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PubMed1992

Chemotherapy of CNS-trypanosomiasis: the combined use of diminazene aceturate or pentamidine with DL-alpha-difluoromethylornithine (DFMO).

The chemotherapy of CNS-trypanosomiasis with DL-alpha-difluoromethylornithine (Eflornithine, DFMO) with the diamidine, pentamidine (Lomidine) or diminazene aceturate (Berenil) was examined using the mouse model for CNS-trypanosomiasis. Although combined DFMO/pentamidine therapy can give complete cures, one or more doses of 100 mg/kg pentamidine was required with continuous administration of DFMO for 14-16 days, and even this treatment failed to cure the mice in a repeat experiment. Diminazene aceturate was more efficient and provided a 40 mg-kg dose was utilised, it was possible to reduce the period of DFMO to approximately 12 days. Attempts to reduce the dose rate of diminazene to less than 40 mg-kg failed. Of the two compounds, diminazene aceturate was the more successful and could possibly be used in combination with DFMO in the treatment of CNS-trypanosomiasis.

Animals↗
PubMed1992

Local application of diminazene aceturate: an effective treatment for cutaneous leishmaniasis?

In a controlled clinical trial we tested the effect of diminazene aceturate (Berenyl, Bayer) in local application against cutaneous leishmaniasis. The study was performed among schoolchildren in Nyala, West-Sudan in 1988 during a major outbreak of cutaneous leishmaniasis in this region. Sixty-six schoolchildren with cutaneous leishmaniasis were enrolled in the study. The children were randomly assigned to either diminazene aceturate (Berenil) or cetrimide 15% + chlorhexidine 1.5% (Savlon) treatment. The study results show a significant faster healing of the ulcers in the children treated with diminazene aceturate (chi-square 7.31, p less than 0.01). We conclude that diminazene aceturate should be considered as a potential topical drug in the treatment of cutaneous leishmaniasis.

Antiprotozoal Agents↗
PubMed1989

Effects of trypanosomal infection on the pharmacokinetics of diminazene aceturate in dogs.

Pharmacokinetics of diminazene aceturate (3.5 mg/kg) was investigated in normal mongrel dogs and in those infected with Trypanosoma brucei brucei. After intravenous injection the decrease in concentration followed a biphasic process with mean elimination half-life (t1/2 beta) of 9.87 hr in healthy dogs and 12.51 hr in T. b. brucei infected dogs. The mean total body clearance (cl) of diminazene aceturate in healthy dogs (0.62 l/kg/hr) was significantly lower (p less than 0.05) when compared to that of the infected animals (0.47 l/kg/hr). The distribution half-life (t1/2 alpha) was significantly (p less than 0.05) decreased in dogs after infection (0.14 hr) compared to 0.2 hr observed in the same animals before infection. The mean diminazene recovered in the urine of normal dogs (28.18%) was not significantly different from that recovered from infected dogs (26.1%). These results indicate that infection with T. b. brucei markedly retards the total body clearance of diminazene and also hastens the distribution of the drug when administered intravenously.

Amidines↗
PubMed1995

Paired-ion extraction and high-performance liquid chromatographic determination of diminazene in cattle plasma: a modified method.

The high-performance liquid chromatographic method published by Aliu & Odegaard (1983) was found to give poor peak separation when used to determine plasma diminazene concentrations in cattle. Before bioequivalence studies could be carried out, the method had to be modified. Solid-phase extraction with acetonitrile/0.025 M Na-octane sulphonate and 2% acetic acid as eluent, followed by sample concentration, gave recoveries of > 90% for diminazene and the internal standard. A mobile phase of acetonitrile/0,005 M Na-octane sulphonate, 0.1% triethylamine, pH 3.2 with acetic acid on a Nova Pak C18 column was used for the analysis. Wavelength switching was used to determine the internal standard (imidocarb) and diminazene at their respective wavelengths of maximum absorbance, resulting in a fivefold increase in the limit of detection for diminazene. The modified method attained a detection limit of 2 ng.m.-1 (peak 4x baseline noise), limit of quantitation of 10 ng.m.-1 (coefficient of variation < 15%) and an accuracy of > 96% over the range from 10-5000 ng.m.-1.

Animals↗
PubMed1996

Changes in haematocrit after treatment of uncomplicated canine babesiosis: a comparison between diminazene and trypan blue, and an evaluation of the influence of parasitaemia.

It has been suggested that the antibabesial drug diminazene causes a rapid decline in haematocrit after treatment of dogs with high Babesia canis parasitaemias, compared with trypan blue. To test this, 19 dogs with clinically mild to moderate, uncomplicated babesiosis were placed in low, moderate or high parasitaemia groups, based on venous parasitaemias, and were allotted randomly to diminazene or trypan blue treatment groups. Haematocrit and parasitaemia were determined before treatment, and at 2, 6, 12, 18 and 24 hours. The drugs were compared for effects on haematocrit and parasite clearance. Changes in haematocrit after treatment were analysed. There were no significant differences between diminazene and trypan blue for haematocrit or parasite clearance. There was no correlation between initial parasitaemia and initial or post-treatment haematocrit. In all dogs, haematocrit fell following treatment. The maximum mean reduction from the baseline (0 h) was 0.046 l/l (range 0.02-0.07 l/l); this most often occurred at 6 or 12 h. The 24 h haematocrit ranged from 70.5-113.6% of baseline (mean absolute haematocrit 0.019 l/l below baseline). All dogs improved clinically during the study period. It was concluded that either diminazene or trypan blue can be safely used to treat dogs with clinically mild or moderate, uncomplicated babesiosis. Parasitaemia need not be taken into account when deciding which antibabesial drug to administer and does not appear to be related to the degree of anaemia.

Analysis of Variance↗
PubMed1978

Gas chromatography chemical ionization mass spectrometric analysis of diminazene in plasma.

A quantitative and sensitive method was developed for the determination of diminazene in plasma. The assay involves the reduction of diminazene to 4-aminobenzamidine and 4-hydrazinobenzamidine. The latter is further reduced to give an additional mole of 4-aminobenzamidine which is extracted, acetylated and condensed with hexafluoroacetylacetone to form a volatile derivative that is subsequently analyzed by gas chromatography chemical ionization mass spectrometry. 4-Aminobenzylamidine was synthesized and used as an internal standard. The method is reproducible and its sensitivity limit using 1 ml of plasma is 0.1 microgram diminazene ml-1. This sensitivity limit is sufficient to detect plasma levels in cattle following therapeutic doses of the drug.

Amidines↗
PubMed1985

Pharmacokinetics of diminazene in sheep.

The pharmacokinetic behavior of diminazene in plasma after administration of 2 mg/kg i.v. and 3.5 mg/kg i.m. was studied in four healthy Dala x Ryggja rams. Following i.v. injection, the data were satisfactorily described by a tri-exponential equation; the apparent volume of distribution at the steady-state was 0.56 +/- 0.04 L/Kg (mean +/- SD; n = 4); total body clearance averaged 1.1 +/- 0.09 ml/kg/min and elimination half-life was 9.30 +/- 1.40 hr. After intramuscular administration peak plasma levels of 6.30-7.57 micrograms/ml were reached in 20 to 45 min and the mean absorption time averaged 5.83 +/- 1.61 hr. Systemic availability relative to the intravenous dose was 95.10 +/- 23.21% and mean residence time averaged 14.16 +/- 1.55 hr. The partition of diminazene between erythrocytes and plasma averaged 0.64 +/- 0.10; plasma protein binding was high (65-85%) and concentration-dependent. Based on the experimental data obtained, an initial i.m. dose of 2.5 mg/kg followed by 2 mg/kg 24 hr later should be safe and effective in cases of babesiosis and trypanosomiasis sensitive to diminazene. A preslaughter withdrawal period of 14-26 days was estimated.

Amidines↗
PubMed1995

Disposition of diminazene aceturate (Berenil) in trypanosome-infected pregnant and lactating cows.

Three cows were repeatedly infected with different strains of Trypanosoma congolense and treated intramuscularly each time with a different dose of diminazene aceturate (Berenil). Biphasic decline was observed of the maximal plasma drug levels, which were attained at 15 min after the first treatment and at 30 min after the second and third treatments. The rate constants for the distribution and terminal phases depended on the period of exposure to parasitaemia of the animal at the time of treatment. Maximal diminazene aceturate residue levels were found in milk 8 h post treatment and declined biexponentially to 4.56 ng ml-1 and 8.76 ng ml-1 at 21 days post treatment after 3.5 mg kg-1 and 7.0 mg kg-1 doses, respectively. In the three cows, higher drug residues were found in the kidney (7.04, 3.92 and 7.99 micrograms g-1) than in liver (3.26, 2.87 and 1.24 micrograms g-1) and heart (1.79, 1.25 and 1.03 micrograms g-1). The results of this study indicate that the level of parasitaemia (degree of anaemia) in the animal at the time of treatment affects the distribution, disposition and elimination of diminazene aceturate in the animal. Furthermore, the residue level in milk after treatment depends on the treatment dose and could easily be bioavailable to the consumer.

Animals↗
PubMed1994

Time-dose response of Trypanosoma congolense bloodstream forms to diminazene and isometamidium.

Trypanosoma congolense bloodstream forms were propagated in vitro axenically in a simplified cultivation medium at 34 degrees C. Viability of a drug-sensitive and a drug-resistant clone were examined for 10 days following exposure to 0.1, 1.0 and 10.0 micrograms ml-1 of diminazene aceturate and 0.1, 1.0 and 10.0 ng ml-1 of isometamidium chloride for various time intervals. Drug-sensitive T. congolense were irreversibly damaged after incubation with 10 micrograms ml-1 or 1 microgram ml-1 diminazene aceturate for 30 min or 2 h, respectively, while drug-resistant trypanosomes were not affected. Exposure to 10 ng ml-1 isometamidium chloride eliminated drug-sensitive trypanosomes after 24 h and drug-resistant trypanosomes after 96 h. The data obtained on in vitro time-dose responses of T. congolense were related to pharmacokinetic data of diminazene and isometamidium in cattle plasma.

Animals↗
PubMed2006

SSCP analysis of the P2 purine transporter TcoAT1 gene of Trypanosoma congolense leads to a simple PCR-RFLP test allowing the rapid identification of diminazene resistant stocks.

Analyses were made on a Trypanosoma congolense contig coding a putative P2-like nucleoside transporter (the contig was named in this study TcoAT1). The sequence includes a start and stop codon and presents a high similarity with the gene TbAT1 of T. brucei (Smallest Sum Probability 2.8e-136). To investigate a possible link between point mutations and diminazene aceturate (DA) resistance in mice, the TcoAT1 putative genes of 26 T. congolense strains, characterised for DA sensitivity in the single dose mouse test, were screened by means of the Single Strand Conformation Polymorphism technique (SSCP). Results showed that the SSCP profiles of 23 out of 26 (88.5%) T. congolense strains were confirmed by the sensitivity test in mice with the commonly accepted criterion for sensitivity to diminazene being a CD80 of 20mg/kg in the mouse test. The remaining T. congolense strains showed a resistant SSCP profile and relapsed in mice after treatment at doses lower than 20mg/kg indicating that the SSCP is more sensitive than the single dose mouse test for the detection of resistance to diminazene. However, none of the strains used in this study showed a sensitive SSCP profile while they were resistant in the single dose mouse test. The sequencing of the TcoAT1 gene of two sensitive, two intermediate and two resistant strains allowed the set up of a PCR-RFLP test for the discrimination between sensitive and resistant strains confirming the SSCP results for the 26 strains of this study.

Animals↗
PubMed2004

Lipid-drug conjugate nanoparticles of the hydrophilic drug diminazene-cytotoxicity testing and mouse serum adsorption.

Sleeping sickness is a widely distributed disease in great parts of Africa. It is caused by Trypanosoma brucei gambiense and rhodiense, transmitted by the Tse-Tse fly. After a hemolymphatic stage, the parasites enter the central nervous system where they cannot be reached by hydrophilic drugs. To potentially deliver the hydrophilic antitrypanosomal drug diminazene diaceturate to the brain of infected mice, the drug was formulated as lipid-drug conjugate (LDC) nanoparticles (NP) by combination with stearic- (SA) and oleic acid (OA). To estimate the in vivo compatibility, the particles were incubated with human granulocytes. Because as potential delivery mechanism the absorption of specific serum proteins (ApoE, Apo AI and Apo AIV) was found to be responsible for the delivery of nanoparticles to the brain, demonstrated using PBCA nanoparticles coated with polysorbate 80 (LDL uptake mechanism) the nanoparticles were incubated with mouse serum and the adsorption pattern was determined using the 2-D PAGE technique. As a result of this study, the cytotoxic potential was shown to decrease when diminazene is part of the particle matrix compared to pure fatty acid nanoparticles and the mouse serum protein adsorption pattern differs from the samples studied earlier in human serum. Especially, the fact concerning Apo-E that could be detected when the particles were incubated in human serum is absent after the mouse serum incubation, potentially, is a critical point for the delivery via the LDL-uptake mechanism but the data demonstrate that LDC nanoparticles, with 33% (wt/wt) drug loading capacity possess the potential to act as a delivery system for hydrophilic drugs like diminazene diaceturate and that further studies have to demonstrate the usability as a brain delivery system.

Adsorption↗
PubMed1977

Determination of diminazene in plasma by high-performance liquid chromatography.

An analytical method is described for determining diminazene levels in plasma of cattle. Diminazene is reduced to 4-aminobenzamidine which is extracted and assayed by high-performance ion pair reverse phase partition chromatography. 3,4-Dimethoxybenzamidine served as an internal standard. Diminazene levels as low as 0.1 microgram per ml were detected.

Amidines↗
PubMed1999

Administration of diminazene aceturate or imidocarb dipropionate for treatment of cytauxzoonosis in cats.

Bobcats (Lynx rufus) are the reservoir hosts for Cytauxzoon felis, the causative agent of cytauxzoonosis. Cytauxzoonosis is a highly fatal tickborne blood protozoal disease of domestic and exotic cats. Treatment of clinically affected cats has generally been unrewarding. In our report, 6 of 7 cats had signs of illness and laboratory findings indicative of cytauxzoonosis and were successfully treated with 2 i.m. injections of diminazene aceturate or imidocarb dipropionate (2 mg/kg [0.9 mg/lb] of body weight, each). One cat died after the first injection of diminazene. Additional treatment with isotonic fluids i.v. and heparin s.c. were used as supportive care for dehydration and disseminated intravascular coagulation that were detected by laboratory testing between diminazene or imidocarb treatments. Atropine was effective in recovery and preventing adverse reactions associated with imidocarb treatment of 1 cat.

Animals↗
PubMed1987

The treatment of Trypanosoma (Nannomonas) simiae in pigs with diminazene aceturate in combination with a 5-substituted 2-nitroimidazole compound (Ro 15-0216).

Swine Trypanosoma (N.) simiae infections were treated with diminazene aceturate and a 5-substituted 2-nitroimidazole compound (Ro 15-0216). This combination of the two trypanocidal compounds has been successful. Ten mg/kg of diminazene aceturate and 50 mg/kg of Ro 15-0216 or 20 mg/kg of diminazene aceturate and 25 mg/kg of Ro 15-0216 were equally effective, while either drug alone was ineffective. Multiple administration of compound Ro 15-0216 (4 x 20 mg/kg; 3 x 50 mg/kg) at 2 hourly intervals did not cure the animals.

Acetanilides↗
PubMed1985

Comparative studies of the effects of quinuronium sulfate and diminazene diaceturate in sheep.

Biochemical parameters in 20 sheep were investigated following administration of quinuronium sulfate or diminazene diaceturate. The usual signs of salivation, micturition, anorexia, depression, muscular tremors and ataxia were observed within 20 min in sheep receiving therapeutic and double doses of quinuronium sulfate. There was an increased dose dependent plasma LDH activity above baseline values following administration of quinuronium sulfate and a non-dose dependent increased trend in diminazene diaceturate treatment. Plasma CK activity had an increased trend (p less than 0.05) above baseline values following administration of the two babesicides. Plasma BUN levels increased significantly (p less than 0.05) following administration of the two drugs. This study indicated that quinuronium sulfate is more organotoxic and hypotensive than diminazene diaceturate at therapeutic and/or above therapeutic dosages.

Amidines↗
PubMed1985

Studies in cattle on the disposition of the anti-trypanosomal drug diminazene diaceturate (Berenil).

After intramuscular injection of ca. 3.5 mg kg-1 diminazene diaceturate-(bis-phenyl-U-14C) to two healthy male calves weighing 185 and 180 kg, levels of radioactivity were determined in blood, plasma, urine, faeces, and in edible tissues. The maximal blood level of 4.6 micrograms and 4.7 micrograms equivalents of diminazene diaceturate ml-1 (calculated from total radioactivity) occurred 15 min (calf C1) and 45 min (calf C2) after administration. The decrease in concentration followed a biphasic process with half lives of 2 and 188 hours. Seven days after treatment 47.1% of the dose had been excreted in the urine and 7.1% in the faeces. The respective values were 72.2% and 10.3% after 20 days. The half lives were similar to those in blood. The main product in urine was unchanged diminazene. Distribution studies showed concentrations which were low in general in edible tissues, i.e. in skeletal musculature and fat (below 1 microgram equivalent g-1), but higher in organs with excretory functions. There were 75.5 micrograms equivalents g-1, corresponding to 22% of the dose, in the liver 7 days after injection. This had decreased to 24.4 micrograms equivalents g-1, corresponding to 15% of the dose, at day 20. Only unchanged deminazene was detected in the liver extracts by thin-layer chromatography. Relay-bioavailability studies showed that the total liver residues were only partially available (mean = 23% of the dose) when fed to rats.

Amidines↗
PubMed1984

The effect of halofuginone, Wellcome 993 C, oxytetracycline, and diminazene diaceturate on Babesia equi-infected lymphoblastoid cell cultures.

The efficacy of halofuginone (DL-trans-7-bromo-6-chloro-3,3-(3-hydroxy-2-piperidyl) acetonyl-4-(3H) quinazolinone), Wellcome 993 C (2-hydroxy-3-cyclohexyl-1,4-naphthoquinone), and oxytetracycline, all of which have been shown to have a schizonticidal effect in the treatment of bovine theileriosis, and the babesicidal drug diminazene diaceturate, were tested against the schizont stages of Babesia equi in cell culture. The in vitro test system measured DNA synthesis in treated and untreated cell lines. Halofuginone (0.02 microgram/ml) and Wellcome 993 C (5 micrograms/ml) suppressed the incorporation of tritiated thymidine by more than 80%. Oxytetracycline was less effective, while diminazene diaceturate showed no notable effect. The insufficient schizonticidal activity may explain the failure of diminazene diaceturate to cure B. equi infections. Schizonticidal drugs either alone, or in combination with known babesicidal drugs, should be tested in the chemotherapy of B. equi infections.

Amidines↗
PubMed1994

[Control of Trypanosoma gambiense trypanosomiasis. Evaluation of a strategy based on the treatment of serologically suspected cases with a single dose of diminazene].

A novel method for the control of T.b. gambiense trypanosomiasis was evaluated in an endemic focus of Zaïre where a high incidence had persisted despite massive participation in active case-finding surveys based on lymph node puncture. All inhabitants of 3 villages were examined with a card agglutination serological test (CATT), and parasitological examinations were performed on those who were CATT+. Individuals in whom we detected trypanosomes were treated as usual. A lumbar puncture was carried out on CATT+/parasitology- subjects; those whose cerebrospinal fluid showed more than 3 white blood cell (WBC) per mm3 were treated with a full course of melarsoprol while those with a CSF WBC count between 1 and 3 per mm3 were given a single injection of diminazene (7 mg/kg). Three such surveys were performed, with a 6-month interval, during which 282 "serological suspects" received diminazene, 39 "clinical cases" were given melarsoprol and 82 "parasitological cases" were treated according to standard protocols. The annual incidence of trypanosomiasis decreased rapidly from 10.4-41.1/1.000 inhabitants (mean: 17.6/1.000) during the 10 years before the intervention to 1.1-2.6/1.000 (mean: 1.7/1.000) in the 3 years following the intervention. No major adverse effect was seen with diminazene. Among the 282 serological suspects, an elevated CSF WBC count was later documented in 12 individuals, who were all cured with melarsoprol. The incidence increased 5 years after the intervention (7.1/1.000 in 1992), which may have been avoided had we carried out similar interventions in adjacent foci.

Agglutination Tests↗