Antineoplastic Agents
Frank A. Barile in Barile’s Clinical Toxicology, 2019
The enzyme L-asparaginase produces tumor cell death through the activation of apoptosis. In particular, the drug deprives the cell of asparagine. This amino acid is crucial for protein synthesis because the enzyme catalyzes the hydrolysis of circulating asparagine to aspartic acid and ammonia. Consequently, L-asparaginase stops the progression of cells through the cell cycle. Its unique mechanism of action supports its inclusion with other antitumor drugs as part of a chemotherapeutic program, especially in the treatment of acute lymphoblastic leukemia and other lymphoid malignancies. The drug is conveniently administered I.V. or intramuscularly (I.M.) in a variety of regimens and schedules but poses a serious toxicity threat due to its bacterial origin—that is, antigenicity. Hypersensitivity and anaphylactic reactions occur in 5 to 20% of patients, most notably when administered intermittently. Other toxicities related to its mechanism of action include hyperglycemia, coagulopathies, immunosuppression, and hemorrhage, all of which are potentially fatal.
Single Amino Acids
Luke R. Bucci in Nutrition Applied to Injury Rehabilitation and Sports Medicine, 2020
Another dietary dispensable amino acid — aspartate (aspartic acid) — has been studied in relation to fatigue in humans.248,249 Several studies from the 1950s found subjective improvements in fatigue, which were not replicated. Further studies found mixed results in terms of ergogenic effects during exercise in humans. The research seemed to support hypothetical mechanisms of action for aspartates: (1) transport of minerals to subcellular sites of action; (2) participant in tricarboxylic acid cycle (cellular energy); and (3) part of urea cycle (removal of ammonia). Thus, aspartate shares some mechanisms in common with arginine, and arginine aspartate has been used with clinical success in human wound healing and immune function preservation. However, no specific information on the effect of high doses of aspartates on animal or human connective tissue healing is available.
Medical Nutrition Therapy for Patients with Type-2 Diabetes
Jeffrey I. Mechanick, Elise M. Brett in Nutritional Strategies for the Diabetic & Prediabetic Patient, 2006
Fructose is associated with a lower postprandial rise in blood sugar than sucrose, but may affect lipids adversely [101–103]. Sugar alcohols produce lower glycemic responses compared to sucrose, fructose, and glucose, but can cause diarrhea [27]. Saccharin, aspartame, acesulfame potassium, and sucralose are the four Food and Drug Administration (FDA)-approved nonnutritive artificial sweeteners [104]. Aspartame (NutraSweet®) consists of two amino acids (aspartic acid and phenylalanine) and is 180 times as sweet as sucrose. It cannot be used in baking or cooking as it is heat-labile. Saccharin is a nonnutritive sweetener which is still being used despite an FDA warning about its potential for bladder carcinogenicity with long-term use [103]. Sucralose (Splenda®) is 600 times sweeter than sucrose and is heat-stable for cooking and baking. The FDA approved its use in 1998 and concluded that this sweetener did not pose carcinogenic, reproductive, or neurological risk to humans [104].
An overview on the current status of cancer nanomedicines
Published in Current Medical Research and Opinion, 2018
Nasimudeen R. Jabir, Khalid Anwar, Chelapram K. Firoz, Mohammad Oves, Mohammad Amjad Kamal, Shams Tabrez
Oncaspar was first drug approved by the US-FDA in 1994 against developed hypersensitivity to the native form of asparaginase in acute lymphoblastic leukemia (ALL) patients. Moreover, in 2006, the US-FDA approved it as the first line of treatment for ALL patients and also as a component of a multi-agent thermotherapy regimen132. Asparaginase is an enzyme produced by microorganisms which hydrolyses asparagines to aspartic acid. The chemotherapeutic potential of asparaginase against ALL was observed in clinical trial133. It is well known that normal cells can make their own asparagines whereas leukemic cells cannot134. Two types of asparaginase, Elspar and Oncaspar, are commercially available in the market134. Elspar is prescribed in six to nine doses three times weekly, whereas one can get the same therapeutic effect by the use of a single dose of Oncaspar because of its longer biological half-life132. This indicates that nanomedicine formulation can effectively alter drug pharmacokinetics and/or pharmacodynamics by enhancing treatment potential and reducing side effects.
Restoring the biological activity of crizanlizumab at physiological conditions through a pH-dependent aspartic acid isomerization reaction
Published in mAbs, 2023
Fabian Bickel, François Griaud, Wolfram Kern, Frieder Kroener, Manuela Gritsch, Jérôme Dayer, Samuel Barteau, Blandine Denefeld, Chi-Ya Kao-Scharf, Manuel Lang, Izabela Slupska-Muanza, Carla Schmidt, Matthias Berg, Jürgen Sigg, Lina Boado, Dirk Chelius
At pH 6.0, basic variants (mainly the BP3 variant) and acidic variants increased, showing that succinimide is formed, which partly hydrolyzes to iso-aspartic acid (AP1 and AP2) and aspartic acid (main). Since the main peak decreases and the acidic peaks 1 and 2 increase, the formation of iso-aspartic acid is finally predominant. This is based on the succinimide hydrolysis to iso-aspartic acid and aspartic acid with a ratio of 3:1.4,12,13 Accumulation of succinimide is known to be accelerated under those mildly acidic conditions8 combined with increased temperatures.11 Independent of the tested pH, the formation of succinimide is not unlimited: although the cyclization reaction is favored at pH conditions below pH 6.3, succinimide also hydrolyzes at those conditions, reflected by an increase of iso-aspartic acid (acidic variants). Even at pH 5.0 the basic variants decrease again after reaching a maximum (data not shown). The equilibrium between the succinimide formation and its hydrolysis is pH dependent, so the maxima that basic variants can reach differ. The lower the pH, the more the equilibrium favors succinimide formation. Higher succinimide maxima are present at lower pH values compared to neutral pH conditions. This behavior is also in agreement with reported rate constants for the succinimide formation, which increase by lowering the pH from 6 to 4. It has been reported that rate constants of the succinimide hydrolysis were increased by raising pH conditions from 6 to 8.5.11
Neurophysiological symptoms and aspartame: What is the connection?
Published in Nutritional Neuroscience, 2018
Arbind Kumar Choudhary, Yeong Yeh Lee
After ingestion; aspartame is metabolized in the intestinal lumen into 50% phenylalanine which is involved in neurotransmitter regulation, 40% aspartic acid which is an excitatory neurotransmitter, and 10% methanol.8 Methanol is further broken down into formaldehyde and formic acid.9 These metabolites increase substantially with aspartame ingestion. Phenylalanine and aspartic acid cross the blood–brain barrier (BBB) by increasing membrane permeability and subsequently reducing the production of catecholamines such as dopamine and serotonin in the brain.8 Aspartic acid is associated with the degeneration of astrocytes and neurons7 (Fig. 1). An important cell for maintaining transport in brain, astrocytes also have protective function of neurons. Astrocytes can be activated with glutamate excess in the extracellular space. Upon activation, astrocytes release toxic substances which then lead to neurodegeneration.10 Aspartate, being a substrate for glutamate, may act as a neurotoxin.7 Glutamate acts on neuronal presynaptic metabotropic glutamate receptors (mGluR receptors) and postsynaptic N-methyl-d-aspartate receptors (NMDA) receptors leading to hyperexcitability of cells, free radical release, oxidative stress and neuronal degeneration. Neurophysiological symptoms may arise, including cognitive impairments, headache, migraines, vision problems, tinnitus, irritable moods, anxiety, depression, and insomnia.6,7
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