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PubMed1984

Metabolism of vinylcyclooctane and partition ratio between epoxide formation and cytochrome P-450 destruction.

Vinylcyclooctane (VCO), which binds to the active site of cytochrome P-450 (P-450) giving a type I difference spectrum, has been found to form the corresponding epoxide as the main metabolite on treatment with liver microsomal monooxygenase obtained from phenobarbital-treated or untreated mice. During this metabolic process about 40% of the microsomal P-450 isozymes are destroyed, but the remainder still demethylates aminopyrine. Approx. 180 molecules of VCO are turned over and 132 of epoxyethylcyclooctane (EECO) are formed for each destructive event.

Animals↗
PubMed1995

Use of analgesics during propofol sedation: a comparison of ketorolac, dezocine, and fentanyl.

STUDY OBJECTIVE: To evaluate the comparative efficacy and side effect profile of ketorolac 60 mg, dezocine 6 mg, and fentanyl 100 micrograms when used as analgesic supplements to a propofol infusion during monitored anesthesia care (MAC). DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Ambulatory surgery facility at a university medical center. PATIENTS: 80 outpatients undergoing breast biopsy or inguinal herniorraphy procedures under MAC. INTERVENTIONS: All patients received midazolam 2 mg intravenously (IV) followed by 1 ml of the study medication containing either dezocine 3 mg IV, ketorolac 30 mg IV, fentanyl 50 micrograms IV, or normal saline. A propofol infusion was initiated at 75 micrograms/kg/min and then varied to maintain a stable level of sedation (i.e., Observer Assessment of Alertness/Sedation scale score of 3). An additional 1 ml of the same study medication was administered IV 2 to 3 minutes prior to infiltration of the local anesthetic solution. During the operation, supplemental (rescue) medication consisted of fentanyl 25 micrograms IV, bolus injections in all four treatment groups. MEASUREMENTS AND MAIN RESULTS: Propofol infusion and supplemental fentanyl dosage requirements, oxygen saturation values, respiratory rates, recovery times, and postoperative side effects were recorded. Visual analog scales were used to assess sedation, anxiety, pain, and nausea preoperatively (baseline), upon entry into the postanesthesia care unit, and at 30-minute intervals until discharge. The fentanyl and dezocine groups required lower average infusion rates of propofol to maintain a stable level of sedation than the control (saline) group. The saline and ketorolac groups required rescue analgesic medication more frequently and/or larger supplemental dosages of fentanyl than the two opioid analgesic treatment groups. Compared with the three analgesic treatment groups, postoperative pain scores were only marginally higher in the control group. Ketorolac-treated patients had consistently (but not significantly) shorter recovery times to oral intake, ambulation, and discharge than those in the dezocine or fentanyl groups. No postoperative nausea, vomiting, or pruritus was reported in the ketorolac group. CONCLUSION: Compared with ketorolac 60 mg, fentanyl 100 micrograms and dezocine 6 mg produced a greater decrease in the propofol sedation requirement during MAC. However, the use of ketorolac in combination with propofol for MAC was associated with an improved recovery profile.

Adult↗
PubMed1995

The proteolytic specificity of the natural enediyne-containing chromoproteins is unique to each chromoprotein.

BACKGROUND: Enediyne chromoproteins are potent antitumor antibiotic agents. They consist of a labile nine-membered enediyne chromophore non-covalently associated with a stabilizing acidic polypeptide. Studies in vitro on three members of this superfamily of natural products--kedarcidin, maduropeptin and neocarzinostatin--demonstrated that their chromophores cleave DNA at sites specific to each chromophore. Recently, we showed that these chromoproteins possess proteolytic activity against histones in vitro, with histone H1 as a preferred substrate. Based on these results, we speculated that this selective proteolytic activity may be important in vivo in the delivery of the enediynes intact to the DNA in chromatin. RESULTS: We show here that each chromoprotein generates a unique set of H1 fragments as revealed by gel analyses of the H1 cleavage reaction products. To probe the observed cleavage specificity, we synthesized a 24-amino-acid peptide representing a basic region of histone H1. This model peptide was incubated individually with similar concentrations of the kedarcidin, neocarzinostatin and maduropeptin chromoproteins as well as the kedarcidin apoprotein. The reaction products were analyzed by electrospray liquid chromatography/mass spectrometry. Our results indicate that all proteins cleave the peptide at selected backbone amides, and that these sites vary according to the chromoprotein used. Moreover, the kedarcidin apoprotein appears to be less specific than the kedarcidin chromoprotein complex. CONCLUSIONS: The small size, unique architecture and very acidic nature of the enediyne chromoproteins are highly unusual. These natural products exhibit the dual functionalities of specific DNA cleavage and selective proteolytic activity. This observation adds to the fascinating properties of these molecules and suggests that it is possible not only to design small moieties to cleave DNA but also to conceive of small proteins to deliver these moieties intact to defined areas of chromatin.

Alkynes↗
PubMed2005

Novel synthesis and anti-inflammatory activities of 2,5-disubstituted-dioxacycloalkanes.

A novel stereospecific synthetic route to obtain a series of 2,5-disubstituted-dioxacycloalkanes is reported. Using an in vivo inhibition assay by monitoring xylene-induced ear edema in mice, the structure-activity relationship of the dioxacycloalkane compounds was studied, and compounds possessing high anti-inflammatory activity were identified.

Animals↗
PubMed2005

Stereoselective synthesis and anti-inflammatory activities of 6- and 7-membered dioxacycloalkanes.

A class of 5-trifluoroacetylamino-1,3-dioxacycloalkanes, 5-benzoylamino-1,3-dioxacycloalkanes, and 5-amino-1,3-dioxacycloalkane compounds were stereoselectively synthesized as potential anti-inflammatory drug candidates. The anti-inflammatory activities of these compounds were tested using the xylene-induced mouse ear edema model, from which multiple compounds possessing anti-inflammatory properties which surpass aspirin were identified; these compounds were then compared to establish structure-activity relationships.

Animals↗
PubMed2006

Normal-phase chiral liquid chromatography-mass spectrometry of non-UV-active compounds: applications for pharmaceutically relevant racemates.

Mixtures of hexane-like ethoxynonafluorobutane with alcohols were used as MS-friendly mobile phases for separation and efficient detection of non-UV-active enantiomers and diastereomers using normal-phase HPLC-APCI-MS. Racemic muscone, camphorsulfonamide, camphorsultam, BOC-protected 1-(3-aminopropyl)-2-pipecoline and diastereomeric 2-methylhexanoyl camphorsultams were resolved on Chiralpak AS and AD and achiral Luna CN columns. The responses of UV and APCI-MS detectors were compared under separation conditions studied, with MS detection achieving lowest detectable quantity in the range of 0.5-2 ng per chromatographic peak. The absolute configuration of crystalline derivatives of racemic 2-methylhexanoic acid with (S)-(-)-2,10-camphorsultam was determined by X-ray analysis after their automatic purification by preparative LC-MS. The technique described can be used to purify and determine the absolute stereochemistry of compounds of unknown structure which contain free carboxy group and lack sufficient UV absorbance.

Butanes↗
PubMed2004

Unexpected reactivity difference between iodo-alkene moieties of steroids possessing remote lactame or cycloalkane structural units: a theoretical approach.

The steroidal ring A possessing cyclohexane vs. delta-valerolactame structures shows a 'long-range effect' on the reactivity of the 'iodovinyl' functionality of the ring D. The strikingly different reactivity of 17-iodo-16-ene functionality of steroids is explained on the basis of the redistribution of kinetic energy of the system. The vibrational energy localized on the 'iodovinyl' moiety proved to be determinant in the CI bond-breaking process. The appearance of the lactame moiety in the ring A supports a redistribution of the kinetic energy on the molecule. As a result, a drastic decrease in C-I bond stretching has been obtained, which could diminish the C-I bond breaking, and therefore, results in decreased reactivity of the iodovinyl moiety in agreement with experimental findings.

Alkenes↗
PubMed2006

Contribution of epoxyeicosatrienoic acids to the hypoxia-induced activation of Ca2+ -activated K+ channel current in cultured rat hippocampal astrocytes.

Brief hypoxia differentially regulates the activities of Ca(2+)-activated K(+) channels (K(Ca)) in a variety of cell types. We investigated the effects of hypoxia (<2% O(2)) on K(Ca) channel currents and on the activities of cytochrome P450 2C11 epoxygenase (CYP epoxygenase) in cultured rat hippocampal astrocytes. Exposure of astrocytes to hypoxia enhanced macroscopic outward K(Ca) current, increased the open state probability (NPo) of 71 pS and 161 pS single-channel K(Ca) currents in cell-attached patches, but failed to increase the NPo of both the 71 pS and 161 pS K(Ca) channel currents recorded from excised inside-out patches. The hypoxia-induced enhancement of macroscopic K(Ca) current was attenuated by pretreatment with tetraethylammonium (TEA, 1 mM) or during recording using low-Ca(2+) external bath solution. Exposure of astrocytes to hypoxia was associated with generation of superoxide as detected by staining of cells with the intracellular superoxide detection probe hydroethidine (HE), attenuation of the hypoxia-induced activation of unitary K(Ca) channel currents by superoxide dismutation with tempol, and as quantitated by high-pressure liquid chromatography/fluorescence assay using HE as a probe. In cultured astrocytes in which endogenous CYP epoxygenase activity has been inhibited with either miconazole or N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MSPPOH) hypoxia failed to increase the NPo of both the 71 pS and 161 pS K(Ca) currents and generation of superoxide. Hypoxia increased the level of P450 epoxygenase protein and production of epoxyeicosatrienoic acids (EETs) from cultured astrocytes, as determined by immunohistochemical staining and LC/MS analysis, respectively. Exogenous 11,12-EET increased the NPo of both the 71 pS and 161 pS K(Ca) single-channel currents only in cell-attached but not in excised inside-out patches of cultured astrocytes. These findings indicate that hypoxia enhances the activities of two types of unitary K(Ca) currents in astrocytes by a mechanism that appears to involve CYP epoxygenase-dependent generation of superoxide and increased production or release of EETs.

Animals↗
PubMed2005

Benzene formation during aquasonolysis of selected cyclic C6Hx hydrocarbons.

Yield and selectivity of benzene produced from aquasonolysis of the selected cyclic C6Hx hydrocarbons, i.e., 1,4-cyclohexadiene, 1,3-cyclohexadiene, cyclohexene, cyclohexane, and methylcyclopentane, have been investigated in this work. Benzene cannot be detected during the aquasonolysis of cyclohexane and methylcyclopentane. The order of yield and selectivity of benzene was as follows: 1,4-cyclohexadiene>>1,3-cyclohexadiene>>cyclohexene. The initial concentrations of substrates can affect the yield of benzene. During the aquasonolysis of 1,3-cyclohexadiene and cyclohexene, other C6 species except benzene were also found. It was suggested that benzene could directly be generated by formal dehydrogenation of cyclic C6Hx hydrocarbons.

Benzene↗
PubMed1969

Inhibition of pyrimidine dimer formation in DNA by cationic molecules: role of energy transfer.

In addition to the acridine dyes, acridine orange and proflavine, we find that three other cationic molecules which bind to DNA-ethidium bromide, chloroquine, and methyl green-inhibit the production of cyclobutyl pyrimidine dimers by ultraviolet radiation. Intercalation is not necessary for dimer inhibition. The long range nature of the inhibition implies that energy transfer is responsible. The transfer is between the lowest excited singlet state of DNA and the acceptor singlet, and seems to involve the Förster mechanism.

Acridines↗
PubMed1996

Opioid antagonist effects of dezocine in opioid-dependent humans.

Dezocine is an opioid mu-partial agonist recently approved for use as an analgesic in the United States. This study characterized the relative agonist versus antagonist effects of dezocine in comparison to naloxone (an opioid antagonist), hydromorphone (an opioid mu-agonist), and placebo (saline solution) in opioid-dependent volunteers. In a residential laboratory, six volunteer male opioid abusers maintained on 30 mg/day oral methadone underwent pharmacologic challenges two to three times per week, 20 hours after the last dose of methadone. Challenges consisted of a double-blind intramuscular injection of dezocine (dose range, 7.5 to 60 mg), hydromorphone (5 and 10 mg), naloxone (0.1 and 0.2 mg), or saline solution. Measures included physiologic indexes, self-reports of drug effects, and observer ratings of drug effects. Naloxone and hydromorphone produced characteristic antagonist-like and agonist-like effects, respectively. Dezocine acted as an opioid antagonist, precipitating a withdrawal syndrome only slightly different from that produced by naloxone. Dezocine's antagonist effects were not directly dose related, but peaked at intermediate doses and declined at higher doses.

Adult↗