Most cited papers:
Potential of low molecular mass chitosan as a DNA delivery system: biocompatibility, body distribution and ability to complex and protect DNA.
Centre for Polymer Therapeutics, School of Pharmacy, University of London, UK.
Cationic polymers have the potential for DNA complexation and it is recognised that they may be useful as non-viral vectors for gene delivery. Highly purified chitosan fractions of < 5000 Da (N1), 5000-10,000 Da (N2) and > 10,000 Daltons (N3) were prepared and characterised in respect of their cytotoxicity, ability to cause haemolysis, ability to complex DNA as well as to protect DNA from nuclease degradation. Also the biodistribution of 125I-labelled chitosans was followed at 5 and 60 min after intravenous injection into male Wistar rats. All chitosan fractions displayed little cytotoxicity against CCRF-CEM and L132 cells (IC50 > 1 mg/ml), and they were not haemolytic (< 15% lysis after 1 and 5 h). Chitosan-DNA interaction at a charge ration of 1:1 was much greater than seen for poly(L-lysine) and complexation resulted in inhibition of DNA degradation by DNase II: 99.9 +/- 0.1, 99.1 +/- 1.5 and 98.5 +/- 2.0% for N1, N2 and N3, respectively. After intravenous injection, all the chitosans showed rapid blood clearance, the plasma levels at 1 h being 32.2 +/- 10.5% of recovered dose for N1 and 2.6 +/- 0.5% of recovered dose for N3. Liver accumulation was molecular mass dependent, being 26.5 +/- 4.9% of the recovered dose for N1 and 82.7 +/- 1.9% of the recovered dose for N3. The observations that the highly purified chitosan fractions used were neither toxic nor haemolytic, that they have the ability to complex DNA and protect against nuclease degradation and that low molecular weight chitosan can be administered intravenously without liver accumulation suggest there is potential to investigate further low molecular weight chitosans as components of a synthetic gene delivery system.
Faculty of Dentistry, The University of Hong Kong, Prince Philip Dental Hospital, Hong Kong SAR, China. email@example.com
This review discusses current trends in the development of dentin adhesives and the possibility that some classes of currently available adhesives are too hydrophilic. Manufacturers have reformulated dentin adhesives to make them more compatible for bonding to intrinsically moist, acid-etched dentin by adding 2-hydroxyethyl methacrylate and other hydrophilic resin monomers. These 3-step adhesives work well but are more time consuming to use and more sensitive to technique than the newer, simplified adhesives. When primers are mixed with adhesives in 2-step single-bottle adhesives and self-etching primers, the adhesives are more permeable to water and hence absorb more water over time than previous generations of adhesives. The most recent single-step self-etching adhesives are even more hydrophilic and hence more permeable to water derived from the underlying bonded dentin. This permeability can lead to a wide variety of seemingly unrelated problems, including incompatibility of chemically or dual-cured composites with simplified adhesives and expedited degradation of resin-dentin bonds.
DRUG INTERACTIONS IN MAN. I. LOWERING EFFECT OF PHENOBARBITAL ON PLASMA LEVELS OF BISHYDROXYCOUMARIN (DICUMAROL) AND DIPHENYLHYDANTOIN (DILANTIN).
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
AIMS: The effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin, two inhibitors of HMG-CoA reductase with different pharmacokinetic properties, were studied. METHODS: Two separate randomized, placebo-controlled, cross-over studies, each involving 10 healthy volunteers, were carried out. The general design was identical in both studies. The subjects took either 100 mg itraconazole or matched placebo orally once daily for 4 days. On day 4, 40 mg fluvastatin or 40 mg lovastatin was administered orally. Plasma concentrations of fluvastatin, lovastatin, lovastatin acid, itraconazole and hydroxyitraconazole were determined up to 24 h. RESULTS: Itraconazole had no significant effect on the Cmax (190 +/- 124 ng ml(-1) vs 197 +/- 189 ng ml(-1)(mean +/- s.d.)) or total AUC (368 +/- 153 ng ml(-1) h vs 324 +/- 155 ng ml(-1) h) of fluvastatin compared with placebo. However, the t1/2,z of fluvastatin was slightly prolonged by itraconazole (2.8 +/- 0.49 h vs 2.4 +/- 0.51 h; P < 0.05). The Cmax of lovastatin was increased about 15-fold (P < 0.01) and the total AUC more than 15-fold (P < 0.01) by itraconazole. Similarly, the Cmax and total AUC of lovastatin acid were increased about 12-fold (95% CI, 5.3 to 17.7-fold; P < 0.01) and 15-fold (95% CI, 4.6 to 26.2-fold; P < 0.01) by itraconazole, respectively. The t1/2,z of lovastatin averaged 3.7 +/- 3.8 h and that of lovastatin acid 4.7 +/- 4.0 h during the itraconazole phase; these variables could not be determined in all subjects during the placebo phase. CONCLUSIONS: Itraconazole, even at a small dosage of 100 mg daily, greatly elevated plasma concentrations of lovastatin and its active metabolite, lovastatin acid. Lovastatin should therefore not be used concomitantly with itraconazole and other potent CYP3A4 inhibitors, or the dosage of lovastatin should be greatly reduced while using a CYP3A4 inhibitor. In contrast, fluvastatin concentrations were not significantly increased by itraconazole, indicating that fluvastatin has much less potential than lovastatin for clinically significant interactions with itraconazole and other CYP3A4 inhibitors.
Cefuroxime is a new broad spectrum cephalosporin antibiotic for administration by injection. It is stable to most beta-lactamases. It is active against gram-positive organisms, including penicillinase-producing staphylococci, and has wide activity against gram-negative bacilli including Enterobacter and many strains of indole-positive Proteus spp. The substance is also highly active against Haemophilus influenzae and Neisseria gonorrhoeae. Studies on human volunteers showed that it produced high, long-lasting blood levels with virtually complete recovery of unchanged antibiotic in the urine. No evidence of toxicity due to cefuroxime was found. Slight, short-lived pain followed intramuscular injection, and the compound was well tolerated intravenously.
Drug Management and Authorization Section, National Cancer Institute, Bethesda, MD 20892.
Taxol, a unique diterpene anticancer compound derived from the bark of the Taxus brevifolia (Pacific yew) tree, induces cytotoxicity by a novel mechanism of action. An antimicrotubule agent, Taxol promotes the formation and stabilization of the tubulin polymer unlike other anticancer agents that induce microtubule disassembly. Because of its poor aqueous solubility, Taxol is formulated as a solution in 50% Cremophor EL and 50% dehydrated alcohol, USP. The Cremophor EL and dehydrated alcohol vehicle used in the formulation of Taxol creates some interesting challenges for its preparation and administration. The pharmaceutical concerns associated with the preparation and administration of Taxol are discussed.
The authors describe a case of combined lithium and haloperidol toxicity characterized by hyperpyrexia, severe rigidity, mutism, and development of irreversible tardive dyskinesia. This case is similar to four other cases described in the literature and to the neuroleptic malignant syndrome. The authors postulate that two types of combined lithium-neuroleptic toxicity occur: a neuroleptic malignant extrapyramidal syndrome and a lithium toxicity that occurs in combination with phenothiazines, primarily thioridazine. Possible mechanisms and preventive measures are discussed.
Factors affecting calcium-phosphate solubility in parenteral nutrition solutions used in neonates were studied. Six neonatal parenteral nutrition solutions were prepared using either Aminosyn or FreAmine III and various amino acid and dextrose concentrations. Phosphorus (as mono- and dibasic potassium phosphate) and calcium (as 10% calcium gluconate) were added in concentrations of calcium 2.5-100 meq/liter and phosphorus 2.5-100 mmol/liter. Duplicate samples were prepared and analyzed either after they were heated in a water bath (37 degrees C) for 20 minutes or after 18 hours at 25 degrees C followed by 30 minutes in a water bath (37 degrees C). Precipitation was detected visually and spectrophotometrically, and pH was measured. Lipid emulsion was added to two Fre-Amine III solutions in a ratio of 7.5:1 (parenteral nutrition solution:lipid) and the resulting pH was measured. Time and temperature affected calcium-phosphate solubility in all solutions tested. Precipitation curves of amount of calcium versus amount of phosphate added were prepared for each solution. Amino acid and dextrose concentrations affected the pH of the solutions, and when a lipid emulsion was added, the pH rose more in the 1% than in the 2% FreAmine III solution. In selected solutions, as much as 120 mg/kg/day calcium and 55 mg/kg/day phosphate can be administered, approximating daily third-trimester accumulation of these minerals. Use of the precipitation curves in this paper, with attention to their limitations, should aid in the safe delivery of calcium and phosphorus intravenously to neonates.