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PubMed1991

Plasma pharmacokinetics of the antitumour agents 5,6-dimethylxanthenone-4-acetic acid, xanthenone-4-acetic acid and flavone-8-acetic acid in mice.

Although the antitumour agent flavone-8-acetic acid (FAA) exhibits remarkable activity against murine solid tumours, its clinical use has a number of pharmacological drawbacks, including low dose potency and dose-dependent pharmacokinetics. Xanthenone-4-acetic acid (XAA) and its 5,6-dimethyl derivative (5,6-MeXAA) were synthesised during a search for better analogues of FAA. The maximal tolerated doses (MTDs) of 5,6-MeXAA, XAA and FAA in BDF1 mice were 99, 1,090 and 1,300 mumol/kg, respectively. At the MTD, 5,6-MeXAA displayed the following pharmacokinetic properties: maximal plasma concentration, 600 microM; mean residence time, 4.9 h; AUC, 2,400 mumol h 1-1; and volume of steady-state distribution, 0.2 l/kg. All compounds displayed nonlinear elimination kinetics at the MTD, but when the logarithm of the AUC was plotted against that of the delivered dose, the slope of the regression line for 5,6-MeXAA was found to be 1.2 as opposed to 1.4 for XAA and 1.98 for FAA. 5,6-MeXAA thus showed only a slight deviation from dose-independent kinetics. 5,6-MeXAA bound to plasma proteins in a manner similar to that exhibited by FAA, although the plasma concentration of free drug was lower for the former than for the latter. As a consequence, the calculated maximal free drug concentration for 5,6-MeXAA in plasma was 23 times lower than that for FAA.

Animals↗
PubMed2005

Facile exchange of glycosyl S,S-acetals to their O,O-acetals and preparation of glycofuranosides from acyclic glycosyl S,S-acetals under metal-free reaction conditions in the presence of 1,3-dibromo-5,5-dimethylhydantoin.

Exchange of acyclic glycosyl dithioacetals to their O,O-acetals has been achieved by a generalized reaction protocol mediated by 1,3-dibromo-5,5-dimethylhydantoin under mild, metal-free and neutral conditions. This methodology has been extended to the synthesis of alkyl glycofuranosides.

Acetals↗
PubMed2006

Pharmacokinetics of chlormadinone acetate following single and multiple oral dosing of chlormadinone acetate (2 mg) and ethinylestradiol (0.03 mg) and elimination and clearance of a single dose of radiolabeled chlormadinone acetate.

BACKGROUND: Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life (t(1/2,z)). MATERIALS AND METHODS: Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for six menstrual cycles. Plasma concentrations of CMA and EE were determined by gas chromatography-mass spectrometry. Single-dose and steady-state pharmacokinetic parameters were calculated. In a separate study, healthy female volunteers were given a single 2-mg dose of radiolabeled CMA. Concentrations of radioactivity in fecal and urine samples were determined via liquid scintillation. Excretion of total radioactivity was calculated as percentage of administered dose. RESULTS: Eighteen women completed the repeated-dose study. Peak plasma concentrations for CMA and EE were reached within 1 and 2 h after taking the study drug. Peak plasma concentrations of CMA were approximately 1600 pg/mL after single-dose administration and 2000 pg/mL after multiple dosing. CMA and EE showed linear pharmacokinetics throughout six cycles, with constant trough values of approximately 400-500 pg/mL for CMA and 20-40 pg/mL for EE. Mass balance factors were 1.2-1.4 for CMA and 1.6-1.7 for EE, and accumulation factors were 1.7-2 for CMA and 1.7-1.8 for EE. Mean t(1/2,z) of CMA was approximately 25 h after single dosing and 36-39 h at steady state. In the excretion balance study, mean dose of CMA recovered was 87.3+/-6.4%, with urinary and fecal excretion accounting for 45% and 42%, respectively. CONCLUSIONS: The pharmacokinetics of CMA and EE is linear after multiple dosing and remains stable during long-term administration, once steady state is reached. The t(1/2,z) of CMA was 36-39 h after multiple dosing, which is considerably shorter than the 80 h often quoted in the literature.

Adolescent↗
PubMed2000

Zuclopenthixol acetate in the treatment of acute schizophrenia and similar serious mental illnesses.

BACKGROUND: People with schizophrenia or other psychotic illnesses may have delusions or hallucinations that may lead them to be aggressive or violent to themselves or others. Medication that is used in this context require the properties of rapid onset of effect (tranquillisation or at least initial sedation in order to quell aggressive or disorganised behaviour, but also antipsychotic effect), low frequency of administration and low levels of side effects, such as cardiological or neurological side effects, or pain at the injection site. Zuclopenthixol is the cis(Z)-isomer of clopenthixol, a neuroleptic of the thioxanthene group, used for treating people with psychotic symptoms. There is one oral preparation and two depot forms: zuclopenthixol acetate and zuclopenthixol decanoate. The acetate version does not stay in the body for very long (a single dose persists for only 72 hours) and is said to have these properties. OBJECTIVES: To estimate the effectiveness of zuclopenthixol acetate for the acute treatment of serious mental illnesses in comparison to other neuroleptic drugs. SEARCH STRATEGY: Searches of the Cochrane Schizophrenia Group's Register of Trials, The Cochrane Library, MEDLINE, abstracts of congresses and trial reference lists were performed. Appeals for unpublished data to the research community and to the Medical Information Department of Lundbeck Limited were also made. Attempts were made to contact relevant authors. SELECTION CRITERIA: Two reviewers independently assessed citations or papers and selected all randomised trials that included people with serious mental illnesses and compared zuclopenthixol acetate with other drug regimes. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers. Attempts were made to contact authors for additional or missing information. Odds-ratios (OR) and 95% confidence intervals (CI) were estimated for binary data. Where possible, OR were pooled using Peto method and intention-to-treat analysis undertaken. Mean differences were used for continuous variables. MAIN RESULTS: Pooled data shows no difference for the outcome 'no important improvement' in psychotic symptoms at the end of the follow-up period (OR 0.84 CI 0. 34-2.05). Sedation was evaluated using different instruments. Only one study presented data which suggested an earlier and more intense sedation in zuclopenthixol acetate users at 4 hours (OR 0.18 CI 0. 04-0.93). Use of additional antipsychotic medication was not avoided in the zuclopentixol acetate group (OR 2.18, CI 0.64-7.42) and data on total number of administrations was not obtainable. Side effect data were poorly reported but there is no evidence of a consistent difference between zuclopenthixol acetate and other 'standard drugs' for either the pattern of side effects or the wish to leave the study early. Hospital and service outcomes, number of aggressive incidents, satisfaction with care and economic outcomes were not addressed by any study. REVIEWER'S CONCLUSIONS: Recommendations on the use of zuclopenthixol acetate for the management of psychiatric emergencies in preference to 'standard' treatment have to be viewed with caution. Most trials present important methodological flaws and findings are poorly reported. This review did not find any suggestion that zuclopenthixol acetate is more effective in controlling aggressive/disorganised behaviour, acute psychotic symptoms, or preventing side effects. There were no data directly related to tranquillisation, but it may produce more earlier and intense sedation than oral haloperidol. Well conducted randomized controlled trials are needed to confirm claims related to the use of zuclopenthixol acetate in emergency psychiatry.

Acute Disease↗
PubMed1980

[The in vivo metabolism of chlormadinone acetate in guinea pig and the uptake of testosterone-3 H and chlormadinone acetate-3 H in prostate of castrated male rat (author's transl)].

The metabolic fate and distribution of the anti-androgenic agent, 17 alpha-acetoxy-6-chloropregna-4, 6-diene-3, 20-dione (chlormadinone acetate, CMA), was investigated using guinea-pigs and rats. In order to elucidate the metabolic outcome, chlormadinone acetate was labelled with 3H at position C-1 and with deuterium at methyl moiety of the 17alpha-acetate. Guineapigs were maintained for 7 days on a diet containing 1% chlormadinone acetate having a ratio of d2/d0=1 and then for 1 day on a diet containing 1% chlormadinone acetate having radioactivity. The isolation and purification of the urinary and fecal metabolites were usually carried out in the manner shown in Fig. 1 and 2. The metabolites identified were as follows: the parent drug, monohydroxychlormadinone acetate having the additional hydroxy function in the steroid skeleton, 15 beta-hydroxy, 2 alpha-, 2 beta-hydroxy and unknown position, dihydroxy chlormadinone acetate, 2 alpha-, 3 beta-dihydroxy, 2 alpha-, 3 alpha-dihydroxychlormadinone acetate. Further, three dechlornated and reduced metabolites were also isolated from urine and feces. These were 17 a-acetoxy-5a-pregnane-3 beta-ol-20-one and its isomer, and 17-acetoxy-5 beta-pregnane-2 beta, 3 beta, 15a-triol-20-one. But 3 beta-hydroxychlormadinone acetate possessd with anti-androgenic activity, one of the main metabolites in humans and rats, was not found in the excreta of the guinea-pigs. However, the main metabolite on the prostate of the guinea-pigs and rats and 3 beta-hydroxychlormadinone acetate. Chlormadinone acetate causes regression of the seminal vesicle and prostate in oral administration to a mammalian. It was therefore hypothesized that chlormadinone acetate might inhibit the uptake and retention of testosterone in these tissues. To elucidate this hypothesis, the accumulation of testosterone-3H and chlormadinone acetate-3H in several organs was determined on castrated rats and normal rats, respectively. When 1.0 muM of testosterone-3H was given to the castrated rats, a maximal accumulation of radioactivity resulted in seminal vesicle and prostate at 15 approximately 120 min. While the treatment of chlormadinone acetate significantly prevented the accumulation of testosterone-3H in the seminal vesicle and prostate, but levels in fat and muscle were not evident. In addition, to prove the accumulation of chlormadinone acetate in androgen target tissues, 3 muM of chlormadinone acetate-3H was similarly administered to castrated rats. The uptake of chlormadinone acetate on the target organs was higher than that in normal rats at 5 approximately 30 min.

Animals↗
PubMed2001

A prospective randomized comparison of routine buserelin acetate and a decreasing dosage of nafarelin acetate with a low-dose gonadotropin-releasing hormone agonist protocol for in vitro fertilization and intracytoplasmic sperm injection.

OBJECTIVE: To compare the efficacy of a draw-back nafarelin acetate protocol with routine buserelin acetate administration for in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). DESIGN: Prospective clinical study. SETTING: Mie University School of Medicine, Tsu, Mie, Japan. PATIENT(S): One hundred sixty-nine women treated with IVF and 183 women treated with ICSI. INTERVENTION(S): Nafarelin acetate and buserelin acetate in ovarian hyperstimulation in IVF and ICSI were administered. MAIN OUTCOME MEASURE(S): The concentrations of estradiol (E(2)), FSH, LH, gonadotropin dosages; the number of oocytes retrieved, oocytes fertilized, and embryos; and pregnancy rates. RESULT(S): A prospective study was conducted with 44 cycles for 34 couples with nafarelin acetate (group 1) and 47 cycles for 40 couples with buserelin acetate (group 2) with a long IVF protocol; 68 cycles for 46 couples with nafarelin acetate (group 3) and 56 cycles for 39 couples with buserelin acetate (group 4) with a short IVF protocol; 39 cycles for 32 couples with nafarelin acetate (group 5) and 50 cycles for 30 couples with buserelin acetate (group 6) with a long ICSI protocol; and 87 cycles for 60 couples with nafarelin acetate (group 7) and 81 cycles for 61 couples with buserelin acetate (group 8) with a short ICSI protocol. Patients were randomized to receive either full-dose nafarelin acetate (200 microg b.i.d.) treatment for 7 days followed by half-dose nafarelin acetate (200 microg daily) or buserelin acetate (300 microg t.i.d.). There were no statistically significant differences in baseline concentrations of E(2) and FSH, concentrations of E(2), P4, FSH, LH on hCG administration, gonadotropin dosage, the number of oocytes retrieved and embryos transferred, or pregnancy rates between groups 1 and 2, groups 3 and 4, groups 5 and 6, and groups 7 and 8. CONCLUSION(S): Full-dose nafarelin acetate treatment for 7 days followed by half-dose nafarelin acetate ("draw-back" protocol) is an effective new protocol for IVF and ICSI.

Abortion, Spontaneous↗
PubMed1993

Colonic acetate in the circulating acetate pool of the infant pig.

To identify potential sites of acetate utilization and synthesis, we studied the contribution of colonic acetate to the circulating acetate pool in six neonatal pigs by the simultaneous i.v. infusion of [3H]acetate and colonic infusion of [14C]acetate. In the fasting state, the mean (+/- SEM) acetate concentration was 17 +/- 1 mumol/L in peripheral venous blood, 28 +/- 4 mumol/L in the femoral artery, and 46 +/- 4 mumol/L in portal blood. This concentration gradient implies that acetate was utilized either by peripheral tissues alone or by both liver and peripheral tissues. At the end of the 2-h intracecal acetate infusion, mean acetate concentration increased in the femoral artery to 186 +/- 20 mumol/L and in the portal vein to 333 +/- 31 mumol/L. In the fasted state, mean acetate concentration in the portal vein was on average 63% higher than the acetate concentration of the femoral artery, whereas specific radioactivity of the [3H]acetate in the portal vein was only 5% of that in the femoral artery. It is possible, therefore, that a high proportion of the arterial input of acetate is utilized by the portal-drained viscera. Our study identified the gastrointestinal tract as an important site of acetate utilization in the fasted state. Further, it showed that colonic acetate was efficiently absorbed and utilized in the gastrointestinal tract of infant pigs.

Acetates↗
PubMed2001

Mechanisms of acetate formation and acetate activation in halophilic archaea.

The halophilic archaea Halococcus (Hc.) saccharolyticus, Haloferax (Hf.) volcanii, and Halorubrum (Hr.) saccharovorum were found to generate acetate during growth on glucose and to utilize acetate as a growth substrate. The mechanisms of acetate formation from acetyl-CoA and of acetate activation to acetyl-CoA were studied. Hc. saccharolyticus, exponentially growing on complex medium with glucose, formed acetate and contained ADP-forming acetyl-CoA synthetase (ADP-ACS) rather than acetate kinase and phosphate acetyltransferase or AMP-forming acetyl-CoA synthetase. In the stationary phase, the excreted acetate was completely consumed, and cells contained AMP-forming acetyl-CoA synthetase (AMP-ACS) and a significantly reduced ADP-ACS activity. Hc. saccharolyticus, grown on acetate as carbon and energy source, contained only AMP-ACS rather than ADP-ACS or acetate kinase. Cell suspensions of Hc. saccharolyticus metabolized acetate only when they contained AMP-ACS activity, i.e., when they were obtained after growth on acetate or from the stationary phase after growth on glucose. Suspensions of exponential glucose-grown cells, containing only ADP-ACS but not AMP-ACS, did not consume acetate. Similar results were obtained for the phylogenetic distantly related halophilic archaea Hf. volcanii and Hf. saccharovorum. We conclude that, in halophilic archaea, the formation of acetate from acetyl-CoA is catalyzed by ADP-ACS, whereas the activation of acetate to acetyl-CoA is mediated by an inducible AMP-ACS.

Acetate-CoA Ligase↗
PubMedDate not supplied

Acetate-specific stress response in acetate-resistant bacteria: an analysis of protein patterns.

Many metabolic byproducts have toxic effects on bacteria, and acetic acid is an excellent model for such molecules. The negative effects of acetate, which include decreased growth rates and specific productivities, appear for Escherichia coli at acetate concentrations lower than 5 g/L. Acetic acid bacteria, however, are naturally resistant to the detrimental effects of acetate in their surroundings; they remain active at acetate levels well over 40 g/L. This study investigated the response to acetate challenges by the naturally acetate-resistant bacteria Acetobacter aceti and Gluconobacter suboxydans to learn more about possible mechanisms of tolerance to otherwise toxic low molecular weight metabolites. Growth studies showed that the resistant bacteria grow more slowly in the presence of acetate but are not slowed nearly so much as is E. coli. In addition, two-dimensional gel electrophoresis (2DE) was applied to study the relative protein patterns of acetate-resistant bacteria during growth in the presence and absence of acetate. In each organism, growth in acetate-containing medium led to elevated levels of many stress response proteins. 2DE analysis of heat-shocked cultures was used to determine which were nonspecific. Elimination of those proteins that were also amplified following heat shock left only eight proteins, here designated acetate-specific stress proteins (Asps), which are overexpressed specifically in response to acetate. Three of these, AspA, AspB, and AspC, appear to be analogous in the two bacterial strains studied, based on their apparent pIs and molecular weights.

Acetates↗
PubMed2001

Recovery of (13)CO2 during rest and exercise after [1-(13)C]acetate, [2-(13)C]acetate, and NaH(13)CO3 infusions.

For estimating the oxidation rates (Rox) of glucose and other substrates by use of (13)C-labeled tracers, we obtained correction factors to account for label dilution in endogenous bicarbonate pools and TCA cycle exchange reactions. Fractional recoveries of (13)C label in respiratory gases were determined during 225 min of rest and 90 min of leg cycle ergometry at 45 and 65% peak oxygen uptake (VO(2 peak)) after continuous infusions of [1-(13)C]acetate, [2-(13)C]acetate, or NaH(13)CO(3). In parallel trials, [6,6-(2)H]glucose and [1-(13)C]glucose were given. Experiments were conducted after an overnight fast with exercise commencing 12 h after the last meal. During the transition from rest to exercise, CO(2) production increased (P < 0.05) in an intensity-dependent manner. Significant differences were observed in the fractional recoveries of (13)C label as (13)CO(2) at rest (NaH(13)CO(3), 77.5 +/- 2.8%; [1-(13)C]acetate, 49.8 +/- 2.4%; [2-(13)C]acetate, 26.1 +/- 1.4%). During exercise, fractional recoveries of (13)C label from [1-(13)C]acetate, [2-(13)C]acetate, and NaH(13)CO(3) were increased compared with rest. Magnitudes of label recoveries during both exercise intensities were tracer specific (NaH(13)CO(3), 93%; [1-(13)C]acetate, 80%; [2-(13)C]acetate, 65%). Use of an acetate-derived correction factor for estimating glucose oxidation resulted in Rox values in excess (P < 0.05) of glucose rate of disappearance during hard exercise. We conclude that, after an overnight fast: 1) recovery of (13)C label as (13)CO(2) from [(13)C]acetate is decreased compared with bicarbonate; 2) the position of (13)C acetate label affects carbon dilution estimations; 3) recovery of (13)C label increases in the transition from rest to exercise in an isotope-dependent manner; and 4) application of an acetate correction factor in glucose oxidation measurements results in oxidation rates in excess of glucose disappearance during exercise at 65% of VO(2 peak). Therefore, bicarbonate, not acetate, correction factors are advocated for estimating glucose oxidation from carbon tracers in exercising men.

Acetates↗
PubMed1982

Acetate and bicarbonate fluctuations and acetate intolerance during dialysis.

Plasma bicarbonate losses during acetate dialysis were prevented by using a combination of acetate and bicarbonate in the dialysate. In 21 patients who were treated with combination dialysate, the fall in mean blood pressure (MBP), and frequency of symptoms, and post-dialysis task performance were all similar to that observed during dialysis with acetate alone. Furthermore, dialysis performed with bicarbonate dialysate resulted in significantly smaller MBP drops, fewer symptoms, and an improved task performance compared to either an acetate or a combination dialysis. These findings indicate that the presence of acetate, rather than a bicarbonate loss, was responsible for the patients' intolerance to acetate dialysis. Patients symptomatic on acetate dialysis had a similar ultrafiltration rate, weight loss, MBP drops, and postdialysis serum acetate levels; they were similar in age and weight to symptom-free patients. Thus, the toxic effect of acetate was not related to serum acetate level. There was no difference in bicarbonate dialysis between patients with symptoms on acetate and the symptom-free patients in reference to MBP drops and task performance. This finding suggests that symptomatic patients were not simply less tolerant to the process of dialysis, but differed from symptom-free patients in their response to the presence of acetate.

Acetates↗
PubMed2002

Evidence for a transition state analog, MgADP-aluminum fluoride-acetate, in acetate kinase from Methanosarcina thermophila.

Aluminum fluoride has become an important tool for investigating the mechanism of phosphoryl transfer, an essential reaction that controls a host of vital cell functions. Planar AlF(3) or AlF(4)(-) molecules are proposed to mimic the phosphoryl group in the catalytic transition state. Acetate kinase catalyzes phosphoryl transfer of the ATP gamma-phosphate to acetate. Here we describe the inhibition of acetate kinase from Methanosarcina thermophila by preincubation with MgCl(2), ADP, AlCl(3), NaF, and acetate. Preincubation with butyrate in place of acetate did not significantly inhibit the enzyme. Several NTPs can substitute for ATP in the reaction, and the corresponding NDPs, in conjunction with MgCl(2), AlCl(3), NaF, and acetate, inhibit acetate kinase activity. Fluorescence quenching experiments indicated an increase in binding affinity of acetate kinase for MgADP in the presence of AlCl(3), NaF, and acetate. These and other characteristics of the inhibition indicate that the transition state analog, MgADP-aluminum fluoride-acetate, forms an abortive complex in the active site. The protection from inhibition by a non-hydrolyzable ATP analog or acetylphosphate, in conjunction with the strict dependence of inhibition on the presence of both ADP and acetate, supports a direct in-line mechanism for acetate kinase.

Acetate Kinase↗
PubMed2005

Progress toward acetate supplementation therapy for Canavan disease: glyceryl triacetate administration increases acetate, but not N-acetylaspartate, levels in brain.

Canavan disease (CD) is a fatal genetic neurodegenerative disorder caused by mutations in the gene for aspartoacylase, an enzyme that hydrolyzes N-acetylaspartate (NAA) into L-aspartate and acetate. Because aspartoacylase is localized in oligodendrocytes, and NAA-derived acetate is incorporated into myelin lipids, we hypothesize that an acetate deficiency in oligodendrocytes is responsible for the pathology in CD, and we propose acetate supplementation as a possible therapy. In our preclinical efforts toward this goal, we studied the effectiveness of orally administered glyceryl triacetate (GTA) and calcium acetate for increasing acetate levels in the murine brain. The concentrations of brain acetate and NAA were determined simultaneously after intragastric administration of GTA. We found that the acetate levels in brain were increased in a dose- and time-dependent manner, with a 17-fold increase observed at 1 to 2 h in 20- to 21-day-old mice at a dose of 5.8 g/kg GTA. NAA levels in the brain were not significantly increased under these conditions. Studies using mice at varying stages of development showed that the dose of GTA required to maintain similarly elevated acetate levels in the brain increased with age. Also, GTA was significantly more effective as an acetate source than calcium acetate. Chronic administration of GTA up to 25 days of age did not result in any overt pathology in the mice. Based on these results and the current Food and Drug Administration-approved use of GTA as a food additive, we propose that it is a potential candidate for use in acetate supplementation therapy for CD.

Acetates↗