Chelation in Metal Intoxication XXXVIII: Effect of Structurally Different Chelating Agents in Treatment of Nickel Intoxication in Rat

FUNDAMENTAL AND APPLIED TOXICOLOGY ARTICLE NO.

31, 141–148 (1996)

0085

Chelation in Metal Intoxication XXXVIII: Effect of Structurally Different Chelating Agents in Treatment of Nickel Intoxication in Rat S. K. TANDON,1 S. SINGH, V. K. JAIN,

AND

S. PRASAD

Chemical Toxicology, Industrial Toxicology Research Centre, Lucknow—226 001, India Received June 12, 1995; accepted December 15, 1995

Chelation in Metal Intoxication XXXVIII: Effect of Structurally Different Chelating Agents in Treatment of Nickel Intoxication in Rat. TANDON, S. K., SINGH, S., JAIN, V. K., AND PRASAD, S. (1996). Fundam. Appl. Toxicol. 31, 141–148. Some structurally different chelating agents viz. a-mercapto-b(2-furyl) acrylic acid (MFA), a-mercapto-b-(2-thienyl) acrylic acid (MTA), meso 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercaptopropane-1-sulfonate (DMPS), diethyl dithiocarbamate (DEDTC), and N-benzyl-D-glucamine dithiocarbamate (NBG-DTC) were evaluated for their efficacy to mobilize nickel and reverse some nickel-induced biochemical alterations in experimental nickel intoxication. MFA, DMSA, and NBG-DTC appear more effective than their corresponding homologs, MTA, DMPS and DE-DTC, respectively, in enhancing urinary and fecal excretion of nickel and lowering tissue burden of nickel in nickel preexposed rats. These, particularly NBG-DTC, appear promising in the treatment of nickel (II) poisoning. However, there seems no definite relationship between the structure of the chelating agents examined and their ability to counteract the effects of nickel. q 1996 Society of Toxicology

Sulfhydryl or sulfur containing chelating agents are effective scavengers of heavy metals, owing to their affinity toward them (Jones, 1985). Meso 2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1-sulfonate (DMPS) have been widely investigated in laboratory animals and found to be quite efficient not only against intoxication by lead, cadmium, mercury, and arsenic but by certain other metals as well (Aposhian et al., 1984, 1992; Kemper et al., 1990; Angle, 1993). While DMSA is an approved drug for childhood lead and human mercury poisonings, DMPS is an accepted antidote for human inorganic as well as organomercury and arsenic poisonings (Campbell et al., 1986; Jones, 1991; U.S. Department of Health and Human Services, 1991; Aposhian et al., 1995). 1

To whom correspondence should be addressed at Chemical Toxicology, Industrial Toxicology Research Centre, Mahatma Gandhi Marg, Post Box 80, Lucknow—226 001, U.P., India. Fax: (91) 522-248227.

N-benzyl-D-glucamine dithiocarbamate (NBG-DTC) and N-(4-methoxybenzyl)-D-glucamine dithiocarbamate have been more effective than their other structural analogs in counteracting experimental cadmium intoxication in rats and they are probably the most efficient chelators of cadmium (Kojima et al., 1986, 1987a; Jones et al., 1991). These appear quite promising in treatment of human cadmium poisoning. However, NBG-DTC was about equally as effective as 2,3-dimercapto propanol (BAL) in removing body inorganic mercury from mercuric chloride pretreated rats but unlike BAL did not promote redistribution of mercury to certain tissues in spite of higher lipophilicity of the NBG-DTC – mercury complex (Kiyozumi et al., 1988; Kojima et al., 1989). Some substituted dithiocarbamates including NBG-DTC have also been effective in lowering hepatic, renal, and bone levels of lead without increasing its brain burden, possibly owing to their relatively lower lipophilicity compared to diethyl dithiocarbamate (DE-DTC) in lead exposed rats (Tandon et al., 1990). Another group of compounds is a-mercapto-b-aryl acrylic acids. Particularly, a-mercapto-b-(2-furyl) acrylic acid (MFA) has been found to be effective in the treatment of cadmium (Tandon et al., 1989), inorganic mercury (Kachru et al., 1989), lead, and nickel (Sharma et al., 1986, 1987) intoxication in animals, although its mechanism of action may differ from one metal to another depending on the dose schedule and the mode of administration (Giroux and Lachmann, 1983, 1984; Tandon et al., 1989; Khandelwal and Tandon, 1991). a-Mercapto-b-(2thienyl) acrylic acid (MTA), a structural homolog of MFA, has also been found to be effective in enhancing the excretion and reducing the renal lead in lead intoxicated rats (Tandon et al., 1988). The investigations on chelation in experimental nickel intoxication have shown that 1,2-cyclohexylene dinitrilotetraacetic acid and DE-DTC were most effective in removing nickel from some vital organs of rats, and calcium disodium ethylenediamine tetraacetate and D-penicillamine were most efficient in preventing mortality from

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acute nickel toxicity in mice (Tandon and Mathur, 1976; Basinger et al., 1980). In subsequent studies, we have observed that MFA, a-mercapto-b-(3,4-dimethoxyphenyl) acrylic acid and b-1,2-phenylene di-a-mercaptoacrylic acid were as effective as DMPS in enhancing urinary excretion and in reducing tissue content of nickel in poisoned rats (Sharma et al., 1986, 1987). Srivastava and co-workers (Athar et al., 1987; Misra et al., 1988) have found that cyclam, cyclam S, and triethylenetetramine were more effective antidotes than a few polyaminocarboxylic acids in preventing acute nickel toxicity and in reversing some nickel-induced alterations in rats, probably owing to their lipophilic character. Dithiocarb (DE-DTC) has been very effective in the treatment of human nickel carbonyl poisoning and can be quite useful in human nickel (II) intoxication (Sunderman and Fraser, 1983; Sunderman, 1990). However, DE-DTC has been found to enhance acute cadmium toxicity given orally and its medicinal use should be avoided in individuals with current exposure to cadmium (Andersen et al., 1988; Andersen and Nielsen, 1989). Kemper et al. (1990) have suggested further investigations on the use of DMPS in human nickel poisoning. In view of the fact that there is limited information available on specific treatment of human nickel (II) poisoning and thus there is a need for more effective nickel (II) antidotes, it was considered worthwhile to investigate the effectiveness of some accepted or promising metal antidotes such as DMSA, DMPS, DE-DTC, NBG-DTC, MFA, and MTA for their relative efficacy to remove nickel- and reverse nickel (II)-induced biochemical alterations in experimental nickel intoxication.

for 24-hr collection of urine and feces after each injection of the chelating agents consecutively for 4 days. All the animals were decapitated 24 hr after the last injection, blood was collected in heparinized vials, and liver, kidney, brain, and heart were removed. Biochemical assays. Standard procedures were used to determine the levels of blood glucose (Dubowski, 1962), plasma ceruloplasmin (Curzon and Vallet, 1960), plasma, and urine total a-amino acids (Merck, 1974). Metal estimations. Acurately weighed fresh samples of blood, liver, kidney, brain, and heart were digested completely in a mixture of concentrated nitric acid, perchloric acid, and sulfuric acid (6:1:1) and the carbon free residue was dissolved in 5 ml of 5% nitric acid. The samples were read for the concentrations of nickel (232.0 nm), zinc (213.9 nm), copper (324.7 nm), and iron (248.3 nm) on a flame atomic absorption spectrophotometer (Perkin – Elmer 5000) using appropriate standards of different metals processed identically (Parker et al., 1967). The standard stock solutions (1 mg ml01, as an element) were prepared by dissolving analytical reagent grade NiSO4r6H2O, CuSO4r5H2O (Merck, Darmstadt, Germany), ZnSO4r7H2O (Merck, India), and FeSO4r7H2O (BDH, Poole, UK) in 5% nitric acid using double glass distilled water. Six working standard solutions within linear range for each element were prepared by appropriate dilutions of the stock. Statistical analysis. Student’s t test was used to calculate the significance between normal animal and nickel-treated animal (control). The

MATERIALS AND METHODS Chelating agents. DMSA and DMPS were purchased from Sigma Chemical Company (St. Louis, MO) and DE-DTC sodium from May and Baker Ltd. (Dagenham, UK). The reported procedures were adopted to synthesize MFA, MTA (Wagner et al., 1977), and NBG-DTC sodium (Kojima et al., 1987b). DMSA, MFA, and MTA were dissolved in double glass distilled water in the presence of sodium bicarbonate. The chemical formulas of the chelating agents are given in Fig. 1. Animals and treatment. Forty-two male albino rats (150 { 5 g) of Industrial Toxicology Research Centre’s colony maintained on standard pellet diet (Lipton Laboratory Feeds, India; metal contents of diet, ppm dry weight: copper, 10.0; manganese, 55.0; cobalt, 5.0; iron, 70.0; zinc, 45.0) and water ad libitum were injected with 1.5 mg/kg/4 ml nickel as nickel sulfate (NiSO4r6H2O), dissolved in normal saline intraperitoneally, 6 days a week, for 30 days. Six rats received no treatment and served as normal group. The nickel-administered animals were divided equally into seven groups and treated intraperitoneally, once daily, for 5 days as follows: Group I, 4 ml/kg, distilled water (control); Group II, 0.3 mmol/4 ml/kg, MFA; Group III, 0.3 mmol/4 ml/kg, MTA; Group IV, 0.3 mmol/4 ml/kg, DMSA; Group V, 0.3 mmol/4 ml/kg, DMPS; Group VI, 0.3 mmol/4 ml/kg, DE-DTC; Group VII, 0.3 mmol/4 ml/kg, NBG-DTC. The animals were kept in stainless steel metabolic cages (one/cage)

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FIG. 1. Chemical formulas of chelating agents.

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TABLE 1 Effect of Chelating Agents on Blood and Tissue Levels of Nickel in Nickel Sulfate Intoxicated Rat Blood

Kidney

(mg/100 ml)

Treatment Normal animal Ni (control) MFA MTA DMSA DMPS DE-DTC NBG-DTC

Liver

0.17 12.07 7.01 9.62 7.17 6.02 8.70 7.45

{ { { { { { { {

0.02 1.46* 0.64** 0.59*** 0.33** 0.36** 0.47**** 0.56**

Brain

Heart

(mg/g, fresh tissue) 0.39 3.29 1.26 3.09 1.27 1.19 2.44 1.41

{ { { { { { { {

0.03 0.22* 0.09** 0.12 0.13** 0.10** 0.14** 0.15**

1.33 5.94 2.25 4.81 2.28 1.74 3.56 1.39

{ { { { { { { {

0.05 0.17* 0.08** 0.12** 0.12** 0.06** 0.10** 0.11**

0.10 1.05 1.08 1.19 0.86 0.90 0.87 0.70

{ { { { { { { {

0.01 0.04* 0.12 0.04 0.04 0.03 0.03 0.06**

0.70 4.27 2.34 3.89 3.06 3.11 2.72 2.60

{ { { { { { { {

0.06 0.11* 0.09** 0.18*** 0.16** 0.09** 0.09** 0.08**

Note. Each value is the mean { SE; n Å 6. * p õ 0.001 compared to normal animal (Student’s t test). ** p õ 0.001 compared to Ni (control) at 5% level of significance (ANOVA). *** p õ 0.05 compared to Ni (control) at 5% level of significance (ANOVA). **** p õ 0.01 compared to Ni (control) at 5% level of significance (ANOVA).

effects of chelating agents were evaluated by one-way analysis of variance (randomized block design) for each parameter separately. The independent variables considered were seven treatment groups (Ni, Ni / MFA, Ni / MTA, Ni / DMSA, Ni / DMPS, Ni / DE-DTC, and Ni / NBG-DTC) in a single block and six replicates in seven different blocks (Zar, 1984).

RESULTS

There was no gross abnormality, clinical sign, or weight loss observed in rats administered nickel sulfate and/or chelating agents. The administration of nickel sulfate for 30 days increased the concentration of nickel in blood, liver, kidney, brain, and heart of rats. The treatment with all the chelating agents thereafter, for 5 days, reduced the levels of nickel in blood, liver, kidney, and heart. The nickel level of brain could be lowered only by NBG-DTC (Table 1). While MFA and NBG-DTC were most efficient in enhancing urinary excretion of nickel, MFA, DMSA, and DMPS were effective in increasing the fecal excretion of the metal (Fig. 2). The nickel exposure decreased ceruloplasmin and blood glucose but increased plasma and urine levels of a-amino acids. The subsequent chelation reversed blood glucose and plasma and urinary a-amino acid levels except by MTA, which caused a further increase in the levels of a-amino acids. The nickelinduced decrease in ceruloplasmin contents was restored appreciably by DMSA, DMPS, DE-DTC, and NBG-DTC (Table 2). While the treatment with all the chelating agents examined depleted endogenous copper, the treatment with MFA, MTA, DE-DTC, and NBG-DTC depleted endogenous zinc and iron via feces. However, urinary excretion

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of zinc and iron rather decreased during the administration of certain chelating agents. The magnitude of fecal elimination of zinc, copper, and iron was much higher than their urinary excretion (Figs. 3 – 5). The administration of nickel decreased the levels of endogenous hepatic zinc and hepatic and heart iron and increased the level of renal iron. The treatment with the chelating agents depleted blood, liver, kidney, and heart but not brain contents of zinc and copper. However, the chelation reversed nickel-induced decrease in hepatic iron but further enhanced the nickel-induced increase in the renal iron and decrease in the heart iron (Tables 3 – 5).

FIG. 2. Effect of chelating agents on urinary and fecal excretion of nickel in nickel sulfate intoxicated rat. Each bar represents the mean { SE; n Å 6. *p õ 0.001; **p õ 0.01; ***p õ 0.05 compared to Ni (control) at 5% level of significance (ANOVA).

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TABLE 2 Efficacy of Chelating Agents in Reversing Nickel-Induced Biochemical Alterations in Nickel Sulfate Intoxicated Rat Plasma

Treatment Normal animal Ni (control) MFA MTA DMSA DMPS DE-DTC NEG-DTC

Blood glucose (mg/100 ml) 64.83 55.95 73.02 81.81 72.40 75.94 87.46 71.80

{ { { { { { { {

2.14 1.21* 1.09*** 2.09*** 2.39*** 2.30*** 5.59*** 2.94***

a-amino acids (mmol/100 ml)

Ceruloplasmin (mg/100 ml) 18.37 6.56 6.27 5.54 10.37 10.45 12.92 10.26

{ { { { { { { {

0.71 0.67** 0.26 0.19 0.58***** 0.61***** 0.29*** 1.80*****

179.08 297.45 244.76 333.01 228.49 232.88 260.80 236.16

{ { { { { { { {

5.12 11.34** 8.62*** 6.00***** 7.49*** 8.35*** 6.22***** 5.02***

Urine a-amino acids (mmol/day/100 g body wt.) 43.50 102.16 90.75 112.92 87.71 75.89 87.03 91.80

{ { { { { { { {

1.52 4.17** 1.15**** 2.38**** 2.05***** 4.86*** 3.50***** 1.99****

Note. Each value is the mean { SE; n Å 6. * p õ 0.01 compared to normal animal (Student’s t test). ** p õ 0.001 compared to normal animal (Student’s t test). *** p õ 0.001 compared to Ni (control) at 5% level of significance (ANOVA). **** p õ 0.05 compared to Ni (control) at 5% level of significance (ANOVA). ***** p õ 0.01 compared to Ni (control) at 5% level of significance (ANOVA).

DISCUSSION

All the chelating agents, irrespective of the number and the groups containing sulfur atoms as the binding site for the metal ion, mobilized nickel from blood and tissues

FIG. 3. Effect of chelating agents on urinary and fecal excretion of zinc in nickel sulfate intoxicated rat. Each bar represents the mean { SE; n Å 6. *p õ 0.001; **p õ 0.01; ***p õ 0.05 compared to Ni (control) at 5% level of significance (ANOVA).

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and reversed some nickel-induced biochemical alterations in the nickel preexposed rats. As MFA with one {SH group, DMSA with two adjacent {SH groups, and NBGDTC with two sulfur atoms were also effective in enhancing both the urinary and/or the fecal elimination of nickel and NBG-DTC was capable of lowering brain burden of

FIG. 4. Effect of chelating agents on urinary and fecal excretion of copper in nickel sulfate intoxicated rat. Each bar represents the mean { SE; n Å 6. *p õ 0.001; **p õ 0.01; ***p õ 0.05 compared to Ni (control) at 5% level of significance (ANOVA).

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seem to be related to either the structure of the chelating agents or their ability to remove body nickel (Foulkes and Gieske, 1973; Gitlitz et al., 1975; Mathur and Tandon, 1981). The restoration pattern of these nickel-sensitive biochemical alterations involving disturbances in amino acid, glucose, or copper metabolisms shows it to be a rather slow process, requiring prolonged treatment with the chelating agents, and/or more time after chelation (Marcilese et al., 1969; Clary and Vignati, 1973; Gitlitz et al., 1975). The better performance of MFA than MTA appears quite reasonable in view of the greater participation of the furan ring ( ) in the former than the thiophene ring ( ) in the latter, in chelating the nickel ion in addition to a {SH group in the two compounds (Tsukube et al., 1986). In other words, more electron density at the oxygen (in furan) than at sulfur (in thiophene), the former being more electronegative than the latter, renders MFA to be a better electron donating compound than MTA (Brown, 1964). While, DE-DTC is lipophilic in nature and thus highly effective in the treatment of volatile nickel carbonyl poisoning (Sunderman and Fraser, 1983; Sunderman, 1990), NBG-DTC is a unique combination of hydrophilic character due to its glucamine moiety and lipophilic character attributable to a benzyl group in the molecule and therefore more effective in removing extracellularly as well as intracellularly bound nickel (Kojima et al., 1986; Kiyozumi et al., 1988). The ability of NBGDTC to mobilize brain nickel may be due to its lipophilic property and is an important feature of this chelator. The difference in the performance of DMSA and DMPS is not large and both the compounds are acceptable for the O

S

FIG. 5. Effect of chelating agents on urinary and fecal excretion of iron in nickel sulfate intoxicated rat. Each bar represents the mean { SE; n Å 6. *p õ 0.001; **p õ 0.01; ***p õ 0.05 compared to Ni (control) at 5% level of significance (ANOVA).

nickel, these three chelating agents appear promising in the treatment of nickel intoxication. Interestingly, MFA, DMSA, and NBG-DTC were comparatively more effective than their corresponding homologs, that is, MTA, DMPS, and DE-DTC, respectively, in terms of reduction in the body burden of nickel and its urinary and/or fecal elimination. However, the reversal of a nickel-induced increase in plasma and urine a-amino acid levels and a decrease in blood glucose and plasma ceruloplasmin contents, indicative of hepatic and renal dysfunction, do not

TABLE 3 Effect of Chelating Agents on Blood and Tissue Levels of Zinc in Nickel Sulfate Intoxicated Rat Liver Treatment Normal animal Ni (control) MFA MTA DMSA DMPS DE-DTC NBG-DTC

Kidney

Blood (mg/ml) 7.66 6.25 3.90 6.02 3.34 3.25 4.95 4.28

{ { { { { { { {

0.48 0.40 0.29** 0.37 0.19** 0.36** 0.38*** 0.35**

Brain (mg/g, fresh tissue)

35.79 30.76 22.61 31.63 22.02 23.53 31.81 30.49

{ { { { { { { {

0.70 0.92* 0.99** 1.04 0.93** 1.47** 0.31 0.28

24.41 22.40 15.74 21.99 17.07 16.43 15.37 22.67

{ { { { { { { {

0.61 1.02 0.64** 1.37 0.47** 0.39** 0.36** 1.06

15.76 16.24 15.32 16.44 14.69 15.31 15.39 15.00

{ { { { { { { {

Note. Each value is the mean { SE; n Å 6. * p õ 0.001 compared to normal animal (Student’s t test). ** p õ 0.001 compared to Ni (control) at 5% level of significance (ANOVA). *** p õ 0.05 compared to Ni (control) at 5% level of significance (ANOVA). **** p õ 0.01 compared to Ni (control) at 5% level of significance (ANOVA).

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Heart

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0.20 0.62 0.29 0.46 0.74*** 0.35 0.27 0.52

25.86 25.71 20.60 24.82 20.02 22.18 19.48 17.17

{ { { { { { { {

0.65 0.62 0.67** 0.58 0.72** 0.93**** 0.69** 0.31**

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TABLE 4 Effect of Chelating Agents on Blood and Tissue Levels of Copper in Nickel Sulfate Intoxicated Rat Blood

Liver

Kidney

(mg/100 ml)

Treatment Normal animal Ni (control) MFA MTA DMSA DMPS DE-DTC NBG-DTC

6.05 5.48 4.37 5.32 3.53 3.83 4.77 4.46

{ { { { { { { {

0.43 0.26 0.33* 0.35 0.25** 0.26** 0.25 0.30*

Brain

Heart

(mg/g, fresh tissue) 5.06 5.60 3.61 4.71 3.23 3.92 4.19 4.43

{ { { { { { { {

0.32 0.19 0.20** 0.38* 0.25** 0.14** 0.21** 0.21***

7.26 7.70 4.82 6.59 5.37 5.30 5.87 6.08

{ { { { { { { {

0.27 0.45 0.28** 0.23* 0.29** 0.11** 0.29** 0.38***

2.59 3.38 3.67 3.68 3.63 3.98 2.56 2.63

{ { { { { { { {

0.16 0.59 0.44 0.41 0.35 0.44 0.20 0.24

2.13 2.62 1.63 1.76 2.06 1.83 1.88 1.87

{ { { { { { { {

0.11 0.20 0.18** 0.22*** 0.14* 0.16*** 0.10*** 0.11***

Note. Each value is the mean { SE; n Å 6. * p õ 0.05 compared to Ni (control) at 5% level of significance (ANOVA). ** p õ 0.001 compared to Ni (control) at 5% level of significance (ANOVA). *** p õ 0.01 compared to Ni (control) at 5% level of significance (ANOVA).

chelation of nickel. However, owing to lesser toxicity, higher therapeutic range, and wide acceptability, DMSA may be preferred over DMPS. Perhaps a major drawback with these chelating agents is their potential to deplete endogenous essential trace metals mainly through feces as reflected by their lowering in blood and tissues in nickel-exposed rats. As the chelator’s induced excretion and/or redistribution of some endogenous essential metals might be of some serious consequence, particularly upon prolonged chelation therapy in humans, the treatment with the chelators may

be given in phases, that is, 5-day treatment followed by a short period of no treatment before the next phase of treatment. This may enable the individuals to regulate the body status of such essential metals. The treatment with the chelators could not reverse the alterations in levels of essential metals caused by nickel administration, except the decrease in hepatic iron, which recovered considerably. As some of the nickel-induced changes in their levels further enhanced upon chelation, the present study shows intertissue redistribution due to nickel – chelator interactions.

TABLE 5 Effect of Chelating Agents on Blood and Tissue Levels of Iron in Nickel Sulfate Intoxicated Rat Blood

Kidney

(mg/ml)

Treatment Normal animal Ni (control) MFA MTA DMSA DMPS DE-DTC NBG-DTC

Liver

10.00 11.08 7.11 11.16 8.31 8.60 8.46 9.53

{ { { { { { { {

0.64 0.608 0.98*** 0.56 0.90**** 0.98 0.78**** 1.02

Brain

(mg/g, fresh tissue) 77.03 62.11 69.50 66.18 72.72 71.31 72.56 73.31

{ { { { { { { {

2.90 2.78* 1.90**** 3.02 2.91*** 1.94**** 2.44*** 2.42***

39.69 52.29 63.17 48.74 66.44 66.17 60.05 62.81

{ { { { { { { {

1.64 1.87** 3.00***** 1.43 1.92***** 3.13***** 0.89*** 1.29*****

42.73 40.96 41.03 39.67 43.58 44.58 41.49 40.87

Note. Each value is the mean { SE; n Å 6. * p õ 0.01 compared to normal animal (Student’s t test). ** p õ 0.001 compared to normal animal (Student’s t test). *** p õ 0.01 compared to Ni (control) at 5% level of significance (ANOVA). **** p õ 0.05 compared to Ni (control) at 5% level of signifiance (ANOVA). ***** p õ 0.001 compared to Ni (control) at 5% level of significance (ANOVA).

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Heart

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{ { { { { { { {

1.10 2.03 2.30 2.55 1.76 1.38 1.32 3.29

83.16 64.93 56.58 60.82 57.26 54.81 59.26 61.64

{ { { { { { { {

2.50 2.41** 1.75***** 2.16 1.81***** 1.21***** 2.45**** 1.33

CHELATING AGENTS IN TREATMENT OF NICKEL TOXICITY

ACKNOWLEDGMENT The authors are thankful to Mr. Neeraj Mathur for statistical analysis, to Mr. Ashok Kumar for technical assistance, and to Mr. Umesh Prasad for processing the manuscript on his computer.

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