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Metabolic & Cardiovascular Disease

Canagliflozin and Dapagliflozin on Diabetes

Canagliflozin and dapagliflozin are sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 is the membrane protein in the kidney which is responsible for reabsorption of glucose. The capability of inhibiting these proteins has proven to effectively control blood sugar, cholesterol, and triglycerides. This type of compound has become the go-to method in the treatment of type 2 diabetes. However, there are also concerns about possible unfavorable side-effects that must be addressed.

A recent study at the Medical University of Silesia looked into the effects that canagliflozin and dapagliflozin may have on bones. The experiment used Wistar rats and induced type 2 diabetes by use of high-fat diet followed by an injection of streptozocin. The chemicals were then administered to the animals once a day by oral gavage for a total of 4 weeks of treatment. During this time, the blood glucose and grip strength were measured weekly. 4 weeks of treatment in the life of a rat is comparable to approximately 2.5 years for a human.

At the end of the treatment, the animals were sacrificed, and the organs, bones, and blood serum were collected and analyzed. Biochemical concentrations in the serum were measured, as well as mechanical properties and mineral composition of the bones.

The results showed that both canagliflozin and dapagliflozin effectively normalized several biochemical metabolic parameters in this diabetic model. However, they were found to also unfavorably affect the skeletal system. Moreover, these SGLT2 inhibitors were not equivalent in regards to their impact on bones. Therefore, each SGLT2 inhibitor ought to be individually assessed for its impact on the skeletal system. In a situation involving both diabetes and high risk of bone fracture, the choice of SGLT2 inhibitor presents a serious concern. Further evaluation of these inhibitors should be continued.

Londzin P, Zych M, Janas A, et al. Effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors, dapagliflozin and canagliflozin, on the musculoskeletal system in an experimental model of diabetes induced by high-fat diet and streptozocin in rats. Biomed Pharmacother. 2025 Mar:184:117912. PMID: 39955854

Acepromazine for Study of Anemia

Acepromazine is a derivative of chlorpromazine which is useful as a veterinary research tool. It has been shown to decrease packed cell volume, a.k.a. hematocrit, a measurement of the proportion of blood that is made up of cells.

Coagulopathy is a common issue in equine illness and requires proper attention and management. Recognizing, predicting, and treating abnormal coagulation is essential. Recently, an equine study made use of acepromazine as a research tool in a study of coagulopathy.

The study involved eight healthy horses and intravenous administration of acepromazine to induce anemia. Several viscoelastic parameters were then evaluated in order to establish the relationship between blood cell mass, hypercoagulability, and hypocoagulability. Understanding these relationship dynamics is essential to correctly interpreting and test results that are produced by an anemic subject.

The results showed acepromazine to be successful in inducing anemia in this model, and showed a connection between red blood cell mass and hypercoagulability. Although this study was limited in size, it does confirm the very different testing profiles found in anemic versus polycythemic subjects. Further studies could increase the understanding and develop appropriate reference ranges expected under these conditions.

Mersich I, Bishop R, Yucupicio S, et al. Decreased circulating red blood cell mass induced by intravenous acepromazine administration alters viscoelastic and traditional plasma coagulation testing results in healthy horses. Animals (Basel). 2024 Oct 28;14(21):3102. PMID: 39518825

 

Levosimendan on Heart Failure

Levosimendan is a calcium sensitizer that produces a potent effect on the heart muscle. Acting as a positive inotrope, it strengthens the heart’s contractions, making it pump more efficiently. In comparison with other inotropes, levosimendan does not cause unwanted arrythmogenic effects.

In an aging population, chronic diseases are expected to have increasing prevalence. One such disease is heart failure with preserved ejection fraction (HFpEF).

Recently, an animal study was completed to investigate the possibility that HFpEF may be controlled using this inodilator. ZSF1 obese rats were used as a preclinical surrogate model for HFpEF. The animals were treated for 6 weeks with 1 mg/kg/day levosimendan in drinking water. Another group was submitted to i.v. levosimendan infusion to determine the acute effects.

Both types of treatment seemed to show beneficial haemodynamic effects in this study. However, as with many animal models of human diseases, this model has some limitations. Further research should carefully appraise the effectiveness of this treatment on an aging population of HFpEF.

Moreira-Costa L, Tavares-Silva M, Almeida-Coelho J, et al. Acute and chronic effects of levosimendan in the ZSF1 obese rat model of heart failure with preserved ejection fraction. Eur J Pharmacol. 2024 Mar 5:966:176336. PMID: 38272343

Beclomethasone Dipropionate and Asthma

Beclomethasone dipropionate is a corticosteroid. In its active form, 17-beclomethasone monopropionate, it binds to glucocorticoid receptors and reduces inflammation. Because of its anti-inflammatory properties, inhaled beclomethasone dipropionate is used to treat asthma and chronic obstructive pulmonary disorder. In Europe, it is used in a drug cocktail with formoterol fumarate, a bronchodilator, and glycopyrronium bromide, which reduces bronchial secretions.

A team of European researchers wanted to confirm whether this drug cocktail reaches the peripheral lungs. If so, there is a much higher chance that it can effectively treat asthma. The researchers recruited ten healthy people and nine people with asthma for a clinical trial. The trial participants first inhaled a drug cocktail that was labelled with technetium-99 (tek-nē-shē-əm).  Then their lungs were imaged using gamma scintigraphy. The study found that about 25% of the inhaled drug was deposited in the lungs, and half of that made it into the peripheral lungs.

There was no significant difference in drug deposition between healthy people and people with asthma. As such, these results are encouraging. It suggests that the beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide cocktail gets delivered correctly for people with asthma.

 

Usmani S, Baldi S, Warren S, et al. Lung deposition of inhaled extrafine beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide in healthy volunteers and asthma: the STORM study. J Aerosol Med Pulm Drug Deliv. 2022 Aug;35(4):179-185. doi: 10.1089/jamp.2021.0046. PMID: 35128939

 

The Metabolic Impact of Kynurenic Acid

Background

Kynurenic acid is a metabolite of tryptophan. This chemical is found throughout the body, and appears to act on glutamate receptors in the brain. One effect of Kynurenic acid on Gpr35 signaling that has been discovered is enhanced cellular respiration.

Interestingly, high levels of kynurenic acid have been found in the brains of patients with schizophrenia. Further research is ongoing to understand its role in that disease. Less is known about its role in the rest of the body.

Kynurenic Acid Combined with Consistent Exercise and Feeding

One relationship that has been discovered is that exercise causes the levels of kynurenic acid to increase in skeletal muscle. Recently, Agudelo et al. sought to tease the effects of kynurenic acid on metabolism apart from the effects of exercise alone.

To accomplish this, mice were dosed with kynurenic acid without changing their exercise habits. Their metabolisms then sped up, but their level of exercise and feeding stayed the same. As a result, the mice lost some weight after two weeks, which came from a reduction in their white fat stores.

Kynurenic Acid Combined with Altered Diets and Genetics

Previous research has shown that kynurenic acid activates the receptor protein Gpr35. Agudelo et al. wanted to test whether Gpr35 was involved in the relationship between kynurenic acid and metabolism.

To test the effect of Kynurenic acid on Gpr35 signaling, they put mice on a high-fat diet that causes them to gain weight. When they dosed the mice on the high-fat diet with kynurenic acid, they prevented the mice from gaining weight.

When they dosed mice that lack Gpr35 with kynurenic acid, the mice gained weight as usual. These results suggest that Gpr35 signaling is important for kynurenic acid’s role in raising metabolism.

 

In conclusion, this study increases the understanding of both kynurenic acid and Gpr35. A therapeutic application for kynurenic acid is a long way off, but worth studying.

 

K977545  Kynurenic Acid

 

Agudelo LZ, Ferreia DMS, Cervenka I, et al. Kynurenic acid and Gpr35 regulate adipose tissue energy homeostasis and inflammation. 2018. Cell Metabolism. 27(2):378-392. PMID: 29414686.

New Product Spotlight: Linagliptin and Empagliflozin

Incidence of diabetes has been growing worldwide over the last 20 years. Due to its impact on health worldwide, a search for novel treatment options for diabetes has been undertaken. Two promising compounds for the treatment of type 2 diabetes mellitus are linagliptin and empagliflozin.

Linagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP-4). DPP-4 is expressed in a wide variety of cells, and performs various functions in these cells. In diabetes, inhibition of DPP-4 leads to an increase of insulin and lowering of blood glucose. Linagliptin is efficacious in rodent models mimicking type 1 diabetes. Linagliptin reduces oxidative stress to levels of normal rats, lessens incidence of cardiac injury. Additionally, linagliptin reduces renal injury and ameliorates kidney fibrosis in the same streptozotocin-induced type 1 diabetes rodent model.

Empagliflozin is an inhibitor of sodium glucose cotransporter type 2 (SGLT-2). Empagliflozin lowers the amount of blood glucose and increases the amount of insulin found in Zucker diabetic fatty rats. It also reduces cardiovascular stress in type 2 diabetes mice models with prolonged treatment.

Combined treatment with lingaliptin/empagliflozin in human subjects showed modest weight loss, and no incidents of hypoglycemia.

Linagliptin and Empagliflozin are now available from LKT Laboratories, Inc. for your research needs.

L337521 Linagliptin

E499601 Empagliflozin

 

 

References:

Hansen HH, Jelsing J, Hansen CF et al. The Sodium Glucose Cotransporter Type 2 Inhibitor Empagliflozin Preserves Beta-Cell Mass and Restores Glucose Homeostasis in the Male Zucker Diabetic Fatty Rat. J Pharmacol Exp Ther. September 2014. 350:657-664. doi: 10.1124/jpet/114/213454.

Kanasaki K, Shi S, Kanasaki M et al. Lingaliptin-Mediated DPP-4 Inhibitions Ameliorates Kidney Fibrosis in Streptozotocin-Induced Diabetic Mice by Inhibiting Endothelial-to-Mesenchymal Transition in a Therapeutic Regimen. Diabetes. June 2014. 63:2120-2131. doi: 10.2337/db13-1029.

Lin B, Koibuchi, N, Hasegawa, Y et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injursy and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovascular Diabetology, 2014, 13:148. doi: 10.1186/s12933-014-0148-1.

Salheen SM, Panchapakesan U, Pollock CA and Woodman OL. The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Preserves Endothelial Function in Mesenteric Arteries from Type 1 Diabetic Rats withouth Decreasing Plasma Glucose. PLoS ONE 10(11): e0143941. doi: 10.10371/journal.pone/0143941.

Woo, V. Empagliflozin/linagliptin single-tablet combination: first-in-class treatment option. Int J Clin Pract, Dec 2015, 69, 12, 1427-1437. doi: 10.1111/ijcp.12720.

Product Spotlight: The Non-Steroidal Anti-Inflammatory Drug ATB 346

A recent study published in PLoS ONE shows that the naproxen analog ATB 346 has chemopreventative effects in a murine cancer model.

ATB 346 is a hydrogen sulfide (H2S) releasing analog of naproxen, a non-steroidal anti-inflammatory drug (NSAID). It acts by inhibiting cyclooxygenase, and decreasing endogenous PGE2. ATB 346 does not have the same GI damaging effect as naproxen, however. Previous studies have shown that in mice, treatment with ATB 346 reduced traumatic brain injury by reducing inflammation and suppressing neural cell death.

In a study by Paul-Clark et al., the effect of ATB 346 was measured in APCMin/+ mice, a model for gastro-intestinal cancer. Researchers found that treatment with ATB 346 reduced the size and formation of intestinal polyps, pre-malignant lesions that form in this model. ATB 346 decreased the formation in comparison to the parent compound naproxen as well. Continuous treatment with ATB 346 significantly reduced polyp formation. Fourteen days of treatment significantly decreased the polyp score for APCMin/+ mice. The effect of ATB 346 was seen starting treatment at both week 6 and week 12 of life for the mice. Additionally, ATB 346 reduced expression of cMYC and β-catenin, two major cancer biomarkers. In all, the study shows that ATB 346 works better than naproxen in this mouse model, and does not exhibit the same GI side effects that appear with naproxen treatment.

ATB 346, as well as naproxen, is available from LKT Labs.

A7604 ATB 346

N0061 D-Naproxen

N0062 D, L-Naproxen

Campolo M., Esposito E. et al. “Hydrogen sulfide-releasing cyclooxygenase inhibitor ATB-346 enhances motor function and reduces cortical lesion volume following traumatic brain injury in mice” Journal of Neuroinflammation. 2014, 11:196 DOI: 10.1186/s12974-014-0196-1

Paul-Clark, M., Elsheikh W. et al., “Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APCMin/+ Mouse Model of Intestinal Tumorigenesis” PLoS ONE (2016), 11(2):e0147289. Doi:10.1371/journal.pone.0147289