Albendazole sulphoxide kinetic disposition after treatment with different formulations in dogs

Dib, A., Palma, S., Suárez, G., Farías, C., Cabrera, P., Castro, S., Allemandi, D., Moreno, L., Lanusse, C., Sánchez Bruni, S. Albendazole sulphoxide kinetic disposition after treatment with different formulations in dogs. J. vet. Pharmacol. Therap. 34 , 136–141. New therapeutic strategies based on the search of alternative formulations of albendazole (ABZ) and albendazole sulphoxide (ABZSO) are under current development to optimize posology and antiparasite efficacy in dogs. In an incomplete block design, nine dogs were randomly divided into three groups (n = 6). Treatments were carried out in two phases as follows. Phase I: Group I (treatment A), animals received ABZ at 25 mg/kg of conventional formulation. Group II (treatment B), dogs received 25 mg/kg of a modified poloxamer‐ABZ formulation. Group III (treatment C), animals were treated with ABZSO in equimolar amount to ABZ doses. After 21 days of wash‐out period the experiment was repeated (Phase II). Blood samples were collected over 24 h and subsequently analysed by high performance liquid chromatography. ABZSO and ABZSO₂ were the analytes recovered in plasma. Significant higher (P < 0.001) ABZSO area under the concentration–time curve (+500%) and C_max (+487%) values were obtained for the treatment C in comparison with treatments A and B. However, no statistical differences on pharmacokinetic parameters were found between formulations A and B. In conclusion, the enhanced plasma concentration profile obtained for the ABZSO formulation used in treatment C may contribute to optimize the anthelmintic control in dogs.     

Thiacetarsamide in dogs with Dirofilaria immitis: influence of decreased liver function on drug efficacy

The influence that decreased functional hepatic mass had on blood arsenic concentrations in dogs after they were treated with thiacetarsamide, on the clearance of indocyanine green (ICG), on arsenic concentrations in the heartworm (Dirofilaria immitis), and on drug efficacy was studied. Dogs which were partially hepatectomized and treated with thiacetarsamide (1.76 mg/kg, 2 times a day for 2 days) had a significantly (P less than 0.01) reduced ICG clearance, significantly (P less than 0.01) higher arsenic levels in heartworms, and a significantly (P less than 0.01) higher proportion of heartworms killed than did dogs that were sham operated and treated with thiacetarsamide or sham operated and untreated. There were no significant differences in blood arsenic (thiacetarsamide) concentrations 2 minutes after injection between hepatectomized and nonhepatectomized groups. More male heartworms were killed than were female worms in the thiacetarsamide-treated groups. Indocyanine green half-life was longer (12.43 minutes) in the hepatectomized group than it was in the nonhepatectomized sham-operated groups (5.09 and 4.94 minutes). Indocyanine green clearance rate was lower in the hepatectomized group (0.54 ml/min/kg) than that in the nonhepatectomized groups (1.36 and 1.56 ml/min/kg). A parallel seemed to exist between ICG and thiacetarsamide removal from the blood by the liver. This parallel also was suggested in the higher worm arsenic (thiacetarsamide) concentrations for the hepatectomized group vs that for nonhepatectomized groups. Apparently, the slower the removal of thiacetarsamide from the blood by the liver, the higher the worm arsenic level and, consequently, the higher the worm kill.     

Indocyanine green disposition in healthy dogs and dogs with mild, moderate, or severe dimethylnitrosamine-induced hepatic disease.

Disposition kinetics of indocyanine green (ICG) were used to evaluate hepatic function in healthy Beagles (group 1; n = 6) and Beagles with progressive hepatic disease induced by oral administration of dimethylnitrosamine, a hepatospecific toxin. Three classes of hepatic disease were defined by histologic features: mild (group 2; n = 5), moderate (group 3; n = 6), and severe (group 4; n = 5). Disposition of ICG was studied 3 weeks following the last dose of toxin. A rapid IV injection of 0.5 mg of ICG/kg was administered and serum samples were obtained at certain intervals during 60-minute periods. Serum ICG was analyzed by use of visible spectrophotometry. Disposition kinetics were determined from serum ICG concentrations vs 15- and 60-minute time curves and compared between one another and among groups. Data based on 60-minute time curves were not significantly different from those based on 15-minute curves. Area under the curve for ICG was greatest in group 3. Clearance of ICG was decreased and mean resident time was increased in groups 3 and 4, compared with those in groups 1 and 2. When disposition data (60 minutes) were normalized for differences in hepatic weight among dogs, group-3 mean resident time was significantly greater than that of group 4. This study supports the diagnostic benefits of using ICG disposition kinetics as a method of evaluating hepatic function in dogs with progressive liver disease.     

Effect of induced pyrexia on the disposition kinetics of ciprofloxacin in dogs

Ciprofloxacin was administered intravenously @ 5 mg/kg body weight to six healthy dogs. After a washout period of two weeks, fever was induced by injecting Escherichia (E) coli endotoxin. Ciprofloxacin was administered again. Blood samples were collected at various time intervals and analyzed for ciprofloxacin with HPLC. The kinetic analysis revealed the volume of distribution in healthy vs. febrile dogs as 2.12 ± 0.32 vs. 1.79 ± 0.43 L/Kg, respectively. The elimination half life was 2.23 ± 0.78 and 2.07 ± 0.74 hours in healthy and febrile dogs, respectively. Similarly, dogs under healthy and febrile conditions showed comparable total plasma clearance of 0.66 ± 0.06 and 0.60 ± 0.07 L/Kg/h, respectively. All these and other investigated kinetic parameters were statistically non significant. This study concludes that the pharmacokinetic behavior of ciprofloxacin is similar under healthy and febrile conditions. Thus, the kinetic studies of fluoroquinolones conducted in normal/healthy animals may be used to depict the pharmacokinetic parameters in diseased animals.     

Clearance of indocyanine green in dogs with partial hepatectomy, hepatic duct ligation, and passive hepatic congestion

Clearance of 5 submaximal doses of indocyanine green (ICG) was measured in 5 dogs to determine the maximal removal rate (0.188 mg/kg of body weight/min) and Michaelis constant (Km, 1.25 mg/kg). From these results, 5 mg of ICG/kg of body weight was chosen on the basis of the recommendation that the dose should be at least 4 X Km to achieve sensitivity as a measure of hepatic function and independence from hepatic blood flow. Clearances of low (0.5 mg/kg) and high (5 mg/kg) doses of ICG were measured in 35 healthy dogs to determine reference values. Fractional disappearance was 15.1 +/- 10%/min for the low dose and 3.9 +/- 1%/min for the high dose; plasma half-life was 6.3 +/- 3.6 minutes and 19 +/- 4.8 minutes, respectively. The sensitivity of 2 doses of ICG was evaluated in dogs with 20% and 40% hepatectomy, nonhyperbilirubinemic obstructive cholestasis, or hepatic congestion; sham-operated dogs served as controls. Fractional disappearance and plasma half-life of ICG in the 40% hepatectomy and hepatic congestion groups were significantly different (P less than 0.05) from those in controls using both ICG doses, indicating that both doses were affected by hepatic perfusion, as well as hepatic mass. The fractional disappearance of the dye in the cholestasis group also differed significantly (P less than 0.05) from that of the controls at the high dose. Plasma clearance of both doses by dogs with 20% hepatectomy was not significantly different from that of controls.     

Deconvolution study of the absorption rate and disposition kinetic values of lindane in sheep.

Absorption rate and plasma and fat disposition of lindane after various lindane percutaneous treatments in shorn and unshorn sheep were investigated. To analyze data with a deconvolution method, IV administration was performed to determine the basic pharmacokinetic values of lindane in sheep. After IV administration, the steady state volume of distribution was very high (8.07 +/- 3.60 L/kg of body weight), and the mean residence time was long (28.1 +/- 11.7 hours). Deconvolution analysis indicated that lindane absorption was continuous until 33 to 41 days after spraying with a 0.025% lindane solution. Total amount of absorbed lindane in shorn (15,171 +/- 4,463 micrograms/kg) sheep was about twice that in unshorn (7,615 +/- 3,128 micrograms/kg) sheep; from deconvolution analysis, it was calculated that the time required for 50% of the available dose to be absorbed was between 115 and 179 hours. After percutaneous lindane administration, the fat concentration was compared with the available lindane dose. The apparent half-life of lindane elimination in fat was 225 +/- 47.4 hours, which is similar to the value calculated for the absorption rate constant. By comparing fat and plasma concentrations, it was calculated that for a mean plasma concentration of 5 ng/ml, the fat lindane concentration was 1.65 +/- 0.87 micrograms/g (ie, lower than the generally accepted tolerance level of 2 micrograms/g).     

Endostatin concentrations in healthy dogs and dogs with selected neoplasms

Endostatin prevents angiogenesis and tumor growth by inhibiting endothelial cell proliferation and migration. The purpose of this study was to determine serum endostatin concentrations in 53 healthy dogs and in 38 dogs with confirmed malignant neoplasms. Endostatin concentration was determined with a competitive enzymatic immunoassay (EIA) with rabbit polyclonal antibody generated against a recombinant canine endostatin protein. Both the presence of cancer and increasing age were associated with increased serum concentration of endostatin. Endostatin concentration in healthy dogs was 87.7 +/- 3.5 ng/mL. Upper and lower limits of the reference range for serum endostatin concentration in healthy dogs were 60 and 113 ng/mL. Dogs with lymphoma (LSA) and hemangiosarcoma (HSA) had endostatin concentrations of 107 +/- 9.3 ng/mL. In conclusion, this study demonstrates that endostatin can be quantified in dogs and that endostatin concentrations are high in dogs with HSA and LSA.     

Serum isoamylase values in normal dogs and dogs with exocrine pancreatic insufficiency

Estimations were made of the serum isoamylase values of normal dogs and of dogs with confirmed exocrine pancreatic insufficiency. A statistically significant difference was demonstrated between the two groups in respect of the values of one of the isoamylase fractions measured. Further study has confirmed that canine salivary tissue lacks amylase activity and that the source of the isoamylase fractions was the pancreas.This knowledge has potential value in the diagnosis of canine exocrine pancreatic insufficiency.     

Urinary incontinence in spayed female dogs: frequency and breed disposition

A follow up study was performed in 412 spayed bitches in order to determine the incidence of urinary incontinence. The period between the operation being performed and the survey being made varied between 3 and 10 years. 83 animals (20.1%) were incontinent independent of the surgical procedure (ovariectomy versus ovariohysterectomy). The onset of incontinence varied between immediately to 12 years with an average period of 2.9 years after surgery. 57 of these incontinent bitches were treated with ephedrine or estrogen. In 73.7% a good response was achieved with ephedrine and a further 23.7% showed some improvement. Generally ephedrine was more successful than estrogen in the treatment of incontinence. There appears to be a strong connection between body weight and the incidence of incontinence. Of bitches with a body weight of less than 20 kg only 9.3% were incontinent. Whereas in bitches with a body weight of more than 20 kg the incidence was 30.9%. Of the breeds Boxers showed a high incidence of incontinence (65%) while breeds such as German Shepherds (10.6%) or Dachshunds (11.1%) showed a low incidence in relation to the average incidence rate (20.1%).     

The kinetics of triclabendazole disposition in sheep

To investigate whether the disposition of triclabendazole (TCBZ) and its metabolites in blood or bile influenced its flukicidal potency, TCBZ was administered intraruminally at 10 mg kg-1 to sheep surgically fitted with a permanent re-entrant bile duct cannula. The profiles of TCBZ metabolites in peripheral plasma and bile were determined using high performance liquid chromatography. In plasma, only TCBZ sulphoxide (TCBZ-SO) and TCBZ sulphone were present and reached their maximum concentrations (greater than 13 micrograms ml-1) at 18 and 36 h, respectively, after administration. TCBZ metabolites were specifically bound to plasma albumin, which is believed to exert a major influence on the duration of plasma TCBZ metabolite concentrations and consequent exposure of liver fluke. In bile, the major TCBZ metabolites were hydroxylated in the 4' position and secreted predominantly as sulphate esters with lesser proportions as glucuronide conjugates. The major biliary metabolite was conjugated hydroxy TCBZ-SO which reached a maximum concentration in excess of 40 micrograms ml-1 and contributed almost half the total conjugated metabolites. The major free biliary metabolite was TCBZ-SO. Of the administered TCBZ dose, 9.7% was secreted as free metabolites in bile whereas 35.8% was secreted as conjugated metabolites. Approximately 6.5% of the dose was excreted in urine.     

Electroencephalographic and histopathologic correlations in eight dogs with intracranial mass lesions

During 1986 and 1987, electroencephalographic examinations were done on 8 dogs with intracranial mass lesions confirmed by computerized tomography, biopsy, necropsy, or a combination of these techniques. Tumor types included 1 astrocytoma, 1 undifferentiated glioma, 2 mixed gliomas, 2 meningiomas, 1 choroid plexus papilloma, and 1 cholesterol granuloma. It was found that no EEG pattern was pathognomonic for tumor type or location. Slow-wave activity was observed in the EEG of most of the dogs; asymmetry in amplitude or frequency was observed in approximately half the cases.     

Isometamidium in goats: disposition kinetics, mammary excretion and tissue residues

The pharmacokinetics of the antitrypanosomal drug isometamidium were studied in lactating goats after intravenous and intramuscular administration at a dose of 0.5 mg/kg body weight, in a crossover design at an interval of 6 weeks. Following intravenous administration, the half-life of the disappearance of the drug from plasma during the terminal phase was 3.2 h, and the mean residence time was 2.4 h. The apparent volume of distribution averaged 1.52 l/kg, and the mean total body clearance was 0.308 l/kg/h. After intramuscular administration, the absolute bioavailability was low, averaging 27%. This was consistent with a low mean maximum concentration of 24 ng/ml which occurred after 6 h. No drug was detectable (less than 10 ng/ml) in milk samples collected over a period of 14 days following drug administration by either the intravenous or intramuscular route. In tissues analysed when the goats were killed 6 weeks after administration of the second dose, no drug was detectable (less than 0.4 micrograms/g wet tissue) in the liver, kidney and muscle. However, at the injection site, drug concentrations varied from less than 0.4 to 18.8 micrograms/g wet tissue.     

Isometamidium in pigs: disposition kinetics, tissue residues and adverse reactions

The disposition and adverse effects of the anti-trypanosomal drug isometamidium in pigs were evaluated. Following intramuscular administration of the drug at doses of 0.5, 15 and 35 mg kg-1, the drug was rapidly absorbed within 15 to 30 minutes to reach maximum plasma concentrations of 12 to 477 (n = 6), 302 to 655 (n = 4) and 1620 (n = 1) ng ml-1, respectively. No drug was detectable in plasma (less than 5 ng ml-1) 24 hours after drug administration at the three doses used. The half-lives of disappearance of the drug from plasma during the terminal phase were 7.12 h for the pigs given a dose of 15 mg kg-1, and 7.20 h for the pig which received a dose of 35 mg kg-1. At all the intramuscular injection sites, high drug concentrations were found six weeks after administration. The most dramatic adverse reactions observed were: one death after intramuscular administration at a dose of 35 mg kg-1 to two animals, and two deaths after intravenous administration at a dose of 2 mg kg-1 to two animals. For all these cases, the immediate cause of death was acute cardiovascular collapse. Biochemical analyses and gross and histological examinations showed that the animals that tolerated the high doses of 15 and 35 mg kg-1 given intramuscularly had extensive and severe tissue damage at the injection sites. Significant increases in plasma gamma-glutamyltransferase and alanine aminotransferase following drug administration suggested a degree of hepatobiliary damage.     

The bioavailability and disposition kinetics of genistein in cats

The absorption and disposition kinetics of the soy isoflavone genistein were determined in cats (n = 6). An oral dose of 100 mg/kg was administered, which has previously been demonstrated to be the minimum oral estrogenic dose, and was administered intravenously at a dose of 20 mg/kg, being the largest practical dose that could be safely administered. Plasma free, and total (conjugated + free) genistein concentrations were determined by HPLC following organic extraction. Noncompartmental analysis revealed a half-life of 21.67 +/- 7.9 h (free) and 9.95 +/- 2.7 h (conjugated), volume of distribution 31.94 +/- 10.38 L/kg (free) and 11.82 +/- 3.96 L/kg (conjugated) following intravenous administration. Following oral administration the half-lives were determined to be 17 +/- 4.8 h (free) and 8.56 +/- 4.65 h (conjugated), with tmax = 4.4 +/- 0.6 h (free) and 4.42 +/- 0.99 h (conjugated), and Cmax = 0.276 +/- 0.1 microg/mL (free) and 6.24 +/- 6.58 microg/mL (conjugated). Oral bioavailabilities were 1.379 +/- 0.9% (free) and 29.85 +/- 22.61% (conjugated). The ratio of total:free genistein ranged from 25.9 to 5.5. Poor oral absorption and efficient conjugation explain the low bioavailability of free genistein. Accumulation of genistein in peripheral lipophilic compartments may occur.     

Serum amylase and isoamylase values in dogs with pancreatic disease

Serum amylase and isoamylase values were determined in three groups of dogs. The first group contained control dogs while the other groups contained dogs with confirmed exocrine pancreatic insufficiency and diabetes mellitus respectively. The trypsin-like immunoreactivity test was also carried out on sera from dogs with exocrine pancreatic disease (EPI). A significant difference was detected in the serum amylase values between the three groups which may be of limited diagnostic value. Dogs with EPI had values lower than normal while those with diabetes mellitus had values higher than control dogs. No evidence of exocrine pancreatic insufficiency was found in dogs with diabetes mellitus.