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Herbal and Supplement Use in Pain Management
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Dosing: Diabetic neuropathy: Cyanocobalamin 0.25 mg three times daily for 9 weeks, methylcobalamin 1500 mcg daily for 3–4 months.133Postherpetic neuralgia: methylcobalamin 100 mcg SC six times weekly for 4 weeks.134Peripheral neuropathy: preliminary clinical research shows that taking a specific product containing 3 mcg vitamin B12, folic acid 400 mcg, and uridine monophosphate 50 mg (Keltican) daily for 60 days reduced pain by 44% and decreased concomitant analgesic requirements by over 75% compared to baseline in patients with peripheral neuropathy, including those with lumbar/lumbosacral radiculopathy, sciatic pain, and cervical radiculopathy.135
Nutrient Metabolism and Fetal Brain Development
Published in Emilio Herrera, Robert H. Knopp, Perinatal Biochemistry, 2020
George E. Shambaugh, Boyd E. Metzger, James A. Radosevich
Despite these mechanisms for sparing carbohydrate, amino acid, and nitrogen, fetal brain growth is retarded during maternal starvation. One potentially contributing factor is that in fetal rat brain slices, ketone bodies interfere with the de novo pathway for purines and pyrimidines.19,20 In the de novo pathway of pyrimidine biosynthesis, β-hydroxybutyrate and acetoacetate inhibit the formation of orotic acid, but do not affect the conversion of orotic acid to uridine monophosphate.20 This highly specific effect is concentration dependent. During maternal starvation in late gestation, a 35% reduction in the formation of uridine monophosphate is seen in the rat. Modest elevations of ketone bodies as seen in human sera from mothers fasted for 18 h,20 reduced formation of uridine monophosphate by 10%.20 Ketone inhibition is limited to the de novo pathways for purine and pyrimidine biosynthesis. The salvage pathways for both purines and pyrimidines are unaffected.19 Since the salvage pathways are utilized in late gestation and neonatal life, the effects of ketone bodies on proliferative growth are limited to the time of intrauterine development.
Interaction of Drugs of Dependence With Receptors
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
Several investigators have studied soluble macromolecules as receptor models for LSD. Studies of nucleic acid binding were stimulated by reports that LSD caused chromosome damage and was teratogenic. Smit and Borst82 and Brady et al.83 recently reviewed these studies. They have shown that although LSD does bind with DNA, it neither intercalates nor induces conformational changes. However, when the drug is photoir-radiated, it causes changes in DNA structure. Smythies et al.2 reported that LSD fluorescence at 1 Mg/ml is quenched best by polyuridine (poly-U), whereas no quenching occurs with uridine monophosphate alone or with other nucleotides. Quenching the LSD fluorescence by 50% required 50 Mg/ml of poly-U. Binding was usually promoted by allowing the polynucleotides to stack at pH 3, in water at 4°. Since poly-U does not stack well at pH 7.5 in saline solution, there may be some question of the relevance of this binding for the pharmacological effects of the drug. In the medium used by Smythies, LSD fluorescence was quenched fivefold more by the stacked polycytidine than by the random coil configuration.
An expert overview of emerging therapies for acute myeloid leukemia: novel small molecules targeting apoptosis, p53, transcriptional regulation and metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Kapil Saxena, Marina Konopleva
DHODH is a necessary enzyme in the cellular pathway of de novo pyrimidine synthesis [126,128,129]. This mitochondrial membrane enzyme mediates the fourth step in the pyrimidine synthetic pathway, catalyzing the conversion of dihydroorotate to orotate [126,128]. The final product of this pathway is the generation of the pyrimidine uridine monophosphate (UMP), one of four nucleotides necessary for RNA synthesis and a precursor for synthesis of other necessary pyrimidine nucleotides [128,129]. Cells can obtain uridine by two pathways, the de novo synthetic pathway mentioned above and a secondary scavenging pathway that utilizes membrane nucleoside transporters to shuttle extracellular uridine into the cell [126,129]. Though cells at rest can likely survive primarily off the uridine scavenging pathway, actively dividing cells have much higher nucleic acid synthetic needs and largely depend on intracellular pyrimidine biosynthesis [129,130]. Increased DHODH activity in myeloid leukemias has been known for over 60 years, with an initial study in the late 1950s demonstrating that leukocytes from patients with AML had significantly increased DHODH enzymatic activity [131]. Interestingly, increased DHODH enzymatic activity does not appear to be a driver of leukemogenesis but rather a necessary cellular response to increased replication demands. DHODH is not known to be mutated or amplified in AML, though it is a target of the oncogenic transcription factor c-Myc [129,130].
Gut–brain and brain–gut axis in Parkinson's disease models: Effects of a uridine and fish oil diet
Published in Nutritional Neuroscience, 2018
Paula Perez-Pardo, Hemraj B. Dodiya, Laus M. Broersen, Hidde Douna, Nick van Wijk, Sofia Lopes da Silva, Johan Garssen, Ali Keshavarzian, Aletta D. Kraneveld
Mice were fed either a control or an active diet 1 week prior to either the start of rotenone administration (oral model) or before surgery (intrastriatal model) and continuing for the duration of the experiment. For both models, animals were divided into four groups (n = 10). Iso-caloric diets were produced by Research Diet Services (Wijk bij Duurstede, The Netherlands) based on standard food for laboratory rodents AIN-93M.36 The control diet contained 14% protein (casein), 5% lipids (soy, coconut, and corn oil), 71% carbohydrates (corn starch, maltodextrin, sucrose, and dextrose), 5% fibers (cellulose), and 5% of standard AIN-93M mineral and vitamin mixes and additives. For the active diet, part of the lipid blend of the control diet was replaced by fish oil, providing DHA (0.74 g/100 g diet) and EPA (0.29 g/100 g diet), and uridine–monophosphate was added as a source of uridine (0.51 g/100 g diet), replacing its weight equivalent of corn starch.
Successes, failures, and future prospects of prodrugs and their clinical impact
Published in Expert Opinion on Drug Discovery, 2019
Leflunomide (10 in Figure 2) is a disease modifying anti-rheumatic drug (DMARD) indicated for the treatment of rheumatoid and psoriatic arthritis. It is a prodrug that inhibits dihydroorate dehydrogenase (DHODH). DHODH is crucial in the synthesis of uridine monophosphate, a key nucleotide required for DNA and RNA synthesis. Leflunomide, itself, is inactive and is rapidly metabolized following absorption by CYP450 to teriflunomide, the pharmacologically active drug. The only difference between leflunomide and teriflunomide (11 in Figure 2) is effectively the opening of the isoxazole ring [38].