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
Administered as its lysine salt, a 500 mg oral tablet of bendazac is well absorbed into the human body with maximum plasma concentrations Cmax ranging from 35 to 55 mg/L being attained within 0.5 to 1 hour in healthy volunteers after oral administration of a single 500 mg dose.
About 60% of a dose of bendazac is eliminated via the urine as its primary metabolite, 5-hydroxybendazac. Approximately 15% of a dose is eliminated as unchanged drug and bendazac glucuronide in the urine as well.
The volume of distribution documented for bendazac is 0.16 L/kg.
The plasma clearance recorded for bendazac is given as 0.018 to 0.054 L/h/kg with a mean of 0.033 L/h/kg.

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Metabolism / Metabolites
Bendazac is largely eliminated by metabolism, where more than 60% of an administered dose is excreted in the urine as the hydroxylated primary metabolite 5-hydroxybendazac and its glucuronide while up to approximately 15% of a bendazac dose is also excreted in the urine unchanged and as a glucuronide. Unfortunately, there is little data available regarding the specific enzymes responsible for bendazac's metabolism.

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Biological Half-Life
The plasma elimination half-life recorded for bendazac is given as 1.7 to 5.2 hours, with a mean of 3.5 hours.

Protein Binding
Bendazac is >99% highly bound to plasma albumin protein in healthy subjects.

[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.

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.
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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Drug Indication
Prior to the withdrawal of bendazac from various international regions of use due to concerns for hepatotoxicity the chemical had demonstrated potential usefulness predominantly as the prescription medication bendazac lysine for the indication of managing the level of vision in patients with mild to moderate cataracts to facilitate delaying the need for surgical intervention. Elsewhere bendazac may still be available in a limited capacity as a non-prescription topical cream product for treating conditions like local pain, inflammation, dermatitis, eczema, pruritis, hives, insect bites, burns, erythema, and others - although such products may also be facing general discontinuation.

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Mechanism of Action
Bendazac seems to elicit an anticataract action by inhibiting the denaturation of ocular lens proteins, although the precise mechanisms by which this action occurs has not yet been formally elucidated - despite there being many proposed mechanisms. In particular, the denaturation of lens proteins may in part be prevented by inhibiting the binding of certain chemicals like cyanates or sugars and 5-hydroxybendazac - the major metabolite of bendazac - has been shown to be capable of inhibiting the glycosylation of lens proteins by sugars like galactose or glucose-6-phosphate in a dose-dependent manner. Moreover, the apparent ability for administered bendazac to elicit free radical scavenger activities due to interactions with protein molecules suggests that the medication may also be able to prevent the oxidation of lens proteins by free radicals in the development of cataracts. Furthermore, bendazac may also be capable of reducing the sulfhydryl group oxidation of lens proteins by the saliva, serum, or urine from patients with cataracts following single dose administration and reduce biological liquid oxidant activity (BLOA) in doing so. Otherwise, it is believed that bendazac also possesses non-steroidal anti-inflammatory actions, as well as analgesic, antipyretic, and platelet-inhibitory effects These effects may be accounted for in part by the substance's capability to inhibit prostaglandin synthesis by inhibiting cyclooxygenase activity in converting arachidonic acid to cyclic endoperoxides - the precursors of prostaglandins.

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Pharmacodynamics
Bendazac principally demonstrates an antidenaturant action on proteins. This effect has been shown to inhibit the denaturation of various proteins like ocular lens proteins by heat, ultraviolet radiation, free radicals, and other chemicals. The medication may be administered to patients via a number of different formulations, including orally as the lysine salt, as eye drops, or even topical applications for the skin. Some preliminary studies have suggested that an apparent improvement of the blood-retinal barrier had been observed in diabetic patients using bendazac lysine 500 mg three times a day for three to six months. Moreover, the use of topical bendazac has also been shown to demonstrate anti-inflammatory effects in animal models and clinical studies to effectively treat varied dermatoses, especially those involving a necrotic component. Additionally, bendazac has also demonstrated choleretic and antilipidaemic activities that have resulted in substantial reductions in beta/alpha lipoprotein ratio, and total lipid, total cholesterol, and triglyceride levels in patients with dyslipidaemia using oral bendazac lysine 500 mg three times daily. The medication has also elicited the inhibition of phytohaemagglutinin 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.)