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PubMed1993

The effect of fluorine substitution on the physicochemical properties and the analgesic activity of paracetamol.

The physicochemical properties and analgesic action of six fluorinated analogues of 4-hydroxyacetanilide (paracetamol) have been investigated. Fluorine substitution adjacent to the hydroxyl group increased lipophilicity and oxidation potential whilst substitution adjacent to the amide had little effect on lipophilicity but led to a greater increase in oxidation potential. Lack of coplanarity and conjugation of the amide group and aromatic ring was also apparent with the analogues that had fluorine in the 2 and 6 positions. Introduction of fluorine into the amide group of paracetamol increased the lipophilicity 4-fold and also increased the oxidation potential of paracetamol. ED50 values for analgesic activity in the phenylquinone-induced abdominal constriction test on male Swiss White mice showed that ring substitution by fluorine reduced activity, especially at the 2,6-positions. Introduction of fluorine into the amide group enhanced activity significantly. Correlation of the analgesic activity with the physicochemical properties indicated that conjugation (and planarity) of the amide group with the aromatic ring is essential for activity and that ease of oxidation may also be an important factor.

Acetaminophen↗
PubMed2001

Metabolism of fluorine-containing drugs.

This article reviews current knowledge of the metabolism of drugs that contain fluorine. The strategic value of fluorine substitution in drug design is discussed in terms of chemical structure and basic concepts in drug metabolism and drug toxicity.

Animals↗
PubMed2002

Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent: implications for rational therapy of restenosis.

BACKGROUND: Restenosis is a serious complication of coronary angioplasty that involves the proliferation and migration of vascular smooth muscle cells (VSMCs) from the media to the intima, synthesis of extracellular matrix, and remodeling. We have previously demonstrated that tissue factor-targeted nanoparticles can penetrate and bind stretch-activated vascular smooth muscles in the media after balloon injury. In the present study, the concept of VSMC-targeted nanoparticles as a drug-delivery platform for the prevention of restenosis after angioplasty is studied. METHODS AND RESULTS: Tissue factor-targeted nanoparticles containing doxorubicin or paclitaxel at 0, 0.2, or 2.0 mole% of the outer lipid layer were targeted for 30 minutes to VSMCs and significantly inhibited their proliferation in culture over the next 3 days. Targeting of the nanoparticles to VSMC surface epitopes significantly increased nanoparticle antiproliferative effectiveness, particularly for paclitaxel. In vitro dissolution studies revealed that nanoparticle drug release persisted over one week. Targeted antiproliferative results were dependent on the hydrophobic nature of the drug and noncovalent interactions with other surfactant components. Molecular imaging of nanoparticles adherent to the VSMC was demonstrated with high-resolution T1-weighted MRI at 4.7T. MRI 19F spectroscopy of the nanoparticle core provided a quantifiable approach for noninvasive dosimetry of targeted drug payloads. CONCLUSIONS: These data suggest that targeted paramagnetic nanoparticles may provide a novel, MRI-visualizable, and quantifiable drug delivery system for the prevention of restenosis after angioplasty.

Animals↗
PubMed1976

Intravenous flunitrazepam as an anesthetic induction agent.

The effects of the fluorinated benzodiazepine compound flunitrazepam were studied in eighty patients. The drug was administered intravenously in a standard dose of 2 mg, 3 mg, or 4 mg to supplement lumbar epidural analgesia. Induction was smooth and pleasant. The sleep onset time was dose related and exceeded one minute in the majority of patients. Sleep was invariably produced in patients receiving 4 mg but at lower dosage some patients failed to become unconscious. Pain in the arm during injection was a common feature. The respiratory rate was slightly increased, but in two patients apnoea occurred at induction. The cardiovascular system was minimally depressed with a small decrease in systolic blood pressure and pulse rate. Recovery from sleep was slow but sequelae were minimal. The sedative and amnesic properties contributed significantly to the high rate of patient acceptance.

Adjuvants, Anesthesia↗
PubMedDate not supplied

Fluoride poisoning: a puzzle with hidden pieces.

Key industry data regarding harm from chronically inhaled fluoride have been unavailable publicly for decades. Recent unveiling of unpublished reports reveals three examples of data mishandling that disguised the need for more stringent occupational standards for particulate and gaseous fluorides and fluorine. Injury reports from workers handling chemicals show that unjustifiable reductions of injury and disability numbers in the process of publication shifted concern from respiratory to mineralized tissue damage. Selective editing and data omissions allowed bias that fluoride reduces caries without detrimental effects. Finally, industry's failure to publish an important industry-funded laboratory study buried knowledge of low thresholds for fluoride-induced lung disease. Data from that study are presented to clarify the dose- and duration-dependent changes caused by chronic inhalation of calcium fluoride.

Air Pollutants, Occupational↗
PubMed2000

Enhancement of fluorouracil uptake in human colorectal and gastric cancers by interferon or by high-dose methotrexate: An in vivo human study using noninvasive (19)F-magnetic resonance spectroscopy.

PURPOSE: To study whether two modulators, high-dose methotrexate (MTX) and interferon alfa-2a (IFNalpha-2a) will alter the intratumoral pharmacokinetics of fluorouracil (5-FU). PATIENTS AND METHODS: Five patients, two with gastric cancer and three with colorectal cancer, who had metastatic tumor nodules in their livers were studied dynamically in vivo after 5-FU injection. In a magnetic resonance imaging unit, noninvasive (19)F-magnetic resonance spectroscopy (MRS) was used to detect (19)F signals from 5-FU and its metabolites. RESULTS: The intratumoral half-life (t(1/2)) of 5-FU in these tumors ranged from 18.8 minutes to 42.3 minutes. Four of the five patients exhibited increases in the t(1/2) of 5-FU after intravenous (IV) administration of MTX or IFNalpha-2a. In the two patients with gastric cancer who received IV high-dose MTX followed by IV 5-FU, increases were seen in either the total t(1/2) of 5-FU (41.8%) or in the t(1/2) of the alpha phase (150%). In the three patients with colorectal cancer who received IV IFNalpha-2a followed by IV 5-FU, the two patients with partial responses had increases in the t(1/2) of 5-FU of 41% and 30.2%, whereas the nonresponder had a nonsignificant increase (5.6%) in the t(1/2) of 5-FU. CONCLUSIONS: These results document that the in vivo modulation of the tumoral pharmacokinetics of 5-FU can be measured noninvasively by (19)F-MRS and suggest that such information correlates with subsequent clinical outcomes. The findings also indicate that IFNalpha-2a and high-dose MTX can increase the intratumoral 5-FU in some patients. Such information, obtained prospectively in vivo, may assist in better individual cancer patient management and in developing novel drug combinations.

Adult↗
PubMed2000

Alpha-bromo-alpha,alpha-difluoroallyl derivatives as synthetic intermediate: nucleophilic substitution of alpha-bromo-alpha,alpha-difluoroallyl derivatives in the presence of palladium catalysts.

The palladium catalyzed nucleophilic substitution of alpha-bromo-alpha,alpha-difluoroallyl derivatives turned out to be an efficient method for the preparation of several fluorinated organic molecules. Several soft carbon nucleophiles regioselectively reacted with 3-bromo-3,3-difluoropropene (BDFP) to give the 3-substituted 1,1-difluoroalkenes. Phenylzinc chloride and tributylphenyltin afforded 1-fluoro-1,3-diphenylpropene. The radical bromination of 3-substituted 1,1-difluoroalkenes provided 1-substituted BDFPs, and a 1-substituted BDFP reacted with carbon nucleophiles to give 1,3-disubstituted 3,3-difluoroalkenes. For the reaction of nitrogen nucleophiles with BDFP, an amine and the sodium salts of the carbamates reacted with BDFP at the gamma-position. However, the sodium salts of the sulfoneamide predominantly attacked at the alpha-position.

Catalysis↗
PubMed2005

Historical comparison of perfluorooctanesulfonate, perfluorooctanoate, and other fluorochemicals in human blood.

The purpose of this investigation was to determine whether there has been a change in the human blood concentration of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and five other fluorochemicals since 1974. Blood samples were collected in 1974 (serum) and 1989 (plasma) from volunteer participants of a large community health study. The study included a total of 356 samples (178 from each time period). These samples were analyzed by high-pressure liquid chromatography/tandem mass spectrometry methods. The median 1974 and 1989 fluorochemical concentrations, respectively, were as follows: PFOS, 29.5 ng/mL vs. 34.7 ng/mL; PFOA, 2.3 ng/mL vs. 5.6 ng/mL; perfluorohexanesulfonate (PFHS), 1.6 ng/mL vs. 2.4 ng/mL; and N-ethyl perfluorooctanesulfonamidoacetate (PFOSAA), less than the lower limit of quantitation (LLOQ; 1.6 ng/mL, vs. 3.4 ng/mL). For N-methyl perfluorooctanesulfonamidoacetate (M570), perfluorooctanesulfonamide, and perfluorooctanesulfonamidoacetate, median serum concentrations in both years were less than the LLOQ values (1.0, 1.0, and 2.5 ng/mL, respectively). Statistical analysis of 58 paired samples indicated that serum concentrations of PFOS, PFOSAA, PFOA, PFHS, and M570 were significantly (p < 0.001) higher in 1989 than in 1974. The data from 1989 were then compared with geometric mean fluorochemical concentrations of serum samples collected in 2001 from 108 American Red Cross adult blood donors from the same region. Except for M570, there were no statistically significant (p < 0.05) geometric mean fluorochemical concentration differences between the 1989 and 2001 samples. In conclusion, based on this study population, PFOS and other serum fluorochemical concentrations have increased between 1974 and 1989. Comparison with other regional data collected in 2001 did not suggest a continued increase in concentrations since 1989.

Adult↗
PubMed2000

Fluorous-phase soluble polymeric supports.

Fluorous phase soluble polymer supports derived from fluoroacrylate polymers are described. N-Acryloxysuccinimide-containing fluoroacrylate polymers were readily prepared from commercially available monomers. The activated acrylates so prepared were then converted into chelating and non-chelating ligands by amidation of the N-acryloxysuccinimide active ester residues. Phosphine ligands attached to these supports were used to prepare neutral and cationic rhodium(I) hydrogenation catalysts as well as palladium(0) catalysts. Similar substitution of pendant active ester groups to form hydroxamic acid ligands for metal sequestration is also feasible. Liquid/liquid extraction readily separated, recycled and reused these polymer-bound ligands and catalysts. While fluorous phase solubility could be attained with polymers containing only heptafluorobutyryl groups, selective solubility in a fluorous phase in contact with an organic phase was only seen with fluoroacrylates that contained larger fluorinated ester groups.

Acrylates↗
PubMed1994

Fluorinated phospholipid-based vesicles as potential drug carriers: encapsulation/sustaining of drugs and stability in human serum.

The release of entrapped 5(6)-carboxyfluorescein from fluorinated vesicles in a buffer or in human serum is considerably less than that from hydrogenated liposomes. The presence of a fluorinated core inside the liposomal membrane definitely reduces its permeability. In some cases, the stability of liposomes made from fluorinated phospholipids alone is better than that of egg phosphatidylcholine cholesterol 1/1 vesicles, which are among the least permeable and most stable hydrogenated liposomes.

Blood Physiological Phenomena↗
PubMed2001

Oral fluoropyrimidine-based combination therapy in gastrointestinal cancer.

Significant emphasis has been placed recently on designing more effective fluorouracil (5-FU)-based combination protocols for gastrointestinal cancer. Promising results were seen with 5-FU/leucovorin in combination with irinotecan (Camptosar) or oxaliplatin (Eloxatin), especially in colorectal cancer. Clinical trials of UFT, with or without leucovorin, demonstrate the safety of this regimen and an efficacy comparable to that of bolus 5-FU/leucovorin in the treatment of gastrointestinal tumors. Two large randomized phase III trials of capecitabine (Xeloda) showed that capecitabine also offers a convenient alternative to bolus 5-FU/leucovorin with a superior safety profile and at least equivalent antitumor activity.

Administration, Oral↗
PubMed2001

Carbinolamines, imines, and oxazolidines from fluorinated propranolol analogs. (19)F NMR and mass spectral characterization and evidence for formation as intermediates in cytochrome P450-catalyzed N-dealkylation.

Formation of carbinolamine, imine, and oxazolidines from the reactions of desisopropylpropranolol (5), its O-methyl ether (10), and 3-(1-naphthoxy)propylamine (11) with trifluoroacetone and trifluoroacetaldehyde methyl hemiacetal was investigated by (19)F NMR and tandem mass spectrometry. Products from the metabolism of the related secondary amine substrates trifluoropropranolol (7), its O-methyl ether (23), and its N-trifluoroethyl-O-methyl ether analog (24) in the presence of rat liver microsomes and CYP1A2 were examined to determine whether these species were formed. The (19)F NMR experiments showed the presence of carbinolamine and imine species from these primary amines and fluorinated carbonyl compounds in solution. Mass spectral experiments under atmospheric pressure chemical ionization and electrospray ionization-ion trap conditions showed formation of imine metabolites (and/or oxazolidine from 7) as well as products of N-dealkylation and aromatic hydroxylation when the secondary amine substrates were incubated with rat liver microsomes or CYP1A2. In spite of mass spectral evidence for these imines as metabolites, we were unable to detect the carbinolamines under the conditions used in these studies. Their presence is inferred from the results of the (19)F NMR experiments.

Animals↗
PubMed2000

[A study of fluoride-containing composite resins: fluoride release, water sorption and dissolution].

OBJECTIVE: To study fluoride release and its impact on the basic properties. METHODS: Fluoride releasing was determined by F-electrodes, water sorption and dissolution of the materials were determined by weight/volume loss technique. RESULTS: The profile of fluoride release from fluoride-containing composites was different from that of compomer. Meanwhile, fluoride-containing materials showed larger values of water sorption (13.05-31.64 micrograms/mm3) and dissolution(5.88-24.80 micrograms/mm3) than controls. CONCLUSIONS: The F- releasing may affect physical and mechanical properties of fluoride-containing composites.

Composite Resins↗