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PubMed1993

Pharmacokinetics of diminazene in female Boran (Bos indicus) cattle.

The disposition kinetics and bioavailability of diminazene in five healthy heifers were determined after single intravenous (i.v.) and intramuscular (i.m.) administration of the drug in sequence with a wash-out period between administrations of 6 weeks. Intact diminazene in plasma, whole blood and urine samples was analysed using high-performance liquid chromatography. Nonlinear regression analysis of the i.v. and i.m. data indicated that, for either route, the plasma disappearance curves of diminazene were best described by triexponential equations. The i.v. bolus was followed by rapid and biphasic distribution with half-life values of 0.04 h and 0.58 h, Vd(ss) was 1.91 +/- 0.42 l/kg, elimination half-life was 31.7 h while Cl averaged 1.74 +/- 0.40 ml/min/kg. Within 30 min of the i.v. dose, the erythrocyte/plasma partition ratio of diminazene was 0.30 +/- 0.15. Diminazene was rapidly absorbed following i.m. administration; t1/2ka was 0.60 h. Cmax, 4.68 +/- 1.12 micrograms/ml, was attained in 10-15 min and systemic availability was 102.42 +/- 7.25%. The half-life of the terminal disappearance phase was 145.48 h. About 8.26% of the i.m. dose was excreted intact in the urine within the first 24 h of treatment. In vitro, diminazene was bound to bovine plasma albumin to the extent of 38.01-91.10%.

Absorption↗
PubMed2004

Effect of diminazene block treatment on live redwater vaccine reactions.

One third of the manufacturer's prescribed dose of diminazene has long been used to block treat the South African unfrozen Babesia bigemina and Babesia bovis (redwater) vaccine reactions, with no known adverse effects. It is known that the inhibitory effect of antibabesial drugs is more pronounced in animals inoculated with the frozen vaccine than those with the unfrozen vaccine. Reports of vaccine failures in some animals in which diminazene was used for block treatment of the reactions following inoculation with frozen South African redwater vaccine led us to reinvestigate the required waiting period before treatment and the reduced dose necessary for successful treatment and development of immunity. Results from febrile reactions in cattle following vaccination indicated day 7 as the optimal day for administering block treatment. Treatment of B. bigemina vaccine reactions in cattle on day 7 at a level of 0.35 mg/kg (1/10, fraction of the normal dose) diminazene killed all the parasites while B. bovis vaccine parasites survived treatment using diminazene at levels between 0.35 mg/kg and 1.16 mg/kg. However, various other factors, such as the degree of natural resistance of different cattle breeds and individual animals, the accuracy of diminazene content according to the manufacturer's label claim and the accuracy of the drug dose administered, all influence the successful immunization of animals. Consequently block treating of Babesia vaccines with diminazene on day 7 after vaccination is not recommended.

Animals↗
PubMed1993

Time-dose-response of Trypanosoma brucei brucei to diminazene aceturate (Berenil) and in vitro simulation of drug-concentration-time profiles in cattle plasma.

Bloodstream form Trypanosoma brucei brucei of axenically growing populations were incubated in the presence of 10.0, 1.0 or 0.1 micrograms/ml diminazene aceturate (Berenil) at 37 degrees C for various periods and, subsequently, either inoculated into mice or further propagated in vitro in drug-free medium. Growth was monitored for 10 days. The ability of trypanosomes of drug-sensitive CP 2137 (clone 1) to grow in vitro was irreversibly damaged after short incubation (< 1 min) with 10.0 micrograms/ml or after 15 min with 1.0 micrograms/ml diminazene aceturate. In contrast, drug-resistant CP 2469 (clone 1) trypanosomes tolerated incubation with 10 micrograms/ml of drug for up to 6 h and 1.0 micrograms/ml of drug for up to 24 h. Differences in drug susceptibility were also detected regarding infectivity to mice and changes in trypanosome cell volume. The results demonstrated that less than 1 min exposure to diminazene aceturate at concentrations as seen in bovine plasma at the initial peak after diminazene aceturate treatment is enough to irreversibly damage drug-sensitive trypanosomes. However, these concentrations were not sufficient to completely eliminate drug-resistant trypanosomes after exposure for 1-6 h; trypanosomes continued to grow for 48 h before the majority of them died and only a few organisms survived to revive the cultures. When drug-sensitive trypanosomes were exposed in vitro for 24 h to diminazene aceturate at the level of concentrations found in cattle after treatment with 3.5 mg/kg, most of the trypanosomes died and none of the surviving parasites could be propagated in vitro in the absence of drug for more than 2 days. However, a small population of drug-resistant trypanosomes was not irreversibly damaged and a few surviving trypanosomes were able to establish growing cultures. The addition of feeder layer cells did not change the outcome of these experiments.

Animals↗
PubMed1992

Response of Trypanosoma congolense in goats to single and double treatment with diminazene aceturate.

Diminazene aceturate is one of a limited number of compounds currently marketed for treatment of trypanosomiasis in cattle, sheep and goats. The pharmacokinetics of the compound in goats suggest that double treatment with diminazene aceturate might enhance the compound's therapeutic activity. A study was therefore conducted in goats using two clones of Trypanosoma congolense, IL 3274 and IL 1180, which were previously shown to be resistant and sensitive, respectively, to single treatment with diminazene aceturate. The results indicated that, as compared to single treatment, double treatment with diminazene aceturate at a dose of 7.2 mg kg-1 bodyweight, at either eight or 24 hour intervals, did not greatly enhance the therapeutic activity of the drug. Furthermore, treatment with the same drug dose eliminated infections with T congolense IL 3274 when treatment was administered 24 hours after infected Glossina morsitans centralis had fed, but failed to do so if treatment was delayed until after goats were detected to be parasitaemic. This suggests that failure of T congolense IL 3274 to respond to treatment with diminazene may not be due to drug resistance per se.

Animals↗
PubMed1993

Variation in sensitivity of Trypanosoma congolense to diminazene during the early phase of tsetse-transmitted infection in goats.

Twenty-five goats were randomly allocated to five groups of five animals each and infected with Trypanosoma congolense IL 3274 via the bites of infected Glossina morsitans centralis. At intervals of 1, 4, 8, 12 or 19 days following infection, each group of five animals was treated intramuscularly with diminazene aceturate at a dose of 7.0 mg kg-1 body weight (b.w.). While treatment on Day 1 eliminated infections in all five goats, treatment on Day 19 did not cure any of the animals; in groups treated 4, 8 or 12 days following infection, two of five goats in each group were cured. Since the alteration in apparent resistance of T. congolense IL 3274 between Day 1 and Day 19 could have been due to alteration in expression of drug resistance by trypanosomes as the population expanded, the experiment was repeated using trypanosomes that reappeared in the animals that had been treated with diminazene aceturate on Day 19. On Day 36, when all five animals were parasitaemic, five groups of teneral G. m. centralis, each containing 160 flies, were fed on one occasion on each of the five goats (one group of testse flies per goat). Thereafter, each group of tsetse flies was maintained on clean rabbits. When infective, five flies from each group were allowed to feed on two naive goats each (i.e. two goats per group of tsetse flies). One animal in each pair was treated 24 h after infection with diminazene aceturate at a dose of 7.0 mg kg-1 b.w., the other was treated on Day 19, when parasitaemic, with the same drug dosage. As before, treatment 24 h following infection eliminated infections in all animals, but when treatment was delayed until Day 19, trypanosomes in all animals were refractory to treatment. Thus, although tsetse flies were infected with trypanosomes that had arisen in infected goats following treatment with diminazene aceturate at a dose of 7.0 mg kg-1 b.w., when the same flies were allowed to feed on clean goats, the resultant infections were sensitive to treatment with the same drug dosage when administered 24 h following infection. These data therefore indicate that there is a significant alteration in diminazene sensitivity of IL 3274 between Day 1 and Day 19 and that this is associated with an alteration in the resistance phenotype of the trypanosomes.

Animals↗
PubMed1996

Trypanocidal value of liposomal diminazene in experimental Trypanosoma brucei evansi infection in mice.

The trypanocidal value of liposomal diminazene was examined. Three hundred mice were divided randomly into six groups of 50 mice each. Groups 1, 2 and 3 were pretreated 2 h before Trypanosoma brucei evansi challenge with 0.2 ml saline solution, 0.2 ml diminazene solution (5 mg ml-1) and 0.2 ml liposomal solution (5 mg diminazene per ml), respectively. Mice in Group 1 all died within 6 days, 33 in Group 2 and four in Group 3 died within 15 days after challenge, respectively. Groups 4, 5, and 6 were treated 4 days after T. b. evansi challenge with 0.2 ml saline solution 0.2 ml diminazene solution (5 mg ml-1) and 0.2 ml liposomal solution (5 mg diminazene per ml), respectively. Mice in Group 4 all died within 6 days, 19 in Group 5 and two in group 6 died within 15 days after challenge, respectively. The remaining mice survived for more than 30 days, were symptom-free and behaved normally. No adverse effects associated with treatment were noted.

Animals↗
PubMed2004

The effects of diminazene aceturate and ceftriaxone on ram sperm.

Effects of diminazene aceturate and ceftriaxone disodium were evaluated on sperm quality of rams. Daily intramuscular injections of diminazene (6 mg/kg) or ceftriaxone (28.5 mg/kg) were given to each of seven Akkaraman rams assigned per drug for two days. Semen samples were collected from the rams at post-treatment 1, 4, 24, 48, 72, 144, 288 and 336 h and examined for sperm characteristics and hyaluronidase activity. Results showed that use of ceftriaxone and diminazene caused significant (P<0.01) decreases in sperm concentration, volume and motility compared to control group within 288 h post-treatment. In addition, hyaluronidase activity increased significantly (P<0.01) in semen of rams treated with ceftriaxone while remained unchanged in those received diminazene. In conclusion, diminazene aceturate and ceftriaxone disodium did not have any deleterious effect on hyaluronidase enzyme. However, both drugs caused impairment of sperm in rams during the 288 h.

Animals↗
PubMed1997

Effect of diminazene aceturate on the infectivity and transmissibility of drug-resistant Trypanosoma congolense in Glossina morsitans centralis.

To determine the duration after treatment of cattle with diminazene aceturate that the drug influences the tsetse infectivity and transmissibility of a drug-resistant Trypanosoma congolense, six Boran cattle were infected with T. congolense IL 3338 via the bites of Glossina morsitans centralis. At the first peak of parasitaemia, different groups of 120 teneral G. m. centralis were fed on one occasion on each animal, 1 h before treatment with diminazene aceturate at a dose of 3.5 mg kg-1 body weight. Thereafter, on Days 1, 2, 3, 7, 14 and 21 after treatment, six different groups of 120 teneral G. m. centralis were similarly fed on each animal. After 28 days maintenance on uninfected goats, all the flies were probed onto slides at 37 degrees C to identify those extruding metacyclic trypanosomes. Flies with mature infections from each group were then fed on one occasion on individual mice to determine the transmissibility index. After dissection of flies on Day 30 after their feed on the cattle, the mean mature (+/-SE) infection rates in the seven groups of flies were 32.1 +/- 2.2, 1.0 +/- 0.7, 0.4 +/- 0.4, 0.5 +/- 0.3, 20.0 +/- 1.7, 33.3 +/- 2.2 and 23.4 +/- 2.0% for flies fed on Days 0, 1, 2, 3, 7, 14 and 21 after treatment with diminazene, respectively. The transmissibility rates for the seven groups ranged from 94 to 100%. Thus, when cattle were infected with a diminazene-resistant T. congolense, treatment with diminazene aceturate caused a substantial reduction in the ability of the trypanosomes to establish mature infections in tsetse for at least the first 7 days after treatment. In contrast, no significant effect on the transmissibility of the parasites to mice was observed at different intervals after treatment.

Animals↗
PubMed1991

Variation in resistance to isometamidium chloride and diminazene aceturate by clones derived from a stock of Trypanosoma congolense.

Nine clones were derived from a drug-resistant Trypanosoma congolense stock (IL 2856) and characterized in mice for their sensitivity to isometamidium chloride and diminazene aceturate. All clones were derived from the stock without drug selection and expressed high levels of resistance to isometamidium chloride (50% curative dose [CD50] values ranging from 1.5 to 5.1 mg/kg) and intermediate to high levels of resistance to diminazene aceturate (CD50 values ranging from 5.1 to 21.0 mg/kg). By contrast, the isometamidium chloride and diminazene aceturate CD50 values for a drug-sensitive clone, T. congolense IL 1180, were 0.018 mg/kg and 2.3 mg/kg, respectively. For both drugs, there appeared to be significantly different levels in expression of drug resistance amongst the 9 clones derived from IL 2856. Isoenzyme analysis of 7 enzymes showed that all 9 clones expressed the same electrophoretic variants. Thus, all 9 clones were identical for these phenotypic markers. The clone which expressed the highest level of resistance to isometamidium in mice (IL 3270) was transmitted to Boran cattle via the bite of infected Glossina morsitans centralis. IL 3270 produced an infection rate in tsetse of 5.0%. The resulting infections in cattle were shown to be resistant to intramuscular treatment with 2.0 mg/kg isometamidium chloride and 14.0 mg/kg diminazene aceturate. This contrasts with doses of 0.25 mg/kg isometamidium chloride or 3.5 mg/kg diminazene aceturate which are deemed sufficient to cure fully sensitive infections. Finally, 9 clones (subclones) were derived from IL 3270 and characterized in mice for their sensitivity to isometamidium chloride.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

The pathogenicity of diminazene aceturate-resistant Trypanosoma brucei in rats after treatment with the drug.

Four groups (A, B, C and D) of 10 rats were used to determine the effect of comparatively high doses of diminazene aceturate on diminazene aceturate-resistant Trypanosoma brucei and the pathogenic effect of relapse infection. Group A rats were uninfected (controls) while group B, C and D rats were inoculated intraperitoneally with 0.5 x 10 (6) diminazene aceturate-resistant T. brucei and treated with diminazene aceturate at 14.0, 17.5 and 21.0mg/kg body weight, respectively, on day 14 post-infection (PI) as a single intraperitoneal injection. Prepatent periods and also levels of parasitaemia were comparable in groups B, C and D. Packed cell volume (PCV) decreased in the infected groups by day 14 PI and returned to pre-infection values by day 63 post-treatment (PT). Anaemia was comparable in groups B, C and D. Relapse parasitaemia occurred in six rats in group B on day 70 PT and in five rats in each of groups C and D on day 77 PT. The PCV of the rats with relapse infection decreased progressively up to day 105 PT, when the experiment was terminated, whereas the PCV of rats without relapse did not. The levels of anaemia and parasitaemia on day 14 post-relapse were significantly higher (P<0.05) than the levels obtained on day 14 PI in the same animals. Thus, comparatively high doses of diminazene aceturate failed to cure drug-resistant T. brucei infection in 50-60% of infected rats and relapse infections were more severe than the primary infections before treatment.

Animals↗
PubMed1991

Combination therapy of trypanosomiasis using diminazene and non-steroidal anti-inflammatory drugs.

The susceptibility of established Trypanosoma brucei (8/18 strain) infection in mice and rabbits to low doses of diminazene (Berenil) in combination therapy with non-steroidal anti-inflammatory drugs (NSAIDs) has been evaluated using piroxicam (Feldene) and pirprofen (Rengasil) as examples of the NSAID. The results show that low doses of diminazene combined with piroxicam cured experimentally infected mice and rabbits with T. brucei. On the other hand, diminazene in combination with pirprofen did not offer any activity against the course of the infection. Mice treated with low doses of diminazene combined with pirprofen did not show reduced parasitemia and died within 3-4 days post infection. The study shows that low doses of diminazene at rates of 2 mg/kg and 1 mg/kg, when combined with piroxicam at a dosage rate of 0.6 mg/kg, can effect permanent cure in experimentally infected mice and rabbits with T. brucei.

Animals↗
PubMed2000

Pharmacokinetics, urinary excretion and dosage regimen of diminazene in crossbred calves.

The pharmacokinetics, urinary excretion and dosage regimen of diminazene were investigated in crossbred male calves following a single intramuscular dose (3.5 mg x kg-1). Following intramuscular administration, the pharmacokinetics of diminazene was described with a one-compartment open model. The absorption rate constant and absorption half-life were 9.86 +/- 3.06 h-1 and 0.121 +/- 0.40 h, respectively. The value of elimination half-life was 107.5 +/- 8.50 h. The apparent volume of distribution was 0.74 +/- 0.07 L x kg-1. Systemic availability following intramuscular administration was 91.7%. Approximately 65% of the administered dose of diminazene was eliminated in the urine within 24 h of its intramuscular administration. Diminazene was bound to plasma proteins to the extent of approximately 32%. The satisfactory intramuscular dosage regimen of diminazene for calves would be 2.24 mg x kg-1 followed by 1.5 mg x kg-1 at 7 days.

Animals↗
PubMed1994

A bioequivalence and pharmacokinetic evaluation of two commercial diminazene aceturate formulations administered intramuscularly to cattle.

The bioequivalence of the diminazene formulation Veriben (Centaur) was determined in cattle (n = 10) by means of a single-dose, randomized cross-over experiment. The results of nine statistical procedures commonly used for bioequivalence evaluation are discussed. Veriben was found to be equivalent to Berenil (Hoechst) with respect to the area under the plasma concentration versus time curve, but not in terms of the maximum plasma drug concentration and the time to maximum plasma drug concentration. Pharmacokinetic parameters were calculated in which bioequivalence data (n = 10) together with data from an additional four cattle were used. A two-compartment model best described the pharmacokinetic behaviour of diminazene in cattle. Peak concentrations of diminazene (3.24 +/- 0.16 micrograms/ml) were reached 49.8 (+/- 7.6) min after intramuscular injection of 3.5 mg/kg drug, with absorption proceeding rapidly (t1/2 alpha = 1.93 +/- 0.95 h). Diminazene was slowly eliminated (t1/2 beta = 222 h), resulting in a mean residence time of 13.27 d. The safe interval necessary between successive treatments of diminazene or before live babesia vaccines should be administered, and a recommended pre-slaughter withdrawal period are also discussed.

Animals↗
PubMed1989

The influence of Trypanosoma congolense infection on the disposition kinetics of diminazene aceturate in the dog.

Diminazene aceturate was administered intravenously at 3.5 mg/kg body weight to mongrel dogs before and after infection with Trypanosoma congolense. Plasma and urine were collected at varying intervals thereafter and analysed for the compound. The mean area under the concentration-time curve (AUC) of diminazene in healthy dogs was 25.8 h.micrograms/ml but was significantly increased (p less than 0.05) to 35.7 h.micrograms/ml after infection with T. congolense. The distribution half-life was significantly reduced (p less than 0.05) in dogs after infection, being 0.12 h compared to 0.17 h in the same dogs before infection. The mean proportion of the diminazene recovered in the urine of infected dogs (25.1%) was not significantly different from that recovered in the urine of healthy dogs (26.8%). These results indicate that infection with T. congolense increases the rate at which diminazene is distributed in the body but that the infection has no marked influence on the urinary excretion of the drug.

Amidines↗
PubMed1990

Expression of resistance to isometamidium and diminazene in Trypanosoma congolense in Boran cattle infected by Glossina morsitans centralis.

Investigations were conducted on the sensitivity to isometamidium chloride (Samorin) and diminazene aceturate (Berenil) of derivatives of three of the Trypanosoma congolense stocks isolated between 1978 and 1983 from Zebu cattle in the Bobo-Dioulasso region of Burkina Faso. Boran cattle were used in the drug-sensitivity tests and were infected using Glossina morsitans centralis. The results showed that T. congolense stock IL 2466 isolated in 1978 was sensitive to the standard therapeutic dose of isometamidium chloride (0.25 mg kg-1) and of diminazene aceturate (a.i. 3.5 mg kg-1). However, T. congolense stock IL 2468 isolated in 1982 was resistant to both the prophylactic (0.5 and 1.0 mg kg-1) as well as the therapeutic doses of isometamidium chloride (up to 1.0 mg kg-1) although the sensitivity to the therapeutic dose of diminazene aceturate (3.5 mg kg-1) was not affected. The T. congolense stock IL 2856 isolated in 1983 was highly resistant to the therapeutic action of diminazene aceturate (up to 10.5 mg kg-1), as well as to the prophylactic (up to 1.0 mg kg-1) and therapeutic action of isometamidium chloride (up to 2.0 mg kg-1). The infection rates of the drug-resistant stocks of T. congolense in G.m. centralis, when goats were used as reservoir hosts, were as high (range, 22.3-56.3%) as of the drug sensitive stock (49.5%). The resistance trait in the two stocks remained stable after their cyclical development in the tsetse vectors. The rate of transmission of the drug-resistant stocks to mice by the infected tsetse was also high (mean 81.3%).

Amidines↗
PubMed2003

Chemotherapy of surra in horses and mules with diminazene aceturate.

During June-July 2000, an outbreak of surra occurred on an equine breeding farm in Khonkaen Province, Thailand. Forty-two percent of pregnant mares aborted or gave stillbirth and 40% (19/47) of horses and 10% (1/10) of mules died from surra. In August 2000 Trypanosoma evansi were detected in the remaining animals (28 horses and nine mules) on the farm by blood smear and/or the haematocrit centrifuge technique. All animals were treated with diminazene aceturate at 3.5 mg/kg body weight by intramuscular injection on days 0 and 41 of the study. Blood samples of eight randomly selected horses and mules were collected on days 0, 1 and once a week until day 56 and examined for T. evansi by various parasitological techniques. The sera were tested for antibodies against T. evansi using an indirect enzyme linked immunosorbent assay (ELISA).The results revealed that diminazene aceturate at 3.5 mg/kg appeared to be effective in the first treatment of horses and mules infected with T. evansi. Parasites were cleared from the peripheral blood of horses on days 1 and 7 and mules on days 1 and 14. Thereafter the number of positive animals increased. After the second treatment, 50% of horses and 25% of mules were still positive to surra 24 h after treatment demonstrating that diminazene had no protective effect. Mild to severe toxicity of diminazene was seen in the horses and mules after injection.

Animals↗
PubMed2002

Determination of diminazene aceturate in pharmaceutical formulations by HPLC and identification of related substances by LC/MS.

A validated, reversed-phase, isocratic high-performance liquid chromatographic method for the simultaneous assay of diminazene aceturate, antipyrine (excipient) and diminazene impurities in pharmaceutical formulations is described. The chromatographic system consisted of a Lichrospher-60 RP-select B column with a mobile phase composition of acetonitrile-methanol-ammonium formate (pH 4.0, 20 mM) (10:10: 80 v/v/v) and UV detection at 254 nm. The method is specific, precise and accurate for the determination of diminazene in the presence of its manufacturing and degradation impurities with a limit of detection and quantification of 50 ng/ml and 10 microgram/ml (RSD<3.0%), respectively. The major manufacturing impurity [1-(4 amidino phenyl)3-(4 carbamoyl phenyl)-triazene] and a degradant (p-aminobenzamidine) of diminazene aceturate have been resolved and identified by liquid chromatography/electrospray ionization-mass spectrometry operated in a positive ion mode.

Chemistry, Pharmaceutical↗
PubMedDate not supplied

The effectivity analysis of accumulation of liposomal, micellar, and water-soluble forms of diminazene in cells and in organs.

The study was aimed at evaluating the effectiveness of liposomal, micellar, and water-soluble drug forms of diminazene for its localization in cells and selective accumulation at the sites of aggregation of pathogenic organisms. Pharmacological and dynamic properties of a new injection micellar diminazene preparation were experimentally determined. These properties were compared with the same parameters obtained for the water-soluble and liposomal diminazene aceturate drug forms. The drug forms studied may be arranged in the following order of decreasing effectiveness of accumulation of diminazene in red and white blood cells and in murine organs: liposome form, micellar form, and water-soluble form.

Animals↗