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[Use of atypical antipsychotics in Charles Perrens psychiatric hospital (Bordeaux) analysis of prescribing practices for Amisulpride, Clozapine, Olanzapine and Risperidone].

UNLABELLED: The commercial introduction of atypical antipsychotics (AAP) constitutes a considerable step forward in the sense that it has led to a world-wide reappraisal of the established treatment strategies for people with psychoses (including schizophrenia and affective psychoses). They have allowed refinements in the pharmacologic management of psychoses but they have a higher acquisition cost than conventional neuroleptics. The cost of the newer AAP had a substantial effect on medical resources: the AAP account for only 43.2% of neuroleptic prescriptions, but 76.1% of medical costs associated with neuroleptic drugs, and in terms of treatment costs, a reduction (50%) was found with risperidone compared with olanzapine for a same number of treated patients. The aim of this paper was to examine the use of these drugs, to compare them and to assess their impact within the context of psychiatric hospital practice, by means of analysis of prescribing practices for amisulpride, clozapine, olanzapine and risperidone for all treated patients. We conducted an observational, naturalistic study at Charles Perrens psychiatric Hospital in Bordeaux (France) that reproduced the clinical conditions in which these new drugs are used. Four photographies of all the medical prescriptions concerning atypical antipsychotic drugs were done between October 1999 (four months after the introduction in France of the olanzapine, the last of the new antipsychotics) and June 2001 (n=682 prescriptions). The total amount of these prescriptions corresponded to 527 patients. Treatment groups were compared - first overall and after by considering 2 groups: psychotic and non-psychotic patients - through descriptive analyses of sociodemographic characteristics of patients, diagnosis, percentages of patients receiving concomitant psychotropic medication and/or receiving treatment-emergent side effects and mean dosages of AAP therapy according to concomitant medication. In the same way, we compared the four AAP through their prescribing practices'evolution during the four survey. RESULTS: AAP drugs account for 43.2% of prescriptions (and conventional neuroleptics 56.8% of them). We recorded a significant increase between the four surveys (p<0.02): 36.6% at the beginning to 47.8% at the end of the study. From the 682 collected prescriptions, 72 (10.6%) included clozapine, 130 (19.1%) amisulpride, 229 (33.6%) olanzapine and 251 (36.8%) risperidone. Sixty five percent of AAP prescriptions involved psychotic patients. A relative stability in characteristics of AAP prescriptions during the four surveys was found. So, no significant differences were observed between amisulpride, olanzapine, risperidone, in terms of age, sex, sociodemographic characteristics, unlike clozapine. However, there were statistical differences between all the AAP in the concurrent use of other neuroleptic agents (p<0.02), hypnotic drugs (p<0.006), mood stabilizer drugs (p<0.03), and anticholinergic drugs (p<0.007). Statistically, the mean dosage of amisulpride increased when a mood stabilizer drug was coprescribed (p<0.0007), but it decreased with an antidepressant drug (p<0.004) or an hypnotic drug (p<0.02); clozapine 's one decreased every time an antidepressant drug was coprescribed (p<0.02); with olanzapine, there was a significant increase every time an other neuroleptic agent (p<0.03) or an anticholinergic drug (p<0.006) was associated; then for risperidone, the mean dosage increased with the coprescription of an other neuroleptic agent (p<0.00002), an anticholinergic (p<0.00003) or an adrenolytic drug (p<0.04). The pattern of prescribing practices that emerges from our four surveys suggests that these new AAP are significantly more and more often associated with a stabilizer mood drug (p<0.009) (particularly the olanzapine) or/and an anxiolytic drug (p<0.05) (like the amisulpride in particular). Considering the four AAP globally, but more with the risperidone, the association with a neurovegetative corrector agent decreased (p<0.004) during the four surveys. Then, concerning the psychoticng the four surveys. Then, concerning the psychotic patients, the AAP were significantly more often associated with other neuroleptic agents (p<0.03), the amisulpride in particular, with anticholinergic drugs (p<0.00005), but significantly less with mood stabilizer drugs (p<0.00003) principally the amisulpride and the risperidone, with antidepressant drugs (p<0.02) particularly the risperidone. This kind of survey, however it is too much rare, is very important because it shows the clinical conditions in which these new drugs are really used. The results show that AAP appear to be the replacements of the older neuroleptics used in the treatment of psychoses, including particularly schizophrenia, but also in the treatment of mood disorders, and they reflect actual clinical practices. Other surveys must be achieved to see if our study confirms the general trend concerning the use of these drugs and so as to reassess these prescribing practices.

Adolescent↗
PubMed1991

Oltipraz-induced amelioration of acetaminophen hepatotoxicity in hamsters. II. Competitive shunt in metabolism via glucuronidation.

Previously, we demonstrated that oltipraz [OTP: 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] prevented the hepatotoxicity of acetaminophen (AAP) in hamsters and that the observed protection was not related to increases in hepatic reduced glutathione (GSH) levels. These experiments were designed to elucidate the mechanism of OTP-induced protection with respect to an apparent non-GSH-dependent system. Marked differences in the relative amounts of hepatic GSH content depleted by AAP in control vs OTP-treated hamsters occurred. Urinary recoveries of AAP and metabolites indicated that more AAP-glucuronide was formed at the expense of other major metabolites (AAP-GSH, -N-acetylcysteine, and -sulfate) in OTP-treated hamsters, while plasma toxicokinetic modeling suggested a greater rate of AAP systemic clearance. An increased apparent formation rate constant for AAP glucuronidation (135%), in concert with significantly lower apparent formation rate constants for those metabolites which reflect the production of the reactive intermediate from AAP (glutathione and N-acetylcysteine), provide the rationale for this shift of metabolism. The biochemical basis for metabolic shunting is significantly elevated hepatic UDP-glucuronic acid content, an increased calculated UDP-glucuronic acid synthetic rate, and an increased liver microsomal UDP-glucuronyl transferase activity in OTP-treated animals. These changes in AAP conjugation were concomitant with decreased fractional clearance of AAP via bioactivation and less in vivo AAP covalent binding. These data support the hypothesis that OTP provides a protecting effect from AAP hepatotoxicity due to an augmented and predisposing glucuronidation capacity.

Acetaminophen↗
PubMed2001

Ca(2+)-calmodulin antagonist chlorpromazine and poly(ADP-ribose) polymerase modulators 4-aminobenzamide and nicotinamide influence hepatic expression of BCL-XL and P53 and protect against acetaminophen-induced programmed and unprogrammed cell death in mice.

Acetaminophen (AAP), the analgesic hepatotoxicant, is a powerful inducer of oxidative stress, DNA fragmentation, and apoptosis. The anti-apoptotic oncogene bcl-XL, and the pro-apoptotic oncogene p53 are two key regulators of cell cycle progression and/or apoptosis subsequent to DNA damage in vitro and in vivo. This study investigated the effect of AAP on the expression of these oncogenes and whether agents that modulate DNA fragmentation (chlorpromazine, CPZ) and DNA repair through poly(ADP-Ribose) polymerase (PARP) activity (4-AB: 4-aminobenzamide) can protect against AAP-induced hepatotoxicity by inhibiting oxidative stress, DNA fragmentation, and/or by altering the expression of bcl-XL and p53. In addition, the protective effect of supplemental nicotinamide (NICO), known to be depleted in cells with high PARP activity during DNA repair, is similarly evaluated. Male ICR mice (3 months old) were administered vehicle alone; nontoxic doses of 4-AB (400 mg/kg, ip), NICO (250 mg/kg, ip) or CPZ (25 mg/kg, ip), hepatotoxic dose of AAP alone (500 mg/kg, ip), or AAP plus one of the protective agents 1 h later. All animals were sacrificed 24 h following AAP administration. Serum alanine aminotransferase activity (ALT), hepatic histopathology and lipid peroxidation, DNA damage, and expression of bcl-XL and p53 (western blot analysis) were compared in various groups. All of the three agents significantly prevented AAP-induced liver injury, lipid peroxidation, DNA damage, and associated apoptotic and necrotic cell deaths, 4-AB being the most effective and NICO the least. Compared to control, there was a considerable decrease in bcl-XL expression, and an increase in p53 expression in AAP-exposed livers. The effect of AAP on bcl-XL was antagonized and that on p53 was synergized by the PARP-modulator 4-AB as well as NICO, whereas the endonuclease inhibitor CPZ was without effect on either bcl-XL or p53 expression. These results suggest that the hepatotoxic effect of AAP involves multiple mechanisms including oxidative stress, upregulation of endonuclease (or caspase-activated DNAse) and alteration of pro- and anti-apoptotic oncogenes. The observed antagonism of AAP-induced hepatocellular apoptosis and/or necrosis by modulators of multiple processes including DNA repair suggests the likelihood that a more effective therapy against AAP intoxication should involve a combination of antidotes.

4-Aminobenzoic Acid↗
PubMed2001

Inhibition of the aminopeptidase from Aeromonas proteolytica by L-leucinephosphonic acid. Spectroscopic and crystallographic characterization of the transition state of peptide hydrolysis.

The nature of the interaction of the transition-state analogue inhibitor L-leucinephosphonic acid (LPA) with the leucine aminopeptidase from Aeromonas proteolytica (AAP) was investigated. LPA was shown to be a competitive inhibitor at pH 8.0 with a K(i) of 6.6 microM. Electronic absorption spectra, recorded at pH 7.5 of [CoCo(AAP)], [CoZn(AAP)], and [ZnCo(AAP)] upon addition of LPA suggest that LPA interacts with both metal ions in the dinuclear active site. EPR studies on the Co(II)-substituted forms of AAP revealed that the environments of the Co(II) ions in both [CoZn(AAP)] and [ZnCo(AAP)] become highly asymmetric and constrained upon the addition of LPA and clearly indicate that LPA interacts with both metal ions. The X-ray crystal structure of AAP complexed with LPA was determined at 2.1 A resolution. The X-ray crystallographic data indicate that LPA interacts with both metal centers in the dinuclear active site of AAP and a single oxygen atom bridge is absent. Thus, LPA binds to the dinuclear active site of AAP as an eta-1,2-mu-phosphonate with one ligand to the second metal ion provided by the N-terminal amine. A structural comparison of the binding of phosphonate-containing transition-state analogues to the mono- and bimetallic peptidases provides insight into the requirement for the second metal ion in bridged bimetallic peptidases. On the basis of the results obtained from the spectroscopic and X-ray crystallographic data presented herein along with previously reported mechanistic data for AAP, a new catalytic mechanism for the hydrolysis reaction catalyzed by AAP is proposed.

Aeromonas↗
PubMed2001

Acetaminophen induces apoptosis of C6 glioma cells by activating the c-Jun NH(2)-terminal protein kinase-related cell death pathway.

Acetaminophen (AAP), a widely used analgesic drug, can damage various organs when taken in large doses. In this study, we investigate whether AAP causes cell damage by altering the early signaling pathways associated with cell death and survival. AAP caused time- and concentration-dependent apoptosis and DNA fragmentation of C6 glioma cells used as a model. AAP activated c-Jun N-terminal protein kinase (JNK) by 5.3-fold within 15 min. The elevated JNK activity persisted for up to 4 h before it returned to the basal level at 8 h. In contrast, activities of other mitogen-activated protein (MAP) kinases and the level of Akt phosphorylation in the cell survival pathway remained unchanged throughout the treatment. Wortmannin, an inhibitor of phosphatidylinositol-3 kinase, or SB203580, an inhibitor of p38 MAP kinase, did not reduce AAP-induced toxicity, indicating that these enzymes do not play a major role in cell toxicity. AAP-induced apoptosis was preceded by the sequential elevation of the pro-apoptotic Bax protein, cytochrome c release, and caspase-3 activity. Treatment with caspase inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (Z-DEVD-FMK) significantly reduced AAP-induced caspase-3 activation and cytotoxicity. Transfection of cDNA for the dominant-negative mutant JNK-KR or stress-activated protein kinase kinase-1 Lys-->Arg mutant (SEK1-KR), an immediate upstream kinase of JNK, significantly reduced AAP-induced JNK activation and cell death rate. The noncytotoxic analog of AAP, 3-hydroxyacetanilide, neither increased JNK activity nor caused apoptosis. Pretreatment with YH439, an inhibitor of CYP2E1 gene transcription, markedly reduced CYP2E1 mRNA, protein content, and activity, as well as the rate of AAP-induced JNK activation and cell death. These data indicate that AAP can cause cell damage by activating the JNK-related cell death pathway, providing a new mechanism for AAP-induced cytotoxicity.

Acetaminophen↗
PubMed1989

Effect of potassium ethylxanthogenate on the toxicity and analgesic effect of acetaminophen.

The effect of potassium ethylxanthogenate (PEX) on the toxicity and the analgesic effect of acetaminophen (AAP) were investigated on male albino mice. PEX in a dose of 80 mg/kg body weight, administered subcutaneously or orally one hour before AAP, or simultaneously with it, induces prolongation of the survival of the experimental animals and increases LD50 of AAP. The protective effect of PEX (s.c. and p.o.) is more pronounced when this agent is introduced one hour before AAP (i.p. and p.o.), compared with the simultaneous administration, and when it is applied orally, compared with the subcutaneous administration. The average lethal dose of the combination (AAP p.o. + PEX p.o. 1 hour previously) increases 2.57 times after observation for 7 days, compared with that of AAP. Although it does not possess its own analgesic effect, PEX potentiates the analgesic effect of AAP (which is more pronounced for the low AAP doses) and reduces its average effective dose. After 14-day administration, AAP potentiates its own analgesic effect in the lower doses. The potentiating effect of PEX on the analgesic effect of AAP is similar on the first and on the 14th day of the treatment. The principal mechanism through which PEX decreases the toxicity and potentiates the analgesic effect of AAP is assumed to be the inhibition of its metabolism by inhibition of the cytochrome P-450-linked monooxygenases, not ruling out the possibility of a certain effect on the AAP absorption.

Acetaminophen↗
PubMed2004

Pharmacokinetic studies of a novel anticonvulsant, 2-(4-chlorophenyl)amino-2-(4-pyridyl)ethane, in rats.

The pharmacokinetic properties of 2-(4-chlorophenyl)amino-2-(4-pyridyl)ethane (AAP-Cl) were studied in rats after intravenous and oral administration. The blood concentrations of AAP-Cl in rats showed a biexponential decline following intravenous administration of pharmacologic doses ranging from 10 to 100 mg/kg in rats. The terminal elimination half-lives (t((1/2)beta)) of AAP-Cl at the 10, 50 and 100 mg/kg dose levels were 5.80+/-0.30, 6.02+/-0.16 and 6.05+/-0.08 h, respectively. The total clearances (CL) of AAP-Cl at the 10, 50 and 100 mg/kg dose levels were 1.29+/-1.10, 1.38+/-0.07 and 1.33+/-0.13l/(h kg), respectively. The apparent volumes of distribution at steady state (V(ss)) of AAP-Cl at the 10, 50 and 100 mg/kg dose levels were 7.96+/-0.51, 8.24+/-0.31 and 8.17+/-0.43l/kg, respectively. The AUC(0-infinity) increased proportionately to the intravenous bolus dose of AAP-Cl given (10-100 mg/kg). Statistical analysis of the t((1/2)beta), V(ss) and CL values for AAP-Cl between doses indicates that AAP-Cl exhibits dose-independent kinetics (P>0.05). AAP-Cl was absorbed rapidly after an oral dose of 100 mg/kg with peak concentrations (C(max)) in blood (3.5+/-0.33 microg/ml) reached after 30 min of drug administration. The oral bioavailability of AAP-Cl was 19.5+/-3.4% following administration of a single 100 mg/kg dose in rats. Urine analysis indicates that 2.5+/-0.45% of the administered dose of AAP-Cl (100 mg/kg, p.o.) is recovered unchanged in urine within 0-24 h. These findings may be useful in designing new aminoalkylpyridine anticonvulsants with improved efficacy and disposition profiles in animal models of epilepsy.

Administration, Oral↗
PubMed2006

Chemoprotective effect of insulin-like growth factor I against acetaminophen-induced cell death in Chang liver cells via ERK1/2 activation.

The insulin-like growth factor (IGF) system and type-I IGF receptor (IGF-IR) signaling are involved in protecting against chemotherapeutic drug-induced cell death in human hepatoma cells. Acetaminophen (AAP) hepatotoxicity is the leading cause of liver failure, and the prevention of AAP-induced cell death has been the focus of many studies. We determined whether IGF-I could protect against AAP-induced cell death in Chang liver cells and investigated the protective mechanism. Based on the results of MTS assays, LDH release assays, Hoechst 33342 cell staining, and DNA fragmentation experiments, AAP induced cell death in a dose-dependent manner. According to Western blot analysis, treatment with AAP increased the level of poly(ADP-ribose) polymerase (PARP) fragments in cells compared with that in control cells; however, caspase-3, a critical signaling molecule in apoptosis, was not activated after AAP overdose. Moreover, combined treatment with AAP and IGF-I inhibited PARP cleavage, which was consistent with the ability of IGF-I to restore the level of glutathione (GSH) and cell viability in GSH and MTS assays, respectively. We investigated whether the protective effect of IGF-I against AAP cytotoxicity is related to the extracellular signal-related kinase ERK1/2, which is generally activated by mitogenic and proliferative stimuli such as growth factors. Compared with AAP treatment alone, IGF-I and AAP co-treatment increased ERK1/2 phosphorylation but inhibited PARP cleavage. Thus ERK1/2 activation is instrumental in the protective effect of IGF-I against AAP-induced cell death in Chang liver cells.

Acetaminophen↗
PubMed2000

Inhibition of the aminopeptidase from Aeromonas proteolytica by L-leucinethiol: kinetic and spectroscopic characterization of a slow, tight-binding inhibitor-enzyme complex.

The peptide inhibitor L-leucinethiol (LeuSH) was found to be a potent, slow-binding inhibitor of the aminopeptidase from Aeromonas proteolytica (AAP). The overall potency (K(I)*) of LeuSH was 7 nM while the corresponding alcohol L-leucinol (LeuOH) was a simple competitive inhibitor of much lower potency (K(I) = 17 microM). These data suggest that the free thiol is likely involved in the formation of the E x I and E x I* complexes, presumably providing a metal ligand. In order to probe the nature of the interaction of LeuSH and LeuOH with the dinuclear active site of AAP, we have recorded both the electronic absorption and EPR spectra of [CoCo(AAP)], [CoZn(AAP)], and [ZnCo(AAP)] in the presence of both inhibitors. In the presence of LeuSH, all three Co(II)-substituted AAP enzymes exhibited an absorption band centered at 295 nm, characteristic of a S --> Co(II) ligand-metal charge-transfer band. In addition, absorption spectra recorded in the 450 to 700 nm region all showed changes characteristic of LeuSH and LeuOH interacting with both metal ions. EPR spectra recorded at high temperature (19 K) and low power (2.5 mW) indicated that, in a given enzyme molecule, LeuSH interacts weakly with one of the metal ions in the dinuclear site and that the crystallographically identified mu-OH(H) bridge, which has been shown to mediate electronic interaction of the Co(II) ions, is likely broken upon binding LeuSH. EPR spectra of [CoCo(AAP)]-LeuSH, [ZnCo(AAP)]-LeuSH, and [Co_(AAP)]-LeuSH were also recorded at lower temperature (3.5-4.0 K) and high microwave power (50-553 mW). These signals were unusual and appeared to contain, in addition to the incompletely saturated contributions from the signals characterized at 19 K, a very sharp feature at g(eff) approximately 6.5 that is characteristic of thiolate-Co(II) interactions. Combination of the electronic absorption and EPR data indicates that LeuSH perturbs the electronic structure of both metal ions in the dinuclear active site of AAP. Since the spin-spin interaction seen in resting [CoCo(AAP)] is abolished upon the addition of LeuSH, it is unlikely that a mu-S(R) bridge is established.

Aeromonas↗
PubMed1999

Inhibition of the aminopeptidase from Aeromonas proteolytica by aliphatic alcohols. Characterization of the hydrophobic substrate recognition site.

Seven aliphatic and two aromatic alcohols were tested as reporters of the substrate selectivity of the aminopeptidase from Aeromonas proteolytica (AAP). This series of alcohols was chosen to systematically probe the effect of carbon chain length, steric bulk, and inhibitor shape on the inhibition of AAP. Initially, however, the question of whether AAP is denatured in the presence of aliphatic alcohols was addressed. On the basis of circular dichroism (CD), electronic absorption, and fluorescence spectra, the secondary structure of AAP, with and without added aliphatic alcohols, was unchanged. These data clearly indicate that AAP is not denatured in aliphatic alcohols, even up to concentrations of 20% (v/v). All of the alcohols studied were competitive inhibitors of AAP with K(i) values between 860 and 0.98 mM. The clear trend in the data was that as the carbon chain length increases from one to four, the K(i) values increase. Branching of the carbon chains also increases the K(i) values, but large bulky groups, such as that found in tert-butyl alcohol, do not inhibit AAP as well as leucine analogues, such as 3-methyl-1-butanol. The competitive nature of the inhibition indicates that the substrate and each alcohol studied are mutually exclusive due to binding at the same site on the enzyme. On the basis of EPR and electronic absorption data for Co(II)-substituted AAP, none of the alcohols studied binds to the dinuclear metallo-active site of AAP. Thus, reaction of the inhibitory alcohols with the catalytic metal ions cannot constitute the mechanism of inhibition. Combination of these data suggests that each of these inhibitors bind only to the hydrophobic pocket of AAP and, consequently, block the binding of substrate. Thus, the first step in peptide hydrolysis is the recognition of the N-terminal amino acid side chain by the hydrophobic pocket adjacent to the dinuclear active site of AAP.

1-Propanol↗
PubMed1995

Infant sleep position: pediatricians' advice to parents.

OBJECTIVE: The American Academy of Pediatrics' (AAP) recommendation for side or supine sleep position in healthy babies has generated much controversy. We surveyed primary care physicians to determine the effect of the AAP statement on physician attitude toward infant sleep position and advice to parents. METHODS: We sent a 23-question survey to 194 physicians in Western New York. The survey addressed their attitude toward the AAP recommendations and its impact on their advice to parents. RESULTS: Of the 149 physicians treating newborns, 121 (82%) completed the questionnaire; 98% were aware of the AAP statement. The most common sources of information were the AAP (86%) and professional literature (77%). Of the respondents, 79% agreed with the AAP statement. Reasons for reservation were lack of data (64%), potential adverse consequences of supine position (52%), and their own experience (47%). Gender, years in practice, and type of reimbursement did not influence attitude toward the AAP recommendation. The AAP statement increased the frequency with which physicians routinely discussed sleep position from 34 to 70% (P < .02). Physicians recommending the prone position decreased from 57 to 7% (P < .001), while those recommending supine sleep position increased from 10 to 42% (P < .001). CONCLUSIONS: Most physicians agreed with the AAP statement and more frequently discussed sleep position following the AAP recommendations. However, they did not routinely recommend supine sleep position. The majority (69%) recommended the side position even though it is unstable. Although the AAP statement has increased discussion of infant sleep position by primary care physicians in WNY, only a minority recommend that infants sleep supine.

Data Collection↗
PubMed1999

Off-flavor compounds in wine and other food products formed by enzymatical, physical, and chemical degradation of tryptophan and its metabolites.

Tryptophan (TRP) and its metabolites are considered as potential precursors of 2-aminoacetophenone (AAP) in different food products causing different off-flavors. AAP is also responsible for the "untypical aging flavor (UTA)" in wine, developing a floor polish-like flavor in white wines within a few months of storage. In this study the formation of AAP was elucidated by GC-MS analysis of volatile components in model systems, grape musts and wines, spiked with TRP and different TRP metabolites like indole-3-acetic acid (IAA) and sulfite. In sulfurized wines and model solutions which were stored at different temperatures (20 degrees C, 45 degrees C) formylaminoacetophenone (FAP) and AAP were formed mainly from IAA with formation rates up to 20 mole%. Minor formation rates of AAP (< 1 mole%) were found in sulfurized solutions of TRP, indole-3-lactic acid, and indole-3-pyruvic acid. The results showed that the formation of AAP in wine can be referred to an oxidative degradation of IAA by superoxide- and hydroxyl-radicals, which can be formed in wine after the sulfuration by cooxidation of sulfite to sulfate. After decarboxylation, pyrrole oxidation, and ring cleavage, FAP was the main volatile compound of the nonenzymatic degradation of IAA by sulfite which was quantitatively hydrolyzed to AAP. The formation of AAP and FAP was significantly lower in white wines than in ethanolic solutions spiked with IAA. However AAP formation rates of up to 5 mole% were still enough for an UTA. Due to the fact that the AAP- and UTA-formation by cooxidation of sulfite and IAA was completely blocked in red wines, it could be deduced that polyphenolic compounds, typical for red wines, have a scavenger effect on the radical oxidation of sulfite. Possibilities for an inhibition of the IAA degradation during winemaking to avoid the UTA in white wines by addition of radical scavengers like grape marc or ascorbic acid are discussed.

Acetophenones↗
PubMed1997

Mechanistic studies on the aminopeptidase from Aeromonas proteolytica: a two-metal ion mechanism for peptide hydrolysis.

The aminopeptidase from Aeromonas proteolytica (AAP) is uncompetitively inhibited by fluoride ion at pH 8.0 with an inhibition constant (Ki) of 30 mM. Thus, fluoride inactivates AAP only after substrate binding, and only a single fluoride ion binds to AAP. On the other hand, chloride ion does not inhibit AAP up to concentrations of 2 M at pH 8.0. The pH dependence of fluoride inhibition of AAP was measured over the pH range 6.0-9.5. Between pH values of 6.0 and 9.0, fluoride ion acts as a pure uncompetitive inhibitor of AAP, and the Ki increases from 1.2 to 370 mM. From a plot of pKi vs pH, a pKa value of 7.0 +/- 0.3 was extracted which corresponds to a single deprotonation process. At pH values higher than 9.0, the fluoride inhibition pattern changes to competitive. This change in inhibition pattern was attributed to a change in ionic strength or perhaps pH of the solution since fluoride ion was also found to become a competitive inhibitor of AAP at pH 8.0 in the presence of 2 M NaCl. These data, taken together with previous kinetic studies of mono- and dinuclear hydrolases with fluoride ion, suggest that a Zn(II)-bound water/hydroxide exists at the dimetal active site of AAP with a pKa of 7.0 and that this water/hydroxide acts as the active site nucleophile. The hydrolysis of L-leucine-p-nitroanilide was measured spectrophotometrically in triplicate between 25 and 85 degrees C at eight substrate concentrations ranging from 5 to 800 microM. From these data, Km values were derived at each temperature studied and were found to increase exponentially with increasing temperature. Moreover, the calculated Vmax values were also found to increase over this temperature range, mimicking the Km values. An Arrhenius plot was constructed from k(cat) values and was found to be linear over the temperature range 25-85 degrees C, indicating that the rate-limiting step in AAP peptide hydrolysis is product formation and does not change as a function of temperature. From the slope of the line, the activation energy (Ea) was calculated to be 36.5 kJ/mol. The enthalpy and entropy of activation at 25 degrees C calculated over the temperature range 298-358 K were found to be 34.0 kJ/mol and -94.2 J/(mol x K), respectively. The free energy of activation at 25 degrees C was found to be 62.1 kJ/mol. Combination of the available X-ray crystallographic data with the present kinetic and thermodynamic results, as well as the previously reported kinetic and spectroscopic data, has allowed a detailed catalytic mechanism for AAP to be proposed.

Aeromonas↗
PubMed1999

Slow-binding inhibition of the aminopeptidase from Aeromonas proteolytica by peptide thiols: synthesis and spectroscopic characterization.

Peptide-derived thiols of the general structure N-mercaptoacyl-leucyl-p-nitroanilide (1a-c) were synthesized and found to be potent, slow-binding inhibitors of the aminopeptidase from Aeromonas proteolytica (AAP). The overall potencies (K(I)) of these inhibitors against AAP range from 2.5 to 57 nM exceeding that of the natural product bestatin and approaching that of amastatin. The corresponding alcohols (2a-b) are simple competitive inhibitors of much lower potencies (K(I) = 23 and 360 microM). These data suggest that the free thiols are involved in the formation of the E. I and E.I complexes, presumably serving as a metal ligand. To investigate the nature of the interaction of the thiol-based inhibitors with the dinuclear active site of AAP, we have recorded electronic absorption and EPR spectra of Co(II)Co(II)-, Co(II)Zn(II)-, and Zn(II)Co(II)-AAP in the presence of the strongest binding inhibitor, 1c. Both [CoZn(AAP)] and [ZnCo(AAP)], in the presence of 1c, exhibited an absorption band centered at 320 nm characteristic of an S --> Co(II) ligand-metal charge-transfer band. In addition, absorption spectra recorded between 400 and 700 nm showed changes characteristic of 1c interacting with each active-site metal ion. EPR spectra recorded at high temperature (19 K) and low power (2.5 mW) indicated that in a given enzyme molecule, 1c interacts weakly with one of the metal ions in the dinuclear site and that the crystallographically identified micro-OH(H) bridge, which has been shown to mediate electronic interaction of the Co(II) ions, is likely broken upon 1c binding. EPR spectra of [CoCo(AAP)]-1c, [ZnCo(AAP)]-1c, and [CoZn(AAP)]-1c were also recorded at lower temperature (3.5-4.0 K) and high microwave power (50-553 mW). The observed signals were unusual and appeared to contain, in addition to the incompletely saturated contributions from the signals characterized at 19 K, a very sharp feature at g(eff) approximately 6.8 that is characteristic of thiolate-Co(II) interactions. These data suggest that the thiolate moiety can bind to either of the metal ions in the dinuclear active site of AAP but does not bridge the dinuclear cluster. Compounds 1a-c are readily accessible by synthesis and thus provide a novel class of potent aminopeptidase inhibitors.

Aeromonas↗
PubMed1996

Synthesis, biotransformation, and pharmacokinetic studies of 9-(beta-D-arabinofuranosyl)-6-azidopurine: a prodrug for ara-A designed to utilize the azide reduction pathway.

As a part of our efforts to design prodrugs for antiviral nucleosides, 9-(beta-D-arabinofuranosyl)-6-azidopurine (6-AAP) was synthesized as a prodrug for ara-A that utilizes the azide reduction biotransformation pathway. 6-AAP was synthesized from ara-A via its 6-chloro analogue 4. The bioconversion of the prodrug was investigated in vitro and in vivo, and the pharmacokinetic parameters were determined. For in vitro studies, 6-AAP was incubated in mouse serum and liver and brain homogenates. The half-lives of 6-AAP in serum and liver and brain homogenates were 3.73, 4.90, and 7.29 h, respectively. 6-AAP was metabolized primarily in the liver homogenate microsomal fraction by the reduction of the azido moiety to the amine, yielding ara-A. However, 6-AAP was found to be stable to adenosine deaminase in a separate in vitro study. The in vivo metabolism and disposition of ara-A and 6-AAP were conducted in mice. When 6-AAP was administered by either oral or intravenous route,the half-life of ara-A was 7-14 times higher than for ara-A administered intravenously. Ara-A could not be found in the brain after the intravenous administration of ara-A. However, after 6-AAP administration (by either oral or intravenous route), significant levels of ara-A were found in the brain. The results of this study demonstrate that 6-AAP is converted to ara-A, potentially increasing the half-life and the brain delivery of ara-A. Further studies to utilize the azide reduction approach on other clinically useful agents containing an amino group are in progress in our laboratories.

Animals↗
PubMed2000

Forming, changing, and acting on attitude toward affirmative action programs in employment: a theory-driven approach.

A model of attitude toward affirmative action programs (AAPs) was applied in 4 studies involving 1,622 participants. In Study 1, attributes people tacitly associate with AAPs were identified by open-ended elicitation. Using those attributes, an instrument was developed and administered in Studies 2, 3, and 4. In those studies, a multiplicative composite of beliefs and evaluations about the AAP attributes predicted AAP attitude, consistent with M. Fishbein and I. Ajzen's (1975) theory of reasoned action. Demographic effects on AAP attitude were partially mediated by this composite. In Studies 3 and 4, an experimental manipulation of AAP information was successful in changing AAP attitude, but in a way that polarized existing demographic differences. Study 4 also showed that AAP attitude and subjective norm jointly and uniquely predicted intentions to perform AAP-related behaviors. Intentions predicted the actual behavior of mailing postcards to political representatives reflecting participants' support for AAPs.

Adult↗
PubMed1999

A highly conserved mechanism of regulated ribosome stalling mediated by fungal arginine attenuator peptides that appears independent of the charging status of arginyl-tRNAs.

The Arg attenuator peptide (AAP) is an evolutionarily conserved peptide involved in Arg-specific negative translational control. It is encoded as an upstream open reading frame (uORF) in fungal mRNAs specifying the small subunit of Arg-specific carbamoyl phosphate synthetase. We examined the functions of the Saccharomyces cerevisiae CPA1 and Neurospora crassa arg-2 AAPs using translation extracts from S. cerevisiae, N. crassa, and wheat germ. Synthetic RNA containing AAP and firefly luciferase (LUC) sequences were used to program translation; analyses of LUC activity indicated that the AAPs conferred Arg-specific negative regulation in each system. The AAPs functioned either as uORFs or fused in-frame at the N terminus of LUC. Mutant AAPs lacking function in vivo did not function in vitro. Therefore, trans-acting factors conferring AAP-mediated regulation are in both fungal and plant systems. Analyses of ribosome stalling in the fungal extracts by primer extension inhibition (toeprint) assays showed that these AAPs acted similarly to stall ribosomes in the region immediately distal to the AAP coding region in response to Arg. The regulatory effect increased as the Arg concentration increased; all of the arginyl-tRNAs examined appeared maximally charged at low Arg concentrations. Therefore, AAP-mediated Arg-specific regulation appeared independent of the charging status of arginyl-tRNA.

Amino Acid Sequence↗
PubMed2006

Aerobic anoxygenic phototrophic bacteria in the Mid-Atlantic Bight and the North Pacific Gyre.

The abundance of aerobic anoxygenic phototrophic (AAP) bacteria, cyanobacteria, and heterotrophs was examined in the Mid-Atlantic Bight and the central North Pacific Gyre using infrared fluorescence microscopy coupled with image analysis and flow cytometry. AAP bacteria comprised 5% to 16% of total prokaryotes in the Atlantic Ocean but only 5% or less in the Pacific Ocean. In the Atlantic, AAP bacterial abundance was as much as 2-fold higher than that of Prochlorococcus spp. and 10-fold higher than that of Synechococcus spp. In contrast, Prochlorococcus spp. outnumbered AAP bacteria 5- to 50-fold in the Pacific. In both oceans, subsurface abundance maxima occurred within the photic zone, and AAP bacteria were least abundant below the 1% light depth. The abundance of AAP bacteria rivaled some groups of strictly heterotrophic bacteria and was often higher than the abundance of known AAP bacterial genera (Erythrobacter and Roseobacter spp.). Concentrations of bacteriochlorophyll a (BChl a) were low ( approximately 1%) compared to those of chlorophyll a in the North Atlantic. Although the BChl a content of AAP bacteria per cell was typically 20- to 250-fold lower than the divinyl-chlorophyll a content of Prochlorococcus, the pigment content of AAP bacteria approached that of Prochlorococcus in shelf break water. Our results suggest that AAP bacteria can be quite abundant in some oceanic regimes and that their distribution in the water column is consistent with phototrophy.

Aerobiosis↗