Dicarboxylic acids (DA) are formed from the omega-oxidation of monocarboxylic acids when the beta-oxidation of free fatty acids is impaired. Medium-chain DA have the peculiar characteristic of being water soluble due to the presence of two carboxylic terminal groups in the molecule. Contrary to both long- and medium-chain triglycerides which are administered as emulsions, they can be given by a peripheral vein as inorganic salts. DA are beta-oxidized at level of both peroxisomes and mitochondria via carnitine-independent pathway. The products of beta-oxidation of odd-chain DA are acetyl-CoA and malonyl-CoA, which cannot be oxidized further, are used in lipogenesis. Moreover even-chain DA produce acetyl-CoA and succinyl-CoA, which is a gluconeogenetic precursor. Azelaic acid (C9), does not show acute or chronic toxicity effects in animals but much of it is lost in urine (more than 50% of the given dose). Sebacic acid (C10) is lost in urine to a smaller extent (about 12% of the administered dose) and its energy density (6.64 kcal/g) is greater than that of C9 (4.97 kcal/g). Dodecanedioic acid (C12) seems to be the best candidate for parenteral nutrition, because it is eliminated in the urine only in minimal amounts (3.90% of the given dose), it is rapidly utilized by tissues, and it has a high energy density (7.20 kcal/g).

Dicarboxylic acids, an alternate fuel substrate in parenteral nutrition: an update

Medium-chain dicarboxylic acids are produced by higher plants and animals via fatty acid ω-oxidation or by β-oxidation of longer-chain dicarboxylic acids. In plants, dicarboxylic acids are components of the natural protective polymers cutin and suberin; in animals, dicarboxylic acids are mainly oxidized in mitochondria, where they are transported through four different pathways. Their energy density is intermediate between glucose and fatty acids. Dicarboxylic acid administration does not require insulin or stimulate insulin secretion, and the β-oxidation of dicarboxylic acids produces succinic acid, a gluconeogenic substrate. Therefore, dicarboxylic acids might be a suitable fuel substrate, particularly in clinical conditions in which marked insulin resistance and/or impairment of aerobic glycolysis occur.

Medium-chain, even-numbered dicarboxylic acids as novel energy substrates: an update

Dicarboxylic acids have been proposed as an alternate lipid energetic substrate for total parenteral nutrition. No data are yet available on the possible effect of dicarboxylic acids on glucose metabolism in humans. Thus, we examined the effect of a continuous intravenous infusion of the sodium salt of the 10-carbon atom alyphatic dicarboxylic acid, sebacate (Sb), on insulin-dependent glucose metabolism in four control subjects, four patients with insulin-dependent diabetes mellitus, and four obese subjects. All subjects received a constant 5-hour infusion of saline or sebacate (6.6 g/h), in a randomized order on two different days. After 3 hours of infusion, a 120-minute euglycemic, hyperinsulinemic clamp procedure was performed (insulin infusion rate = 40 mU/m2 per minute). Glucose uptake, plasma sebacate, insulin, glucagon, C-peptide, and ketone bodies were measured. No significant differences in insulinemia were found among groups either during the saline infusion or the sebacate infusion. On the contrary, glucose uptake (molar) was significantly reduced during the sebacate vs the saline day in all three groups: 6.7 +/- 0.04 vs 3.7 +/- 1.3 in control subjects (p < .001), 4.6 +/- 0.4 vs 2.5 +/- 1.2 in patients with insulin-dependent diabetes mellitus (p < .001), and 4.8 +/- 0.5 vs 2.7 +/- 0.2 mg/kg per minute in obese subjects (p < .001). In conclusion, Sb administration was associated with a glucose-sparing effect as shown by the reduced glucose uptake in all patients studied. Sebacate did not stimulate insulin secretion, inasmuch as no modification of C-peptide plasma levels was observed after 3 hours of Sb infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Dicarboxylic acids and glucose utilization in humans: effect of sebacate

Autotaxin-lysophosphatidic acid (ATX-LPA) signaling has a predominant role in immunological and fibrotic processes, including cancer. Several ATX inhibitors and LPA receptor antagonists have been clinically evaluated, but none in patients with solid tumors. Many cancers are burdened with a high degree of fibrosis and an immune desert phenotype (so-called 'cold' tumors). In these cold tumors, the fibrotic stroma provides an intrinsic cancer-supporting mechanism. Furthermore, the stroma prevents penetration and limits the effectiveness of existing therapies. IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile.In vitro and in vivo pharmacology studies have been carried out to elucidate the pharmaceutical properties and mechanism of action of IOA-289. A phase I clinical study in healthy volunteers was carried out to determine the pharmacokinetics and pharmacodynamics of IOA-289 following a single oral dose.In vitro and in vivo studies showed that IOA-289 is a potent inhibitor of ATX and, as a monotherapy, is able to slow progression of lung fibrosis and tumor growth in mouse models. In a clinical study, IOA-289 showed a dose-dependent increase in plasma exposure levels and a corresponding decrease in circulating LPA.Our data show that IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Our data support the further development of IOA-289 as a novel therapeutic approach for the treatment of cancer, particularly those with a high fibrotic and immunologically cold phenotype. 

https://doi.org/10.1016/j.iotech.2023.100384

Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors

Pharmacokinetic analysis of azelaic acid disodium salt. A proposed substrate for total parenteral nutrition

Aliphatic dioic acids have been proposed as alternative nutrients in selected clinical situations. In this study, their possible insulinotropic action was investigated in isolated rat pancreatic islets prepared from fed rats. Azelaic acid, sebacic acid and tridecanedioic acids, when tested at a 10.0 mm concentration, were found to augment insulin release evoked by D-glucose (7.0 mm) in the pancreatic islets. Likewise, glycerol-1,2,3-tris(dodecanoedioate), when used at concentrations close to 1.0 mm, increased the secretory response to the hexose. It is speculated that these findings may extend to insulin-producing cells, the knowledge that aliphatic dioic acids or their esters may act as energy substrates, e.g. in parenteral nutrition.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/090743870666DC231EE37E627CEB546A/S0007114500002099a.pdf/div-class-title-effects-of-aliphatic-dioic-acids-and-glycerol-1-2-3-tris-dodecanedioate-on-d-glucose-stimulated-insulin-release-in-rat-pancreatic-islets-div.pdf

Effects of aliphatic dioic acids and glycerol-1,2,3-tris(dodecanedioate) on D-glucose-stimulated insulin release in rat pancreatic islets.

Several aliphatic dioic acids were recently reported to stimulate insulin release in isolated rat pancreatic islets incubated at close-to-physiological D-glucose concentrations. In order to gain insight into the mode of action of these acids in pancreatic islet B-cells, the oxidation of [1,12-14C]dodecanedioic acid (5.0 mM) was now measured in rat islets. Expressed as pmol of [1, 12-14C]dodecanedioic acid equivalent, the production of 14CO2 was close to 1.0 pmol/islet per 120 min, representing about 8% of that attributable to the oxidation of D-[U-14C]-glucose (8.3 mM). The dioic acid and the hexose failed to exert any significant reciprocal effect upon their respective oxidation rate. These findings support the view that the insulinotropic action of dodecanedioic acid, and presumably other aliphatic dioic acids, is causally linked to their capacity to act as nutrients in pancreatic islet cells.

Oxidation of [1,12-14C]dodecanedioic acid by rat pancreatic islets

Validation of an LC-MS/MS method for the quantification IOA-289 in human plasma and its application in a first-in-human clinical trial.

A selective and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for accurate determination of CHF6550 and its main metabolite in rat plasma and lung homogenate samples. All biological samples were prepared by simple protein precipitation method using deuterated internal standards. The analytes were separated on a HSS T3 analytical column with 3.2 min run time at flow rate of 0.5 mL/min. The detection was performed on a triple-quadrupole tandem mass spectrometer equipped with positive-ion electrospray ionization by selected-reaction monitoring of the transitions at m/z 735.3 → 98.0 for CHF6550 and m/z 638.3 → 319.2 and 638.3 → 376.2 for CHF6671. The calibration curves for plasma samples were linear between 50 and 50000 pg/mL for both analytes. The calibration curves for lung homogenate samples were linear within 0.1-100 ng/mL for CHF6550 and 0.3-300 ng/mL for CHF6671. The method was successfully applied to a 4-week toxicity study.

Development and validation of a bioanalytical method for the quantification of CHF6550 and its metabolite (CHF6671) in rat plasma and lung homogenate using LC-MS/MS.

Oxidation of [1,12-14C]dodecanedioic acid by rat pancreatic islets.

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