Evidence for diazotization of 14C-sulfamethazine [4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] in swine. The effect of nitrite

Dietary nitrite greatly enhanced the conversion of orally administered 14C-sulfamethazine (4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide; 14C-sulmet) to 14C-desaminosulfamethazine [N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide; 14C-DA-sulmet] in swine. The disposition of 14C orally administered to swine as 14C-sulfamethazinediazonium tetrafluoroborate (4-[N-(4,6-dimethyl-2-pyrimidinyl)sulfonamido] [U-14C]diazonium tetrafluoroborate) was very similar to the disposition of 14C given to swine as 14C-sulmet in combination with nitrite. These results and other information discussed in the text provide evidence that 14C-sulmet, in the presence of nitrite under the acid conditions in the gastrointestinal tract, was diazotized and that this diazonium intermediate was converted to 14C-DA-sulmet and other unidentified 14C-labeled products.     

The effect of nitrite on 14C-sulphathiazole (4-amino-N-2-thiazolyl[U-14C]benzenesulphonamide) metabolism in the rat

1. Rats given a meal containing 613 p.p.m. of 14C-sulphathiazole (4-amino-N-2-thiazolyl[14C]benzenesulphonamide) excreted less 14C-activity in urine and more 14C-activity in faeces as nitrite in the meal was increased (0, 10, 100 or 1000 p.p.m.). As nitrite in the meal was increased from 0 to 1000 p.p.m. the total 14C-residues in the gastrointestinal tract six hours after dosing increased, but decreased in other tissues. 2. High nitrite in the meal resulted in increased methanol insoluble 14C-activity in the gastrointestinal tract but had little or no effect on the methanol-insoluble activity in liver and blood. 3. Conversion of 14C-sulphathiazole to 14C-desaminosulphathiazole (N-2-thiazolyl[U-14C]benzenesulphonamide) in the rat was greatly increased by nitrite in the meal.     

Metabolism of 1,3-di-(4-[N-(4,6-dimethyl-2-pyrimidinyl)sulphamoyl] phenyl)triazene (DDPSPT) in the rat

1. Six hours after rats were orally dosed with 1,3-di-(4-[N-(4,6-dimethyl-2-pyrimidinyl)sulphamoyl][U-14C]phenyl) triazene (14C-DDPSPT), approx. 81% of the 14C remained in the gastrointestinal tract (gut) and less than 3% was excreted in the urine. 2. Six hours after dosing, more than half of the 14C in the gut was present as DDPSPT. 14C-Labelled metabolites in the gut included 4-amino-N-(4,6-dimethyl-2-pyrimidinyl)-benzenesulphonamide (Sulmet), N4-glucosyl-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulphonamide (N4-gluc-Sulmet), 4-acetamido-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulphonamide (N4-acetyl-Sulmet), and [N-4,6-dimethyl-2-pyrimidinyl) benzenesulphonamide] (desamino-Sulmet). 3. 14C-Labelled compounds in the blood, liver and skeletal muscle included DDPSPT, Sulmet, N4-gluc-Sulmet, N4-acetyl-Sulmet and desamino-Sulmet. 4. There was little or no reaction of DDPSPT with cysteine, bovine serum albumin, AMP, GMP, or calf thymus deoxyribonucleic acid in vitro (pH 3, 5, 7 or 8).     

Characterization of products formed by the reaction of 14C-sulphamethazinediazonium tetrafluoroborate with natural products

1. When bovine serum albumin (BSA) was incubated with 4-[N-(4,6-dimethyl-2-pyrimidinyl)sulphonamido] [U-14C]benzenediazonium tetrafluoroborate (14C-SDTFB) in vitro approx. half of the 14C-activity was bound (14C-BSA). Cysteine, N-ethylmaleimide, p-chloromercuribenzoate and iodoacetamide inhibited the formation of 14C-BSA. 2. When SDTFB was reacted with cysteine four major products were formed. These were identified as 3-(4-[N-(4,6-dimethyl-2-pyrimidinyl)benzenesulphonamido] diazothio)-2-aminopropionic acid (cys-SDAS), 3-(4-[4,6-dimethyl-2-pyrimidinyl) benzenesulphonamido]thio)-2-aminopropionic acid (cys-Sulmet), 4-hydroxy-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulphonamide (hydroxy-Sulmet) and N-(4,6-dimethyl-2-pyrimidinyl)benzenesulphonamide (desamino-Sulmet). Diazosulphides were also formed when SDTFB was incubated with thiophenol and glutathione. 3. The diazosulphides reacted with N,N-dimethylaniline (DMA) and 2-naphthol to yield diazo compounds in 22-29% yield; when 14C-BSA was reacted with DMA under the same conditions, a diazo compound was formed-but only in 2% yield. 4. Cys-SDAS when incubated overnight (approx. 16 h) in aqueous solutions (pH 3, 5 and 8) decomposed to yield desamino-Sulmet (30-39%), hydroxy-Sulmet (13-21%), and other unidentified soluble products (24-36%); when 14C-BSA was incubated under the same conditions only 3-4% of the 14C became dissociated from BSA and only a trace amount of desamino-Sulmet was formed. 5. When 14C-SDTFB was incubated with calf thymus DNA at pH3, some of the 14C became associated with the DNA (14C-DNA). However, most of the 14C became dissociated from 14C-DNA when the latter was incubated overnight in aqueous solutions; a minor dissociation product was identified as 14C-desamino-Sulmet.     

The effect of nitrite on 14C-sulphathiazole (4-amino-N-2-thiazolyl[U-14C]benzenesulphonamide) metabolism in the rat

1. Rats given a meal containing 613 p.p.m. of ¹⁴C-sulphathiazole (4-amino-N-2-thiazolyl[¹⁴C]benzenesulphonamide) excreted less ¹⁴C-activity in urine and more ¹⁴C-activity in faeces as nitrite in the meal was increased (0, 10, 100 or 1000 p.p.m.). As nitrite in the meal was increased from 0 to 1000 p.p.m. the total ¹⁴C-residues in the gastrointestinal tract six hours after dosing increased, but decreased in other tissues.

2. High nitrite in the meal resulted in increased methanol insoluble ¹⁴C-activity in the gastrointestinal tract but had little or no effect on the methanol-insoluble activity in liver and blood.

3. Conversion of ¹⁴C-sulphathiazole to ¹⁴C-desaminosulphathiazole (N-2-thiazolyl[U-¹⁴C]benzenesulphonamide) in the rat was greatly increased by nitrite in the meal.     

Lactose conjugation of sulphonamide drugs in the lactating dairy cow.

1. 14C-Sulphamethazine (4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene-[U-14C]-sulphonamide; 220 mg/kg of body weight) was given orally or i.v. to lactating dairy cows. Milk collected from 0-48 h after dosing accounted for 2.0% (oral dose) and 1.1% (i.v. dose) of the total 14C-activity administered. 2. Sulphamethazine accounted for 70-79% (oral dose) and 54-75% (i.v. dose) of the total 14C in milk samples collected from 0-48 h after dosing. N4-acetylsulphamethazine accounted for 1-2% (oral dose) and 1-4% (i.v. dose) of the 14C in milk. 3. The major 14C-labelled metabolite in the milk was isolated and identified as the N4-lactose conjugate of sulphamethazine, a unique type of metabolite not previously reported. This metabolite accounted for 10-14% (oral dose) and 9-20% (i.v. dose) of the 14C-activity in the milk collected from 0-48 h after dosing with 14C-sulphamethazine. 4. N4-lactose conjugates of sulphapyridine, sulphamerazine, sulphathiazole, sulphadimethoxine and sulphaquinoxaline were present in the milk from cows orally dosed with these five sulphonamide drugs.     

Depletion kinetics of 14C-sulfamethazine [4-amino-N-(4, 6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] metabolism in swine

Swine weighing 60-70 kg were orally administered 14C-sulfamethazine [4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] at 12-hr intervals for 7 days (165 mg/dose; 0.126-5.04 mCi/mmol). The animals were sacrificed at 8 hr or 2, 5, or 10 days after the last dose was given and tissues were assayed for total 14C activity. The presence of 14C-labeled sulfamethazine, N4-acetylsulfamethazine, desaminosulfamethazine, and the N4-glucose conjugate of sulfamethazine in blood, liver, kidney, skeletal muscle, and adipose tissue was verified by HPLC and GC-MS analysis. Total 14C residue levels in all tissues examined had dropped to less than 0.1 ppm sulfamethazine equivalents by day 10 of the depletion period. The mean half-life (t1/2) for sulfamethazine, the N4-glucose conjugate of sulfamethazine, and N4-acetylsulfamethazine was estimated to be 0.8 day. In some tissues, the depletion of the N4-glucose conjugate of sulfamethazine and N4-acetylsulfamethazine had decreased significantly between days 5 and 10, resulting in an approximate doubling of the t1/2 for that period. In contrast, the half-life of desaminosulfamethazine varied from a mean of 0.96 day during the 8-hr-5-day depletion period to 3.7-9.1 days during the 5- 10-day depletion period. In most tissues, the t1/2 for the 14C-activity in the methanol-insoluble fraction increased by 3-5-fold between days 5 and 10 of the depletion period. No predictable relationship was observed between blood sulfamethazine or metabolite levels and total residue levels in the tissues.     

The metabolism and deamination of [14C]sulphamethazine in a germ-free pig: the influence of nitrate and nitrite

Twenty-four hours after feeding nitrite in combination with [14C]sulphamethazine to a germ-free and a conventional control pig the level of [14C]desaminosulphamethazine in tissues from both pigs was high, accounting for 11 to 30% of the total tissue 14C. When another germ-free pig was fed [14C]sulphamethazine in combination with nitrate, a trace amount of [14C]desaminosulphamethazine was found by gas chromatography-mass spectroscopy in the skeletal muscle but not in other tissues. When a control pig was fed [14C]sulphamethazine and nitrate, [14C]desaminosulphamethazine was found in all tissues examined. The results from this study show that feeding pigs nitrite together with sulphamethazine increases the amount of desaminosulphamethazine in the tissues. Most of the desaminosulphamethazine found in the tissues of the control pig fed nitrate was presumably the secondary effect of bacterial reduction of nitrate to nitrite.     

Formation of a diazonium cation intermediate in the metabolism of sulphamethazine to desaminosulphamethazine in the rat

14C-Sulphamethazinediazonium tetrafluoroborate (14C-SDTFB) when orally administered to rats was converted primarily to 14C-labelled desaminosulphamethazine (desaminosulmet) and methanol-insoluble residues in the gastrointestinal tract (gut). 14C-labelled sulphamethazine (sulmet), N4-acetylsulmet, the N4-glucose conjugate of sulmet and other unidentified products were also observed in the tissues and urine of rats given 14C-SDTFB. 2. When 14C-sulmet, nitrite and dimethylaniline were simultaneously administered to a rat by the oral route, one of the 14C-labelled products formed in the stomach was isolated and identified as 4-dimethylaminophenyl [4-(N-4,6-dimethyl-2-pyrimidinyl)sulphamidophenyl] diazene, providing evidence that 14C-sulmet was diazotized in the stomach of the animal. 3. SDTFB was weakly mutagenic when evaluated by the Ames test. 4. The methanol-insoluble 14C-labelled residues in the gut of rats dosed orally with 14C-SDTFB and 14C-sulmet + nitrite were partially converted to 14C-labelled desaminosulmet, sulmet, N4-acetylsulmet and other unidentified products when fed to recipient rats.     

Steady state kinetics of 14C-sulfamethazine [4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] metabolism in swine

Swine were dosed orally with 14C-sulfamethazine [4-amino-N-(4, 6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] for 3, 5, or 7 days (two 165-mg doses/day; 0.46 muCi/mg) and killed 8 hr after the last dose. The concentration of carbon-14 in the tissues increased by an average of 21% from day 3 to day 5 of dosing. However, there was no further increase from day 5 to day 7, indicating that a steady state level of carbon-14 in the tissues was attained by dosing on 5 consecutive days. Liver, kidney, skeletal muscle, blood, and adipose tissue from all animals were analyzed for 14C-labeled sulfamethazine, N4-acetylsulfamethazine, desaminosulfamethazine [N-(4, 6-dimethyl-2-pyrimidinyl)benzenesulfonamide], and the N4-glucose conjugate of sulfamethazine. The identity of these compounds (the hydrolysis product of N4-glucose conjugate) was confirmed by HLPC and gas-liquid chromatography/mass spectral analysis after methylation. The relative distribution of 14C-sulfamethazine and these metabolites varied somewhat among the tissues analyzed but did not vary within a tissue after different periods of dosing.     

The isolation and identification of 14C-sulfamethazine (4-amino-n-(4,6-dimethyl-2-pyrimidinyl)[14C]benzenesulfonamide) metabolites in the tissues and excreta of swine

Pigs were given a single oral dose of 14C-sulfamethazine (4-amino-N(I4,6-dimethyl-2-pyrimidinyl)[14C]benzenesulfonamide). Approximately 78% of the 14C was eliminated in the urine and 18% was eliminated in the feces within 192 hr after dosing. The percentage of the 14C remaining in the animals after dosing was as follows: 6 hr, 88%; 24 hr, 49%; 48 hr, 14%; 192 hr, less than 1%. The 14C-labeled compounds in the tissues and excreta were isolated by solvent extraction and by conventional and high-pressure liquid chromatography, and then derivatized and characterized by infrared and mass-spectral analysis. Chemical structures were confirmed by synthesis. The major 14C-labeled compounds in the skeletal muscle, liver and kidney were identified as sulfamethazine, N4-acetylsulfamethazine, the N4-glucose conjugate of sulfamethazine, and N-(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamide (desaminosulfamethazine). The major 14C-labeled compounds in the urine and feces were identified as sulfamethazine and N4-acetylsulfamethazine.     

In vitro formation of a triazene compound by reaction of sulphadimidine and nitrite

The interaction between the veterinary drug sodium sulphadimidine and nitrite has been studied under acid conditions and the formation of 1,3-di-(4-[N-(4,6-dimethyl-2-pyrimidinyl)sulphamoylphenyl)triazene (DDPSPT) was demonstrated. This compound was not mutagenic when tested on Salmonella typhimurium and Drosophila melanogaster. In addition to the formation of DDPSPT, desaminosulphadimidine was identified as a minor reaction product.     

The disposition of N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide in the rat

Rats given a single oral dose of N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide (14C-DAS) excreted 64.2% of the 14C in the urine and 22.4% in the feces within 96 hr. Compounds accounting for 86% of the 14C in the 0-24-hr urine were isolated by a variety of chromatographic techniques and identified by IR, NMR, and MS analysis. Approximately 4% of the 14C in the urine was the parent compound. The structures of 14C-metabolites in the urine indicated that 14C-DAS was metabolized by at least three pathways which included: 1) hydroxylation and glucuronic acid conjugation at the 4-position of the benzene ring; 2) hydroxylation, and sulfate ester and glucuronic acid conjugation at the 5-position on the heterocyclic ring; and 3) hydroxylation and glucuronic acid conjugation of one methyl group on the heterocyclic ring.     

Formation of a diazonium cation intermediate in the metabolism of sulphamethazine to desaminosulphamethazine in the rat

¹⁴C-Sulphamethazinediazonium tetrafluoroborate (¹⁴C-SDTFB) when orally administered to rats was converted primarily to ¹⁴C-labelled desaminosulphamethazine (desaminosulmet) and methanol-insoluble residues in the gastrointestinal tract (gut). ¹⁴C-labelled sulphamethazine (sulmet), N⁴-acetylsulmet, the N⁴-glucose conjugate of sulmet and other unidentified products were also observed in the tissues and urine of rats given ¹⁴C-SDTFB.

2. When ¹⁴C-sulmet, nitrite and dimethylaniline were simultaneously administered to a rat by the oral route, one of the ¹⁴C-labelled products formed in the stomach was isolated and identified as 4-dimethylaminophenyl[4-(N-4,6-dimethyl-2-pyrimidinyl)sulphamidophenyl]diazene, providing evidence that ¹⁴C-sulmet was diazotized in the stomach of the animal.

3. SDTFB was weakly mutagenic when evaluated by the Ames test.

4. The methanol-insoluble ¹⁴C-labelled residues in the gut of rats dosed orally with ¹⁴C-SDTFB and ¹⁴C-sulmet + nitrite were partially converted to ¹⁴C-labelled desaminosulmet, sulmet, N⁴-acetylsulmet and other unidentified products when fed to recipient rats.     

Synthesis and anti-HIV activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulfonamide and its derivatives.

4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its derivatives were synthesized by reaction of isatin and its derivatives with sulphadimidine. Their chemical structures have been confirmed by IR, (1)H NMR data and elemental analysis. Investigation of anti-HIV activity of compounds were tested against replication of HIV-1 (IIIB) and HIV-2 (ROD) strains in acutely infected MT-4 cells and the activity compared with standard azidothymidine. Among the compounds tested, 4-[(1,2-dihydro-2 oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its N-acetyl derivative were the most active compounds.     

Synthesis and anti-HIV activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulfonamide and its derivatives

4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its derivatives were synthesized by reaction of isatin and its derivatives with sulphadimidine. Their chemical structures have been confirmed by IR, ¹H NMR data and elemental analysis. Investigation of anti-HIV activity of compounds were tested against replication of HIV-1 (IIIB) and HIV-2 (ROD) strains in acutely infected MT-4 cells and the activity compared with standard azidothymidine. Among the compounds tested, 4-[(1,2-dihydro-2 oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its N-acetyl derivative were the most active compounds.     

The lazaroid, U-74389G, inhibits inducible nitric oxide synthase activity, reverses vascular failure and protects against endotoxin shock

The aim of our study was to investigate the effect of the 21-aminosteroid U-74389G [21- < 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl-pregna-1,4,9,(11) triene-3,20-dione(z)-2-butenedionate] on the l-arginine-nitric oxide (NO) pathway in a rat model of endotoxin shock. Endotoxin shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg/kg of Salmonella Enteritidis lipopolysaccharide (LPS). Rats were treated with U-74389G (7.5, 15 and 30 mg/kg i.v.) or vehicle (1 ml/kg i.v.) 5 min after endotoxin challenge. Lipopolysaccharide administration reduced survival rate (0%, 72 h after endotoxin administration) decreased mean arterial blood pressure, enhanced plasma concentration of bilirubin and alanine aminotransferase and increased plasma nitrite concentrations. Lipopolysaccharide injection also increased the activity of inducible NO synthase in the liver and in the aorta. Furthermore aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (1 nM-10 microM). In addition lipopolysaccharide (50 microg/ml for 4 h) in vitro stimulation significantly increased nitrite production in peritoneal macrophages harvested from normal rats. Treatment with U-74389G (15 and 30 mg/kg i.v., 5 min after endotoxin challenge) significantly protected against lipopolysaccharide-induced lethality (90% survival rate 24 h and 80% 72 h after lipopolysaccharide injection, respectively, following the highest dose of the drug), reduced hypotension, ameliorated liver function, decreased plasma nitrite levels, restored the hyporeactivity of aortic rings to their control values and inhibited the activity of inducible NO synthase in the liver and in the aorta. Finally, U-74389G in vitro (12.5, 25 and 50 microM) significantly inhibited nitrite production in endotoxin stimulated peritoneal macrophages. The data suggest that U-74389G may exert beneficial effects in an experimental model of septic shock by inhibiting the activity of the inducible NO synthase.     

Excretion and distribution of nitrite-treated or untreated 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid in rats

The excretion and distribution of 14C were studied in rats given by oral intubation 14C-labelled (-)-(1S,3S)-1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and its stereoisomer, (-)-(1R,3S)-1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (MTCAs), compounds that are known to become mutagenic on reaction with nitrite. For comparison, another group of rats was given by oral intubation products of the in vitro treatment of [14C]MTCAs with nitrite. When rats were given the untreated [14C]MTCAs, most of the 14C was excreted in the faeces within 24 hr and was noted only in the intestine on autoradiograms of rats killed 30 min and 6 hr after dosing. In contrast, when rats were given the nitrite-treated [14C]MTCAs, 14C was mainly excreted in the urine within 24 hr and was noted not only in the intestine but also in the liver and kidney on autoradiogram. These results suggest that the majority of MTCAs pass rapidly through the gastro-intestinal tract, while the bulk of the reaction products of MTCAs with nitrite are absorbed from the gastro-intestinal tract and excreted in the urine.     

Modification of intracellular glucose metabolism in human skin fibroblast preincubated with p-chlorophenoxyisobutyrate.

1. The effect of p-chlorophenoxyisobutyrate (CPIB) on glucose metabolism human skin fibroblasts was examined. 2. CPIB increased the incorporation of 2-deoxy-D-[U-14C]glucose into skin fibroblasts. 3. CPIB decreased [14C]CO2 production from D-[U-14C]glucose but did not affect pyruvate dehydrogenase activity. 4. CPIB reduced fatty acid oxidation activity and cholesterol synthesis but increased triglyceride synthesis. 5. These effects of CPIB were observed both in the presence and in the absence of insulin. 6. One possible mechanism of CPIB on reducing plasma glucose may be due to the increase of glucose incorporation into the cells and triglyceride synthesis in the cells.     

Mediation of the schistosomicidal effect of praziquantel through nitric oxide

The effect of praziquantel (CAS 55268-74-1) on serum nitrate/nitrite level (a marker for nitric oxide (NO) synthesis) in S. mansoni infected mice was studied. The effects of the NO precursor (L-arginine) and NO-synthase inhibitor (NG-nitro-L-arginine methyl ester, L-NAME) on the effect of praziquantel on nitrate/nitrite level as well as on its antischistosomal activity were also evaluated. Praziquantel increased nitrate/nitrite level in serum of infected mice in a dose dependent manner. An oral dose of 75 mg/kg praziquantel produces a significant (p < 0.05) increase in serum nitrate/nitrite level by about 3.5 fold. Administration of L-arginine (200 mg/kg orally) induced a significant (p < 0.05) increase in nitrate/nitrite level (to about 5 fold) compared to praziquantel 75 mg/kg alone. Praziquantel-induced increase in nitrate/nitrite level was significantly reduced by administration of L-NAME 100 mg/kg. The antischistosomal activity of praziquantel was evaluated using two models: hepatic shift model and reduction of worm burden. In the hepatic shift model, praziquantel increased the percentage of worms in the liver (from 5% in control to 60%). Praziquantel-induced hepatic shift was not significantly affected by concurrent L-arginine or L-NAME administration. In the second model, praziquantel induced a significant decrease of the worm burden (p < 0.05) and the action of praziquantel was significantly increased by L-arginine and reduced by L-NAME administration. In conclusion, NO is possibly involved in the antibilharzial effect of praziquantel and administration of L-arginine with praziquantel produces beneficial antibilharzial effect.