Drug Evaluation

Drugs 39 (4): 575-596. 1990 0012-6667/90/0004-0575/$11.00/0 © ADiS Press Limited All rights reserved. DREND295

Bendazac Lysine A Review of its Pharmacological Properties and Therapeutic Potential in the Management of Cataracts

Julia A. Balfour and Stephen P. Clissold ADIS Drug Information Services , Auckland, New Zealand

Various sections of the manuscript rev iewed by: L. Bonoml, Inst itute of Clinical Ophthalmology, Uni vers ity of Verona, Verona, Italy ; P.F. Ferraris De Gaspare, Ospedale Civile, Divisione Oculistica, Bassano del Grappa, Ital y; J.J. Harding, Uni versit y of Oxford , Nuffield Laboratory of Ophthalmology, Oxford, England; O. Hockwin, Department of Experimental Ophthalmology, University of Bonn , Bonn , West Germany; I.H. Leopold, Department of Ophthalmology, University of California, Irvine California College of Medicine, Irvine, California, USA; V. Rovel, Centre de Recherche Delalande, RueilMalmaison , France; D.R. Sanders, Center for Clinical Research, Department of Ophthalmology, Un iversity of l1linois at Chicago , Ch icago, Illinois , USA; K. Segawa, Department of Ophthalmology, Shinshu Un iver sity School of Med icine, Matsumoto, Japan; O. Schmut, Un ivers ity Eye Hospital, Auenbruggerplatz, Graz, Austria; B. Sllvestrini, Institute of Pharmacology and Pharmacognosy, University of Rome 'La Sapienza', Rome, Ital y; D.H. Youn, Department of Ophthalmology, College of Medi cine, Seoul National Un iversity , Seoul, Korea

Contents

Summa ry I. Pharmacodynamic Properties 1.1 Pathophysiology of Cataract Formation 1.2 Protein Antidenaturant Effects 1.3 Antinecrotic and Topical Anti-Inflammatory Effects 1.4 Choleretic and Antilipidaemic Effects 1.5 Other Effects 1.6 Mechanism of Action 2. Pharmacokinetic Properties 2.1 Absorption 2.2 Distribution 2.2.1 Oral Administrat ion 2.2.2 Ocular Administration 2.3 Elimination 2.4 Influence of Age and Renal and Hepatic Disease on Pharmacokinetics 3. Therapeut ic Use of Bendazac Lysine in the Management and Prophylaxis of Cataract

,

576 578 578 579 580 580 581 581 582 582 582 582 583 583 584 584

Drugs 39 (4) 1990

576

3.1 Methodological Considerations 3.2 Noncomparative Studies with Oral Bendazac Lysine 3.3 Comparative Studies with Oral Bendazac Lysine 3.3.1 Comparisons with Untreated Groups 3.3.2 Controlled Comparative Studies 3.4 Prophylaxis of Cataract Following Closed Vitrectomy and Silicone Oil Injection for Retinal Detachment 3.5 Bendazac Lysine Eyedrops 4. Adverse Effects 5. Dosage and Administration 6. Place of Bendazac Lysine in Therapy

585 586 587 587 587 591 591 591 593 593

Summary Synopsis

Bendazac is an oxyacetic acid with anti-inflammatory. antinecrotic, choleretic and antilipidaemic properties. but its principal effect is to inhibit the denaturation ofproteins. 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 ofpreliminary studies using objective photographic and densitometric methods have suggested that oral bendazac lysine. usually at a dosage of500mg 3 times daily. can stabilise the progression oflens 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 oflens status. Preliminary studies evaluating bendazac lysine 0.5% eyedrops have reported comparable results to those obtained with oral treatment. Overall. tolerability ofthe 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.

Pharmacodynamic Properties

The principal action ofbendazac is an antidenaturant effect on protein. The drug has been shown in vitro to inhibit denaturation of various types of protein, including bovine serum albumin, serum and crystaIline lens proteins by heat, ultraviolet radiation, free radicals and chemicals. In vivo protection of lens proteins has also been demonstrated in animals administered the drug orally as the lysine salt. Apparent improvement of the blood-retinal barrier has been observed in a preliminary study involving diabetic patients treated with bendazac lysine 500mg 3 times daily for 3 to 6 months. Topical bendazac has demonstrated anti-inflammatory activity in animal models and in clinical studies, and has proved effective in the treatment of various dermatoses, particularly those with a necrotic component. The drug also has choleretic and antilipidaemic effects. Significant reductions in total lipid, total cholesterol and triglyceride levels and beta/alpha lipoprotein ratio have been reported in patients with dyslipidaemia receiving oral bendazac lysine 500mg 3 times daily. Bendazac has also been shown to inhibit phytohaemagglutinin-induced lymphocyte transformation in vitro and it has been suggested that this may contribute to its anticataract activity.

Bendazac Lysine: A Review

577

Pharmacokinetic Properties

Following oral administration of bendazac lysine 500mg to healthy subjects mean maximum plasma concentrations of 42 to 49 rng/L were attained within 0.5 to 3 hours. Repeated administration of bendazac lysine 500mg 3 times daily resulted in peak and trough plasma concentrations of approximately 15 to 30 mg/L and 3 to 5 mg/L respectively, within the first 24 hours. Bendazac is more than 99% bound to plasma albumin and has a low volume of distribution (0.16 L'kg). Animal studies have indicated that the drug accumulates in the lens following repeated oral or ocular administration. In healthy subjects, bendazac is eliminated mainly by metabolism to 5-hydroxybendazac, approximately 60% of a dose being excreted in the urine as the major metabolite and its glucuronide . The mean plasma elimination half-life ofbendazac was 3.5 hours, while the mean plasma clearance was 0.033 L/h/kg . The pharmacokinetic profile of bendazac was not significantlyaltered in elderly patients or those with moderate or severe renal impairment; however, an increase in the unbound fraction of bendazac in haemodialysis patients (I % vs 0.4% for healthy subjects) resulted in some minor changes in other pharmacokinetic variables. In patients with severe liver disease, impaired metabolism indicates the need for reduced dosage. There is, at present, no published information regarding the pharmacokinetics of bendazac lysine following ocular administration in humans.

Therapeutic Trials

Bendazac lysine, usually at a dosage of 500mg 3 times daily orally, has been evaluated in the treatment of cataract in uncontrolled and double-blind placebo-controlled studies of up to 2 years' duration. Comparison of results between different studies is difficult owing to the variety of methods used for assessment. Data from a very small number of studies using photographic and densitometric methods to objectively study alterations in the transparency of the lens suggest that bendazac lysine treatment can slow the progression of lens opacification . Further studies of this nature in large numbers of patients are required to confirm this finding. Several researchers have reported apparent individual improvements in lens transparency following bendazac lysine treatment, using serial subjective assessment of lens appearance by traditional ophthalmoscopy and biomicroscopy, but this has not been confirmed by objective methods to date. Several studies have documented a significant increase in mean and individual visual acuities in treated groups compared with baseline measurements and analysis of pooled data from controlled trials has indicated that deterioration of visual acuity occurs in a significantly higher proportion of placebo recipients compared with patients receiving bendazac lysine. However, visual acuity testing alone is not regarded as an acceptable method for evaluating the efficacy of an anticataract agent. Controlled clinical trials using visual acuity at variable contrast or contrast sensitivity as parameters have also reported a beneficial effect ofbendazac lysine, but in the majority of these studies subjective testing methods have been employed. Treatment with bendazac lysine 500mg 3 times daily orally for I year was reported to be effective in reducing the incidence of postoperative cataract development in a group of patients undergoing closed vitrectomy and silicone oil injection for retinal detachment, although further research is required to confirm this preliminary finding. Bendazac lysine eyedrops 0.5%, at a dosage of 2 drops 3 times daily, have been evaluated in a small number of open and placebo-controlled studies, with results comparable to those obtained with the oral formulation.

Adverse Effects

At present, clinical experience with bendazac lysine is limited and it is not possible to give accurate incidence rates for individual adverse effects. However, oral bendazac lysine appears to have been well tolerated in therapeutic trials of up to 2 years' duration. Gastrointestinal symptoms such as gastralgia, nausea and a dose responsive laxative effect have been the most frequently encountered problems. Bendazac lysine eyedrops 0.5% have been well tolerated ; a transient burning sensation on instillation has been the most frequently reported adverse symptom.

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Drugs 39 (4) 1990

Dosage and Administration

The recommended starting oral dosage ofbendazac lysine is 500mg (adults) or 250mg (children) 3 times daily after meals, with temporary dosage reduction if a laxative effect occurs . Courses of 3 to 6 months are recommended, with regular monitoring of liver function during prolonged treatment. Bendazac dosages should be halved in patients with severe liver disease and concurrent treatment with choleretic drugs should be avoided. For ocular treatment, instillation of 2 drops of a 0.5% solution 3 times daily is recommended.

1. Pharmacodynamic Properties Bendazac is an oxyacetic acid with a chemical structure similar to that of nonsteroidal anti-inflammatory agents such as indomethacin (see fig. I). A topical formulation of bendazac has been marketed in a number of countries for the treatment of various dermatoses, but this review focuses on bendazac lysine, which shows superior oral absorption to the parent compound and is advocated for the management of cataracts, either as an oral or an ocular formulation. The principal action of bendazac is an antidenaturant effect on protein , but the drug also has anti-inflammatory, anti necrotic, choleretic and antilipidaemic properties, all of which may be relevant to its anticataract action .

Bendazac

CH3°OCrCH2COOH CH

I

N

3

c-o~ CI -

oII

Indomethacin Fig. 1. Structural formulae of bendazac and indomethacin.

1.1 Pathophysiology of Cataract Formation The ocular lens is an avascular, normally transparent, structure containing a greater proportion of protein than any other body organ (35% by weight). Its primary function is to focus light rays onto the retina . Opacification of the lens, or cataract, is the most common lens disease and is most frequently associated with ageing, although congenital, metabolic, traumatic, toxic and other types of cataract also occur. Opacification results when the normally transparent fibres of the lens start to scatter light as a consequence of alteration in their constituent proteins or of water permeating the lens fibres and separating the protein molecules. Denaturation of the lens proteins is followed by aggregation of damaged protein material and precipitation of insoluble protein. Although cataract predominantly affects elderly individuals (hence the term 'senile cataract'), it has been suggested that lenticular opacification is a multifactorial process which is facilitated, but not directly caused, by age-associated changes in the lens (Chen et al. 1988; Hockwin 1985). Various factors, including diabetes mellitus, hypocalcaemia, hypertension, hyperlipidaemia, hyperuricaemia, diarrhoea, renal failure, myopia, glaucoma, cardiac disease, poor nutrition, prolonged exposure to solar radiation and oral hypoglycaemic, diuretic or corticosteroid therapy have been found to increase the risk of cataract development (Chen et al. 1988; Hockwin 1985). Agerelated lenticular changes include a decrease in metabolic activity, an increase in disulphide crosslinkages resulting from the oxidation of sulfhydryl groups, the nonenzymatic glycosylation of proteins

Bendazac Lysine : A Rev iew

(particularly of high molecular weight o-crystallins) and alteration in various enzymes. These tend to be more evident in the nucleus, which is the oldest part of the lens. A decrease in the proportion of low molecular weight crystalline protein and increasing production of water-insoluble aggregates of high molecular weight occur (Hockwin 1985). Various naturally occurring toxic substances such as peroxide or other free radicals and cyanate produced from urea may interact with lens proteins to cause denaturation and precipitation. Quinoid compounds, produced from altered amino acid metabolism, may also react with soluble lens proteins to form less soluble substances (Silvestrini 1986). Oxidative mechanisms appear to be particularly important in the opacification process. The normal lens contain's various substances which protect against oxidation, including glutathione, glutathione peroxidase , NADPH , catalase, ascorbic acid and superoxide dismutase (Hockwin 1985; Spector & Garner 1981). This protective system appears to be less effective in old lens tissue (Hockwin 1985). It has been postulated that patients with high urea levels - for example those with severe protracted diarrhoea or renal failure - are particularly at risk from cyanate-induced lens damage (Harding & Rixon 1980), and increased risk of cataract has been confirmed in patients with severe diarrhoea and dehydration (Minassian et al. 1984; Van Heyningen & Harding 1986). The high incidence of cataract in some tropical countries may reflect the prevalence of diarrhoeal disease (Harding & Rixon 1980; Minassian et al. 1984). Diabetic subjects tend to develop cataract more frequently and at an earlier age than nondiabetics. True diabetic cataract, however, is a rare, rapidly developing condition affecting patients with severe juvenile diabetes. Diabetic cataract appears to result from accumulation of sorbitol , produced from glucose in the lens by the enzyme aldose reductase , which causes water retention in the lens fibres. Cataract development is also a feature of galactosaemia, an hereditary condition characterised by high plasma levels of the hexose sugar galactose. It is also of interest to note that high glucose con-

579

centrations in vivo or in vitro have been found to result in glycosylation of lysine residues in rat and bovine lens crystallins (Stevens et al. 1978). In vitro glycosylation by glucose or glucose 6-phosphate increased the susceptibility of the crystallins to sulfhydryl oxidation, resulting in disulphide crosslinkage, the formation of high molecular weight aggregates and opalescence of crystallin solutions. Thus, a number of hypotheses have been presented to account for the opacification of the lens in cataractogenesis: a better understanding of the mechanisms involved could lead to a more rational approach to the management of the disease. 1.2 Protein Antidenaturant Effects Bendazac has been shown to inhibit the in vitro denaturation of various types of protein , including albumin, serum and crystalline lens protein, by heat , ultraviolet radiation, free radicals and chemicals.In vivo protection oflens protein has also been demonstrated in experimental animals. Bendazac and phenylbutazone both inhibited heat-induced denaturation of bovine serum albumin , egg albumin, rat serum and rat plasma in vitro. Bendazac also inhibited the denaturation of bovine serum albumin by ultraviolet light (Silvestrini et al. 1970). Silvestrini et al. (1983) studied the protective action of bendazac and bendazac lysine against heat-induced denaturation oflens proteins , both in vitro and in vivo, in various animal species. Bendazac produced a dose-related protective effect against heat-induced denaturation of protein in rat, rabbit and pig lenses in vitro. Electrophoretic studies indicated that the drug inhibited changes in the a-crystallin region caused by denaturation. Bendazac, at a concentration of I mmol/L, prevented or markedly reduced the formation of larger aggregates of protein within the lens (thought to be a-crystallin) which was observed in control lenses on ultramicroscopy. Bendazac, salicylic acid and indomethacin demonstrated similar dose-related inhibitory effects against heat-induced denaturation of serum , but bendazac was markedly superior to the 2 other drugs in protecting lens proteins,

Drugs 39 (4) 1990

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producing 87% inhibition at a concentration of I mrnol/L, Oral administration ofbendazac lysine to rats produced dose-related protection against lens protein denaturation and aggregation. A protective effect was apparent after I to 2 weeks when the drug was administered at a concentration of 0.5% in the diet or after only 2 to 5 days when a dosage of 200mg 3 times daily was administered by gavage. Oral administration of bendazac lysine 0.25 g/ kg/day to rabbits, either as a single dose or for 3 days, appeared to protect against the cataractogenic agent 2,4-dinitrophenol. Transmission electron microscopy indicated that there was better preservation of cellular membranes and a lesser degree of intracellular fusion and cytoplasmic damage in the lenses of animals receiving bendazac lysine, compared with control animals that had received dinitrophenol alone (Bauchiero et al. 1987). 1.3 Antinecrotic and Topical AntiInflammatory Effects Bendazac appears to inhibit the necrotic component of inflammatory processes in experimental animals, but has not demonstrated any anti-inflammatory action when administered systemically (Cioli et al. 1984; Silvestrini et al. 1969). The drug inhibited urea-induced cutaneous necrosis in rats when administered topically or subcutaneously (Silvestrini et al. 1969) or orally, at a dosage of 100 mg/kg of the lysine salt (Cioli et al. 1984). Topically applied bendazac has demonstrated anti-inflammatory activity in several animal models of inflammation. A 3% ointment had similar efficacy to pimeprofen 5% or bufexamac 5%, and was superior to indomethacin I% in suppressing croton oil-induced ear oedema in rats. This bendazac formulation also had similar efficacy to bufexamac , but was less effective than pimeprofen and indomethacin against carrageenan-induced skin oedema in rats , delayed hypersensitivity to picryl chloride (assessed by ear swelling) in mice, and ultraviolet ray-induced erythema in guinea-pigs (Tsuji et aI. 1982). Bendazac was also less effective

than pimeprofen or bufexamac against histamineinduced skin oedema in rats. Both bendazac and hydrocortisone, applied topically as 3% ointments, inhibited acetic acid-induced erythema in mice. Bendazac also inhibited heat-induced burns in rats, whereas hydrocortisone was ineffective (Lisciani et aI. 197I). Bendazac as a topically applied 3% cream or 1% paste has been found to be effective in the clinical treatment of various inflammatory skin conditions, including gluteal erythema, intertrigo, eczema and seborrhoeic dermatitis in infants (Paolucci 198I) and eczema, contact dermatitis, angiodermatitis and varicose ulcer in adults (Bruno & Claudio 1981; Carboni et aI. 198I). The drug was particularly effective in treating those conditions with a necrotic component (Carboni et aI. 198I). 1.4 Choleretic and Antilipidaemic Effects Intraperitoneal injection ofbendazac lysine 100 rug/kg significantly increased the production of bile in rats (Cioli et aI. 1984). This choleretic action may account for the drug's ability to lower plasma lipid levels (Madzarovova 1982). The antilipidaemic effects of bendazac lysine (500mg 3 times daily) were investigated in a doubleblind placebo comparison involving 37 patients with type lIb or IV dyslipidaemia (Fredrickson & Lees classification). All patients had total serum lipid and triglyceride levels above 10 and 2 g/L, respectively, 2 weeks after starting a low-calorie and low-fat diet. This diet was continued during the 6week treatment period and reductions of 27.5%, 2 I% and 53% in mean serum total lipid, total cholesterol and triglyceride levels, respectively , were achieved in the bendazac lysine-treated group, compared with 14%, 4% and 24% for placebo recipients. The mean beta/alpha lipoprotein ratio was decreased by 40% and 18.5% in bendazac lysineand placebo-treated patients, respectively (Madzarovo~a 1982). Pathological changes in the blood lipid profile have been documented in patients with cataract (unpublished data on file; Angelini), but whether there is any correlation between these disease states

Bendazac Lysine: A Review

or whether the antilipidaemic properties of bendazac contribute to its anticataract effects is not clear. 1.5 Other Effects

In an in vitro study using lymphocytes from diabetic and nondiabetic subjects , bendazac sodium 60 mg/L significantly inhibited phytohaemagglutinin-induced lymphocyte transformation independently of glucose concentration, but only when present during the entire incubation (Sensi et al. 1988). However, the drug did not appear to affect the expression of interleukin 2 receptors on lymphocytes following mitogen stimulation. The authors suggested that the anticataract activity of bendazac might be partly due to an effect on lymphocyte activity, resulting in decreased antibody production. However, in vivo studies are required to confirm this hypothesis. Treatment with bendazac lysine 500mg 3 times daily for 3 to 6 months appeared to improve the blood-retinal barrier, as evidenced by vitreous fluorophotometry, in 12 insulin-dependent diabetics with mild retinopathy (Nuzzi et al. 1987). Prior to treatment, all patients showed abnormal leakage of fluorescein into the vitreous humour, with a mean fluorescein vitreous penetration coefficient of 0.573, which decreased to 0.318 on completion ofbendazac lysine treatment and increased to 0.568 6 months later . However, the authors acknowledged that this apparent decrease in the penetration of fluorescein into the vitreous humour might be attributable to an effect of bendazac on fluorescein metabolism. 1.6 Mechanism of Action The denaturation of constituent proteins plays a central role in the development of most types of lens opacity and a variety of underlying mechanisms have been postulated (section 1.1). Bendazac appears to exert an anticataract action by inhibiting the denaturation of lens proteins, but the exact mechanism(s) by which this effect is produced is unclear.

581

Denaturation of lens proteins might be prevented by inhibiting the binding of various agents such as cyanates or sugars. Although bendazac did not appear to prevent binding of galactose or glucose-6-phosphate to bovine lens proteins, its major metabolite, 5-hydroxybendazac, inhibited glycosylation by either sugar in a dose-dependent manner (Lewis & Harding 1988). Furthermore, inhibition of the carbamylation of soluble lens proteins has been demonstrated in vitro with bendazac, 5-hydroxybendazac (Lewis et al. 1986) and aspirin (Crompton et al. 1985). It has .been suggested that oxidation oflens proteins by free radicals may be an early event in the development of cataract (see section 1.1). Schmut et al. (1987) studied the free radical scavenger activity of bendazac, alone and in combination with human serum. Bendazac lysine 5 mmol/L and serum both inhibited in vitro depolymerisation of hyaluronic acid by free hydroxyl and superoxide radicals from a sodium ascorbate system, but the maximum inhibitory effect was observed when the two were used in combination. Serum from patients treated with bendazac lysine for a period of 4 weeks showed a slight, but nonsignificant, increase in in vitro free radical scavenging activity compared with baseline values . The mean plasma concentrations of bendazac in these treated patients (approximately 30 to 40 mg/L) were, however, significantly lower than those used in the earlier part of the study. Although bendazac inhibited in vitro denaturation of bovine serum albumin by urea, heat, and free peroxide , superoxide and hydroxyl radicals from a xanthine/xanthine oxidase system, the drug did not inhibit the reduction of ferricytochrome C resulting from superoxide flux from the xanthine/ xanthine oxidase system and showed only a slight protective effect against ferrous or ferric-induced peroxidation of lecithin liposomes. This suggests that bendazac has scavenger-like activity due to an interaction with protein molecules, rather than with free radicals (Musci & Silvestrini 1987). Several drugs including bendazac lysine, benzydamine, benoxaprofen, flunoxaprofen, flurbiprofen and phenylbutazone have been found to reduce

582

in vitro sulfhydryl group oxidation of bovine lens protein by saliva, serum or urine from patients with cataract following single-dose administration (Testa et al. 1986, 1987a,b). Reduction of biological liquid oxidant activity (BLOA) ranged from 5 to over 20% in around 40% of cataractous patients who received bendazac lysine 50 or 500mg, or benzydamine 50mg. The 2 bendazac doses produced comparable reductions in BLOA. Diabetic subjects and those aged over 65 years showed the greatest reductions and significant improvements in vision occurred in a markedly higher proportion ofBLOA test responders after 2 months' treatment with bendazac lysine or benzydamine compared with unscreened individuals. Moreover, improvement of vision was not evident in any screened patients who did not exhibit BLOA reduction (Testa et al. 1986). It was suggested that an antioxidant metabolite is responsible for both BLOA reduction and anticataract effect, and that the BLOA test may be useful for predicting which patients are most likely to benefit from NSAID treatment. Treatment with bendazac lysine, or flunoxaprofen (dosages not specified) for 2 months produced improvement of vision in 45% and 82% of patients, respectively , in a controlled stud y involving patients with progressive cataract not selected by the BLOA test (Testa et al. 1987b; see section 3).

Drugs 39 (4) 1990

2.1 Absorption Superior absorption ofbendazac lysine has been demonstrated over the parent compound following oral administration (Catanese et al. 1982). Maximum plasma bendazac concentrations (Cmax) ranging from 34 to 55 (mean 49) mg/L were attained in 5 healthy volunteers within 0.5 to I hour after oral administration of a single dose of bendazac lysine 500mg, with concentrations declining to around 5 mg/L after 8 hours and 0.3 mg/L after 24 hours (Catanese et al. 1982). Rovei et al. (l987b, 1988; see table I) reported similar mean values for C max in 10 healthy subjects at 0.5 to 3 hours after administration of the same dose. However, wide individual variation in the time to attain C max was noted in these studies (Catanese et al. 1982; Rovei et al. 1987b). Within the dosage range 125 to 500mg both the C max and area under the plasma concentration-time curve (AVe) of bendazac increased in proportion to the dose administered (Rovei et al. 1987a). Repeated adm inistration of bendazac lysine 500mg 3 times daily to healthy subjects produced peak and trough bendazac concentrations of approx imately 15 to 30 mg/L and 3 to 5 mg/L, respectively. No accumulation was observed over a 21-day treatment period (Barillari et al. 1983). 2.2 Distribution

2. Pharmacokinetlc Properties The pharmacokinetics of orally administered bendazac lysine have been studied in healthy young and elderly subjects, following single and repeated doses, and in patients with renal or hepatic impairment, following single doses. Data from selected studies are presented in table I. The pharmacokinetics of the drug following ocular administration have been stud ied in rabbits , but no results from human studies are available. High performance liquid chromatography has been used for quantitative anal ysis ofbendazac and its major metabolites in blood, plasma and urine.

2.2.1 Oral Administration In common with other acidic drugs, bendazac is highly bound to plasma albumin (>99% for plasma from healthy subjects). This probably accounts for the low volume of distribution of bendazac (0.16 L'kg) reported by Rovei et al. (l987b). However, bendazac was reported not to displace, or be displaced by, salicylic acid, tolbutamide or warfarin, from albumin binding sites (Rovei et al. I987a). Tissue distribution studies in the rat indicate that the highest concentrations of drug are found in the plasma, liver and lungs (unpublished data on file, Angelini) and that the rate of elimination from the lens is much slower than that from the plasma (Ca-

Bendazac Lysine: A Review

583

Table I. Mean pharma cokinet ic data following a single oral dose of bendazac lysine 500mg in healthy vounteers and in patients with hepatic or renal dysfunction (Rovei et al. 1987b, 1988) Study popu lation (number)

(h)

Cmax (mg/L)

(h)

AUCo_oo (mg/L· h)

CL/F (L/h/kg)

CLR (L/h/kg)

Vd/ F (L/kg)

Plasma protein binding at Cmax (%)

Healthy volunteers (10) Hepatic ctrrhoslss (11) Moderate renal insufficiencyb (5) Severe renal insufficiencyC (5) Haemodialysis patients (5)

1.6 1.5 1.6 1.4 1.7

41.9 36.4 27.6 31.2 25.5

3.5 8.0 4.7 3.8 3.1

159 339 150 149 84

0.033 0.014 0.038 0.036 0.062

0.0021 0.0014 0.0007 0.0003 0

0.16 0.16 0.22 0.18 0.25

99.6 98.8 99.2 99.3 99.0

t ma x

t'h~

a Direct bilirubin 14-134 I'mol/L, y-glutamyltransferase 20-585 U/L. b Creatinine clearance 48-90 ml/min . c Creatin ine clearance 12-28 ml/m in. Abbreviations: t max = time to peak plasma drug concentration ; Cmax = peak plasma concentration: tl/2~ = plasma elimination halflife: AUCo-oo = area under plasma concentration-time curve from time zero to infinity : CL/F = apparent plasma clearance: CLR = renal clearance : Vd/F = apparent volume of distribution; F = systemic availability .

tanese et al. 1985; Silvestrini et al. 1983), This appears cons istent with the observation that the lens does not ha ve a direct blood supply and metabolic exchange therefore occurs via the aqueous humour. Also, the metabolic rate of the lens is low compared with that of other tissues. Repeated oral administration of radiolabelled bendazac lysine 200 mg/kg 3 times dail y to rats for 6 days produced serum and lens concentrations of 190.2 rng/L and 1.7 mg/kg, respectively . 72 hours after the last dose, serum concentrations had declined to 10.7 mg/L, compared with 0.9 mg/kg in the lens (Silvestrini et al. 1983).

2.2.2 Ocular Administration Instillation of 0.05ml of a radiolabelled 0.5% bendazac lysine solution into the eyes of rabbits resulted in high drug concentrations in the cornea, iris, ciliary bodies, retina and aqueous humour with much lower concentrations in the vitreous humour and lens (Valeri et al. 1987). Plasma concentrations of up to 143 Ilg/L were observed in this study. 24 hours later , bendazac concentrations were markedly decreased in all tissues except the lens. Repeated application of 0.05ml 3 times daily for 6 da ys produced drug concentrations approximately lO-fold higher in the lens, and 2-fold higher in the

other ocular compartments, compared with singledose application. 2.3 Elimination In healthy subjects , bendazac is eliminated mainly by metabolism to 5-hydroxybendazac, with about 60% of a dose being recovered in the urine as the major metabolite and its glucuronide. Approximately 15% is eliminated as unchanged drug and bendazac glucuronide (Rovei et al. 1987a). Comparison of AVC values in healthy subjects has indicated that, following single-dose administration of bendazac lysine 500mg, unchanged bendazac represents approximately 80% and 5-hydroxybendazac (in free or conjugated form) approximately 20% of the total plasma concentrations of the drug . The renal clearance of 5-hydroxybendazac was found to be over 20-fold higher than that of bendazac (Catanese et al. 1986). Plasma elimination half-lives ranging from 1.7 to 5.2 hours, with a mean of 3.5 hours and plasma clearance values varying from 0.018 to 0.054 L/h/ kg with a mean of 0.033 L/h/kg, were reported by Rovei et al. (1987b, 1988), following administration of single doses of bendazac lysine 500mg to healthy subjects. The mean plasma elimination half-

584

life of 5-hydroxybendazac was 7.3 hours. Renal clearance of bendazac accounted for less than 10% of total body clearance. 2.4 Influence of Age and Renal and Hepatic Disease on Pharmacokinetics In 10 elderly healthy subjects (aged 65 to 74 years), the pharmacokinetic parameters of bendazac following administration of single doses of bendazac lysine 500mg were not significantly different from values obtained in 10 young healthy subjects (aged 20 to 27 years) [Rovei et aJ. 1987a). Rovei and colleagues studied the pharmacokinetics of bendazac following single-dose oral administration of bendazac lysine 500mg to 15 pat ients with various degrees of renal impairment (Rovei et aJ. I987b) and to II patients with hepatic cirrhosis (Rovei et aJ. 1988; see table I). The renal clearance of bendazac was found to decrease in relation to the degree of renal insufficiency, while the rate and extent of drug absorption , and elimination half-life, were not significantly modified by moderate or severe renal insufficiency. In contrast, a significant increase in the unbound fraction of bendazac in patients with end-stage renal failure undergoing haemodialysis (I % vs 0.4% for healthy subjects) resulted in an increased volume of distribution (0.25 vs 0.16 L/kg) and apparent plasma clearance (0.062 vs 0.033 L/ h/kg) , and decreased maximum plasma concentration (25.5 vs 4\.9 mg/L) and AVe, compared with values for healthy subjects. The maximum plasma concentration of 5-hydroxybendazac was markedly elevated in patients with renal failure (5.44 vs 2.70 mg/L for healthy subjects), as were values for its AVe (51 vs 17 mg/L> h). As the plasma half-life of 5-hydroxybendazac in patients with renal failure was not significantly different from values in healthy subjects, it would appear that elimination of ·this metabolite in renal failure occurs by formation of the glucuronide, which accumulated accord ing to the degree of renal insuffic iency. Overall, the changes reported for the pharmacokinetic profile of bendazac in patients with renal impairment do not appear to be clinically significant and

Drugs 39 (4) 1990

the authors suggest that dosage modifications are not necessary. The maximum plasma concentration, time to maximum plasma concentration, renal clearance and apparent volume of distribution of bendazac were not significantly altered following single-dose administration to patients with severe hepatic insufficiency (table I). However, as a result of impaired metabolism, plasma clearance was decreased approximately 2-fold, with a corresponding increase in elimination half-life and AVe, in patients with liver disease compared with values obtained in healthy subjects. The authors therefore recommended that the daily dosage of bendazac lysine should be halved in patients with severe hepatic impairment (Rovei et aJ. 1988).

3. Therapeutic Use of Bendazac Lysine in the Management and Prophylaxis of Cataract Senile cataract is generally a progressive and bilateral degenerative condition, causing increasingly blurred vision, visual distortion and sensit ivit y to glare, and resulting in blindness in severe cases. Surgical extraction of the lens is indicated when visual impairment interferes with the patient's normal activities or if glaucoma secondary to lens swelling develops. Following lens removal, aphakic spectacles, contact lenses or an intraocular implant are required. Development of an opaque secondary membrane (after-cataract), requiring further surgery or laser treatment, occurs in almost all paediatric patients and approximately 50% of adult patients after extracapsular cataract extraction. Oral bendazac lysine, usually at a dosage of 500mg 3 times daily, has been evaluated in the management of cataract in noncomparative and placebo-controlled trials of up to 2 years' duration, and in a comparative study with flunoxaprofen . The drug has also been studied in the proph ylaxis of cataract following closed vitrectomy and silicone oil injection for detachment of the retina. Bendazac lysine eyedrops 0.5% (2 drops 3 times daily) have been evaluated in the treatment of cataract

Bendazac Lysine: A Review

in a small number of noncomparative and placebocontrolled clinical trials. Comparison of results from studies ofbendazac lysine is complicated by the different methods of assessment used and the different exclusion criteria applied with regard to underlying disease, localisation of cataract and baseline visual acuity. Most studies have included only idiopathic senile or presenile cataract and have excluded patients with diabetes, glaucoma or other eye conditions known to induce cataract. However, Testa et al. (1984a) included juvenile cataract and patients with underlying diabetes or hypocalcaemia; furthermore, a diabetic subgroup was included in a study comparing bendazac lysine with placebo (Testa et al. 1987b). Eyes with total cataract have been excluded from evaluation. I

3.1 Methodological Considerations Clinical evaluation of a treatment for cataract is compl icated by the variable progressive course of the disease and the difficulty of developing objective methods to assess lens function. The most widely studied parameter is visual acuity, which tends to decrease in proportion to the density of the cataract , but also varies according to the localisation of the opacity. Visual acuity is also dependent on other factors, such as the integrity of the retina, which may be suspect in elderly or diabetic patients.' Visual acuity testing is most frequently performed (with correction for distance) using Snellen letter charts; or occasionally, Landolt's ring test is used (Testa et al. 1982). The value corresponding to the smallest line which can be read on a letter chart can conveniently be expressed in tenths or as a decimal. However, conventional visual acuity tests have been widely criticised as being too subjective and may be influenced by small differences in examination conditions and by learning phenomena. Variable density Snellen letter charts have been found to be capable of demonstrating subtle alterations in visual acuity not revealed by standard methods (Penne et al. 1987). Interferometric visual acuity testing, which has been performed in some studies, can exclude the effects on

585

visual function of any macular or optic nerve dysfunction (Baraldi et al. 1989; Penne etal. 1987). The Arden grating test has been used to detect variations in the sensitivity to contrast at various spatial frequencies and the Miller-Nadler glare test to evaluate sight deficiency in various glare conditions (Arienzo et al. 1987). The intraocular scattering caused by cataract alters the perception of large objects in a manner which cannot be predicted simply by measurement of visual acuity or contrast sensitivity with stimuli at high spatial frequencies. At high spatial frequencies, there is correlation between sensitivity to contrast and visual acuity, whereas the sensitivity to contrast at low spatial frequencies provides an index of the degradation of the image. Therefore it has been recommended that contrast threshold should be measured over a wide range of spatial frequencies (Ponte et al. 1989) when examining the visual function of patients with cataracts. Refractive error, expressed as the dioptres oflens required to obtain optimum visual acuity, has been assessed in some studies (luglio & Iuliano 1984; Testa et al. 1982, 1983, 1984a). However, variations in this parameter have been equivocal and interpretation is difficult since the hypermetropia or myopia-inducing effect of the cataract may be unknown . Several studies have used traditional examination by ophthalmoscopy and slit lamp biomicroscopy with direct light and retroillumination to follow the course of lens opacities. Apparent stabilisation or improvement of lens opacification has been reported after bendazac lysine treatment, with a trend towards worsening in placebo groups, in such studies (e.g. Arienzo et al. 1987; Carlentini et al. 1987; Courtis et al. 19~; Cvintal et al. 1987; Testa et al. 1983, 1984b; Youn et al. 1987). However, as acknowledged by most of these authors, serial assessment of this parameter by these subjective methods alone cannot give reliable results. Photographic and densitometric methods have been employed to document objectively and quan titatively alterations in the morphology and density of lenticular opacities (Baraldi et al. 1989; Gandolfo et al. 1987; Hockwin et al. 1989; Penne

586

Drugs 39 (4) 1990

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et at. 1987). Scheimpflug photography of the anterior eye segment with densitometric image analysis offilm blackening caused by intraocular light scattering provides hard data on the state of the lens and is reported to be a reliable and reproducible method of documenting lens transparency over time (Hockwin et at. 1989). Echobiometry of the lens, in which the speed of ultrasound in the lens is measured (Arienzo et al. 1987) and static photoptic perimetry (Gandolfo et at. 1987) have also been used to examine changes in lenticular opacity.

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Double-blind placebo-controlled stud ies Carlentini et B 28 [50) C,SC al. (1987) P 10 [19)

D'Andrea & Bucci (1987)

Noncomparative studies Cati 39 [69) Giovannelli & Chiriaco (1988)

Reference

Table V. Summary of selected clinical trials examining the influence of bendazac lysine eyedrops 0.5% (2 drops 3 times daily) on visual acuity in patients with cataract

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Bendazac Lysine: A Review

ertness (7%), idiosyncratic reactions (rash, stomatitis ; 5.4%), hallucinations (5%) and insomnia (5%). A further 71 patients stopped treatment after the second month because of poor tolerability. Unfortunately, this study was not reported in full detail: no comparison was made with other treatment groups and the dosage regimen used was not clearly stated. In contrast, a study involving 75 patients treated with oral bendazac lysine 500mg 3 times daily for 12 to 24 months reported no withdrawals because of adverse effects. Four patients experienced gastrointestinal symptoms, which responded to temporary discontinuation of treatment and reinstitution at a lower dosage (Tittarelli & Attorresi 1987). Similarly, Testa et al. (1984a) reported gastrointestinal symptoms (gastralgia and/or diarrhoea), requiring temporary discontinuation of therapy, in 4 of 67 patients receiving bendazac lysine 500mg 3 times daily for I to 5 months. Barillari et al. (1983) did not observe any significant changes from baseline values in clinical or laboratory parameters among 5 healthy volunteers who received bendazac lysine 500mg 3 times daily orally for 21 days and Baraldi et al. (1989) reported that I year's treatment with the drug did not induce any systemic toxic effects on the basis of laboratory tests in lOS patients with cataract, although gastrointestinal disturbances occurred in 3 cases. Hepatotoxicity, thought to be due to idiosyncratic metabolic handling, has been reported in 2 patients during therapeutic treatment with bendazac 500 to 1500mg daily (Ballesteros et al. 1987). Since biliary stasis with other signs of liver impairment has been observed in subchronic toxicity studies in dogs receiving very high doses of bendazac lysine (200 to 300 rug/kg/day orally), monitoring of liver function during long term clinical use of the drug is recommended as a precaution at this early stage of the drug's development. It should be noted that such hepatotoxic effects may be species-specific, particularly as the elimination half-life of bendazac in the dog is about 44 hours (compared with about 4 hours in humans; see section 2.3) and drug accumulation would therefore be ex-

593

pected with daily administration of high dosages (data on file, Angelini). Bendazac lysine eyedrops 0.5% have generally been well tolerated in the limited number of clinical trials reported to date, which have involved small numbers of patients treated for up to 16 months. A transient burning sensation on instillation of the eyedrops has been noted by up to 38% of patients. Other symptoms have included conjunctival hyperaemia, lacrimation, foreign-body sensation and photophobia (Carlentini et al. 1987; Cati Giovannelli & Chiriaco 1988; D'Andrea & Bucci 1987). However, Carlentini et al. (1987) reported a higher incidence of adverse symptoms in placebo-treated patients than in those receiving bendazac lysine.

5. Dosage and Administration The recommended starting oral dosage of bendazac lysine is 500mg for adults and 250mg for children, 3 times daily after meals. A laxative effect may be experienced by some patients, in which case temporary dosage reduction is advisable. Courses of 3 to 6 months' duration are recommended, with regular monitoring of liver function during prolonged treatment. It has been suggested that the dosage of bendazac lysine should be halved in patients with severe hepatic insufficiency (see section 2.4; Rovei et al. 1988). Concurrent treatment with choleretic drugs such as dehydrocholic acid should be avoided. The recommended dosage for bendazac lysine 0.5% eyedrops is 2 drops 3 times daily.

6. Place of Bendazac Lysine in Therapy Cataract is the most common worldwide cause of blindness and is estimated to blind more than 2 million individuals annually. Senile cataract is an increasingly common medicosocial problem in developed countries because of the increasing lifespan of the general population. In developing countries, cataract is a more serious problem because of its earlier onset and the inadequacies of health care services. Despite the introduction of a

594

Drugs 39 (4) 1990

number of agents, there is no currently accepted pharmacological treatment for cataract, and surgery, with its attendant risks, is not an ideal solution, particularly considering the need to correct vision afterwards. Since a variety of underlying mechanisms have been postulated to account for opacification of the lens, it may be that no single agent would prove suitable for the management of all types of cataract. The long term consumption of aspirin, paracetamol (acetaminophen) or ibuprofen has been found to reduce the risk of cataract by over 50% in a casecontrol study (Van Heyningen & Harding 1986). This highlights the possible usefulness of certain nonsteroidal drugs for slowing the development of lens opacification. Overall, bendazac lysine has been well tolerated at recommended dosages. Results from studies which have used objective methods of evaluation suggest that bendazac lysine may be able to delay the progression of cataract. Although some improvements in lens transparency have been reported during bendazac lysine therapy, these findings were based on subjective criteria and there is no strong evidence to date that the drug is capable of reversing existing opacity. This being the case, bendazac lysine is most likely to be of value in protecting the level of vision in patients with mild to moderate disease, thus delaying the need for surgical intervention.

References Arienzo G, Corvino C. Cennamo G. Rosa N, Bonavolonta A. Controlled clinical evaluation of bendazac-Iysine in senile cataract : comparison between different tests. In D'Ermo F et al. (Eds) Recent developments in the pharmacological treatment of cataract, pp. 121-137. Kugler Publications. Amsterdam. 1987 Ballesteros JA, Badosa AM. Usandizaga I, Amengual M. Hepatotoxicity due to bindazac. Lancet 2: 1030-1031, 1987 Baraldi P, Fonda S, Toschi P. Benassi B, Luppi ML. et al. Medical treatment of senile cataract: clinical investigation of bendazac lysine using objective and subjective methods. Graefe's Archive of Ophthalmology. in press, 1989 Barillari G, Iorio E, Galli Angeli D. Catanese B. Oral absorption of bendazac lysine salt in man after repeated administrations. Pharmacological Research Communications 15: 461-471,1983 Bauchiero L, Franzone M, Brogliatti B. Galli R. Experimental cataract and lysine salt ofbendazac: a study on the drug's effect in the experimental animal under the transmission electronic microscope. In D'Ermo F et al. (Eds) Recent deve lopments in

the pharmacologica l treatment of cataract , pp. 99-106, Kugler Publications. Amsterdam , 1987 Bonomi L. Marchini G. De Franco I. Perfetti S. De Gregorio M. Bendazac lysine salt in treatment of cataracts: a controlled study. Current Therapeutic Research 33: 727-732. 1983 Bruno P. Claudio V. Clinical experiment with a topic antiinflammatory non steroid. Revista Brasileira de Medicina 38: 291294, 1981 Carboni GP, Longhi-Gelati M. Pierfelice V. The use ofbendazac in the topical treatment of dermatitis. Revista Brasileira de Medicina 38: 419-424. 1981 Carlentini S. Setti A. Soregaroli PA. Ferraris De Gaspare PF. Bendalina eye-drops: a new topical treatment of cataract. Bollettino di Oculistica 67: 253-261. 1987 Catanese B. Barillari G. Iorio E. Silvestrini B. A comparative study of the oral absorption in man of bendazac and its lysine salt. Bolletino Chimico Farmaceutico 121: 87-90. 1982 Catanese B. Barillari G, Picollo R. Corradino C. Plasma levels and metabolism of benda zac lysine salt in man . Bollettino Chimico Farmaceutico 125: 298-302. 1986 Catanese B, Valeri P. Durando L. Gismondi A. Tissue distribution, urinary , fecal and biliary excretion of 14C bendazac Llysine salt in rats. Pharmacological Research Communications 17: 425-432. 1985 Cati Giovannelli B. Chiriaco D. Clinical evaluation of topical bendazac lysine in treatment of senile cataract. Bollettino di Ocu1istica 67: 25·30. 1988 Chen TT , Hockwin 0 , Dobbs R. Knowles W. Eckerskorn U. Cataract and health status : a case-control study. Ophthalmic Research 20: 1-9, 1988 Cioli V. Corradino C, Mazzanti G, Silvestrini B. General pharmacological investigations on bendazac lysine. In Cioli V. and co-workers. Farmaco Edizione Pr 39: 438-454. 1984 Crompton M, Rixon KC, Harding JJ . Aspirin prevents carbamylation of soluble lens proteins and prevents cyanate-induced phase separate opacities in vitro : a possible mechanism by which aspirin could prevent cataract. Experimental Eye Research 40: 297-311, 1985 Courtis 1M. Clinical experience with bendazac-lysine in the treatment of cataract. In D'Ermo F et al. (Eds) Recent developments in the pharmacological treatment of cataract. pp. 43-47, Kugler Publications. Amsterdam. 1987 Cvintal T, Violante AC, Baltrukonis D. A double-blind clinical study in patients with senile and presenile cataract treated with bendazac-Iysine over a one-year period. In D'Ermo F et al. (Eds) Recent developments in the pharmacological treatment of cataract, pp, 33-41. Kugler Publications. Amsterdam. 1987 D'Andrea D, Bucci MG. Bendalina eye drops in the treatment of the cataract: clinical experimental investigations . Bollettino di Oculistica 66: 393-40 I. 1987 De Molfetta V, Arpa P, De Casa N. Vinciguerra P, Zenoni S. Use ofbendazac to prevent catara ct formation in patients operated for retina l detachment by closed vitrectomy and silicone oil. In D'Ermo F et al. (Eds) Recent developments in the pharmacological treatment of cataract , pp. 117-119, Kugler Publications. Amsterdam. 1987 Gandolfo E, Burtolo C, Calabria G. Murialdo U. Zingirian M. Long term follow-up of patients with cataract undergoing treatment with bendazac-lysine. In D'Errno F et al. (Eds) Recent developments in the pharmacological treatment of cataract, pp. 49-52, Kugler Publications. Amsterdam, 1987 Gianfranceschi G, Barbaresi F. Bendalina eye drops in the treatment of senile idiopathic cataract. Bollettino di Oculistica 66: 45-51. 1987

Bendazac Lysine: A Review

Hard ing JJ . Rixon KC Carbamylatio n ofle ns protein: a possible facto r in cataractogenesis in some tro pical countries. Experimental Eye Research 31: 567-571. 1980 Hockwin O. Th e causes and prevent ion of catara ct blindn ess. Endeavour. New Series 9: 132- 138. 1985 Hockwin O. Laser H. De Gregorio M. Carrieri MP. Bend azac lysine in selected types of human senile cataract : a long-term dou ble-masked placebo-controlled clinical trial with multil inear densitom etric image analysis of Scheimpflu g photograph s. Ophthalmic Research 21: ' 4 1-154. 1989 luglio N. Iulian o G. The effect of bendazac lysine salt on cataractous hum an eyes. Current Therapeutic Research 35: 119-122. 1984 Lewis BS. Hardin g JJ. Th e major metabolite ofbendaza c inh ibits the glycosylation of soluble lens protein s: a possible mechanism for a delay in cataractogenesis. Experimental Eye Research 47: 2 17-225. 1988 Lewis BS. Rixon KC. Harding JJ. Bendazac prevent s cyanate binding to soluble lens proteins and cyanate-induced phaseseparat ion opacities in vitro: a possible mechani sm by which bend azac could delay cataract. Experimental Eye Research 43: 973-979. 1986 Lisciani R. Scorza Barcellona P, Silvestr ini B. Top ical activi ty of bend azac on experimenta l burns . Japanese Journal of Pharm acology 21: 69-73. 197 \ Madzarovova A. Clinical study on the effect of bendaza c lysine salt (AF 1934) in the treatm ent of dyslipemia . Acta Th erapeutica 8: 257-266. 1982 Maione M. Mamm arella E. Bon tempell i C. Graziosi P. Vaira F. La sensibilita'a l contrasto nei catarattosi sotto post i a trattamen to cronico con collirio al sale di lisina del bendazac (Bendalina@). Annali di Otta lmologia e Clinica Oculistica 114: 10011020. 1988 Minassian DC. Mehra V. Jon es BR. Dehydration al crises from severe dia rrhoea or heatstro ke and risk of cataract. Lancet I: 75 1-752. 1984 Musci G . Silvestrini B. Mechan ism of the scavenger-like activity ofbe ndazac . Drugs Under Experim ental and Clinical Research 13 (5): 289-292. 1987 Nuzzi G. Venturini I. Bonacini M. Sarzi-Arnade R. Impro vem ent of the blood-re tinal barr ier induced by bendaza c lysine: prelim inary clinical observat ion in insulin-d epend ent diabetics. Archives of O phthalmology 105: 1165-1166. 1987 Paolucci G . Clinical eva luatio n of bend azac in cutaneo us afections of the infant child. Pesquisa Clinica 38: 47-50. 1981 Penn e A. Fonda S. Baraldi P. Luppi ML. Mazza C. et al. Subjectiv e and objective methods for the evaluation of the medical treatment of senile cataract. First result s of a study on the effects of bendazac lysine . In D'Erm o F et al. (Eds) Recen t developments in the pharmac ological treatm ent of cataract. pp. 73-8 I, Kugler Publicati ons. Amsterd am . 1987 Pont e F, G iuffre G. Cuttitta A. Psychoph ysical and electrophysiological cont rast sensitivity in cataractous patients treated with Bend alina, submitted for publicat ion . 1989 Rovei V, Campistron G . Dueymes J-M, Ego D, Conte JJ. et al. Pharm acokinetics of benda zac-Iysine and 5-hydroxybe ndazac in patient s with renal insufficiency. European Journal of Clinical Pharm acology 33: 303-310. 1987b Rovei V. Ego D. Cata nese B. Pharm acokinet ics and metabolism of bendazac-Iysine. In D'Errn o F et al. (Eds) Recent developments in thc pharm acological treatmen t of catarac t. pp. 1523, Kugler Publications. Amsterda m, 1987a Rovei V. Escour rou J. Cam pistro n G. Ego D. T hiola A, et al. T he phar macoki nctics of bcndazac- Iysine and 5-hydroxybc ndazac .

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its main meta bolite, in patients with hepat ic cirrhosis. European Journal of Clinical Pharmacology 35: 391-396, 1988 Sande rs DR. De Gregorio M. Pioggia M. Bendazac-lysine (Bendalina@) as an anticataract agent: review of basic clinical data. In D'Erm o F et al. (Eds) Recent developm ents in the pharmacological treatment of catarac t. pp, 25-32, Kugler Publications, Amsterdam, 1987 Schmut O. Fellinger C, Hofmann H. Bendazac lysine: a protective substance against oxygen-free radicals. In D'Erm o F et al. (Eds) Recent developm ents in the pharmacological treatment of cataract, pp, 69-72, Kugler Publicat ions . Amsterdam. 1987 Sensi M. Cioccia G P. Bruno MR. Gh irlanda G. Valente L. et al. The in vitro effect of bendazac on the expression of interleukin 2 receptors and lymph ocyte transformation in norm al and d iabetic pat ients . Medical Science Research 16: 327-328. 1988 Silvestr ini B. Problem s in the experimental research for antica taract agent s. Proceedings of the XXVth International Congress of Ophthalmology. Rome. Italy. May 4-10. pp. 2510-2516, 1986 Silvestrini B. Catanese B. Barillari G, Iorio E. Valeri P. Basic data supporting the use of the l-lysine salt of bendaza c in cataract. International Journ al of T issue Reaction s 5: 217-225, 1983 Silvestrini B. Catanese B. Lisciani R. Alessandron i A. Stud ies on the mechan ism of act ion of bendazac (AF 983). ArzneimittelForschung 20: 250-253. 1970 Silvestrini B, Cioli V, Burberi S. Pharmacological properties of bend azac (AF 983) with part icular reference to its topical action on some experimental inflamm atory processes. Arzneimittel-Forschung 19: 30-36, 1969 Specto r A. Ga rner WH oHydrogen peroxide and hum an cataract. Experimental Eye Research 33: 673-681, 1981 Steve ns VJ, Rouzer CA. Monn ier VM. Cera mi A. Diabetic cataract form ation: potenti al role of glycosylation of lens crystal. lins. Proceedings of the Nat ional Academy of Sciences of the United States of America 75: 29 18-2922. 1978 Testa M. Iuliano G. De Gregorio M, Pioggia M. A doubl e blind clin ical study on the anticata ract effect of bendazac lysine salt. Acta T herapeutica 9: 235-252, 1983 Testa M, Iuliano G. De Gregorio M. Pioggia M. Anti-cataract activity of bendazac lysine salt: a clin ical stud y. Acta Therapeut ica 10: 343-355. 1984a Testa M. Iuliano G, De Gregorio M. Pioggia M. A controlled clinical study on bendazac lysine salt treatment in senile catarac t. Acta Therapeutica 10: 177-190. 1984b Testa M, Iuliano G. Marino E. Buongiovanni C. Forgione A. et al. Higher efficacy of flunoxaprofen over bendazac and other anticataract nonst eroidal anti -inflammatory drugs in the treatment of cata racts. Current Therapeutic Research 42: 182-189. 1987b Testa M. Iuliano G. Mar ino E. Buongiovann i C. Iaccarin o G, et al. Personalized and indi vidualized top ical treatment using the anti oxidant metabolites of flunoxapr ofen and other nonsteroidal ant i-inflammatory drugs in the treatment of cataracts in rats and humans. Curre nt Therapeutic Research 42: 195-205, 1987a Testa M. Iuliano G. Marin o E, Buongiovan ni C. Paolercio F, et al. Bendazac and benzydamin e for treatm ent of cataract: individualized therap y by the ' BLOA Test' . Journ al of Ocular Pharm acology 2: 25 1-266. 1986 Testa M. Iuliano G, Silvestrini B. "Pilot study of bendaza c for treatm ent of cata ract. Lancet I: 849-850, 1982 T ittarelli R. Attorresi L. Prospects for the treatment of cataract with bend azac-Iysine. In D'Ermo F et al. (Eds) Recent devel-

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opm ents in the pharmacological treatm ent of cataracts, pp. 5356, Kugler Publicati ons, Amsterda m, 1987 Ts uji M, Saita M. Taniguchi Y, Takenoshita H, Noda K, et al. Ant i-inflammatory effects of pimep rofen ointment and cream, in com parison with bufexam ac, bendazac and indometh acin. Pharm acom etr ics 23: 567-576, 1982 Valeri P, Palmery M, Martinelli B, Catanese B. Absorptio n of bend azac lysine after topical appli cat ion to the rabb it eye, Pharm acological Research Comm unications 19: 517-525, 1987 Van Heyningen R, Harding JJ. Do aspirin-l ike analgesics protect against cataract? Lancet I: 1111-1113, 1986

Drugs 39 (4) 1990

Youn DH , Lee J, Choi 0 , Rhee SW, Jung HR. The effect of bend azac-lysine (Bendalina'P) in cataract: dose range study in an Asiatic patient population. In D'Erm o F et al. (Eds) Recen t de velopm ents in the pharmacological treatment of cataract, pp. 59-68, Kugler Publications, Amsterdam, 1987

Authors' address: Julia Balfour, ADIS Press Limited, 41 Centorian Dr ive, Private Bag, Mairangi Bay, Auckland 10, New Zealand .