NSAID; COX-1/2

Bendazak is an anti-inflammatory drug that effectively treats a range of inflammatory skin conditions because of its protein-antidenaturing qualities. It has been demonstrated that bendazak is a highly reactive substrate in chemical oxidation systems that resemble the biological processes involved in the production of hydroxyl radicals [2]. Bendazak was demonstrated to inhibit the denaturation of bovine serum albumin (BSA) by urea, heat, and free radicals produced in the xanthine/xanthine oxidase system through the use of EPR spectroscopy of spin-labeled BSA [2].

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. https://onlinelibrary.wiley.com/doi/10.1111/j.1440-1681.2006.04515.x

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Bendazac is an oxyacetic acid with anti-inflammatory, antinecrotic, choleretic and antilipidaemic properties, but its principal effect is to inhibit the denaturation of proteins. The lysine salt, which is better absorbed than the parent compound after oral administration, has been evaluated as a treatment for cataract, a condition which appears to result mainly from the denaturation, aggregation and precipitation of proteins within the lens. Results from a very small number of preliminary studies using objective photographic and densitometric methods have suggested that oral bendazac lysine, usually at a dosage of 500 mg 3 times daily, can stabilise the progression of lens opacification in patients with cataract. Significant improvements in individual and mean visual acuities in treated patients have been reported by several studies, but this parameter is not universally accepted as a reliable index of lens status. Preliminary studies evaluating bendazac lysine 0.5% eyedrops have reported comparable results to those obtained with oral treatment. Overall, tolerability of the drug has been good in studies to date. A dose-related laxative effect and other gastrointestinal disturbances are the most common adverse effects associated with oral therapy, and a transient burning sensation is the most commonly reported symptom occurring with eyedrop application. Bendazac lysine is one of a number of agents which have been introduced for the management of cataract. Although the results of preliminary studies have suggested that the drug may be useful for delaying the progression of cataract, further clinical studies using proven objective methods are required to fully establish its value in the management of this condition and its long term tolerability[1].

By using EPR spectroscopy of spin-labelled bovine serum albumin (BSA), bendazac was shown to prevent the BSA denaturation induced by urea, heat and free radicals produced in the xanthine/xanthine oxidase system. Bendazac did not inhibit the reduction of ferricytochrome c due to the superoxide flux in the above system nor did it possess a significant antioxidant activity on Fe(II) or Fe(III)-induced peroxidation of lecithin liposomes. It is concluded that the scavenger-like activity of bendazac is due to its interaction with protein molecules, rather than free radicals[3].

Oxidative damage to lens components is associated with cataract formation and reactive oxygen species (ROS) overproduction at inflammation sites is thought to lead to the development of inflammatory disorders. Bendazac is a non-steroidal anti-inflammatory drug able to delay the cataractogenic process. Aim of the present study is to characterize, both chemically and biologically, the activity of this anticataract agent as a radical scavenger. Bendazac has been shown to be a strong reacting substrate in a chemical oxidizing system, which mimics a physiological pathway of hydroxy radical generation. In the Fenton-Cier reaction the drug rapidly forms a mixture of hydroxylated derivatives, among which 5-hydroxybendazac, bendazac's main metabolite, being a hydroxy radical scavenger itself. Moreover, by means of a rapid and sensitive flow cytometric method able to determine reactive oxygen intermediate production, bendazac and its 5-hydroxy derivative were shown to inhibit oxidative burst activation in polymorphonuclear neutrophil leukocytes (PMNLs)[2].

Diabetic animals and protocol [https://onlinelibrary.wiley.com/doi/10.1111/j.1440-1681.2006.04515.x] 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%).

Absorption, Distribution and Excretion
When bendaazole is administered in lysine salt form, a 500 mg oral tablet is well absorbed by the body. In healthy volunteers, the maximum plasma concentration (Cmax) is reached within 0.5 to 1 hour after a single oral dose of 500 mg, ranging from 35 to 55 mg/L.
Approximately 60% of the bendaazole dose is excreted in the urine as its major metabolite, 5-hydroxybendaazole. Approximately 15% of the dose is excreted in the urine as the unchanged drug and bendaazole glucuronide.
The volume of distribution of bendaazole is 0.16 L/kg.
The plasma clearance of bendaazole ranges from 0.018 to 0.054 L/h/kg, with an average of 0.033 L/h/kg.

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Metabolism/Metabolites
Bendazole is primarily eliminated through metabolism. Over 60% of the administered dose is excreted in the urine as the hydroxylated major metabolite 5-hydroxybenzazole and its glucuronide, while approximately 15% of the dose is also excreted in the urine as the parent drug and glucuronide. Unfortunately, data on the specific enzymes responsible for the metabolism of benzac are scarce.

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Biological Half-Life
The plasma elimination half-life of benzac has been recorded as 1.7 to 5.2 hours, with an average of 3.5 hours.
Biochemical Half-Life
The plasma elimination half-life of benzac ranges from 1.7 to 5.2 hours, with an average of 3.5 hours.

Protein Binding
In healthy subjects, benzac bound to plasma albumin at a rate of >99%.

[1]. Balfour JA, et al. Bendazac lysine. A review of its pharmacological properties and therapeutic potential in the management of cataracts. Drugs. 1990;39(4):575-596.
[2]. Guglielmotti A, et al. Radical scavenger activity of bendazac, an anticataract non-steroidal anti-inflammatory agent. Pharmacol Res. 1995;32(6):369-373.
[3]. Musci G, et al. Mechanism of the scavenger-like activity of bendazac. Drugs Exp Clin Res. 1987;13(5):289-292.

Bendaazole 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. Bendaazole 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 effect that has been shown to primarily help control and delay the progression of cataracts [A39863]. However, due to the potential risk of hepatotoxicity, bendaazole 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 localized pain, inflammation, dermatitis, eczema, itching, urticaria, insect bites, burns, erythema, and other conditions—although such products may also face complete discontinuation.Mechanism of Action
Bendazac appears to exert its anti-cataract effect by inhibiting the denaturation of proteins in the eye's lens, although its exact mechanism of action has not been formally elucidated—although many mechanisms have been proposed. In particular, inhibiting the binding of certain chemicals (such as cyanates or sugars) may partially prevent the denaturation of lens proteins, and 5-hydroxybenzac, the main metabolite of benzidazac, 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 benzidazac through its interaction with protein molecules suggests that the drug may help prevent the oxidation of lens proteins by free radicals during cataract development. In addition, after a single dose, benzidazac may also reduce the sulfhydryl oxidation of lens proteins in the saliva, serum, or urine of cataract patients, thereby reducing biological fluid oxidation activity (BLOA). Furthermore, benzidazac is believed to have 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 and preventing the conversion of arachidonic acid to cyclic intraperoxides (prostaglandin precursors).

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Pharmacodynamics
Bendazazole primarily exhibits anti-denaturing effects on proteins. This effect has been shown to inhibit the denaturation of various proteins (such as lens proteins) induced by heat, ultraviolet radiation, free radicals, and other chemicals. The drug can be administered in various formulations, including oral lysine salts, eye drops, and even topical application. Some preliminary studies have shown that diabetic patients taking 500 mg of benzazolyl lysine three times daily for three to six months exhibited significant improvements in blood-retinal barrier function. Furthermore, animal models and clinical studies have demonstrated that topical application of benzazolyl has anti-inflammatory effects and can effectively treat various skin diseases, especially those with necrotic components. Benzazolyl also possesses 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. The drug can also inhibit phytohemagglutinin-induced lymphocyte transformation in vitro.

C16H14N2O3

282.299

282.1

C, 68.08; H, 5.00; N, 9.92; O, 17.00

20187-55-7

Bendazac L-Lysine;81919-14-4

2313

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

1.3±0.1 g/cm3

508.2±35.0 °C at 760 mmHg

161-163ºC

261.1±25.9 °C

0.0±1.4 mmHg at 25°C

1.630

3.06

1

4

5

21

357

0

O(C([H])([H])C(=O)O[H])C1C2=C([H])C([H])=C([H])C([H])=C2N(C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])N=1

BYFMCKSPFYVMOU-UHFFFAOYSA-N

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

2-(1-benzylindazol-3-yl)oxyacetic acid

Bendazolic acid; Ilevro; Amnac; bendazac; 20187-55-7; Bendazolic acid; Bindazac; 2-(1-Benzyl-1H-indazol-3-yloxy)acetic Acid; Zildasac; Versus; 2-((1-Benzyl-1H-indazol-3-yl)oxy)acetic acid; Nevanac; 1-Benzylindazole-3-oxyacetic acid; Zildasac; Versus

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 (e.g. under nitrogen), avoid exposure to moisture and light.

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

DMSO : ~250 mg/mL (~885.61 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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