NSAID; COX-1/2
Aldose reductase (AR) – AR activity was measured in erythrocytes (values: normal 6.90 U, diabetic 27.29 U, BDL treatment reduced to 18.38, 16.92, 6.39 U at 100, 200, 400 mg/kg respectively) [1]

Oxidative stress – total antioxidative capability (T-AOC) was increased by BDL [1]

Advanced glycation end products (AGE) – BDL decreased AGE levels in serum and kidney cortex [1]

Transforming growth factor β1 (TGF-β1) – BDL reduced relative quantity of TGF-β1 mRNA in kidney cortex [1]

Bendazac is a monocarboxylic acid that is glycolic acid in which the hydrogen attached to the 2-hydroxy group is replaced by a 1-benzyl-1H-indazol-3-yl group. Although it has anti-inflammatory, antinecrotic, choleretic and antilipidaemic properties and has been used for the treatment of various inflammatory skin disorders, its principal effect is to inhibit the denaturation of proteins. Its lysine salt is used in the management of cataracts. It has a role as a radical scavenger and a non-steroidal anti-inflammatory drug. It is a member of indazoles and a monocarboxylic acid.

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Bendazac is an oxyacetic acid. Despite possessing anti-inflammatory, anti-necrotic, choleretic, and anti-lipidemic characteristics, most research has revolved around studying and demonstrating the agent's principal action in inhibiting the denaturation of proteins - an effect that has primarily proven useful in managing and delaying the progression of ocular cataracts [A39863. A39863]. Bendazac, however, has since been withdrawn or discontinued in various international regions due to its capability or risk for eliciting hepatotoxicity in patients although a small handful of regions may continue to have the medication available for purchase and use either as a topical anti-inflammatory/analgesic cream or eye drop formulation.

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To investigate the preventive and protective effects of Bendazac lysine (BDL) on experimental early diabetic nephropathy (DN) rats.
Results: The physical behaviors of early DN rats were hypopraxia, cachexia, and polyuria, while those treated with high doses of BDL were vibrant and vigorous. For BDL-treated DN rats, when compared with vehicle-treated DN rats, the blood glucose level and the intensity of oxidative stress were ameliorated. Also, the microalbuminuria level, AGE either in serum or in renal, and AR activity were significantly reduced. Furthermore, the expression of TGF-beta1 mRNA in the kidney cortex was declined and the thickness of glomerular base membrane was decreased significantly. The ultrastructure of glomerulus and mesangial matrix of BDL-treated DN rats were ameliorated.
Conclusion: BDL has protective effects on several pharmacological targets in the progress of DN and is a potential drug for the prevention of early DN.[1]

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Diabetic neuropathy is a many faceted complication of both type I and II diabetes. The aim of the present study was to investigate the effects of bendazac lysine (BDL), an anticataract drug, on experimental diabetic peripheral neuropathy (DPN) in rats.
Diabetes was induced in rats by intraperitoneal injection of 75 mg/kg streptozotocin (STZ) dissolved in 0.1 mol/L citrate buffer (pH 4.4). Bendazac lysine was administered to rats at doses of 50, 100 and 200 mg/kg twice a day for 12 weeks.
Diabetic rats without treatment showed hypopraxia, polydipsia, polyuria, slow weight gain, cataract, increased tail-flick threshold temperature, decreased motor nerve conduction velocity (nd induced pathological morphological changes of myelinated nerve fibres. All these symptoms were ameliorated in diabetic rats treated with BDL. Bendazac lysine ameliorated the blood glucose concentration, glycosylated haemoglobin levels and insulin levels in the plasma of diabetic rats, reduced aldose reductase activity in erythrocytes and advanced glycation end-products in both nerves and serum and increase the activity of glutathione peroxidase in the nerves and Na+/K+-ATPase in the nerves and erythrocytes.
Bendazac lysine exerts its protective effects against the progression of diabetic peripheral neuropathy in STZ-diabetic rats through multiple mechanisms and is a potential drug for the prevention of deterioration in DPN. [2] https://onlinelibrary.wiley.com/doi/10.1111/j.1440-1681.2006.04515.x

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In streptozotocin (STZ)-induced early diabetic nephropathy (DN) rats, oral administration of bendazac lysine at 100, 200, and 400 mg/kg for 8 weeks produced the following effects: [1]

- Improved physical behaviors: hypopraxia, cachexia, polyuria were ameliorated; high-dose treated rats became vibrant and vigorous. [1]

- Reduced blood glucose level: DN group 18.26±6.98 mmol/L; BDL 400 mg/kg group 10.28±3.82 mmol/L (P<0.01 vs DN). [1]

- Reduced microalbuminuria (urinary albumin/creatinine ratio): DN group 29.07±9.98 μg/(mol Cr); BDL 100 mg/kg 9.72±3.30, 200 mg/kg 6.56±2.95, 400 mg/kg 4.22±2.34 (P<0.01 vs DN). [1]

- Slightly reduced kidney index (not significant). [1]

- Decreased laminin level in kidney cortex: significant only at high dose (P<0.01 vs DN). [1]

- Decreased thickness of glomerular basement membrane (GBM): DN group significantly increased vs normal; BDL treatment decreased GBM thickness in a dose-dependent manner (P<0.05 or P<0.01 vs DN). [1]

- Reduced aldose reductase (AR) activity in erythrocytes: DN 27.29 U; BDL 100 mg/kg 18.38 U, 200 mg/kg 16.92 U, 400 mg/kg 6.39 U (all P<0.01 vs DN). [1]

- Reduced AGE levels in both kidney cortex and serum: e.g., serum AGE: DN 17.25±2.50 AUP/mg protein; BDL 400 mg/kg 5.03±1.35 (P<0.01 vs DN). [1]

- Increased total antioxidative capability (T-AOC) in serum: DN 6.94±1.81 kU/L; BDL 100 mg/kg 10.45±0.85, 200 mg/kg 11.13±1.37, 400 mg/kg 12.46±1.23 (all P<0.01 vs DN). [1]

- Reduced relative quantity of TGF-β1 mRNA in kidney cortex (RT-PCR): DN group significantly increased vs normal; BDL at all three doses caused significant decrease (P<0.01 vs DN). [1]

- Ameliorated morphological changes: light microscopy showed reduced glomerular mesangial hyperplasia; transmission electron microscopy showed that high-dose BDL (400 mg/kg) nearly normalized glomerular capillary loops, GBM, pedicels and mesangial matrix. [1]

Aldose reductase (AR) activity measurement: AR activity was determined by fluorospectrophotometer using β-NADPH and DL-glyceraldehyde as substrates. Activity was defined as the amount of micromole of β-NADPH oxidized per minute at 37°C. Erythrocyte samples were used for the assay. [1]

Total antioxidative capability (T-AOC) measurement: 2.0 mL of ABTS [2,2′-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid)]/myoglobin reagent was mixed with 20 μL of sample and 180 μL of diluent. Then 250 μL of hydrogen peroxide (0.675 mmol/L) was added as the reaction initiator to reach a final concentration of 75 μmol/L in the cuvette. After a 6-minute incubation, the optical density (OD) of ABTS was read at 734 nm by spectrophotometer, and the total antioxidative capability value was calculated. [1]

AGE measurement: AGE levels in renal cortex or serum were measured by fluorescence spectrophotometry. The concentration of AGE was represented by the fluorescence optical density (OD). The final value of AGE in tissue was normalized by the total protein in tissue measured by biuret colorimetry. [1]

Diabetic animals and protocol [2]
Male Sprague-Dawley rats with a mean bodyweight of 200 ± 10 g were used. Diabetic rats were induced by intraperitoneal injection of 75 mg/kg STZ dissolved in 0.1 mol/L citrate buffer (pH 4.4). Three days (72 h) after STZ injection, rats with fasting blood glucose levels over 13.9 mmol/L were used in the experiments. Diabetic rats were treated with low, medium and high doses of BDL (50, 100 and 200 mg/kg, respectively). Other groups of diabetic rats were treated with EPS 50 mg/kg (EPS group) and 1% CMC (5 mL/kg) only (DPN group). Age- and weight-matched male Sprague-Dawley rats that had not been made diabetic were used as controls and were treated with 1% CMC (5 mL/kg) only (NS group). All drugs were administered by oral gavage twice a day for 12 weeks. Experimental animals were given standard pellet diet and water ad libitium, kept in the laboratory animal house under specific pathogen-free (SPF) and constant temperature (25 ± 1°C) conditions and a 12 h light–dark cycle.
Bendazac lysine (BDL) was suspended in 1% carboxymethyl cellulose (CMC) at different concentrations (1.0, 2.0 and 4.0%).

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Induction of Diabetic nephropathy (DN) model and study protocol [1]
Diabetic rats were induced with an ip injection of 60 mg/kg of STZ (dissolved in pH 4.5 citrate buffer immediately before injection), while controlled normal standard rats (NS group, n=10) received 2.5 mL/kg of citrate buffer. Induction of the diabetic state was confirmed by measuring the blood glucose level at the 72 h after the injection of STZ. The rats whose blood glucose concentrations were ≥13.88 mmol/L were randomly allotted into 5 groups: DN rats treated with 1% CMC solution (DN group, n=10); DN rats treated with 100, 200, and 400 mg/kg of Bendazac lysine (BDL) for BL group (low dose, n=10), BM group (moderate dose, n=11), and BH group (high dose, n=10), respectively; and DN rats treated with 100 mg/ kg of epalrestat (EPS group, n=10). The same volume of CMC solution was administered to the NS group (n=10). The animals were housed in a controlled environment (24±1 °C, 12-h light: 12-h dark cycle, onset of light at 07:00 AM) and were allowed food and water ad libitum.

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Induction of early diabetic nephropathy (DN) model: Male Sprague-Dawley rats (weight 162.5±6.7 g, range 150-175 g) were injected intraperitoneally with 60 mg/kg of streptozotocin (STZ) dissolved in citrate buffer (pH 4.5) immediately before injection. Normal control rats received 2.5 mL/kg of citrate buffer. Diabetes was confirmed by measuring blood glucose level 72 h after STZ injection; rats with blood glucose ≥13.88 mmol/L were considered diabetic. [1]

Drug administration: Bendazac lysine was dissolved in 1% carboxymethyl cellulose (CMC) solution. Diabetic rats were randomly allotted into groups: DN group (1% CMC solution), BDL low-dose (100 mg/kg), moderate-dose (200 mg/kg), high-dose (400 mg/kg), and positive control epalrestat (100 mg/kg). The same volume of CMC solution was administered to normal control group. All treatments were administered for 8 weeks. Animals were housed under controlled environment (24±1°C, 12 h light/dark cycle) with free access to food and water. After 8 weeks, urine and blood samples were collected, then animals were sacrificed. Kidney cortices were collected for various analyses (light microscopy, electron microscopy, biochemical assays, RT-PCR). [1]

Morphological observation: Kidney cortex samples were fixed in formaldehyde, embedded in paraffin, stained with HE for light microscopy. For electron microscopy, 1 mm³ cubes of kidney cortices were fixed in 2.5% glutaraldehyde, embedded in epoxy resin, cut into ultrathin sections, stained with plumbum citrate, and observed under transmission electron microscope (magnification ×10,000). GBM thickness was measured using an image analysis system. [1]

Rats: Oral LD50 3100 mg/kg; Behavior: ataxia; Lung, chest, or respiratory: dyspnea. (Medicamentos de Actualidad., 19(649), 1983) Mouse: Oral LD50 1600 mg/kg; Behavior: ataxia; Lung, chest, or respiratory: dyspnea. (Medicamentos de Actualidad., 19(649), 1983)

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[1]. Protective effects of bendazac lysine on early experimental diabetic nephropathy in rats. Acta Pharmacol Sin. 2005 Jun;26(6):721-8.

[2]. PROTECTIVE EFFECTS OF BENDAZAC LYSINE ON DIABETIC PERIPHERAL NEUROPATHY IN STREPTOZOTOCIN-INDUCED DIABETIC RATS. Clin Exp Pharmacol Physiol. 2006 Dec;33(12):1231-8.

Bendazac is a monocarboxylic acid, a derivative of glycolic acid, in which the hydrogen at the 2-hydroxyl group is replaced by a 1-benzyl-1H-indazole-3-yl group. While it possesses anti-inflammatory, anti-necrotizing, choleretic, and lipid-lowering properties and has been used to treat various inflammatory skin diseases, its primary action is the inhibition of protein denaturation. Its lysine salt is used to treat cataracts. It is a free radical scavenger and a nonsteroidal anti-inflammatory drug. It belongs to the indazole class of compounds and is a monocarboxylic acid. Bendazac is an oxyacetic acid. Despite its anti-inflammatory, anti-necrotizing, choleretic, and lipid-lowering properties, most research has focused on investigating and demonstrating that the drug's primary action is the inhibition of protein denaturation—an action that has been shown to primarily help control and delay the progression of cataracts [A39863]. However, due to the potential risk of hepatotoxicity, Bendazac has been withdrawn or discontinued in several international regions. Nevertheless, it remains available and used in a few areas in the form of topical anti-inflammatory/analgesic creams or eye drops.

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Drug Indications
Before bendazac was withdrawn from several international regions due to hepatotoxicity issues, this chemical had shown potential use, primarily as a prescription bendazac lysine, for treating patients with mild to moderate cataracts to control vision and thus delay the need for surgical intervention. In other regions, bendazac may still be available in limited quantities as an over-the-counter topical cream for treating symptoms such as localized pain, inflammation, dermatitis, eczema, itching, urticaria, insect bites, burns, and erythema—although such products may also face complete discontinuation.

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Pharmacodynamics
Bendazac primarily has an anti-denaturing effect on proteins. Studies have shown that this effect can inhibit the denaturation of various proteins, such as lens proteins, caused by heat, ultraviolet radiation, free radicals, and other chemicals. The drug can be administered in various dosage forms, including oral lysine salts, eye drops, and even topical application. Some preliminary studies have shown that diabetic patients taking 500 mg of bendazac lysine three times daily for three to six months may have observed a significant improvement in blood-retinal barrier function. Furthermore, animal models and clinical studies have shown that topical application of benzidazac has anti-inflammatory effects and can effectively treat various skin diseases, especially those with necrotic components. Benzidazac also has choleretic and lipid-lowering activities, significantly reducing the β/α lipoprotein ratio and levels of total lipids, total cholesterol, and triglycerides in patients with dyslipidemia. Patients take 500 mg of benzidazac lysine orally three times daily. This drug can also inhibit phytohemagglutinin-induced lymphocyte transformation in vitro. Mechanism of Action
Bendazidazac appears to exert its anti-cataract effect by inhibiting the denaturation of lens proteins. Although several mechanisms have been proposed, its exact mechanism of action is not fully elucidated. Specifically, inhibiting the binding of certain chemicals (such as cyanates or sugars) may partially prevent lens protein denaturation. The major metabolite of benzidazac, 5-hydroxybenzidazol, has been shown to inhibit the glycosylation of lens proteins by sugars such as galactose or glucose-6-phosphate in a dose-dependent manner. Furthermore, the free radical scavenging activity exhibited by Bendazac through its interaction with protein molecules suggests that the drug may also prevent the oxidation of lens proteins by free radicals during cataract development. In addition, after a single dose, Bendazac may reduce the oxidation of sulfhydryl groups in lens proteins in the saliva, serum, or urine of cataract patients, thereby reducing biological fluid oxidation activity (BLOA). Furthermore, Bendazac is believed to possess nonsteroidal anti-inflammatory effects, as well as analgesic, antipyretic, and platelet-inhibiting effects. These effects may be partly attributed to the substance's ability to inhibit prostaglandin synthesis, specifically by inhibiting cyclooxygenase activity to convert arachidonic acid into cyclic intraperoxides (prostaglandin precursors).

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Bendazac lysine is an oxyacetic acid derivative with protein antidenaturant, anti-inflammatory, antinecrotic, choleretic and antilipidemic properties. It has been introduced for the management of cataracts, protecting vision and delaying the need for surgical intervention. Its principal effects are to inhibit the denaturation of proteins and aldose reductase activity, responsible for sorbitol accumulation and water retention in lens fibers. It also has antioxidative effects and inhibits glycosylation. The major metabolite of bendazac inhibits glycosylation by sugar in a dose-dependent manner, and bendazac and its metabolite (5-hydroxybendazac) inhibit carbamylation of soluble lens proteins in vitro. Bendazac also has scavenger-like activity as a result of its interaction with protein molecules. [1]

C16H14N2O3.C6H14N2O2

428.48152

428.205

C, 61.67; H, 6.59; N, 13.08; O, 18.67

81919-14-4

Bendazac;20187-55-7

13041095

Typically exists as White to off-white solid at room temperature

698.4ºC at 760 mmHg

178-181ºC

376.2ºC

3.475

4

8

10

31

463

1

[C@@H](N)(C(=O)O)CCCCN.C(C1C=CC=CC=1)N1N=C(OCC(=O)O)C2C=CC=CC1=2

OCOCFNMFLNFNIA-ZSCHJXSPSA-N

InChI=1S/C16H14N2O3.C6H14N2O2/c19-15(20)11-21-16-13-8-4-5-9-14(13)18(17-16)10-12-6-2-1-3-7-12;7-4-2-1-3-5(8)6(9)10/h1-9H,10-11H2,(H,19,20);5H,1-4,7-8H2,(H,9,10)/t;5-/m.0/s1

2-(1-benzylindazol-3-yl)oxyacetic acid;(2S)-2,6-diaminohexanoic acid

Bendazac L-lysine; Bendazac lysine; 81919-14-4; Bendalina; Bendaline; Bendazaco lisina; bendazac lysine salt; AF 1934;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~25 mg/mL (~58.35 mM)

Solubility in Formulation 1: 50 mg/mL (116.69 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)