Comparative analysis of organophosphorus versus carbamate pesticide poisoning: a case study.

Organophosphorus poisoning is a critical condition that can cause central nervous system depression, respiratory failure, and death early on. As its clinical manifestations closely resemble those of carbamate pesticide poisoning, the aim of this case study is to present a case of misdiagnosis, initially identifying carbofuran poisoning as organophosphate in a patient suspect of a heatstroke. We also present a case of intentional self-poisoning with organophosphate dichlorvos to underline the likelihood of pesticide poisoning in patients exhibiting acute cholinergic symptoms when the ingested substance is not known. In such cases, empirical treatment with atropine and oxime can be started pending timely differential diagnosis to adjust treatment as necessary.

Plasma Protein Binding Determination for Unstable Ester Prodrugs: Remdesivir and Tenofovir Alafenamide.

Remdesivir (RDV) and tenofovir alafenamide (TAF) are prodrugs designed to be converted to their respective active metabolites. Plasma protein binding (PPB) determination of these prodrugs is important for patients with possible alteration of free fraction of the drugs due to plasma protein changes in renal impairment, hepatic impairment, or pregnancy. However, the prodrugs' instability in human plasma presents a challenge for accurate PPB determination. In this research work, two approaches were used in the method development and qualification for PPB assessment of RDV and TAF. For RDV, dichlorvos was used to inhibit esterase activity to stabilize the prodrug in plasma during equilibrium dialysis (ED). The impact of dichlorvos on protein binding was evaluated and determined to be insignificant by comparing the unbound fraction (fu) determined by the ED method with dichlorvos present and the fu determined by an ultrafiltration method without dichlorvos. In contrast to RDV, TAF degradation in plasma is ∼3-fold slower, and TAF stability cannot be improved by dichlorvos. Fit-for-purpose acceptance criteria for the TAF PPB method were chosen, and an ED method was developed based on these criteria. These two methods were then qualified and applied for PPB determinations in clinical studies.

Temporal changes in distribution, prevalence and intensity of northern fowl mite (Ornithonyssus sylviarum) parasitism in commercial caged laying hens, with a comprehensive economic analysis of parasite impact.

Establishment and spread of Ornithonyssus sylviarum were documented through time on sentinel hens (50 per house of 28,000-30,000 hens) in the first egg production cycle of three large commercial flocks (12 houses) of white leghorn hens. Mites were controlled using acaricide, and the impacts of treatment on mite populations and economic performance were documented. Mite prevalence and intensity increased rapidly and in tandem for 4-8 weeks after infestation. Intensity declined due to immune system involvement, but prevalence remained high, and this would affect mite sampling plan use and development. Early treatment was more effective at controlling mites; 85% of light infestations were eliminated by a pesticide spray (Ravap), versus 24% of heavy infestations. Hens infested later developed lower peak mite intensities, and those mite populations declined more quickly than on hens infested earlier in life. Raw spatial association by distance indices (SADIE), incorporating both the intensity and distribution of mites within a house, were high from week-to-week within a hen house. Once adjusted spatially to reflect variable hen cohorts becoming infested asynchronously, this analysis showed the association index tended to rebound at intervals of 5-6 weeks after the hen immune system first suppressed them. Large, consistent mite differences in one flock (high vs. low infestation levels) showed the economic damage of mite parasitism (assessed by flock indexing) was very high in the initial stages of mite expansion. Unmitigated infestations overall reduced egg production (2.1-4.0%), individual egg weights (0.5-2.2%), and feed conversion efficiency (5.7%), causing a profit reduction of $0.07-0.10 per hen for a 10-week period. Asynchronous infestation patterns among pesticide-treated hens may have contributed to a lack of apparent flock-level economic effects later in the production cycle. Individual egg weights differed with mite loads periodically, but could be either higher or lower, depending on circumstances and interactions with hen weight. Individual hen weight gains were depressed by high/moderate mite loads, but the heavier hens in a flock harbored more mites. This led to compensatory weight gains after mites declined. Tradeoffs between resource allocation to body growth or production versus immune system function appeared to be operating during the early and most damaging mite infestation period, when high egg production was beginning and the hens were gaining weight. The results were related to other studies of mite impact on domestic hens and to wild bird-ectoparasite studies. Much of the mite economic damage probably is due to engaging and maintaining the immune response.

Poor efficacy of the most commonly used anthelmintics in sport horse nematodes in Morocco in relation to resistance.

Sport and leisure horses in Morocco are treated with several anthelmintics, organophosphates (dichlorvos), benzimidazoles (mostly thiabendazole) or tetrahydropyrimidines (mostly pyrantel pamoate) against nematodes. We studied three horse stables in Rabat, one in Meknes and one in Bouznika. Two of the Rabat and Bouznika stables had introduced a large number of horses from countries (Argentina or Europe) where resistance to benzimidazoles is frequent, whereas the Meknes stud farm remained without foreign introduction. The number of treatments was not very frequent (twice a year in adult horses) but the same anthelmintics were used repeatedly. No resistance to dichlorvos was detected whereas benzimidazole and pyrantel pamoate resistances were detected for the first time in African horses, outside South Africa.

The persistent efficacy of doramectin pour-on against biting and sucking louse infestations of cattle.

A repeated-exposure challenge model was used to evaluate the pour-on formulation of doramectin in preventing the establishment of louse infestations in cattle. Twenty calves cleared of preexisting biting and sucking louse infestations were randomly and equally allocated to either a doramectin-treated or untreated control group, with five replicates per group. Doramectin pour-on was administered topically at a dose rate of 500 microg/kg body weight. Every 14 days, from a pool of seeder calves with infestations of at least 50 biting and 50 sucking lice each, 10 calves were selected and 1 was placed in each replicate pen. Every week during the 112-day study, 9 predilection sites on the doramectin-treated and untreated calves were examined to estimate the louse population density. A calf met the infestation criterion for a louse species when two or more live lice were counted on two or more body regions for two consecutive count days. Because only 4 of 10 untreated calves acquired Solenopotes capillatus infestations, the persistent efficacy of doramectin against S. capillatus was not evaluated. Bovicola bovis and Linognathus vituli infestations in the untreated calves developed shortly after exposure to infested seeder calves. The acquisition of B. bovis and L. vituli infestations in the doramectin-treated group was delayed for 77 days and 105 days, respectively.

Comparative efficacy of fenbendazole, dichlorvos, and levamisole HCI against gastrointestinal nematodes of pigs.

Forty-two weanling pigs raised under similar management conditions were used to compare the effectiveness of fenbendazole, dichlorvos, and levamisole HCl against Oesophagostomum dentatum, O. quadrispinulatum, Ascaris suum, Trichuris suis, Hyostrongylus rubidus, and Strongyloides ransomi. All three drugs were given in the feed. Eleven pigs served as unmedicated controls; 11 pigs received fenbendazole (3 mg/kg) on days 1, 2, and 3; 10 pigs received dichlorvos (17 mg/kg) on day 3; and 10 pigs received levamisole HCl (8 mg/kg) on day 3. Fecal specimens from all 11 pigs were collected before and after anthelmintic treatment and examined for nematode eggs. All pigs were killed on day 7, and residual nematodes were counted. The calculated efficacies against the above species, respectively, were: fenbendazole, 99.9, 100, 92.4, 66.0, 99.9, and 0%; dichlorvos, 99.4, 99.9, 100, 99.9, 99.9, and 86.9%; levamisole HCl, 97.1, 99.7, 97.9, 26.1, 94.4, and 99.9%.

Studies on the development and chemotherapy of larvae of Parascaris equorum (Nematoda: Ascaridoidea) in experimentally and naturally infected foals.

Experimentally induced infections of Parascaris equorum in worm-free pony foals required 14 to 17 days for migration of the larvae through the liver and lungs, and 79 to 110 days to become gametogenically functional. Treatment of experimentally infected or naturally exposed foals during the parenteral phase of development, using levamisole at 8 mg/kg, a mixture of levamisole at 8 mg/kg plus piperazine at 88 mg base equivalent/kg, or dl-tetramisole at 10 mg/kg, was quite efficacious in (1) reducing the number of P. equorum larvae recovered from the small intestines of the foals at necropsy, or (2)delaying the appearance of ascarid eggs in the feces of treated foals beyond the time period observed for the untreated foals. Three formulations of dichlorvos at doses of 10, 20, 30, or 40 mg/kg, and 2 formulations of trichlorfon at 20 or 40 mg/kg, were not effective when treatment was given on or before the 14th day after infective eggs were administered. Treatment with a gel formulation of dichlorvos at 20 mg/kg 17 to 28 days after experimental infection was 100% effective in removing ascarid larvae from the small intestines of poly foals.

Controlled tests of pastes of dichlorvos and thiabendazole against induced Strongyloides westeri infections in pony foals in 1973-1974.

In 1973-1974, 4 controlled tests were performed in pony foals (n = 17) raised parasite-free and experimentally infected with Strongyloides westeri. Administration of infective larvae by stomach tube in 1 test resulted in low-grade infections and tended to invalidate the test. Intraoral and percutaneous (intra-aural) administration of larvae resulted in suitable test infections for 1 and 2 tests, respectively. A paste formulation of dichlorvos at 36.3 mg/kg of body weight removal from 4 ponies. Treatment of 4 the dosage rate of 44 mg/kg was consistently effective (greater than 99% to 100%) for eliminating intestinal infections of S westeri.

Efficacy of two dichlorvos formulations against larval and adult Hyostrongylus rubidus in swine.

Coated (V-13) and uncoated (V-22) formulations of dichlorvos were used to treat experimentally established Hyostrongylus rubidus infections of pigs at intervals after exposure to infective larvae. Both dichlorvos formulations were efficacious against the adult stomach worm H rubidus, but showed little or no activity against 5- or 15-day-old worms. Neither formulation was as effective against H rubidus in sows as in barrows and gilts.

Efficacy of dichlorvos, fenbendazole, and ivermectin in swine with induced intestinal nematode infections.

Anthelmintic efficacies of dichlorvos, fenbendazole, and ivermectin were compared in specific-pathogen-free crossbred weanling pigs inoculated with Ascaris suum, Trichuris suis, and Oesophagostomum dentatum. On postinoculation day (PID) 50, 24 pigs in each treatment group were treated orally with 43 mg of dichlorvos/kg of body weight, 3 X 3 mg of fenbendazole/kg, or 300 micrograms of ivermectin/kg, SC. Twenty-four pigs were not treated. On posttreatment day 7 (PID 57), 12 pigs from each treatment group (phase I) were slaughtered, and the anthelmintic efficacy of each treatment was determined. Efficacies against A suum, T suis, and O dentatum, respectively, were: dichlorvos, 100%, 99.9%, and 100%; fenbendazole, 100%, 99.8%, and 100%; and ivermectin, 98.7%, 53.9%, and 87.6%. Weight gains and feed conversions of the remaining pigs were monitored until they reached market weight (phase II). The average weight gains (kg) and feed conversions (kg of feed/kg of gain) at posttreatment day 81 (PID 131), respectively, were: 73.6 and 3.44 for nontreated controls, 78.9 and 3.31 for dichlorvos-treated pigs, 72.1 and 3.36 for fenbendazole-treated pigs, and 74 and 3.48 for ivermectin-treated pigs. Differences in average weight gains and feed conversions were not significant (P greater than 0.05).

Activity of organophosphorus compounds against oral stages of gasterophilus intestinalis and Gasterophilus nasalis.

Controlled tests of the efficacy of bot-active compounds, dichlorvos, trichlorfon, trichlorfon butonate, and carbon disulfide on the larvae of Gasterophilus intestinalis and Gasterophilus nasalis during their migratory period in the tissue of the mouth of horses and ponies were completed on experimentally induced and naturally acquired infections. Against the experimental parasitisms in pony foals, the resin-pellet formulation of dichlorvos given on the feed at the dose level of 37 mg/kg, 2 formulations of trichlorfon given by stomach tube at the dose level of 40 mg/kg, another of trichlorfon given on the feed, and trichlorfon butonate given intragastrically at the dose level of 43 mg/kg were 100% efficacious. Against naturally acquired parasitisms in horses, a broad-spectrum gel formulation of dichlorvos given intraorally at the dose level of 36 mg/kg was quite efficacious, whereas liquid carbon disulfide given by stomach tube at the dose level of 2.4 ml/45.45 kg was ineffective.

Activities of dichlorvos or disophenol against the hookworm (Uncinaria lucasi) and sucking lice of northern fur seal pups (Callorhinus ursinus) on St. Paul Island, Alaska.

One controlled and six critical tests were conducted in July, 1977 with northern fur seal pups (Callorhinus ursinus) to determine the efficacies of a single dose of dichlorvos capsules at 29.3 to 32.8 mg/kg, tablets at 10.5 to 11.5 mg/kg, or disophenol at 9.9 mg/kg given subcutaneously against natural infections of adult Uncinaria lucasi. In the controlled test, 20 pups were treated and 10 pups were nontreated. Removal of hookworms in this test was 99% for five pups receiving dichlorvos capsules, 99% for five pups receiving dichlorvos tablets, and 77% for 10 pups receiving disophenol. Also, both formulations of dichlorvos and the formulation of disophenol were highly active against natural infestations of two species of sucking lice (Proechinophthirus fluctus and Antarctopthirus callorhini). In critical tests with four pups treated with dichlorvos capsules at 28.6 to 30.6 mg/kg, removal of hookworms was uniformly 100%. Disophenol at 9.9 mg/kg removed 100% and less than 1% of hookworms in two pups, respectively, in critical tests.

A field evaluation of pro-benzimidazole, benzimidazole, and non-benzimidazole anthelmintics in horses.

The effectiveness of 1 pro-benzimidazole (pro-BZD) drug, 3 benzimidazole (BZD) drugs, and 3 non-benzimidazole (non-BZD) drugs in keeping fecal egg counts below 50 eggs per gram 2 and 4 weeks after treatment at 6-week intervals was compared in groups of brood mares and yearlings at 2 Standardbred farms. In a preliminary study (December 1978 to April 1979) as well as major study (April to November 1979), horses were kept in the same groups in the same areas. In the major study, treatments were arranged in a Latin square design. On farm 1, which had a history of repeated use of BZD drug since 1964, the non-BZD drugs, dichlorvos and pyrantel pamoate, rated 83%-100% in their ability to suppress egg counts below 50 eggs per gram. They were significantly better (P less than 0.05) than pro-BZD (febantel) or BZD (cambendazole, fenbendazole, mebendazole) drugs, which rated 13%-58%. Phenothiazine-piperazine-carbon disulfide rated 60%-77% on farm 1 and also was significantly better (P less than 0.05) than pro-BZD or BZD drugs. On farm 2, which had a history of limited use BZD drugs, there was no significant difference between the 3 classes of anthelmintics, which all rated between 67% and 100%. Results of larval culture showed small strongyles to be the major source of high egg counts. In all groups of horses, irrespective of the treatment, there was a marked increase in fecal egg counts by 6 weeks after treatment.

Efficacy of dichlorvos administered orally in single and repeated doses for removal of canine whipworms.

A single dose of dichlorvos (2,2-dichlorovinyl dimethyl phosphate) was administered orally at a dosage of 30 mg/kg to 19 dogs naturally infected with Trichuris vulpis and to 13 dogs experimentally infected with T vulpis. Based on the presence or absence of whipworm eggs in the feces, 10 to 14 days after treatment, dogs were either killed and the number of remaining worms counted, or the dogs were given a 2nd treatment. After the initial treatment, 18 dogs had a mean of 0.5 worms (SD +/- 0.5) remaining, and 14 dogs had a mean of 55 worms (SD +/- 85) remaining. After these 14 dogs were given a 2nd treatment, the number of womrs remaining decreased to a mean of 14 (SD +/- 28). Although a high degree of efficacy was attained in 56% of the dogs after the 1st dose, the data suggested that additional treatment may often be necessary.

Caval syndrome in a Dirofilaria immitis-infected dog treated with dichlorvos.

In the dog of this report, lesions found were compatible with death attributable to acute circulatory collapse induced by caval syndrome and compounded by microfilarial death. Hepatic centrilobular hemorrhage and necrosis were suggestive of circulatory collapse, renal hemosiderosis was suggestive of disseminated intravascular coagulopathy, and multifocal subacute hepatic inflammation associated with microfilariae was similar to lesions attributed to microfilarial death. Treatment with dichlorvos may have precipitated these events. Previous descriptions of dichlorvos toxicity in microfilaremic dogs have suggested that death is attributable to shock, but pathogenic mechanisms have not been established. Although generalizations from a single case must be made with caution, lesions in this dog suggest that toxic effects may be mediated through effects on adult and larval heartworms.

Experimental chemotherapy in horses infected with benzimidazole-resistant small strongyles.

The presence of benzimidazole-resistant strains of equine small strongyles was confirmed in horses at two properties in north west England by a series of faecal egg counts and larval cultures after treatment with mebendazole. A trail formulation of mebendazole in combination with piperazine citrate gave greater reductions in faecal egg counts than mebendazole alone but was much less effective than pyrantel embonate or dichlorvos.

Utilization of dichlorvos and trichlorfon in salmonid farming in Norway during 1981-1988.

The main objectives of this investigation were to quantify the use of dichlorvos and trichlorfon in the treatment of salmon lice infestations, to evaluate the prescribing of these drugs, and to estimate possible changes in the salmon lice problem by use of drug statistics. This study has shown that the use of trichlorfon increased from 4.9 tons in 1981 to 28.3 tons in 1985. This figure declined to 3.2 tons in 1988. The use of dichlorvos increased from 0.3 tons in 1986 to 3.2 tons in 1988. The change in the prescribing from trichlorfon to dichlorvos has dramatically reduced the pollution caused by these substances in the marine environment. Moreover, if necessary safety rules are observed, this change reduces the exposure of the workers on fish farms to these drugs, and also reduces the possibilities of intoxications of the fish during the treatment procedure. The sales figures of dichlorvos and trichlorfon, related to the calculated biomass of farmed salmonids in the sea, indicate a dramatic increase in the salmon lice problem.

Clinical use of dichlorvos (Nuvan) and trichlorfon (Neguvon) in the treatment of salmon louse, Lepeophtheirus salmonis. Compliance with the recommended treatment procedures.

Veterinarians representing one third of the Norwegian fish farms were asked about the clinical use of dichlorvos and trichlorfon by use of a questionnaire. A total of 45 veterinarians had experience in treatment of salmon lice with these organophosphates. Fourty-nine percent of the veterinarians reported that the fish farmers in their region solely used the recommended treatment equipment when delousing the fish, of these 1/4 always oxygenated the treatment solution. Repeated treatment were always prescribed by 24% of the veterinarians, while 44% did this occasionally. Of the 45 veterinarians 7% were often present and 44% were occasionally present at the fish farms in connection with the treatment. The answers showed that compliance with the recommended treatment procedures was unsatisfactory.

Antifeeding effect of several insecticidal formulations against Ctenocephalides felis on cats.

Evaluation of insecticidal activity of flea products is generally based on counting live fleas in the animal's coat 24 and 48 hours following artificial infestation. This approach, however, does not allow to specify whether the fleas have had the opportunity to bite and take a bloodmeal prior to their death. To address this question, 30 cats were alloted to six groups of five animals. Each cat was housed in a separate cage. At Day 0, each group of cats received a single treatment as follows: Group 1: spot-on application of imidacloprid: cats < 4 kg: 40 mg/cat, cats > or = 4 kg: 80 mg/cat (Advantage). Group 2: spot-on application of fipronil: 50 mg/cat (Frontline spot-on). Group 3: spray application of fipronil: 7.5 mg/kg b.w. (Frontline spray). Group 4: foam application of permethrin 40/60: 50 mg/kg b.w. (Defencat). Group 5: aerosol spray application of dichlorvos + fenitrothion: one second/kg b.w. (NuvanTop). Group 6: control group: cats were left untreated. One hour after treatment, each cat was infested with 50 unengorged young adult fleas, Ctenocephalides felis, deposited along the dorsal midline. One hour later, each cat was carefully combed using a fine-toothed comb (13 teeth/cm). Collected fleas were swatted to deteci blood in their abdomen. To the manufacturers respective product use instructions and efficacy claims, reeinfestations were made at Days 3, 7, 14 in all groups; at Days 21 and 30 in Groups 1, 2, 4, 6; at Days 35 and 42 in Groups 3 and 6. The cats were combed one hour after each reinfestation. The results indicate that the topical application of imidacloprid or fipronil does not prevent fleas from biting and feeding within the first hour after infestation prior to being killed while the topical application of dichlorvos/fenitrothion and permethrin let to a better than 80% decrease of the number of engorged fleas for three and seven days post treatment, respectively.

Pathological infection of thoroughbred horses with Gastrodiscus aegyptiacus.

Contrary to common belief, Gastrodiscus aegyptiacus can be pathogenic to horses. History of cases of a particular stud, necropsy findings, diagnosis, and successful treatment with hexachlorophene and with dichlorvos are recorded. The presence of eggs can be established by a special flotation technique.