SD) VAS was lower for LET than for EMLA (10.9 +/- 9.0 mm vs 22.7 +/- 17.1 mm, P < 0.001). Erythema secondary to vasodilatation occurred more frequent in the LET group than in the EMLA group (33 vs 3, P < 0.001). One subject with a history of atopy developed a rash at the LET application site. CONCLUSION: Liposome-encapsulated tetracaine can provide a more effective topical anaesthesia than EMLA for intravenous catheterization after 60 min application. Clinical evaluations are necessary to determine the efficacy and safety of LET in providing topical anaesthesia for various invasive percutaneous procedures in other patient populations.

Administration, Topical↗
PubMed1996

Grand canonical ensemble Monte Carlo simulation of the dCpG/proflavine crystal hydrate.

The grand canonical ensemble Monte Carlo molecular simulation method is used to investigate hydration patterns in the crystal hydrate structure of the dCpG/proflavine intercalated complex. The objective of this study is to show by example that the recently advocated grand canonical ensemble simulation is a computationally efficient method for determining the positions of the hydrating water molecules in protein and nucleic acid structures. A detailed molecular simulation convergence analysis and an analogous comparison of the theoretical results with experiments clearly show that the grand ensemble simulations can be far more advantageous than the comparable canonical ensemble simulations.

Binding Sites↗
PubMed1996

Superficial siderosis--a cause of audiovestibular failure.

Bilateral vestibular end organ failure in adult life is a rare condition with some specific known causes, such as relapsing polychondritis, autoimmune inner ear disease, Lues venerium, and an acute effect of gentamicin. This case report draws attention to a rare condition that is potentially recognizable early in its development. The patient has superficial siderosis, which is iron deposits over the cerebrum, resulting in progressive neurologic failure involving all of the systems. Early in its course before other symptoms appear, there is development of progressive hearing loss and vestibular failure. This case report and literature review are given, including a potential for attempts at therapy if the disorder is recognized early.

Brain Diseases↗
PubMed1995

A role for amplified protein kinase C activity in the pathogenesis of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a human neurodegenerative disorder of unknown origin that is characterized by progressive degeneration of corticospinal tracts and anterior horn cells in the brainstem and spinal cord. Previous studies have indicated that motoneuron degeneration associated with ALS may be triggered by mechanisms leading to increased intracellular Ca2+. In the present report, Ca(2+)-activated phospholipid-dependent protein kinase C (PKC) was evaluated in cervical spinal cords from ALS patients and control subjects. In patients who died with ALS, PKC histone H1 phosphotransferase activity was significantly increased by 330% in cytosolic- and 118% in particulate-derived extracts compared with controls. This increase in PKC phosphotransferase activity appeared to be partially due to an increase in the amount of PKC protein present in ALS spinal cord tissue. PKC histone H1 phosphotransferase activities of cytosolic- and particulate-derived extracts from motor and visual cortex of ALS patients and controls were not statistically different, nor were there differences in PKC histone H1 phosphotransferase activity in platelets and leukocytes. The specific nature of PKC alterations in affected regions of the CNS supports a role for PKC in the events leading to motoneuron death in sporadic ALS.

Aged↗
PubMed1995

Pharmacokinetics of inhaled liposome-encapsulated fentanyl.

BACKGROUND: Pulmonary administration of fentanyl solution can provide satisfactory but brief postoperative pain relief. Liposomes are microscopic phospholipid vesicles that can entrap drug molecules. Liposomal delivery of fentanyl has the potential to control the uptake of fentanyl by the lungs and thus provide sustained drug release. To demonstrate that inhalation of a mixture of free and liposome-encapsulated fentanyl can provide a rapid increase and sustained plasma fentanyl concentrations (CfenS), this study determined the pharmacokinetic profiles after the inhalation of free and liposome-encapsulated fentanyl in healthy volunteers. METHODS: After obtaining institutional approval and informed consent, ten healthy volunteers (five men, five women) were studied. Each subject received 200 micrograms intravenous fentanyl and inhaled 2,000 micrograms of free (50%) and liposome-encapsulated fentanyl (50%) on separate occasions. Frequent venous blood samples were collected, and CfenS were determined by radioimmunoassay. The pharmacokinetics and absorption characteristics of the inhaled mixture of free and liposome-encapsulated fentanyl were determined using moment analysis and least-squares numeric deconvolution. RESULTS: The mean (+/- SD) volume of distribution at steady-state and clearance of fentanyl after the intravenous administration were comparable to previous studies: 435 +/- 1821 and 0.584 +/- 0.209 l.min-1, respectively. The mean (+/- SD) peak Cfen was significantly greater for the intravenous administration compared to the aerosol mixture of free and liposome-encapsulated fentanyl (4.67 +/- 1.87 vs. 1.15 +/- 0.36 ng.ml-1). However, CfenS at 8 and 24 h after aerosol administration were greater compared to intravenous (0.25 +/- 0.14 and 0.12 +/- 0.16 ng.ml-1 for aerosol versus 0.16 +/- 0.10 and 0.05 +/- 0.06 ng.ml-1 for intravenous). The peak absorption rate, time to peak absorption, and bioavailability after inhalation were 7.02 (+/- 2.34) micrograms.min, -1(16) (+/- 8.0) min, and 0.12 (+/- 0.11), respectively. CONCLUSIONS: The data suggest that this analgesic method offers a simple and noninvasive route of administration with a rapid increase of Cfen and a prolonged therapeutic fentanyl concentration. Future studies are required to determine the optimal liposome composition that would produce a sustained stable Cfen within analgesic therapeutic concentrations.

Adult↗
PubMed1994

Liposomes as carriers for topical and transdermal delivery.

The delivery of active agents to the skin by liposome carriers is an interdisciplinary topic of great interest today. Data accumulated over the last decade strongly point to important advantages of these drug delivery systems. A symposium devoted to classic and new approaches in the use of liposomal systems was organized and chaired by M. Mezei and E. Touitou as a part of the Jerusalem Conference on Pharmaceutical Sciences and Clinical Pharmacology, held on May 24-30, 1992, in Jerusalem, Israel. The presentations focused on liposomes as tools in the mechanistic study of absorption promoters (T. Nagai), drug liposomal delivery in the skin strata and structures (N. Weiner), interaction of liposomes and niosomes with the human skin (H.E. Junginger), and design and characterization of caffeine liposomal systems for use in hyperproliferative diseases (E. Touitou). Mezei reviewed biodisposition and clinical studies on liposomal dosage forms containing various drugs.

Administration, Cutaneous↗
PubMed1994

Absorption of liposome-encapsulated tetracaine versus nonliposome-encapsulated tetracaine from open wounds in rabbits.

The plasma tetracaine concentration versus time profiles for liposome-encapsulated tetracaine (LET) versus nonliposome-encapsulated tetracaine (NLET) were determined after topical application to open wounds in six rabbits (three in LET and three in NLET). H3-tetracaine preparations of LET or NLET were applied randomly to uniform dermal lacerations in anesthetized rabbits. Plasma tetracaine concentrations (ng/mL) of arterial blood samples obtained were measured at predetermined intervals (0.25, 0.5, 1.0, 2.0, and 24 hours) by isotope tracer assay. Results (mean +/- standard deviation) showed the peak plasma tetracaine concentration (Cmax) and the time to Cmax were 40.8 +/- 5.1 ng/mL and 40.1 +/- 7.3 minutes for LET, and 117.8 +/- 9.7 ng/mL and 49.1 +/- 50.2 minutes for NLET. Plasma tetracaine concentrations at all samples times were significantly lower for LET versus NLET. Liposome encapsulation of topically applied tetracaine significantly decreases both the peak and overall plasma tetracaine concentrations compared with the nonencapsulated form. The data suggest that liposome encapsulation of topically applied local anesthetics such as a solution of tetracaine, adrenaline, and cocaine, might reduce the potential systemic toxicity caused by rapid absorption of these compounds.

Absorption↗
PubMed1991

Intracellular delivery of drugs by liposomes containing P0 glycoprotein from peripheral nerve myelin into human M21 melanoma cells.

The effect of P0 protein (a cell adhesion molecule from avian peripheral nerve myelin) on the rate of interaction of liposomes with human M21 melanoma cells was investigated. Liposome uptake by the cells was quantitated using radioactive lipids and liposome-entrapped drugs under various conditions. Liposomes containing P0 protein and [14C]dipalmitoylphosphatidylcholine:cholesterol (10:1 molar ratio) had an interaction rate with M21 cells three times higher than control vesicles of the same lipid composition but without the protein after incubation at 37 or 4 degrees C. The presence of P0 protein could be detected on the surface of melanoma cells by immunofluorescence after incubation. Binding to the cell surface and endocytosis of P0 liposomes was suggested from the sensitivity of cell-associated proteoliposomes to trypsin, metabolic inhibitors, and low temperature. Liposomal encapsulation highly increased the association of model compounds [( 3H]methotrexate and [3H]inulin) with cells. The proteoliposomes appeared to be leaky in the incubation medium, which led to the delivery of a lower amount of drug into cells than could be expected from their initial drug content. The results suggest that the attachment of liposomes to the cell surface can increase their drug delivery potential, because the binding triggers endocytic processes or a juxtapositional temporary permeability increase of liposome and cellular membrane that can lead to the uptake of drug from liposomes.

Cell Adhesion Molecules, Neuronal↗
PubMed1991

Inhibition of human renal cancer by monoclonal antibody targeted methotrexate-containing liposomes in an ascites tumor model.

The monoclonal antibody DAL K29 against a human renal cell carcinoma associated cell surface antigen was covalently linked to small unilamellar lipid vesicles (SUV) containing the antifolate, methotrexate (MTX), with full retention of antibody activity. In an ascites tumor model developed after intraperitoneal inoculation of 5 x 10(6) cells of the human kidney cancer line Caki-1 per pristane primed nude mouse, the DAL K29 linked MTX-containing SUV was a more potent tumor inhibitor (P less than 0.0005) than the drug or MAB alone, MTX-containing SUV, a mixture of DAL K29 and MTX-containing SUV or MTX-containing SUV linked to an isotype matched nontumor specific IgG.

Animals↗
PubMed1990

Computational analysis of the effects of site-specific phosphate alkylation in the DNA oligomer (d-[GGAATTCC])2.

Alkylation of the sugar-phosphate backbone of DNA can result upon exposure to several potent carcinogens, inducing DNA misfunction. In order to assess the structural and energetic changes in DNA helices induced by such alkylation, we have performed AMBER-based analyses on phosphotriester containing analogues of (d-[GGAATTCC])2. Fourteen analogues of the nonalkylated oligomer were examined, each bearing a single alkylation of known stereochemistry. Results indicate that although there is minimal effect on the aromatic bases, the presence of a phosphotriester disturbs the sugar-phosphate backbone in complex ways. For most analogues, total minimum energies are lower for the Sp-alkylations than for the Rp-alkylations which point directly into the major groove of the helix; however, different energetic contributions follow different, or no, trends in dependence on alkylation site and/or stereochemistry. Where data is available, experimental nmr results agree with the calculations reported here.

Alkylation↗
PubMed1989

Targeting of methotrexate-containing liposomes with a monoclonal antibody against human renal cancer.

The potential of monoclonal antibody-linked small unilamellar vesicles containing methotrexate [(MTX)SUVs] in cancer chemotherapy was investigated. (MTX)SUVs prepared by probe sonication [50 +/- 20 (SD) nm in diameter] were linked covalently to Dal K29 (an IgG1 monoclonal antibody against human renal cancer), normal mouse IgG, or a nonspecific mouse myeloma IgG1. After incubation with a human kidney cancer cell line, CaKi-1, for 2 h, Dal K29-linked (MTX)SUVs showed 6 and 8 times more binding to CaKi-1 cells than nonspecific mouse myeloma IgG1-linked (MTX)SUV or (MTX)SUVs unlinked. After incubation with Dal K29-linked ([3H]MTX)SUVs, a higher amount of radioactivity was associated with CaKi-1 cells at 37 degrees C than at 4 degrees C. Membrane immunofluorescence revealed aggregation and capping of Dal K29-linked SUVs around CaKi-1 cells after incubation at 37 degrees C for 2 h and endocytosis at 4 and 6 h. Electron microscopic examination confirmed the aggregation of Dal K29-linked SUVs on the surface of CaKi-1 cells and their presence in endocytic vesicles at 4 and 6 h. After incubation with Dal K29-linked gold containing SUVs at 37 degrees C, gold-containing SUVs were seen on the surface as well as inside endocytic vesicle of CaKi-1 cells at 2 and 4 h. A colony inhibition assay showed that Dal K29-linked (MTX)SUVs were 5 and 40 times more potent than Dal K29-MTX and equimolar amounts of free untrapped MTX in inhibiting the growth of the target CaKi-1 cells but were not toxic to a human melanoma line (that did not react with Dal K29).

Antibodies, Monoclonal↗
PubMed1989

Effect of liposomes on hamster oral mucosa.

The histologic reaction to topically applied or intramucosally injected DPPC/chol (2:1 molar ratio) liposomes was investigated. No reaction to liposomes was observed 4 days after daily topical application. However, a mild focal immune type inflammatory reaction was observed after 21 days topical treatment. Intramucosal injection of liposome produced no irritation but a macrophage reaction limited to the injection site, which was followed by healing and complete tissue regeneration.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1989

Inhibition of human renal cancer by methotrexate linked to a monoclonal antibody.

The monoclonal antibody DAL K29 against a human renal cell carcinoma associated cell surface antigen was covalently linked to the antifolate methotrexate with full retention of antibody reactivity and partial retention of drug activity. In a colony inhibition assay, antibody-conjugated methotrexate was 400% more potent in inhibiting the growth of the human kidney cancer line Caki-1 than equimolar amounts of the free drug. Comparable amounts of the antifolate linked to normal mouse IgG did not inhibit the growth of Caki-1 cells. Furthermore, the methotrexate-DAL K29 conjugate had no effect on the two nontarget human cell lines tested, melanoma M21 and B cell leukemia D10-1 cells, even when the conjugate contained amounts of methotrexate equivalent to the 50% inhibitory concentration of the free drug for the nontarget cell lines or an amount equivalent to the 50% inhibitory concentration of the conjugated drug for Caki-1 cells.

Antibodies, Monoclonal↗
PubMed1988

Antibody directed targeting of methotrexate-containing small unilamellar vesicles.

The potential of antibody-linked SUVs containing MTX in anticancer therapy was investigated. The SUVs, mean diameter 50 +/- 20 nm, were prepared by probe sonication of MTX-containing MLVs and were covalently linked either to a RAMG or NRG. After incubation with M21 melanoma cells for 2 h, RAMG-linked SUVs showed 2 and 4 times more binding than NRG-linked MTX-containing SUVs or MTX-containing SUVs unlinked to any Ig. Furthermore, on incubating M21 melanoma cells with RAMG-linked 3H MTX-containing SUVs for 2, 4, and 8 h at 4 degrees C or 37 degrees C, a higher radioactivity was associated with cells at 37 degrees C than at 4 degrees C. Membrane immunofluorescence revealed aggregation of and cap formation by RAMG-linked SUVs after 2 h (37 degrees C) and endocytosis at 4 and 8 h at 37 degrees C. Electron microscopic and autoradiographic studies confirmed aggregation of 3H MTX-containing SUVs around and on the surface of M21 cells. Electron microscopy also revealed these SUVs inside invaginations of and under the plasma membrane of melanoma cells. A colony inhibition assay showed that RAMG-linked, MTX-containing SUVs were 60 times, 8 times, and 4.5 times more growth inhibitory than free MTX, NRG-linked MTX-containing SUV, and MTX-containing SUVs unlinked to any Ig, but not toxic to a human kidney cancer line (that did not react with RAMG).

Antibodies, Neoplasm↗
PubMed1988

Topical anesthesia of the skin by liposome-encapsulated tetracaine.

The potential of a liposomal local anesthetic formulation to provide topical anesthesia of the intact skin was investigated. Tetracaine base 0.5% was encapsulated into multilamellar phospholipid vesicles. The topical anesthetic effects of the liposomal and a control (Pontocaine cream) preparation were evaluated by pinprick technique in adult volunteers. Liposomal tetracaine-produced anesthesia, which lasted at least 4 hours after 1 hour application under occlusion. Pontocaine cream was ineffective. The liposomal formulation appeared to be suitable to provide long lasting anesthesia of the skin with low drug concentration.

Administration, Cutaneous↗