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Seven esters derivatives of Nitroxinil were prepared and their structures were assigned by IR and 1H-NMR spectroscopy. The rate of plasma and hepatic hydrolysis were evaluated in vitro in sheep and rabbit. In view of this profile of activity, pivaloyl derivative merits evaluation, in vivo.
Nitroxynil distribution and the period of its retention in the organism of sheep and calves subcutaneously treated with therapeutical doses of the Bulgarian patent medicine fasciolid which contains N-methylglucaminic-nitro-xynil salt were followed. Comparative studies were carried out using the patent medicine dovenix "Specia". The polarographic method, based on nitro-group reduction over a dripping mercury electrod was applied for nitroxynil determination. It was established that fasciolid and dovenix applied to sheep and cattle in a prophylactic-therapeutic dose did not differ significantly in their distribution and retention in the organism.
Hepatic biotransformation of the flukicidal agent nitroxynil (3-iodo-4-hydroxy-5-nitrobenzonitrile) (I) has been studied with rat liver subcellular fractions as the source of enzymes: two metabolites, 3-iodo-4--hydroxy-5-aminobenzonitrile (II) and 3-iodo-4-hydroxy-5-nitrobenzamide (III) have been identified by standard analytical techniques (TLC, GLC and MS). The nitroaromatic reduction product (II) is formed in the hepatocyte in a process in which cytosol and endoplasmic reticulum enzymes cooperate. This formation is maximal in anaerobic conditions, but takes also place aerobically and in the absence of electrogenic cofactors. Cytochrome P-450 plays a major role in the denitrification process, and consequently could be the cellular site most exposed to damage by the intermediate arylhydroxylamine formed by reduction.
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Liver fluke infection (Fasciola hepatica) depresses the drug-metabolizing capacity of the hepatic mixed function oxidase (MFO) and glucuronosyltransferase (GT) enzyme systems, throughout a free radicals mediated lipid peroxidation process. Glutathione (GSH, CAS 70-18-8) administered chronically (100 mg/kg i.p. once daily for 40 days) to experimentally infested rats from the onset to the maximal development of the infection (40th day), greatly reduced the damage to membrane lipids of the liver tissue (primary event of the disease), as judged by malonic dialdehyde (MDA) content (decreased by 80%) and diene conjugation absorption (delta E 1% value falls from 1.94 to 0.67). As a consequence, serum glutamate-oxaloacetate (GOT) and glutamate-pyruvate (GPT) transaminases levels, liver GSH and phospholipid (PL) contents, cytochrome P-450, NADPH-cytochrome-P-450 reductase and some typical cytochrome P-450-dependent activities (p-nitroanisole O-demethylase, aniline hydroxylase, as well as UDP-glucuronosyltransferase (GT) activity, all markedly affected in the acute stage of the disease, tend to recover to the control values. The efficacy of GSH in preventing the impairment of the hepatic drug metabolizing capacity was also demonstrated by using as substrate the widely employed flukicidal agent nitroxinil (3-iodo-4-hydroxy-5-nitrobenzonitrile). The in vitro cytochrome P-450-dependent nitroxinil detoxification (reduction to 3-iodo-4-hydroxy-5-aminobenzonitrile), drastically impaired in infested animals (-80%), is markedly restored (3-fold increase) in GSH-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
The frequency of liver fluke disease in fattening units was determined by the analysis of random faeces samples issued from 1,513 Belgian White Blue bulls aged from 5 to 7 months and weighing from 200 to 300 kg. 12.5% of the investigated bulls were positive for liver fluke disease. These bulls were spread over 56.5% of the investigated fattening units. Furthermore the infestation rate varied from 0 to 33.3% inside the fattening units. In order to assess the economic consequences of bovine fascioliasis in double-muscled cattle and the beneficial effects of a treatment against such a disease, a trial including 30 Belgian White Blue bulls, weighing 365 +/- 9 kg and aged from 10 to 12 months, was conducted in a selected fattening unit. On the basis of faecal examinations, the 30 animals were subdivided in negative (group A; n = 10) and positive animals (n = 20) for fascioliasis, the latter being either treated with nitroxinil (group B; n = 10) or not (group C; n = 10) on day 0 of this trial which was conducted during 75 days. The daily body gains in group C (1.661 +/- 0.140 kg) were significantly lower than those in group A (1.975 +/- 0.120 kg). On the other hand there was no significant difference between the daily body gains registered in group B (1.960 +/- 0.085 kg) and A. The estimated financial loss, due to flukes and accounted on a 75 day-period, averaged 2,748 Belgian Francs per bull in group C.(ABSTRACT TRUNCATED AT 250 WORDS)
Studies on the metabolic fate of aromatic nitriles, in contrast to their aliphatic counterparts, have been minimal and the subject of controversy. The in vitro metabolic fate of several aromatic nitriles with varying substituents was investigated by using rat liver subcellular fractions, with a particular emphasis on the nitrile moiety. Benzonitriles and 4-cyanophenols underwent oxidative metabolism to produce ring-hydroxylated metabolites. On the other hand, 2-cyanophenol was resistant to metabolism. o-Tolunitrile was metabolized and produced o-cyanobenzyl alcohol and phthalide. Phthalide, however, was chemically derived from o-cyanobenzyl alcohol, the initial metabolite. 4-Nitrobenzonitrile was resistant to oxidation on the ring, but was readily reduced to the corresponding amine metabolite under both aerobic and anaerobic conditions. Nitroxynil (3-iodo-4-hydroxy-5-nitrobenzonitrile) was metabolized to produce 3-iodo-4-hydroxy-5-nitrobenzamide and 3-iodo-4-hydroxy-5-nitrobenzoic acid. The enzyme(s) responsible for this hydrolytic metabolism was primarily localized in the cytosol. Among the nitriles tested, o-tolunitrile and nitroxynil produced metabolites in which the nitrile moiety was modified. Nitroxynil, however, was the only compound that was directly metabolized on the nitrile moiety by the rat liver enzyme(s).
Two experiments were carried out to assess the effects of nitroxynil (10 mg/kg p.o.) and rafoxanide (6.7 mg/kg p.o.) against 2,4, 6 or 8 weeks old F. hepatica in rabbits. The results show that the efficacy and incidence of stunted and abnormal surviving flukes were directly related to the age of infection at treatment. Rafoxanide was the more potent compound against immature forms. The testes were the most consistently abnormal reproductive organs in flukes surviving treatment with both drugs and spermatogenesis per se was disrupted.
Male Sprague-Dawley rats were dosed orally with nitroxynil at a concentration of 40 mg/kg and adult Fasciola hepatica recovered after 24 h, 48 h and 72 h. Surface changes to the flukes were monitored by means of SEM. After the 24 h treatment, extensive swelling and blebbing of the tegument was observed on both surfaces, although the dorsal anterior region was more severely affected than either the posterior dorsal region or entire ventral surface. At high magnification, microvillus-like projections were evident, giving the surface a roughened appearance. After 48 h, the changes evident at 24 h had become more severe and some tegumental loss had occurred in the oral region of the fluke. Surface disruption was particularly evident along the lateral margins of the fluke in this region. In some specimens a single large swelling was present in the dorsal midbody region. The swelling was a more typical feature of flukes recovered. After 72 h, tegumental loss was more widespread, occurring over the oral cone and anterior midbody on the dorsal surface. Overall the dorsal surface was consistently more severely affected than the ventral surface, and the anterior region of the fluke was more disrupted than the posterior region. After 24 h in vitro incubation, the oral cone and midbody exhibited considerable spine loss and swelling. Overall, the dorsal surface was more disrupted than the ventral surface and the anterior region of the fluke was more disrupted than the posterior region. Regional differences in the response of the fluke to nitroxynil will be compared to previously published data with other fasciolicides. The results indicate that the tegument is an important target for nitroxynil action. Disruption of this, the fluke's main line of defence, would allow the drug access to other internal tissues, leading to more widespread damage.
The effects of a wide range of fasciolicides on the in vitro motility of Fasciola hepatica have been determined by means of an isometric transducer system. Carbon tetrachloride and diamphenethide do not affect movement at concentrations up to 500 and 100 micrograms/ml, respectively; at 1000 micrograms/ml, however, carbon tetrachloride induces a rapid tonic paralysis. Brotianide and the deacetylated metabolite of diamphenethide cause a rapid flaccid paralysis of the fluke at concentrations of 1.0 micrograms/ml and above. In contrast, the effect of MK-401 is a long-term one, a flaccid paralysis occurring after 20 hr only at 200 micrograms/ml. Praziquantel also produces a flaccid paralysis of the fluke, but this follows an initial increase, then decrease in muscle tone. The effect is rapid at 500 micrograms/ml, but long-term at 100 and 200 micrograms/ml; at these lower concentrations there is also a stimulation of activity. Oxyclozanide , rafoxanide, niclofolan , bithionol, and hexacholorophene induce a rapid spastic paralysis of the fluke at concentrations of 1.0 micrograms/ml and above. Both phasic and tonic components are evident in the response at concentrations of 1.0 micrograms/ml and below; the phasic component disappears at higher concentrations. Nitroxynil produces a similar effect, evident at higher concentrations. Among the benzimidazoles, mebendazole, oxfendazole, and albendazole sulphoxide cause a suppression of motility, whilst thiabendazole and albendazole produce a stimulation of movement. The effects are not rapid, however, for only mebendazole at 500 micrograms/ml causes total inactivity of the fluke within a 12-hr period. Possible explanations for these effects on fluke motility are discussed.
A sensitive and specific method is described for the determination of nitroxynil (fasciolicide) residues in cow milk. The milk samples were extracted with acetone and acetonitrile, following clean-up using a simple liquid-liquid extraction step. Nitroxynil was separated from the matrix peaks by reversed-phase high-performance liquid chromatography and detected using dual-electrode coulometric detection. The mobile phase was a mixture (20:80, v/v) of acetonitrile and 0.05 M potassium dihydrogenphosphate with the pH adjusted to 4.0. The flow-rate was 1 ml/min at 40 degrees C. The applied potentials of detectors 1 and 2 were maintained at -0.7 and +0.2 V, respectively. Average recoveries (n = 5) of nitroxynil from milk samples spiked at concentrations of 0.01 and 0.1 micrograms/ml were found to be 92.0% and 97.0% with coefficients of variation of 6.2% and 2.2%, respectively. The detection limit of nitroxynil in milk was 0.7 ng/ml. During the analysis of 30 raw cow milk and 140 market milk samples, nitroxynil was detected at a level of 4 ng/ml in one raw cow milk sample.
An improved hemagglutination (HA) test using the purified specific f2 antigen of Fasciola hepatica has been evaluated with regard to its potential use for the prediction of chemotherapeutic success in natural bovine infections with F. hepatica. Lactating cows (n = 16) from a herd naturally infected with F. hepatica were successively treated with nitroxynil (Dovenix, Specia) and with oxyclozanide (Zanil, ICI) 1 month later. Their f2-specific antibodies were significantly lower than those of a non-treated control group (n = 15) from the second month after the first treatment, and continued to decline thereafter to negative values 5-6 months post-treatment. In a second experiment, culled and fattened cows (n = 32) of unknown fasciolosis history were treated with closantel (Janssen Pharmaceutica). Three months after treatment, f2-specific antibodies of the serologically positive animals (n = 24) were reduced nine-fold. In contrast, in the control group (n = 28), the titers of f2-specific antibodies of the serologically positive animals (n = 21) were not modified significantly. The results show that the f2-HA test is useful for the prediction of chemotherapeutic success in bovine fascioliasis.
Two separate field trials involving naturally infected cattle were carried out on two farms known to have a history of Fasciola hepatica infection. On the first farm, 15 animals per group were allocated as follows: G1, triclabendazole (TCBZ) four times a year; G2, TCBZ twice a year (May and September); G3, untreated control. All groups grazed together and after 3.5 years the animals were slaughtered and their livers examined by federal meat inspectors who condemned 100% of livers in G3 and 8.3% in G2 owing to the presence of lesions of fasciolosis. In G1 no livers were condemned. Significant differences in weight gains were not detected and fluke counts remained at low levels in the treated groups. Also, in the control group, egg counts started to decrease when animals were 2 years old. On the second farm, groups of 20 animals were treated as follows: G1, TCBZ three times a year (May, September and December); G2, TCBZ twice a year (May and September); G3, nitroxynil twice a year (May and September); G4, rafoxanide twice a year (May and September); G5, untreated controls. All animals were weighed and faecal samples examined at approximately 28-day intervals. During the period of the study, larger weight gains were detected in the TCBZ treated groups than in the others. TCBZ treatment kept F. hepatica egg counts at a lower level for longer periods than the other drugs and significant differences in weight gains were only obtained between the group receiving TCBZ three times a year and the control group.
In vitro metabolism by liver tissue of the flukicidal agent nitroxynil has been studied in cattle naturally infected with Fasciola hepatica. A dramatic impairment of the cytochrome P-450-dependent nitroxynil metabolism both in the acute and in the milder stage of the disease has been observed and this is due to a loss in the integrity and functionality of the cytochrome P-450 enzyme system. These results suggest that in bovine fascioliasis the in vivo metabolism of nitroxynil will be decreased with consequent increase of nitroxynil retention in the animal's body.
A high-performance liquid chromatographic method for the determination of the anthelmintic nitroxynil has been developed. The drug was extracted from cattle muscle tissue with 1% triethylamine in acetonitrile. The extract was evaporated to dryness and taken up in 0.1 M ammonium acetate-acetonitrile (50:50, v/v). The extract was then injected onto a polymeric anion-exchange precolumn. After clean-up with 0.1 M ammonium acetate-acetonitrile (50:50, v/v) for 5 min, the precolumn was eluted with 1% aqueous trifluoroacetic acid-acetonitrile (50:50, v/v) onto a PLRP-S polymer column and chromatographed with a mobile phase of 0.01 M phosphate pH 7-acetonitrile (80:20, v/v). Detection was by ultraviolet at 273 nm. Average recoveries at four levels from 0.005 to 1.000 mg kg-1 were > 88%. The limit of determination was 0.005 mg kg-1.
The electrochemical behavior of the anthelmintic veterinary drug nitroxynil at the mercury electrode was studied in a series of Britton-Robinson universal buffer of pH 1.9-11 containing 20% (v/v) ethanol using dc-polarography cyclic voltammetry and controlled-potential coulometry. The voltammograms exhibited two irreversible cathodic steps over the pH range 1.9-10.2; the height of the first step is double that of the second one. Controlled-potential coulometry in the B-R universal buffer of pH 1.9-10 at a mercury pool working electrode revealed the consumption of four and two electrons via the first and second reduction steps, respectively, which attributed to reduction of the NO2 group to the hydroxylamine stage (first step), and then to the amine stage (second step). Three voltammetric analytical procedures including dc-polarography, differential-pulse adsorptive stripping voltammetry and square-wave adsorptive stripping voltammetry were optimized for the direct determination of bulk nitroxynil. The three proposed procedures were applied for analysis of bulk nitroxynil with limits of detection of 3 x 10(-5), 1.31 x 10(-8) and 8.4 x 10(-10)M and limits of quantification of 1 x 10(-5), 4.36 x 10(-8) and 2.80 x 10(-9)M, respectively. The three procedures were successfully applied to the determination of nitroxynil in formulation (Dovenix, 25% nitroxynil injection solution) without the necessity for sample pretreatment and/or time-consuming extraction steps prior to the analysis.
This paper describes an exceptional spectrum of multiple anthelmintic resistance in two strains of Haemonchus contortus in South Africa, one from Howick in KwaZulu-Natal, and the other from Badplaas, in Mpumalanga. Apparently for the first time, a helminth strain is described with resistance to compounds from all five of the modern anthelmintic groups used for nematode control in sheep; also, two strains of H. contortus show resistance to the two substituted phenols, dinitrophenol and nitroxynil. Only closantel at 5 mg kg-1 of nine compounds tested appears to have undiminished efficacy against the Howick strain, but even in the case of closantel, the residual activity and minimal effective level need to be tested before it can be concluded that its efficiency is unaffected. The exceptional resistance of the Howick strain is demonstrated by the fact that sequential daily drenching of sheep infected with the strain, with levamisole at 18 mg kg-1, oxfendazole at 20 mg kg-1, levamisole at 20 mg kg-1 and a mixture of fenbendazole at 10 mg kg-1 plus trichlorfon at 132 mg kg-1 on the fourth day, failed to clear sheep of the infection. There are strong indications that side-resistance occurs between dinitrophenol and nitroxynil, on the one hand, and the salicylanilides, on the other, and it is suggested that, before long, strains of H. contortus will be found with high levels of resistance to all the currently available anthelmintics.
The effect of oxyclozanide, hexachlorophene, nitroxynil, rafoxanide and diamphenethide on malate dehydrogenase activity of homogenates of Fasciola gigantica, Fasciolopsis buski and Paramphistomum explanatum was investigated. The ratio of oxaloacetate reduction to malate oxidation in homogenates of Fasciola gigantica, Fasciolopsis buski and P. explanatum was 4.5:1, 3.6:1 and 5.2:1 respectively. Oxyclozanide and rafoxanide at 10(-3) M inhibited enzyme activity by 100% in homogenates from all three species while hexachlorophene at 10(-3) M also caused 100% inhibition in homogenates from Fasciola gagantica and P. explanatum but only 65% of malate oxidation in Fasciolopsis buski homogenates. Nitroxynil at 10(-3) M produced 60% inhibition in F. buski homogenates yet had little effect at this concentration on preparations from the other species. Little inhibition was seen with diamphenethide, even at high concentrations. Rapid death of Fasicola gigantica and P. explanatum resulted in vitro when 10(-3) M oxyclozanide, hexachlorophene, nitroxynil or rafoxanide, were added to the incubation medium. Fasciolopsis buski was killed by 10(-3) M oxyclozanide but at this concentration the remaining compounds only caused reduced activity. Assay of malate dehydrogenase following drug treatment in vitro failed to show any appreciable reduction in enzyme activity in Fasciola gigantica and P. explanatum but oxyclozanide and hexachlorophene produced inhibition in Fasciolopsis buski. The mode of action of these compounds is discussed.