Pharmacokinetics of imidocarb dipropionate in horses after intramuscular administration

The objective of this study was to determine the pharmacokinetic behaviour of imidocarb in horses following a single i.m. injection at the dose commonly administered to treat Babesia caballi infections or to prevent babesiosis. Eight horses were injected i.m. with a single dose of 2.4 mg imidocarb dipropionate/kg bwt and blood, faecal, urine and milk samples were collected. For imidocarb determination, a high-performance liquid chromatographic method (HPLC) was used after weak cation-exchange solid phase, or liquid-liquid, extraction procedures. Twelve hours after treatment, no detectable plasma concentrations were recorded in any of the treated animals. The distribution and elimination patterns of the drug suggested that it is quickly sequestrated in some storage tissues and remains in the body for a long time. Its prolonged presence in the body may confer a reservoir effect to imidocarb in some tissues, therefore making it undetectable in the plasma of animals but sufficient to produce its described therapeutic and prophylactic activities.     

Pharmacokinetics of imidocarb dipropionate in white-tailed deer (Odocoileus virginianus) after single intramuscular administration

This study was designed to investigate the pharmacokinetics of imidocarb, a carbanilide derivative, in white-tailed deer (Odocoileus virginianus). The pharmacokinetic properties of a single intramuscular (IM) dose of imidocarb were determined in 10 deer. A single IM injection of 3.0 mg/kg imidocarb dipropionate was administered, and blood samples were collected prior to, and up to 48 hr after imidocarb administration. Plasma imidocarb concentrations were determined by high-performance liquid chromatography with ultraviolet detection. The disposition of plasma imidocarb was best characterized by a two-compartment open model. The mean ± SE maximal imidocarb concentration in deer was 880.78 ± 81.12 ng/ml at 38.63 ± 5.30 min postinjection. The distribution phase had a half-life (t_1/2α) of 25.90 ± 10.21 min, and plasma imidocarb concentration declined with a terminal elimination half-life (t_1/2β) of 464.06 ± 104.08 min (7.73 ± 1.73 hr). Apparent volume of distribution based on the terminal phase (V_Z/F) was 9.20 ± 2.70 L/kg, and apparent total body clearance (Cl/F) was 15.97 ± 1.28 ml min⁻¹ kg⁻¹.     

头孢噻呋注射液在猪体内的药动学和相对生物利用度

研究并比较了头孢噻呋注射液和速解灵注射液在猪体内药物代谢动力学特征和相对生物利用度。20头健康猪,随机均分为2组,进行单次给药剂量(5mg/kg)肌注头孢噻呋注射液(洛阳惠中)和速解灵注射液(美国辉瑞),前腔静脉采血,高效液相色谱法检测猪血浆中头孢噻呋的浓度。采用药动学软件WinNonlin 5.2.1的非房室模型分析方法,计算出药物的动力学参数。猪肌注头孢噻呋注射液和速解灵注射液后的药动学参数分别为:达峰时间(Tmax):(2.63±0.74)、(3.38±1.92)h;峰质量浓度(Cmax):(14.06±2.21)、(9.48±1.84)mg/L;消除半衰期(t1/2β):(17.65±2.07)、(17.70±2.43)h;平均滞留时间(MRT):(23.21±2.68)、(22.11±2.50)h;药时曲线下面积(AUClast):(240.81±47.73)、(182.51±36.12)μg·h·mL-1。参数Cmax、AUClast统计差异极显著(P<0.01),头孢噻呋注射液较速解灵注射液吸收迅速、完全,达峰时间短,峰浓度显著升高;参数Tmax、t1/2β、MRT统计差异不显著(P>0.05),头孢噻呋注射液的相对生物利用度为132%,高于速解灵注射液。结果表明头孢噻呋注射液肌注后吸收迅速、完全,达峰时间短,峰浓度高,生物利用度高。     

Absorption, distribution, and excretion of imidocarb dipropionate in sheep

Spectrophotometric and thin-layer chromatographic methods for determination of imidocarb in biological specimens are described. Following intravenous injection of imidocarb (2.0 mg/kg) into 3 sheep, plasma concentrations, initially averaging 10.8 microgram/ml, decreased to an average of 1.9 microgram/ml within 1 hour and then to less than 1 microgram/ml within the next 4 hours. When imidocarb (4.5 mg/kg) was injected intramuscularly (IM) into 7 sheep, peak plasma concentrations averaging 7.9 microgram/ml were achieved within 4 hours and then rapidly decreased to 4.6 microgram/ml within the next 2 hours. Plasma values then decayed very slowly by first-order kinetics and trace amounts were still present 4 weeks after treatment. Imidocarb was bound to plasma proteins and the apparent volume of distribution was estimated to be slightly higher than the total body water. The concentrations of the drug in the plasma and in the erythrocytes were approximately equal. Detectable amounts were present in all examined tissues 4 weeks after IM administration Twenty-four hours after IM administration, the highest concentrations were in kidney, liver, and brain. The 14C-labeled imidocarb could be detected in all regions of the central nervous system examined, in the hypophysis, and in the pineal body. Metabolic or biotransformation products were not detected by the methods used. Of the administered IM dose, 11 to 17% was excreted in the urine within 24 hours; thereafter, the excretion rate was low, and detectable amounts were still present in the urine for 4 weeks. Renal clearance of imidocarb was less than glomerular filtration rate, indicating net tubular reabsorption. The relatively high concentration of imidocarb in the bile suggests that the bile is an important route of excretion. High concentrations were also found in the mild of lactating ewes, but the drug could not be detected in the plasma of lambs fed milk from these ewes.     

Pharmacokinetics of imidocarb in normal dogs and goats

The pharmacokinetics of imidocarb were studied in seven mongrel dogs and eight crossbred goats. An intravenous bolus dose (4 mg/kg) of 12% imidocarb dipropionate solution wasinjected into the cephalic vein in dogs and the jugular vein in goats. The plasma concentration of imidocarb was measured by spectro-photometry. The experimental data were analysed using a two-compartment open model. The apparent volume of the central compartment was significantly higher ( P <0.01) in dogs than in goats. The significantly larger ( P <0.05) apparent specific volume of distribution in goats than in dogs may be attributed to passive diffusion followed by ion trapping of the drug in rumen fluid. Neither the half-life nor body clearance differed significantly between dogs ( t _1/2, 207 ± 45 min; Cl_B , 1.47 ± 0.38 ml/min kg) and goats ( t _1/2, 251 ± 94 min; Cl_B , 1.62 ± 0.50 ml/min kg). While almost 80% of the dose had been eliminated at 8 h in. both species, the high ratio of the imidocarb level in the peripheral-to-central compartment in goats suggests that a prolonged period may be required for complete elimination of the drug.     

Chemotherapeutic efficacy of imidocarb dipropionate on experimentalEperythrozoon ovis infection in sheep

Summary Non-splenectomised Cheviot and Soay sheep experimentally infected with Eperythrozoon ovis were treated subcutaneously with two doses of 4 mg/kg of imidocarb dipropionate 24 hours apart. A rapid reduction in E. ovis parasitaemias following the first injection of imidocarb was observed and E. ovis organisms were not demonstrable 48 hours after the first treatment. However, recrudescences of infection were observed 14 and 28 days after treatment in the Soay and Cheviot sheep respectively. Side-effects associated with treatment were registered in the Cheviot sheep but not in the Soay sheep.

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Resumen Ovejas no esplenectomizadas de las razas Cheviot y Soay infectadas experimentalmente conEperythrozoon ovis, fueron tratadas subcutáneamente con dos dosis de 4 mg/kg de dipropionato de imidocarb, con un intervalo de 24 horas. Se notó una sensible reducción delE. ovis despues de la primera inyección, desapareciendo el organismo a las 48 horas del primer tratamiento. Sin embargo, se observaron recaídas a los 14 y 28 días despues del tratamiento en las ovejas Soay y Cheviot respectivamente. Se notaron efectos colaterales asociados al tratamiento en ovejas Cheviot pero no en las Soay. Intoxicaciones fueron observadas en los animales Cheviot pero no en los Soay.

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Résumé Des moutons non splénectomisés des races Cheviot et Soay, expérimentalement infectés parE. ovis, ont été traités par inoculation sous-cutanée de deux doses de 4 mg/kg de propionate d’Imidocarb à 24 heures d’intervalle. On constate une réduction rapide des parasitémies àE. ovis après la première injection;E. ovis ne pouvait plus être mis en évidence 48 heures après le premier traitement. Cependant, une récurrence de l’infection a été observée 14 jours après le traitement pour la race Soay et 28 jours pour la race Cheviot. Des effets secondaires associés au traitement ont été enregistrés chez les Cheviots mais non sur les Soays.

     

Adverse effects of imidocarb dipropionate (Imizol®) in a dog

One of 13 healthy dogs used in a pharmacokinetic study of imidocarb dipropionate died due to difficulty in breathing, tachycardia, weakness and profuse diarrhoea. Autopsy findings showed marked pulmonary congestion and oedema. Kidneys were grossly enlarged and markedly congested with extensive haemorrhage in the cortex and medulla. Marked tubulonephrosis was also exhibited microscopically. Liver and spleen were moderately enlarged and congested. The adverse effects of imidocarb may be due to excessive acetylcholine action.     

Efficacy of atovaquone and azithromycin or imidocarb dipropionate in cats with acute cytauxzoonosis

Background: Imidocarb or a combination of atovaquone and azithromycin (A&A) has been suggested for treatment of cats with cytauxzoonosis, but neither has been prospectively evaluated for efficacy. Hypothesis/Objectives: That survival to hospital discharge is improved by treatment with A&A as compared with imidocarb. Animals: Eighty acutely ill cats with Cytauxzoon felis infection treated at one of 18 veterinary clinics in 5 states. Methods: An open‐label, randomized prospective study compared survival in cats treated with atovaquone (15 mg/kg PO q8h) and azithromycin (10 mg/kg PO q24h) or imidocarb (3.5 mg/kg IM). All received heparin, fluids, and supportive care. Clinical and clinicopathologic data from initial presentation were collated. Parasitemia was quantified (n = 79) and pathogens genotyped (n = 60). Logistic regression was used to determine the impact of treatment group on the primary endpoint, survival to hospital discharge or death. Covariants were analyzed by rank‐sum testing. Results: Of 53 cats treated with A&A, 32 (60%) survived to discharge while only 7 of 27 cats (26%) treated with imidocarb survived (P= .0036; odds ratio 7.2, 95% CI 2.2, 24). Cats with a lower parasitemia were more likely to survive, as were cats with higher white blood cell counts and lower total bilirubin. Unique pathogen genotypes were identified from 15 cats, while genotype isolated from 21 cats had been described previously. There were multiple pathogen genotypes identified in 24 cats. Conclusions and Clinical Importance: Survival to discharge was more likely in cats treated with A&A as compared with imidocarb, although case fatality rate remained high.     

Failure of imidocarb dipropionate to clear experimentally induced Ehrlichia canis infection in dogs

The recommended treatment for canine ehrlichiosis is tetracycline or its analog doxycycline, although recent reports have documented ineffective clearing of Erchlichia canis after doxycycline administration. Imidocarb dipropionate is used as an alternative treatment to tetracycline or is used in conjunction with doxycycline. The effectiveness of imidocarb dipropionate in clearing Ehrlichia species from the blood and tissues of dogs with E. canis infection has not been thoroughly evaluated. Fifteen dogs were experimentally infected with E. canis. Ten dogs were treated with imidocarb dipropionate (6.6 mg/kg, IM, 2 injections given 2 weeks apart). Five infected control dogs were not treated. Blood samples from all 15 dogs were E. canis DNA positive by PCR assay by 3 weeks after inoculation (PI), and E. canis antibodies were detected by IFA assay by 1 week PI. Blood platelet counts in all dogs were below the reference interval by 4 weeks PI. E. canis DNA was detected in bone marrow and splenic aspirates by PCR assay 4 weeks PI but not before infection. Bone marrow aspirates were E. canis DNA positive by PCR assay in 14/15 dogs, and splenic aspirates were E. canis DNA positive by PCR assay in 13/15 dogs. Blood samples from all treated and control dogs remained positive for E. canis DNA by PCR assay, and platelet counts remained below preinoculation values 13 weeks PI (6 weeks after 2nd treatment). As administered in this study, imidocarb dipropionate did not clear experimental E. canis infection in dogs.     

Therapeutic and prophylactic efficacy of imidocarb dipropionate on experimental Babesia ovis infection of lambs

The objective of this study was to evaluate the therapeutic and prophylactic efficacy of imidocarb dipropionate (IMDP) against babesiosis and to determine specific antibodies against Babesia ovis in experimentally infected lambs. Thirty-six 6-month-old splenectomized lambs were used. The lambs were randomly divided into six groups with six animals each, and were intravenously inoculated with 50 mL B. ovis-infected erythrocytes as follows: group I (therapy group) was treated with IMDP (1.2 mg/kg body weight) starting on the day of onset of clinical signs of babesiosis after the inoculation; group II (untreated control animals) was not treated with any therapeutic treatment after the inoculation; groups III, IV, V and VI (prophylaxis groups) were administered IMDP (2.4 mg/kg body weight) 1, 2, 3 and 4 weeks before the inoculation, respectively. The animals were housed in a tick-proof room with water and food ad libitum up to the 30th day post-inoculation (PI). The lambs were monitored from the first day PI by recording the manifestation of clinical disease, rectal temperature, and the degree of parasitaemia. All the lambs became infected with B. ovis, except five animals from group III, which were treated 1 week prior to experimental infection. Other animals showed signs of acute clinical babesiosis. The animals treated with IMDP (group I) were able to clear the parasite from the blood circulation after 48 h post-treatment. The recrudescence of B. ovis was observed in two lambs 7 days after treatment, and they were treated with the second similar dose of the drug. Six lambs (1, 1, 2 and 2 lambs in group III, IV, V and VI, respectively) from the prophylaxis groups died within 7-17 days after showing high parasitaemia and clinical symptoms of the disease. Regardless of the clinical symptoms, 83.30% and 66.66% of the lambs which were administered IMDP 1-2 and 3-4 weeks before, were determined to be protected against the virulent field strain of B. ovis.     

Pharmacokinetics of theophylline in swine: a potential model for human drug bioavailability studies

The pharmacokinetics of theophylline in swine were investigated following die oral and intravascular administration of single doses of theophylline free base. The mean half-life of theophylline following intravascular administration was 11.0 h, and the apparent specific volume of distribution was 0.61 liter/kg. Following oral administration, theophylline in solution was absorbed quite rapidly with a bioavailability of 79%. The similarity of the pharmacokinetics of theophylline in swine and humans suggests that swine may provide a useful model for the study of the bioequivalency of theophylline dosage forms intended for human use. The pharmacokinetic characteristics of theophylline also favor its consideration for usage as a therapeutic agent in swine.     

Comparative efficacy of diminazene diaceturate and imidocarb dipropionate against Babesia equi infection in donkeys

Diminazene diaceturate (Berenil, Hoechst) at 12 mg/kg intramuscularly (i/m) and repeated after 24 hours controlled the rising parasitaemia of Babesia equi infection in four out of five splenectomised donkeys. The drug was more effective in the early stages of the disease and had a prophylactic effect for at least 30–35 days.A new babesicide, imidocarb (Imizol, Burroughs Wellcome), was 100% effective in three splenectomised donkeys at 5 mg/kg, i/m and repeated after 48 hours. However, imidocarb at 5 or 2 mg/kg i/m with a single injection was only partially effective or ineffective.     

Efficacy, toxicity and metabolism of imidocarb dipropionate in the treatment of Babesia ovis infection in sheep

An intramuscular dose of 1.2 mg kg-1 of imidocarb dipropionate (IMDP) was effective in controlling fatal infections with Babesia ovis in sheep. The sheep were infected by the intravenous injection of sheep blood containing B ovis. A severe recrudescence of infection occurred in most sheep 10 to 14 days after therapy but this could be controlled by a second dose of 1.2 mg kg-1 IMDP. Studies on the toxicology, residues and metabolism of IMDP showed this to be a safe dosage regimen. Transient or mild signs of toxicity were seen at 2.4 and 4.8 mg kg-1 IMDP. Severe toxicity was observed in sheep treated with 9.6 mg kg-1.     

Clinical and clinicopathological changes in 6 healthy ponies following intramuscular administration of multiple doses of imidocarb dipropionate

Haematological variables and selected serum indices, particularly those affected by changes in renal and hepatic function, were examined in 6 healthy ponies following 4 intramuscular doses of 4 mg/kg imidocarb dipropionate administered every 72 hours. This treatment regime has been reported to sterilise experimental Babesia equi infections in horses and may have value in preventing the spread of this disease during exportation of possible carrier horses to non-endemic countries. Serum bile acids and serum gamma glutamyltransferase activity were measured to evaluate the effect of this treatment regime on hepatic function. Owing to the absence of any increase in these variables it was concluded that this treatment regime had no clinically detectable deleterious effect on hepatic function in healthy ponies. Urinary gamma glutamyltransferase : creatinine ratios (IU/g), serum creatinine and fractional clearance of sodium, potassium and phosphate (%) were calculated as a measure of renal function. Urinary GGT and urinary GGT : creatinine ratios were significantly elevated on Day 5 of the trial, with 2 of the trial animals also exhibiting mild azotaemia indicative of changes in renal function. The changes in urine GGT : urine creatinine ratios observed in this study also provides evidence of the value of this ratio for the early detection of renal toxicity, following exposure to nephrotoxic agents.