Toxicology of Selected Pesticides, Drugs, and Chemicals
0195-5616/90 $0. 00
+ .20
lvermectin and Piperazine Toxicoses in Dogs and Cats
Randall A. Lovell, DVM, PhD*
Recently developed anthelmintics used in veterinary medicine generally are less toxic, more efficacious, and have wider spectrums of activity than those available previously. The toxicology of anthelmintics, however, has become more complex because of the number of formulations available and the variability in mechanisms of action and associated toxic effects. The Illinois Animal Poison Information Center (IAPIC) database was utilized in developing this article. Each IAPIC report involving adverse effects in dogs and cats following anthelmintic exposure between January 1, 1986, and August 10, 1988, was reviewed and only those assessed as toxicoses or suspected toxicoses are presented (Table 1). Although ivermectin (extralabel use) and piperazine had the greatest number of reports of toxicoses and suspected toxicoses, this should not be construed to mean that they represent the greatest hazard because the frequency of use of these and other anthelmintics were not quantified. A large majority of the IAPIC reports in dogs involving adverse effects after the administration of Heartgard were assessed as doubtful toxicoses.
IVERMECTIN Ivermectin, a mixture of 22,23-dihydro avermectin B1a (~80%) and B1b (::s20%), is produced by Streptomyces avermitilis, an actinomycete. I vermectin is a macrocyclic lactone disaccharide that is structurally similar to the milbemycins. 10 Ivermectin is active against nematodes and arthropods. 3• 5 • 10 In 1987, the drug was approved for use in dogs at monthly doses of 6 f.Lg/kg for the prevention of heartworm infection and it had been approved previously as an anthelmintic for use in cattle, horses, and swine at 200 or 300 f.Lg/kg. *Research Toxicologist, Ricerca, Inc, Toxicology and Animal Metabolism, Painesville, Ohio Veterinary Clinics of North America: Small Animal Practice-Val. 20, No. 2, March 1990
453
454
RANDALL A. LOVELL
Table 1. The 10 Anthelmintic(s), Anthelmintic Group(s), or Anthelmintic Combination(s) with the Greatest Number of Reports Assessed as Toxicoses and Suspected Toxicoses in Dogs and Cats by the IAPIC between january 1, 1986 and August 10, 1988 ANTHELMINTIC
lvermectin* Piperazine Diethylcarbamazine Toluene/dichlorophen Levamisole Benzimidazole carbamates (oxibendazole, mebendazole, fenbendazole, etc.) Pyrantel Organophosphorus compounds (trichlorfon, dichlorvos) Butamisole N-butyl chloride
NO. DOG REPORTS
150 (24)t
NO. CAT REPORTS
40
47
83
82 (13)t 41 23 23
5 51 2 1
20 15
1 4
10
4 5
7
*These ivermectin data do not include any reports of adverse effects associated with Heartgard. tNumber of additional reports with adverse effects attributed to the microfilaricidal activity of ivermectin or diethylcarbamazine.
Mechanism of Action Avermectin B1 stimulates gamma-aminobutyric acid (GABA)-mediated chloride conductance and appears to block interneuron-motorneuron transmission in nematodes 49 and neuromuscular transmission in arthropods. 31 Moreover, picrotoxin, a GABA antagonist, reverses the resistance changes produced by avermectin B1 • 31 · 49 Avermectin B1 appears to stimulate the release of GABA from nerve endings and enhance the binding of GABA to its receptor (Fig. 1). 60 • 72 • 105 Although avermectin B1 causes a marked and sustained increase of GABA release from rat brain synaptosomes, 72 it is less toxic to mammals than nematodes and arthropods. 10 In mammals, GABAergic neurons are found only in the central nervous system (CNS), 73 • 105 and ivermectin does not appear to cross the blood-brain barrier readily. 10
Pharmacokinetics Intravenously administered ivermectin (200 j.Lg/kg) in dogs had a short distributive phase, a large volume of distribution (2.4 Llkg), and a long terminal half-life in plasma (1.8 days). 55 The maximum avermectin B1a concentration in 10 male beagle dogs (9. 2-12.2 kg) administered 272 1-Lg of ivermectin (four 68 j.Lg tablets) after an overnight fast was 19.1 ng/ml at 3 hours. 52 Ivermectin plasma concentrations were not significantly different between sensitive and nonsensitive collies after oral (PO) administration of 100 j.Lg/kg. 102 In studies with tritium-labeled ivermectin (300-400 j.Lg/kg intraruminally, PO or subcutaneously [SC]) in cattle, sheep, swine, and rats, only 0.5-2% of the administered radioactivity was excreted in the urine regardless of the route of administration. The remainder of the radioactivity appeared in the feces. The highest tissue residues of radiolabel in all species occurred in the liver and fat, and the major hydrolysis product in both
IVERMECTIN AND PIPERAZINE TOXICOSES IN DOGS AND CATS
455
Acetylcholine increases sodium conductance. Physostigmine--inhibits cholinesterase which increases the persistence and effects of acetylcholine.
lvermectin increases presynaptic release and postsynaptic binding of GABA. GABA increases chloride conductance. Picrotoxin blocks binding of GABA. Low doses of lvermectin
(Stimulation via depolarization due to inrush of sodium)
excluded by blood brain barrier.
Figure l. Mechanisms of action of ivermectin presynaptically and postsynaptically at gamma-aminobutyric acid (GABA)-mediated chloride channels. The effects of GABA most commonly counterbalance the effects of acetylcholine (ACh).
tissues was the 24-hydroxymethyl metabolite. The brain of male rats contained the lowest maximum ivermectin concentrations (20 ppb) and these peaked between 2 and 12 hours after an intravenous (IV) dose of 300 ~J-g/kg. 10, 47
Genetic and Reproductive Effects lvermectin was nonmutagenic in the Ames microbiological assay and in a mammalian assay using a mouse lymphoma cell line. Similarly, ivermectin did not cause unscheduled DNA synthesis in a human fibroblast cell culture. 88 No ivermectin-related effects in bitches or their fetuses were observed when pregnant bitches were given ivermectin in sesame oil orally at 500 1-1g/kg on four occasions during gestation (days 5, 15, 25, and 35; or days 10, 20, 30, and 40). Bitches given repeated oral doses of ivermectin at 600 1-1glkg at least twice, at monthly intervals prior to breeding, and then on days 10, 25, and 45 of gestation, and again at least once after whelping exhibited no adverse effects on reproduction. 63 • 88 Similarly, ivermectin had no adverse effects on fertility, spermatogenesis, or reproductive performance of male beagle dogs when administered monthly for eight treatments in oral doses of 600 1-1g/kg. 21 Adverse Clinical Effects
Studies in Dogs. Acute and subacute toxicity studies using various formulations of ivermectin in non-collie dogs have documented a wide oral margin of safety. A single oral dose of ivermectin in sesame oil at 2500 !J-g/ kg produced only mydriasis. A single subcutaneous dose of the micellar
456
RANDALL
A.
LOVELL
formulation of ivermectin in excess of 9400 ~J-g/kg resulted in mydriasis, hypersalivation, ataxia, depression, and death. No treatment-related effects were observed in dogs dosed orally for 14 weeks with ivermectin in sesame oil at 500 !J-g/kg/day. 11 • 87 lvermectin toxicoses have been reported repeatedly in collie dogs at suspected doses of 100-500 ~J-g/kg* and appear to result from greater penetration of the blood-brain barrier than in other breeds. 73 Injection of 1 ml of lvomec (10,000 1-Lg ivermectin) in a 2-year-old collie bitch caused mydriasis, ataxia, depression, apparent blindness, spasmodic movements of the neck and limbs when handled, no response to sound, bradycardia, slow respiration rate, and coma for 7 weeks. 26 Seven of 14 collies exhibited seizure-like activity, nonresponsiveness, recumbency, and coma after a 200 ~J-g/kg oral dose of ivermectin, while 3 of 14 collies exhibited hypersalivation/ drooling, vomiting, confusion, ataxia, and tremors after 100 ~J-g/kg. 67 Increased susceptibility to ivermectin is not present in all individuals of the collie breed and is not related to sex, collie-eye anomaly, or hair coat type. 67, 73, 88 A suspected ivermectin toxicosis was also reported in a 2.5-year-old male old English sheepdog-type dog following oral dosing at 150 ~J-g/kg. Severe hindlimb ataxia, hypersalivation, hyperventilation, recumbency, miosis, absence of menace response, ventromedial to ventrolateral strabismus, bradycardia, and periods of deep sleep were observed. 41 Adverse reactions have been reported in several studies following ivermectin treatment of dogs with circulating microfilariae (D. immitis). Although these reactions (anorexia, lethargy, pyrexia, and/or vomitingf· 45 · 46 • 58 · 71 · 82 · 97 have generally been mild and transitory, shock (pale mucous membranes, rapid respiration, weakness, weak rapid pulse, and/or ataxia) also has occurred, often within 5 hours of dosing. 45 · 46 Reluctance and/or refusal to move and noticeable swelling and warmth in the carpi were noted within 14 hours after subcutaneous administration of ivermectin in a 10-month-old male Doberman infected with Sarcoptes scabei var. canis. 50 Studies in Cats. Oral or subcutaneous administration of single or multiple ivermectin doses at 200 to 1330 ~J-g/kg are well tolerated in cats. 6 · 13 • 14 • 30 · 51 • 74 · 75 Oral administration of presumably large doses of equine product has, however, resulted in vocalization, extreme ataxia (dragging hindlimbs), disorientation, anorexia, dementia (crying, biting, scratching), whole body tremors, mydriasis, apparent blindness (walking into walls, circling, head pressing, bilateral loss of menace reflex, slow and incomplete pupillary light reflex), bradycardia, hypothermia, very slow respiratory rate, pale mucous membranes, loss of most reflexes, coma, and/or death. 42 • 79 IAPIC Data lvermectin was the anthelmintic with the greatest number of reports assessed as toxicoses and suspected toxicoses in dogs (see Table 1). Ivermectin toxicosis should be suspected in dogs (non-collie-related breeds) or cats if one or more of the following signs occur within 24 hours after an *References 4, 26, 48, 67, 73, 86, 88, 90, 92, 98.
IVERMECTIN AND PIPERAZINE TOXICOSES IN
Docs AND
457
CATS
estimated exposure to > 1000 fLg/kg (Table 2): ataxia, abnormal behavior, tremor, mydriasis, lethargy, weakness/recumbency, apparent blindness, hypersalivation/drooling (dog only), and/or coma (Table 3). Adverse effects attributed to microfilaria die-off should be suspected in adult dogs exhibiting shock, dyspnea, and/or vomiting within 24 hours (usually 110 and :S165 mg/kg >165 mg/kg Unknown
17 18 6 21 11
DOGS
%of All Reports 12.0 20.5 21.7 7.2 25.3 13.5
lO
No. Times Reported
%of All Reports
5 15 5 2
10.6 31.9 10.6 4.3 21.3 21.3
lO lO
CATS
ESTIMATED ONSET INTERVALt
:S2 hr >2 hr and :s6 hr >6 hr and :s12 hr > 12 hr and :S24 hr Not available
DOGS
No. Times Reported
%of All Reports
No. Times Reported
%of All Reports
12 18 36 16 1
14.5 21.7 43.4 19.3 1.2
9 8 19 11 0
19.1 17.0 40.4 23.4 0.0
*Forty cat and 16 dog reports involved multiple daily piperazine exposures (maximum number of known doses = three) that were administered within the past 7 days. Reports with adverse effects at estimated daily oral dose(s) of 20 to 110 mg/kg in cats were described more often following single piperazine exposure than after multiple exposures. t After the most recent exposure.
dogs or cats precludes their use. Although death was described in two reports (both involving seizuring dogs), most dogs and cats seem to recover uneventfully in a few days with detoxification measures and good symptomatic and supportive care. The acute oral LD 50 of piperazine adipate in male mice (11.4 g/kg) 19 may cause underestimation of the potential for neurotoxic effects from piperazine in carnivores, given that adverse effects in dogs and cats are not uncommonly reported at :SllO mg/kg. Piperazine should be used with added caution in cats and dogs with preexisting kidney and/or CNS lesions. In all cats and dogs, exposure to piperazine medicated water intended for other species should be prevented. If a piperazine product intended for swine, cattle, or horses is used in dogs and cats, one should be certain to adjust the dose downward to account for the twofold difference in therapeutic dosage between these species (llO versus 45-65 mg/kg). SUMMARY Review of all reports involving anthelmintics in dogs and cats to the IAPIC between January 1, 1986 and August 10, 1988, revealed that ivermectin (extra-label use) and piperazine accounted for over 50% of the calls assessed as toxicoses and suspected toxicoses. Both ivermectin and
464
RANDALL
A.
LOVELL
piperazine are gamma-aminobutyric acid (GABA) agonists and their major effects appear to be on the central nervous system. lvermectin toxicoses at estimated doses of ~100-
0195-5616/90 $0. 00
+ .20
lvermectin and Piperazine Toxicoses in Dogs and Cats
Randall A. Lovell, DVM, PhD*
Recently developed anthelmintics used in veterinary medicine generally are less toxic, more efficacious, and have wider spectrums of activity than those available previously. The toxicology of anthelmintics, however, has become more complex because of the number of formulations available and the variability in mechanisms of action and associated toxic effects. The Illinois Animal Poison Information Center (IAPIC) database was utilized in developing this article. Each IAPIC report involving adverse effects in dogs and cats following anthelmintic exposure between January 1, 1986, and August 10, 1988, was reviewed and only those assessed as toxicoses or suspected toxicoses are presented (Table 1). Although ivermectin (extralabel use) and piperazine had the greatest number of reports of toxicoses and suspected toxicoses, this should not be construed to mean that they represent the greatest hazard because the frequency of use of these and other anthelmintics were not quantified. A large majority of the IAPIC reports in dogs involving adverse effects after the administration of Heartgard were assessed as doubtful toxicoses.
IVERMECTIN Ivermectin, a mixture of 22,23-dihydro avermectin B1a (~80%) and B1b (::s20%), is produced by Streptomyces avermitilis, an actinomycete. I vermectin is a macrocyclic lactone disaccharide that is structurally similar to the milbemycins. 10 Ivermectin is active against nematodes and arthropods. 3• 5 • 10 In 1987, the drug was approved for use in dogs at monthly doses of 6 f.Lg/kg for the prevention of heartworm infection and it had been approved previously as an anthelmintic for use in cattle, horses, and swine at 200 or 300 f.Lg/kg. *Research Toxicologist, Ricerca, Inc, Toxicology and Animal Metabolism, Painesville, Ohio Veterinary Clinics of North America: Small Animal Practice-Val. 20, No. 2, March 1990
453
454
RANDALL A. LOVELL
Table 1. The 10 Anthelmintic(s), Anthelmintic Group(s), or Anthelmintic Combination(s) with the Greatest Number of Reports Assessed as Toxicoses and Suspected Toxicoses in Dogs and Cats by the IAPIC between january 1, 1986 and August 10, 1988 ANTHELMINTIC
lvermectin* Piperazine Diethylcarbamazine Toluene/dichlorophen Levamisole Benzimidazole carbamates (oxibendazole, mebendazole, fenbendazole, etc.) Pyrantel Organophosphorus compounds (trichlorfon, dichlorvos) Butamisole N-butyl chloride
NO. DOG REPORTS
150 (24)t
NO. CAT REPORTS
40
47
83
82 (13)t 41 23 23
5 51 2 1
20 15
1 4
10
4 5
7
*These ivermectin data do not include any reports of adverse effects associated with Heartgard. tNumber of additional reports with adverse effects attributed to the microfilaricidal activity of ivermectin or diethylcarbamazine.
Mechanism of Action Avermectin B1 stimulates gamma-aminobutyric acid (GABA)-mediated chloride conductance and appears to block interneuron-motorneuron transmission in nematodes 49 and neuromuscular transmission in arthropods. 31 Moreover, picrotoxin, a GABA antagonist, reverses the resistance changes produced by avermectin B1 • 31 · 49 Avermectin B1 appears to stimulate the release of GABA from nerve endings and enhance the binding of GABA to its receptor (Fig. 1). 60 • 72 • 105 Although avermectin B1 causes a marked and sustained increase of GABA release from rat brain synaptosomes, 72 it is less toxic to mammals than nematodes and arthropods. 10 In mammals, GABAergic neurons are found only in the central nervous system (CNS), 73 • 105 and ivermectin does not appear to cross the blood-brain barrier readily. 10
Pharmacokinetics Intravenously administered ivermectin (200 j.Lg/kg) in dogs had a short distributive phase, a large volume of distribution (2.4 Llkg), and a long terminal half-life in plasma (1.8 days). 55 The maximum avermectin B1a concentration in 10 male beagle dogs (9. 2-12.2 kg) administered 272 1-Lg of ivermectin (four 68 j.Lg tablets) after an overnight fast was 19.1 ng/ml at 3 hours. 52 Ivermectin plasma concentrations were not significantly different between sensitive and nonsensitive collies after oral (PO) administration of 100 j.Lg/kg. 102 In studies with tritium-labeled ivermectin (300-400 j.Lg/kg intraruminally, PO or subcutaneously [SC]) in cattle, sheep, swine, and rats, only 0.5-2% of the administered radioactivity was excreted in the urine regardless of the route of administration. The remainder of the radioactivity appeared in the feces. The highest tissue residues of radiolabel in all species occurred in the liver and fat, and the major hydrolysis product in both
IVERMECTIN AND PIPERAZINE TOXICOSES IN DOGS AND CATS
455
Acetylcholine increases sodium conductance. Physostigmine--inhibits cholinesterase which increases the persistence and effects of acetylcholine.
lvermectin increases presynaptic release and postsynaptic binding of GABA. GABA increases chloride conductance. Picrotoxin blocks binding of GABA. Low doses of lvermectin
(Stimulation via depolarization due to inrush of sodium)
excluded by blood brain barrier.
Figure l. Mechanisms of action of ivermectin presynaptically and postsynaptically at gamma-aminobutyric acid (GABA)-mediated chloride channels. The effects of GABA most commonly counterbalance the effects of acetylcholine (ACh).
tissues was the 24-hydroxymethyl metabolite. The brain of male rats contained the lowest maximum ivermectin concentrations (20 ppb) and these peaked between 2 and 12 hours after an intravenous (IV) dose of 300 ~J-g/kg. 10, 47
Genetic and Reproductive Effects lvermectin was nonmutagenic in the Ames microbiological assay and in a mammalian assay using a mouse lymphoma cell line. Similarly, ivermectin did not cause unscheduled DNA synthesis in a human fibroblast cell culture. 88 No ivermectin-related effects in bitches or their fetuses were observed when pregnant bitches were given ivermectin in sesame oil orally at 500 1-1g/kg on four occasions during gestation (days 5, 15, 25, and 35; or days 10, 20, 30, and 40). Bitches given repeated oral doses of ivermectin at 600 1-1glkg at least twice, at monthly intervals prior to breeding, and then on days 10, 25, and 45 of gestation, and again at least once after whelping exhibited no adverse effects on reproduction. 63 • 88 Similarly, ivermectin had no adverse effects on fertility, spermatogenesis, or reproductive performance of male beagle dogs when administered monthly for eight treatments in oral doses of 600 1-1g/kg. 21 Adverse Clinical Effects
Studies in Dogs. Acute and subacute toxicity studies using various formulations of ivermectin in non-collie dogs have documented a wide oral margin of safety. A single oral dose of ivermectin in sesame oil at 2500 !J-g/ kg produced only mydriasis. A single subcutaneous dose of the micellar
456
RANDALL
A.
LOVELL
formulation of ivermectin in excess of 9400 ~J-g/kg resulted in mydriasis, hypersalivation, ataxia, depression, and death. No treatment-related effects were observed in dogs dosed orally for 14 weeks with ivermectin in sesame oil at 500 !J-g/kg/day. 11 • 87 lvermectin toxicoses have been reported repeatedly in collie dogs at suspected doses of 100-500 ~J-g/kg* and appear to result from greater penetration of the blood-brain barrier than in other breeds. 73 Injection of 1 ml of lvomec (10,000 1-Lg ivermectin) in a 2-year-old collie bitch caused mydriasis, ataxia, depression, apparent blindness, spasmodic movements of the neck and limbs when handled, no response to sound, bradycardia, slow respiration rate, and coma for 7 weeks. 26 Seven of 14 collies exhibited seizure-like activity, nonresponsiveness, recumbency, and coma after a 200 ~J-g/kg oral dose of ivermectin, while 3 of 14 collies exhibited hypersalivation/ drooling, vomiting, confusion, ataxia, and tremors after 100 ~J-g/kg. 67 Increased susceptibility to ivermectin is not present in all individuals of the collie breed and is not related to sex, collie-eye anomaly, or hair coat type. 67, 73, 88 A suspected ivermectin toxicosis was also reported in a 2.5-year-old male old English sheepdog-type dog following oral dosing at 150 ~J-g/kg. Severe hindlimb ataxia, hypersalivation, hyperventilation, recumbency, miosis, absence of menace response, ventromedial to ventrolateral strabismus, bradycardia, and periods of deep sleep were observed. 41 Adverse reactions have been reported in several studies following ivermectin treatment of dogs with circulating microfilariae (D. immitis). Although these reactions (anorexia, lethargy, pyrexia, and/or vomitingf· 45 · 46 • 58 · 71 · 82 · 97 have generally been mild and transitory, shock (pale mucous membranes, rapid respiration, weakness, weak rapid pulse, and/or ataxia) also has occurred, often within 5 hours of dosing. 45 · 46 Reluctance and/or refusal to move and noticeable swelling and warmth in the carpi were noted within 14 hours after subcutaneous administration of ivermectin in a 10-month-old male Doberman infected with Sarcoptes scabei var. canis. 50 Studies in Cats. Oral or subcutaneous administration of single or multiple ivermectin doses at 200 to 1330 ~J-g/kg are well tolerated in cats. 6 · 13 • 14 • 30 · 51 • 74 · 75 Oral administration of presumably large doses of equine product has, however, resulted in vocalization, extreme ataxia (dragging hindlimbs), disorientation, anorexia, dementia (crying, biting, scratching), whole body tremors, mydriasis, apparent blindness (walking into walls, circling, head pressing, bilateral loss of menace reflex, slow and incomplete pupillary light reflex), bradycardia, hypothermia, very slow respiratory rate, pale mucous membranes, loss of most reflexes, coma, and/or death. 42 • 79 IAPIC Data lvermectin was the anthelmintic with the greatest number of reports assessed as toxicoses and suspected toxicoses in dogs (see Table 1). Ivermectin toxicosis should be suspected in dogs (non-collie-related breeds) or cats if one or more of the following signs occur within 24 hours after an *References 4, 26, 48, 67, 73, 86, 88, 90, 92, 98.
IVERMECTIN AND PIPERAZINE TOXICOSES IN
Docs AND
457
CATS
estimated exposure to > 1000 fLg/kg (Table 2): ataxia, abnormal behavior, tremor, mydriasis, lethargy, weakness/recumbency, apparent blindness, hypersalivation/drooling (dog only), and/or coma (Table 3). Adverse effects attributed to microfilaria die-off should be suspected in adult dogs exhibiting shock, dyspnea, and/or vomiting within 24 hours (usually 110 and :S165 mg/kg >165 mg/kg Unknown
17 18 6 21 11
DOGS
%of All Reports 12.0 20.5 21.7 7.2 25.3 13.5
lO
No. Times Reported
%of All Reports
5 15 5 2
10.6 31.9 10.6 4.3 21.3 21.3
lO lO
CATS
ESTIMATED ONSET INTERVALt
:S2 hr >2 hr and :s6 hr >6 hr and :s12 hr > 12 hr and :S24 hr Not available
DOGS
No. Times Reported
%of All Reports
No. Times Reported
%of All Reports
12 18 36 16 1
14.5 21.7 43.4 19.3 1.2
9 8 19 11 0
19.1 17.0 40.4 23.4 0.0
*Forty cat and 16 dog reports involved multiple daily piperazine exposures (maximum number of known doses = three) that were administered within the past 7 days. Reports with adverse effects at estimated daily oral dose(s) of 20 to 110 mg/kg in cats were described more often following single piperazine exposure than after multiple exposures. t After the most recent exposure.
dogs or cats precludes their use. Although death was described in two reports (both involving seizuring dogs), most dogs and cats seem to recover uneventfully in a few days with detoxification measures and good symptomatic and supportive care. The acute oral LD 50 of piperazine adipate in male mice (11.4 g/kg) 19 may cause underestimation of the potential for neurotoxic effects from piperazine in carnivores, given that adverse effects in dogs and cats are not uncommonly reported at :SllO mg/kg. Piperazine should be used with added caution in cats and dogs with preexisting kidney and/or CNS lesions. In all cats and dogs, exposure to piperazine medicated water intended for other species should be prevented. If a piperazine product intended for swine, cattle, or horses is used in dogs and cats, one should be certain to adjust the dose downward to account for the twofold difference in therapeutic dosage between these species (llO versus 45-65 mg/kg). SUMMARY Review of all reports involving anthelmintics in dogs and cats to the IAPIC between January 1, 1986 and August 10, 1988, revealed that ivermectin (extra-label use) and piperazine accounted for over 50% of the calls assessed as toxicoses and suspected toxicoses. Both ivermectin and
464
RANDALL
A.
LOVELL
piperazine are gamma-aminobutyric acid (GABA) agonists and their major effects appear to be on the central nervous system. lvermectin toxicoses at estimated doses of ~100-
