Psychotropic drugs in acute intermittent porphyria.

Acute intermittent porphyria is one of a group of metabolic diseases called the porphyrias that may lead to symptoms of the central nervous system during an acute exacerbation. Certain drugs such as barbiturates are known to precipitate attacks of acute intermittent porphyria, but unfortunately there is little information regarding the safety of many psychotropic drugs in this disorder, especially the newer antidepressants and atypical antipsychotics. We report a case of an elderly patient with acute intermittent porphyria who was treated with a variety of psychotropic agents for a severe depression with psychotic features. Although many of the agents did not improve the psychiatric status of the patient, all the drugs were tolerated without precipitating an episode of acute intermittent porphyria. To our knowledge, this is the first report of the safe use of sertraline, venlafaxine, olanzapine, risperidone, clozapine, buspirone, trazodone, lorazepam, and clonazepam in a patient with documented acute intermittent porphyria. Our report also supports the safety of trifluoperazine. Although response and sensitivity to drugs may vary greatly among patients with this disorder, clinicians may want to consider the possibility of the above drugs to treat psychiatric symptoms in patients with acute intermittent porphyria.

Eprinomectin: a novel avermectin for use as a topical endectocide for cattle.

Eprinomectin (MK-397 or 4"-epi-acetylamino-4"-deoxy-avermectin B1) is a novel avermectin selected for development as a topical endectocide for all cattle, including lactating dairy cows. Herein, we show its anthelmintic, insecticidal and miticidal activity. To determine its anthelmintic capabilities, eprinomectin was tested topically on Jersey calves at 0.08, 0.2, or 0.5 mg kg-1 in a probe formulation against experimental infections of adult Haemonchus placei, ostertagia ostertagi, Trichostrongylus axei, T. colubriformis, Cooperia oncophora, C. punctata, Nematodirus helvetianus, Oesophagostomum radiatum and Dictyocaulus viviparus. Eprinomectin removed > or = 99% and > or = 98% of the adult stage of every species at the 0.5 and 0.2 mg kg-1 dosage levels, respectively. The lowest dosage (0.08 mg kg-1) produced maximal or near maximal efficacy against most of the adult endoparasites with the exception of T. colubriformis (87%) and C. oncophora (88%). In a separate test, eprinomectin was evaluated topically against the immature stages of species at the same dosages. Results showed > or = 99% and > or = 98% removal of the immature stages of each species at the 0.5 and 0.2 mg kg-1 dosage levels, respectively. The 0.08 mg kg-1 dosage maintained > or = 97% efficacy against 6 species with reduced activity against H. placei (42%) and N. helvetianus (66%). For ectoparasites, eprinomectin was tested topically at 0.16, 0.24, 0.32 or 0.5 mg kg-1 on mixed breed cattle naturally infested with the sucking louse, Linognathus vituli. Complete elimination of lice at all dosages was observed by day 14. Topical delivery of eprinomectin at 0.16, 0.24, 0.32 or 0.5 mg kg-1 to Holstein calves experimentally challenged with horn fly, Haematobia irritans, produced 100% efficacy to challenge by week 2 post-treatment in all dosages groups and 94% and 99% efficacy to challenge at the 0.32 and 0.5 mg kg-1 dosage groups, respectively, at week 4. Topical delivery of eprinomectin at 0.16, 0.24 or 0.5 mg kg-1 to Deutsches Fleckvieh cattle infested with mange mites, Chorioptes bovis, produced > or = 95% control at all dosages levels by day 14 post-treatment and was maintained at or near this efficacious level for the 6-week duration of the trial. No adverse reaction was observed in any animal in any of these tests. In summary, these experimental data indicate that eprinomectin is an excellent broad-spectrum endectocide for cattle and is suitable for topical delivery.

Quantitative studies on aluminum deposition and its effects on neurofilament protein expression and phosphorylation, following the intraventricular administration of aluminum maltolate to adult rabbits.

The deposition of aluminum (Al) in the brain and spinal cord of adult male New Zealand white rabbits was monitored following the intraventricular administration of Al maltolate. Although decreasing concentrations of Al were observed from the injection site (approximately 10 micrograms/g dry tissue) to the lumbar cord (2.1 micrograms/g), argyrophilic tangles were present in the perikarya and proximal neurites of neurons as far distal as the lumbar and sacral cord areas. Quantitative immunoblot studies of the three neurofilament protein isoforms failed to detect changes resulting from Al maltolate treatment. Similarly no significant alterations in the total phosphate content of these cytoskeletal proteins were observed. Lastly, on Northern blots, the expression of genes encoding for the 200 kDa and 68 kDa neurofilament proteins also was unaffected by Al maltolate treatment.

Anthelmintic activity of paraherquamide in dogs.

Paraherquamide, an oxindole alkaloid metabolite of Penicillium paraherquei and Penicillium charlesii, was tested against the common gastrointestinal nematodes of dogs at a single oral dosage of 0.5, 1.0, or 2.0 mg kg-1. Efficacy was poor (less than 85%) against Ancylostoma caninum, Uncinaria stenocephala, Toxascaris leonina, Trichuris vulpis, and Strongyloides stercoralis at the low- and mid-dosage levels. At the high dosage level, good efficacy (91%) was observed only against S. stercoralis. Adverse reactions were observed in all dogs at every dosage level and included depression, ataxia, and protrusion of the nictitating membrane.

Efficacy of ivermectin in a beef-based chewable formulation against Ancylostoma caninum and Uncinaria stenocephala in dogs.

The effective dosage of a chewable formulation of ivermectin was determined in 35 young dogs with induced infections of Ancylostoma caninum and Uncinaria stenocephala. Dogs were inoculated with these parasites and held until the infections were patent. Within each of 7 replicates, dogs were allocated randomly to 1 of 5 treatment groups: vehicle control, or ivermectin at 6, 12, 18, or 24 micrograms/kg. Chewable treatments were tailored to body weight. Seven or 8 days after treatment, parasites were recovered using standard techniques. All 7 controls had adult A. caninum (geometric mean = 35.5) and U. stenocephala (geometric mean = 82.6). Against A. caninum, the efficacy of ivermectin was 52%, 98%, 95%, and 97% at 6, 12, 18, and 24 micrograms/kg, respectively. The statistical model that best described the dose response was linear to 12 micrograms/kg with a plateau thereafter. Using this model, the estimated reduction from the predicted control mean was 97.2%; the estimated dose to eliminate 90% of the worms (ED90) was 8.4 micrograms/kg, and the ED95 was 10.5 micrograms/kg. Against U. stenocephala, the dose response was linear in the range studied, with an ED90 of 20.8 micrograms/kg; it was estimated that 93.2% of the worms would be eliminated.

An evaluation of ivermectin in the treatment of sarcoptic mange in dogs.

A colony of mixed-breed dogs (n = 298) naturally infested with Sarcoptes scabiei was treated, twice, with 200 micrograms of ivermectin/kg of body weight subcutaneously at 14-day intervals. After the initial injection, positive skin scrapings from 20 treated dogs decreased from 7 to 1 and the degree of pruritus decreased. In contrast, positive skin scrapings from 22 nontreated dogs increased from 10 to 14, and there was an additional deterioration in the condition of the skin and an increase in the degree of pruritus. Complete control was noticed in all treated dogs by posttreatment day 28 (14 days after a 2nd injection) based on negative skin scrapings.

Ivermectin plasma concentrations in collies sensitive to ivermectin-induced toxicosis.

Five Collies sensitive to toxic effects of ivermectin and 7 nonsensitive Collies were given 100 micrograms of ivermectin/kg of body weight, PO. Blood samples were collected from each dog before treatment; at posttreatment hours 1, 2, 3.5, 5, and 8; and at posttreatment days 1, 2, 4, 7, 14, and 21. Each sample was assayed for ivermectin concentration, and statistical analyses were performed on the resulting plasma concentration data to determine differences in absorption and clearance of drugs between the 2 groups. Variables measured were area under the curve (using the trapezoidal rule), peak plasma concentration, and the time to peak concentration. Differences between sensitive and nonsensitive Collies for variables analyzed were not significant (P greater than 0.05).

Clinical observations in collies given ivermectin orally.

An oral liquid form of ivermectin was administered to 14 purebred Collies (12 rough coated, 2 smooth coated). All Collies were given ivermectin at dosages of 100 and then 200 micrograms/kg of body weight. Three of the dogs developed mild clinical signs of toxicosis (salivation, vomiting, confusion, ataxia, and tremors) with the 100 micrograms/kg dosage. After the 200 micrograms/kg dosage, 7 dogs (including 1 smooth-coated Collie) developed severe toxicosis (seizure-like activity, recumbency, nonresponsiveness, and coma). Because dogs that developed severe toxicosis were not retreated, only the 7 remaining dogs were given ivermectin at 600 micrograms/kg. Severe toxic signs were not observed in the dogs given the 600 micrograms/kg dosage, and only 1 of these 7 dogs developed severe toxicosis when given ivermectin at 2,500 micrograms/kg. Dogs that developed severe toxicosis were given supportive care while in the comatose state. All dogs recovered completely. The results indicated that Collies (including the smooth-coated Collies) have a wide range of sensitivity to ivermectin-induced toxicosis.

Reproductive evaluation of male beagles and the safety of ivermectin.

Ivermectin had no adverse effects on spermatogenesis, fertility, or reproductive performance of Beagle dogs when administered orally at 600 micrograms/kg (0.6 mg/kg) of body weight monthly for 8 treatments. Semen was collected every 3 days from 28 days before treatment began until 83 days thereafter from 6 ivermectin-treated Beagles and 6 similar water-treated controls (38 collections/dog). All dogs were then bred to 2 nontreated bitches each; litter size, birth weights, and pup abnormalities and mortalities were evaluated. After all pups were whelped, each dog was euthanatized and necropsied, and the testis and epididymis were examined microscopically.