The synthesis of Coenzyme A (CoA) from pantothenate is regulated primarily by pantothenate kinase, an enzyme that is inhibited by the pathway end products, CoA and acyl CoA.
/P/antothenic acid is required for intermediary metabolism of carbohydrates, proteins, and lipids. Pantothenic acid is a precursor of coenzyme A which is required for acetylation (acyl group activation) reactions in gluconeogenesis, in the release of energy from carbohydrates, the synthesis and degradation of fatty acids, and the synthesis of sterols and steroid hormones, porphyrins, acetylcholine, and other compounds.
Absorption Coenzyme A (CoA). CoA in the diet is hydrolyzed in the intestinal lumen to dephospho CoA, phosphopantetheine, and pantetheine, with the pantetheine subsequently hydrolyzed to pantothenic acid. Pantothenic acid was the only one of these pantothenate-containing compounds absorbed by rats in studies on absorption of the various forms. Absorption is by active transport at low concentrations of the vitamin and by passive transport at higher concentrations in animal models. Because the active transport system is saturable, absorption will be less efficient at higher concentrations of intake, but the intake levels at which absorptive efficiency decreases in humans are not known.
Intestinal microflora have been observed to synthesize pantothenic acid in mice, but the contribution of bacterial synthesis to body pantothenic acid levels or fecal losses in humans has not been quantified. If microbial synthesis is substantial, balance studies in humans may have underestimated pantothenic acid absorption and requirements.
Coenzyme A (CoA) is hydrolyzed to pantothenate in a multiple-step reaction. The pantothenic acid is excreted intact in urine, ... . The amount excreted varies proportionally with dietary intake over a discrete yet wide range of intake values.
Although the clinical importance has not been established, the miotic effects of anticholinesterase ophthalmic preparations (eg, echothiophate iodide (no longer commercially available in the US), isoflurophate) reportedly may be potentiated by pantothenic acid.
The hypolipidemic effects of pantothenic acid derivatives (phosphopantothenate, panthenol and pantethine) were studied in mice with hypothalamic obesity ... induced by single injection of aurothioglucose (300 mg/kg body wt, ip). All the tested substances were administered during the last 10 days before decapitation (im, of dosage equivalent to 150 mg/kg body wt of phosphopantothenate). The studied substances inhibited the weight gain of the animals with hypothalamic obesity over the last 10 days of the experiment. The treatment with aurothioglucose increased food intake and mean body weight, blood glucose level; insulin, serum total cholesterol, triglyceride, the sum of LDL + VLDL and LDL-cholesterol concentration; triglyceride and cholesterol fractions in the liver; triglyceride and FFA content as well as lipoprotein lipase activity in adipose tissue of experimental mice. The administration of the assay compounds lowered food intake and mean body weight, insulin and glucose levels and decreased the content of triglycerides, total cholesterol and cholesterol esters in serum and adipose tissue as well as raised the activity of lipoprotein lipase in adipose tissue and serum lipolytic activity in obese mice. Among the compounds studied the reverse effect of panthenol was especially pronounced. The mechanism of hypolipidemic effects of pantothenic acid derivatives can be related to the reduced resistance to insulin and activation of lipolysis in serum and adipose tissue. /Panthenol, Phosphopantothenate, Pantethine/
A combination of 1.2 g of calcium pantothenate, 0.6 g of pyridoxine, 3 g of niacinamide, and 3 g of ascorbic acid taken daily for 6 weeks was associated with elevations in serum transaminase levels in children. One of these doses or the combination may therefore cause hepatotoxicity, but it is not possible from this study alone to ascribe to pantothenic acid the reported adverse effect in liver function.
... Pregnant CD-1 mice were administered a teratogenic dose of valproic acid (VPA) prior to neural tube closure and embryonic protein levels were analyzed. ... VPA (400 mg/kg)-induced NTDs (24%) and VPA-exposed embryos with a neural tube defect (NTD) showed a 2-fold increase in p53, and 4-fold decreases in NF-kappaB, Pim-1, and c-Myb protein levels compared to their phenotypically normal littermates (P<0.05). Additionally, VPA increased the ratio of embryonic Bax/Bcl-2 protein levels (P<0.05). Pretreatment of pregnant dams with either folic acid or pantothenic acid prior to VPA significantly protected against VPA-induced NTDs (P<0.05). Folic acid also reduced VPA-induced alterations in p53, NF-kappaB, Pim-1, c-Myb, and Bax/Bcl-2 protein levels, while pantothenic acid prevented VPA-induced alterations in NF-kappaB, Pim-1, and c-Myb...
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Pantothenic acid is absorbed in the small intestine by active transport at low concentrations of the vitamin and by passive transport at higher concentrations. Because the active transport system is saturable, absorption is less efficient at higher concentrations of intake. However, the exact intake levels at which absorption decreases in humans are not known. Pantothenic acid is excreted in the urine in amounts that are proportional with dietary intake over a wide range of intake values.
Pantothenic acid is readily absorbed from the GI tract. It is present in all tissues, in concentrations ranging from 2-45 ug/g. Pantothenic acid apparently is not destroyed in human body since intake and excretion ... are approximately equal. About 70% of unchanged pantothenic acid is excreted in urine and about 30% in feces.
Pantothenic acid is readily absorbed from the GI tract following oral administration. Normal serum pantothenate concentrations are 100 ug/mL or greater. /Pantothenic acid/ is widely distributed into body tissues, mainly as coenzyme A. Highest concentrations are found in the liver, adrenal glands, heart, and kidneys. Milk of nursing mothers receiving a normal diet contains about 2 ug of pantothenic acid per mL. About 70% of an oral dose of pantothenic acid is excreted unchanged in urine and about 30% in feces.
... /N/ewborn pantothenic acid levels are significantly greater than maternal levels. At term, mean pantothenate levels in 174 mothers were 430 ng/mL (range 250-710) and in their newborns 780 ng/mL (range 400-1480). Placental transfer of pantothenate to the fetus is by active transport, but it is slower than transfer of other B complex vitamins. In one report, low-birth-weight infants had significantly lower levels of pantothenic acid than did normal weight infants.
Stable pantetheine derivatives for the treatment of pantothenate kinase associated neurodegeneration (pkan) and methods for the synthesis of such compounds
The present invention relates to oligoesters and their use or the creation of additives. Oligoester containing additives and/or oligoesters themselves may be used for formulating pharmaceutical preparations, cosmetics or personal care products such as shampoos and conditioners. These oligoesters are particularly useful for the creation of multi-purpose additives that can impart conditioning, long substantivity and/or UV protection. Individual oligoesters and oligoester mixtures are described.
Novel indole derivatives as selective androgen receptor modulators (SARMS)
申请人：Lanter C. James
公开号：US20050245485A1
公开（公告）日：2005-11-03
The present invention is directed to novel indole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.
The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.
CHLORO-PYRAZINE CARBOXAMIDE DERIVATIVES WITH EPITHELIAL SODIUM CHANNEL BLOCKING ACTIVITY
申请人：Parion Sciences, Inc.
公开号：US20140171447A1
公开（公告）日：2014-06-19
This invention provides compounds of the formula I:
and their pharmaceutically acceptable salts, useful as sodium channel blockers, compositions containing the same, therapeutic methods and uses for the same and processes for preparing the same.
The present invention is directed to novel compounds of Formula (I) and pharmaceutically acceptable salts thereof,
pharmaceutical compositions and their use as dual chromaphores having inhibitory activity against PDE4 and muscarinic acetylcholine receptors (mAChRs), and thus being useful for treating respiratory diseases.
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