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Michel Baltas - One of the best experts on this subject based on the ideXlab platform.
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Solvent-Free Pivalic Acid/Copper Chloride Jointly Promoted Chlorination of 1,2,3-Triazoles
Synlett, 2012Co-Authors: Christophe Menendez, Nathalie Saffon, Christian Lherbet, Michel BaltasAbstract:A novel chlorination reaction on the 5-position of 1,2,3-triazoles, directly from 5H-substituted 1,2,3-triazoles was developed by using copper(II) chloride in Pivalic Acid. A series of triazoles were thus chlorinated in low to good yields.
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solvent free Pivalic Acid copper chloride jointly promoted chlorination of 1 2 3 triazoles
Synlett, 2012Co-Authors: Christophe Menendez, Nathalie Saffon, Christian Lherbet, Michel BaltasAbstract:A novel chlorination reaction on the 5-position of 1,2,3-triazoles, directly from 5H-substituted 1,2,3-triazoles was developed by using copper(II) chloride in Pivalic Acid. A series of triazoles were thus chlorinated in low to good yields.
Ingalill Nordin - One of the best experts on this subject based on the ideXlab platform.
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Effect of short-term treatment with Pivalic Acid containing antibiotics on serum carnitine concentration--a risk irrespective of age.
Biochemical and molecular medicine, 1995Co-Authors: Kate Abrahamsson, Elisabeth Holme, Ulf Jodal, Sven Lindstedt, Ingalill NordinAbstract:Abstract Treatment with Pivalic Acid containing prodrugs has been shown to cause carnitine depletion by loss of pivaloyl carnitine in urine. A 7-day standard pivmecillinam treatment of adults lead to a marked decrease of the free serum carnitine concentration (44.6 to 12.9 μmol/liter), whereas no change was seen in those given norfloxacine (40.0 to 40.5 μmol/liter). In some patients irrespective of age the free serum carnitine concentration was decreased to levels (around 10 μmol/liter) at which an impaired ketone-body production may occur. Therefore, there is reason for cautious use of this type of drug irrespective of the age of the patients.
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Impaired ketogenesis in carnitine depletion caused by short-term administration of Pivalic Acid prodrug.
Biochemical medicine and metabolic biology, 1994Co-Authors: Kate Abrahamsson, Elisabeth Holme, Ulf Jodal, Sven Lindstedt, B. O. Eriksson, Ingalill NordinAbstract:Long-term treatment with Pivalic Acid prodrug results in impaired ketone-body production. Therefore, it was of interest to investigate whether short-term treatment had any influence on the fatty Acid oxidation. In this study six healthy males were given 1200 mg per day of pivmecillinam for 12 days to induce carnitine deficiency. The concentration of free carnitine in serum was reduced from a mean of 42.8 mumol/liter (range, 31-48) to 11.6 mumol/liter (range, 7.0-24), but the muscle carnitine concentration was not reduced. A 36-h fasting test was performed before and after drug administration to study the effect on ketone-body production. After treatment, the two subjects with the lowest level of serum free carnitine at the end of the fasting period had impaired ketogenesis. This indicates a carnitine deficiency in the liver which was reflected in the free carnitine concentration for by mobilization of muscle carnitine. We conclude that there is a substantial risk to develop carnitine deficiency and impaired fatty Acid oxidation in the liver during short-term treatment with drugs conjugated with Pivalic Acid.
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Effects of Pivalic Acid-containing prodrugs on carnitine homeostasis and on response to fasting in children
Scandinavian journal of clinical and laboratory investigation, 1992Co-Authors: Elisabeth Holme, Ulf Jodal, S Linstedt, Ingalill NordinAbstract:Treatment of 17 children aged 2-9.5 years with a combination of pivmecillinam and pivampicillin (250-500 mumol 24 h-1) for more than 1 year resulted in a reduction of the free carnitine concentration in serum and muscle to less than 10% of the mean reference value. The decline in serum was slow, with an estimated half-life of about 5 months. Spontaneous replenishment occurred at about the same slow rate. Thus, there is no increase in endogenous carnitine synthesis as a response to increased demand of carnitine for detoxification. Supplementation with carnitine during treatment required at least a four-fold molar excess over Pivalic Acid to achieve and sustain a normal carnitine concentration. The replenishment of carnitine occurred with a half-life of 1.1-3.0 months. From determination of muscle-carnitine concentration in patients treated with pivaloyl-containing antibiotics and in patients with organic Aciduris, we conclude that serum carnitine is a good predictor of carnitine stores in the body. Six non-supplemented patients with a serum free-carnitine concentration of 0.7-2.6 mumol l-1 had an inadequate ketone-body increase during a 24-h fast. Vomiting, nausea and tiredness occurred in three cases following the fasting period. After normalization of the serum-carnitine concentration, a normal response to fasting was observed. Thus, in some organic Acidurias, for example medium-chain acyl-CoA dehydrogenase deficiency, a low liver concentration of carnitine may be an important contributing factor to hypoglycaemic and Reye-like attacks. We believe that prodrugs which contain Pivalic Acid should be avoided if acceptable alternatives exist. If used, supplementation with at least four-fold molar excess of carnitine is advisable.
Christophe Menendez - One of the best experts on this subject based on the ideXlab platform.
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Solvent-Free Pivalic Acid/Copper Chloride Jointly Promoted Chlorination of 1,2,3-Triazoles
Synlett, 2012Co-Authors: Christophe Menendez, Nathalie Saffon, Christian Lherbet, Michel BaltasAbstract:A novel chlorination reaction on the 5-position of 1,2,3-triazoles, directly from 5H-substituted 1,2,3-triazoles was developed by using copper(II) chloride in Pivalic Acid. A series of triazoles were thus chlorinated in low to good yields.
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solvent free Pivalic Acid copper chloride jointly promoted chlorination of 1 2 3 triazoles
Synlett, 2012Co-Authors: Christophe Menendez, Nathalie Saffon, Christian Lherbet, Michel BaltasAbstract:A novel chlorination reaction on the 5-position of 1,2,3-triazoles, directly from 5H-substituted 1,2,3-triazoles was developed by using copper(II) chloride in Pivalic Acid. A series of triazoles were thus chlorinated in low to good yields.
Derk Willem Frederik Brilman - One of the best experts on this subject based on the ideXlab platform.
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Mass transfer effects in the H2SO4 catalyzed Pivalic Acid synthesis
Catalysis Today, 2001Co-Authors: Derk Willem Frederik Brilman, Willibrordus Petrus Maria Van Swaaij, N.g. Meesters, Geert VersteegAbstract:The synthesis of carboxylic Acids from alkenes, carbon monoxide and water according to the Koch process is usually carried out in a stirred gas–liquid–liquid multiphase reactor. Due to the complex reaction system with fast, equilibrium reactions and fast, irreversible reactions the yield and product distribution depend on a number of process parameters. The effect of some of these parameters was studied for the production of Pivalic Acid, using sulfuric Acid as a catalyst. For the 96 wt.% sulfuric Acid catalyst solution used the main reactions are relatively fast with respect to mass transfer and mixing. Therefore, aspects like the position of the injection point, inlet concentration, agitation intensity and injection rate all influence the yield obtained. The presence of an inert organic liquid phase was found to be beneficial, due to a combined effect of enhanced gas–liquid mass transfer and a ‘local supply’ effect for carbon monoxide near the hydrocarbon reactant inlet.
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Gas-liquid-liquid reaction engineering: The Koch synthesis of Pivalic Acid from iso- and tert-butanol; Reaction kinetics and the effect of a dispersed second-liquid phase
Chemical Engineering Science, 1999Co-Authors: Derk Willem Frederik Brilman, Willibrordus Petrus Maria Van Swaaij, Geert Frederik VersteegAbstract:In gas-liquid-liquid reaction systems with fast parallel and consecutive reactions the effects of mass transfer and mixing on the product yield can be significant. The Koch synthesis of Pivalic Acid, using sulfuric Acid as catalyst, was chosen to study these effects. Reaction kinetics and the effect of the catalyst-phase composition have been investigated by using isobutanol as reactant. For studying the effect of an immiscible liquid phase on the reaction products obtained, the more reactive tert-butanol was used. Pivalic Acid can be produced from isobutanol using sulfuric Acid as a catalyst solution with 2-methylbutanoic Acid as main byproduct, if gas-liquid mass transfer limitations are excluded. The selectivity towards 2-methylbutanoic Acid is generally less than 20% and decreases strongly with decreasing Acidity. The reaction is first order in isobutanol and dehydration is likely to be rate determining. The presence of Pivalic Acid and isobutanol strongly reduces the apparent reaction rate constant by decreasing the solution Acidity (Ho). For the industrially applied backmixed reactors in the Koch synthesis, this may imply that these operate at much lower values for Ho. On addition of an immiscible heptane phase, the reaction products are extracted to some extent and this adds to maintaining a high catalyst solution Acidity. Using tert-butanol, the yield and Pivalic Acid selectivity was found to depend strongly on CO transport to the reaction zone through gas-liquid mass transfer and mixing. The presence of an immiscible heptane phase increased the product yield and selectivity towards Pivalic Acid significantly.
Tetsuya Ito - One of the best experts on this subject based on the ideXlab platform.
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Children's toxicology from bench to bed--Liver injury (1): Drug-induced metabolic disturbance--toxicity of 5-FU for pyrimidine metabolic disorders and Pivalic Acid for carnitine metabolism.
The Journal of Toxicological Sciences, 2009Co-Authors: Tetsuya ItoAbstract:Congenital disorders of metabolism show a wide spectrum of symptoms as a consequence of impairment of a certain metabolic pathway by mutated enzymes resulting in abnormal accumulation of enzyme substrates, deficiency of expected products, and abnormal burden to collateral metabolic pathways, etc. However, in some occasions, depending on which pathway up to what degree of disturbance, it can be asymptomatic until a certain kind of burden is placed on to the patient. Enzyme deficiency involved in pyrimidine degradation, such as Dihydropyrimidine dehydrogenase (DPD) and Dihydropyrimidinase (DHP), has been reported with convulsion or autism as symptoms, but many asymptomatic cases are also reported. However, when the patients are treated with 5-fluorouracil, a pyrimidine analogue anticancer drug, lethal side-effects can be seen even in asymptomatic patients. Some oral cephem antibiotics have Pivalic Acid side chain to increase absorption rate at intestine. These antibiotics degrade into active antibiotics and Pivalic Acid at the intestinal wall. This Pivalic Acid is carnitine-conjugated and excreted into urine. Carnitine acts as a carrier of long chain fatty Acid to mitochondria and to beta-oxidation, thus an important molecule for energy production by beta-oxidation and maintenance of mitochondrial function. Because of this, long term administration of such antibiotics could induce depletion of carnitine from the body and lead to low ketotic hypoglycemia, convulsion and consciousness disturbance. This paper reports some possible serious side effects closely linked to drug metabolism.
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Carnitine-Associated Encephalopathy Caused by Long-term Treatment With an Antibiotic Containing Pivalic Acid
Pediatrics, 2007Co-Authors: Yasuko Makino, Tokio Sugiura, Tetsuya Ito, Naruji Sugiyama, Norihisa KoyamaAbstract:An 18-month-old boy was treated with an antibiotic containing Pivalic Acid for 6 months for intractable otitis media and then developed repeated convulsions and loss of consciousness. Laboratory data showed hypoglycemia and hypocarnitinemia. Intravenous administration of glucose was ineffective against the seizures and loss of consciousness. However, the patient regained consciousness and recovered soon after intravenous infusion of carnitine. To our knowledge, intravenous carnitine administration that contributed to marked improvements in neurologic deficit caused by administration of an antibiotic containing Pivalic Acid has not been reported previously. These findings indicate that long-term use of such antibiotics should be avoided.
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Alteration of ammonia and carnitine levels in short-term treatment with Pivalic Acid-containing prodrug
The Tohoku journal of experimental medicine, 1995Co-Authors: Tetsuya Ito, Naruji Sugiyama, Masanori Kobayashi, Kiyoshi Kidouchi, Tamiko Itoh, Osamu Uemura, Kohachiro Sugiyama, Hajime TogariAbstract:ITO, T., SUGIYAMA, N., KOBAYASHI, M., KIDOUCHI, K., ITOH, T., UEMURA, O., SUGIYAMA, K. and TOGARI, H. Alteration of Ammonia and Carnitine Levels in Short-Term Treatment with Pivalic Acid-Containing Prodrug. Tohoku J. Exp. Med., 1995, 175 (1), 43-53-We investigated the influence on mitochondrial functions in carnitine deficiency caused by short-term treatment of cefteram-pivoxil (CFTM-PI) which is one of pivaloyloxymethyl-esterified antibiotics in adult volunteers and diseased children. Administration of CFTM-PI caused hypocarnitinemia in all cases, and we observed a significant elevation of blood ammonia levels compared with those after its withdrawal in diseased children. A significant negative correlation was found between the levels of serum free carnitine and blood ammonia, and a positive correlation was observed between serum carnitine and blood glutamine levels in all adult samples and samples during administration in diseased children. Our data suggest that these antibiotic medications affect the mitochondrial function even in a short-term treatment and that L-carnitine supplementation would be necessary for patients treated with CFTM-PI.
