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PubMed2006

Complexes of poly(ethylene oxide)-block-poly(L-glutamate) and diminazene.

Nanoparticles with a mean hydrodynamic radius of 16 nm and low polydispersity (P.I. = 0.1) were spontaneously formed by the complexation of poly(ethylene oxide)-block-poly(L-glutamate) (PEO-b-PLGlu) with diminazene. Only one of two possible binding sites of each diminazene molecule was involved in complexation. As determined by UV-vis difference spectra measurements, the complex binding constant is on the order of 1-2 x 10(4) M(-1). Circular dichroism measurements showed that the highly water-soluble diminazene can induce and stabilize the alpha-helical secondary structure of a PLGlu block.

Journal Article↗
PubMed1988

The Effect of Diminazene Aceturate on Spienectomized Dogs with Babesia gibsoni Infection.

The effect of diminazene aceturate on splenectomized and nonspienectomized dogs with Babesia gibsoni (B. gibsoni) infection was investigated. In splenectomized dogs, the fissional and multiplicational stages of B. gibsoni were observed in peripheral blood films, and hemoglobinuria was frequently observed. These findings were different from previous reports and were not changed by administration of diminazene aceturate. It is clear that the intramuscular administration of diminazene aceturate at the dose of 3 mg/kg body weight for 3 days is not effective against B. gibsoni infection in splenectomized dogs.

Journal Article↗
PubMed1991

The effect of diminazene aceturate and isometamidium chloride on cultured procyclic forms of susceptible and drug-resistant Trypanosoma congolense.

Cultures of insect forms of Trypanosoma congolense stocks and clones with different susceptibilities to trypanocidal drugs in vivo were initiated from bloodstream trypomastigotes harvested from mammalian hosts and maintained axenically in vitro at 27 degrees C. Growth inhibition of procyclic forms of susceptible and drug-resistant T. congolense occurred after incubation for 48 h with 0.1 ng isometamidium chloride ml or 500 ng diminazene aceturate/ml. Procyclic forms were propagated in vitro in the presence of 10 or 100 ng diminazene aceturate/ml for 20 days without or with only minor loss of growth. In the presence of 0.1 or 1 ng isometamidium chloride/ml the trypanocidal effect was detectable after 6-8 days and the cultures died after 10-12 days. Concentrations of 1 or 10 ng isometamidium chloride/ml had an irreversible effect when the trypanosomes were exposed to the drug for 24 h. Both drugs used in this study thus showed antitrypanosomal activity on T. congolense procyclic forms but it was not possible to distinguish between drug-resistant and susceptible stocks or clones employing the criteria of growth inhibition or death of trypanosomes in culture.

Animals↗
PubMed1993

Epidemiology of bovine trypanosomiasis in the Ghibe valley, southwest Ethiopia. 3. Occurrence of populations of Trypanosoma congolense resistant to diminazene, isometamidium and homidium.

In July 1989, blood samples were collected from parasitaemic cattle in the Ghibe valley, Ethiopia, frozen in liquid nitrogen and transported to Nairobi, Kenya. Twelve of the stabilates were inoculated into individual Boran (Bos indicus) calves and characterised for their sensitivity, in turn, to diminazene aceturate (Berenil), isometamidium chloride (Samorin) and homidium chloride (Novidium). All 12 stabilates produced infections which were shown to be Trypanosoma congolense and resistant to treatment with diminazene aceturate at a dose of 7.0 mg kg-1 body weight (b.w.). Eleven of the infections were also resistant to isometamidium chloride at a dose of 0.5 mg kg-1 b.w. and homidium chloride at a dose of 1.0 mg kg-1 b.w. The drug-sensitivity phenotypes of three of the same isolates were also determined in goats which were each treated with only one of the three trypanocides: all expressed the same phenotypes as the populations expressed in the aforementioned Boran calves. Five clones were derived from one of the isolates which expressed a high level of resistance to all three trypanocides; each clone expressed high levels of resistance to all three trypanocides when characterised in mice. Thus, the multi-resistance phenotype of the parental isolate was associated with expression of mutli-resistance by individual trypanosomes. Finally, molecular karyotypes and electrophoretic variants of six enzymes were determined for seven and eight of the isolates, respectively. Six different karyotypes were observed and all eight of the latter isolates belonged to different zymodemes, indicating that the multi-resistance phenotype at Ghibe was associated with many genetically distinct populations.

Animals↗
PubMed1994

Pharmacokinetics of diminazene in plasma and cerebrospinal fluid of goats.

The pharmacokinetics of diminazene in the cerebrospinal fluid (CSF) and plasma of five uninfected goats treated with single intramuscular doses of 3.5 mg diminazene base kg-1 bodyweight was investigated. The concentrations of the drug were determined by high performance liquid chromatography, and were three to four times lower in CSF than in plasma. The kinetics of the drug in CSF and plasma differed significantly with respect to Cmax, tmax, AUC0-48h, AUMC0-48h, Cl and Vd(ss).

Animals↗
PubMed1986

Chemoprophylactic activity of imidocarb, diminazene and oxytetracycline against Babesia bovis and B. bigemina.

Splenectomized calves treated with imidocarb, diminazene, and oxytetracycline were exposed to Babesia bigemina and B. bovis stabilates at various time intervals following treatment to evaluate prophylactic efficacy. Diminazene showed no residual activity against a B. bigemina challenge given 54 days after treatment. Oxytetracycline appeared responsible for an increased incubation time when given 2 days prior to B. bigemina exposure. Imidocarb showed marked prophylactic efficacy against both B. bigemina and B. bovis. Treatment with 1 or 2 mg kg-1 imidocarb, followed by Babesia exposure on the day of treatment, 7 days after treatment, then every 14 days for 91 days, delayed patent B. bigemina infections for 49 days and patent B. bovis infections for 42 days. Imidocarb at 4 or 5 mg kg-1, followed by similar Babesia exposures, delayed patent B. bovis infections for 68 days, and delayed B. bigemina for 81-103 days, and in some instances prevented infections. The delayed onset of infection due to either B. bigemina or B. bovis, following imidocarb treatment was accompanied by a significantly milder clinical response. Calves not responding to the primary challenge were fully susceptible to stabilate challenge 196 days after treatment. Calves experiencing a mild clinical response to B. bovis following imidocarb treatment and exposure failed to show any signs of response to a 196-day challenge exposure. Calves experiencing a mild clinical response to B. bigemina following imidocarb treatment and exposure did, in some instances, show a second mild response when challenged 196 days after initial treatment.

Amidines↗
PubMed1990

Effects of the combination of DL-alpha-difluoromethylornithine and diminazene aceturate in Trypanosoma congolense infection of dogs.

The therapeutic activity of a combination of difluoromethylornithine (DFMO) with diminazene aceturate was investigated in mongrel dogs experimentally infected with Trypanosoma congolense. The criteria used in the assessment of the trypanocidal effect of the therapy include the examination of the blood for parasites, as well as clinical and haematological changes at intervals following treatment. Diminazene aceturate and DFMO alone and in combination produced intermittent aparasitaemia in the dogs. Although relapse infection occurred with all three treatment regimes, the drug combination gave the best result. The packed red cell volume, haemoglobin concentrations and red blood cell values decreased significantly following parasite inoculation but increased after treatment. The total leucocyte counts decreased in all the infected dogs but improved with treatment, and the differential leucocyte counts indicated neutropenia in all the infected animals prior to treatment.

Animals↗
PubMed1990

Teratological assessment of the antiprotozoal, diminazene diaceturate, in rats.

Diminazene diaceturate was dissolved in deionized water and administered to pregnant rats by oral gavage once daily on days 8-15 of pregnancy at dose levels of 0, 100, 250, 500 and 1000 mg/kg. On day 21 of pregnancy, the dams were killed and the number of implants, resorptions and live fetuses counted. All fetuses were examined by routine teratological method. A significant increase in fetal resorptions and decrease in fetal body weights were found at the 1000 mg/kg dose. No significant increase in the incidence of anomalous fetuses was observed in external, skeletal and internal examinations even at the maternally toxic dose of 1000 mg/kg. Thus, these data indicate that diminazene diaceturate is not teratogenic in rats.

Administration, Oral↗
PubMedDate not supplied

RNA-interference silencing of the adenosine transporter-1 gene in Trypanosoma evansi confers resistance to diminazene aceturate.

Drug resistance of trypanosomes is now a problem, but its underlying mechanisms are not fully understood. Cellular uptake of the major trypanocidal drugs is thought to occur through an adenosine transporter. The adenosine transporter-1 gene, TbAT1, encoding a P2-like nucleoside transporter has previously been cloned from Trypanosoma brucei brucei, and when expressed in yeast, it showed very similar substrate specificity to the P2-nucleoside transporter, but could not transport diamidines (pentamidine and diminazene). We have cloned and sequenced a similar gene (TevAT1) from Trypanosoma evansi and found it to have 99.7% identity to the TbAT1 gene. To elucidate the role of the TevAT1 gene on diamidine trypanocidal effect, we genetically engineered T. evansi for conditional knock-out of the TevAT1 gene by RNA interference (RNAi). Induction of the RNAi resulted in 10-fold depletion of TevAT1 mRNA, with concomitantly significant resistance to diminazene aceturate (berenil). The induced parasites propagated normally and attained peak cell density at an in vitro concentration of berenil, 5.5-fold higher than the IC(100) of the wild-type. TevAT1 knock-out had no effect on the trypanocidal activity of suramin and antrycide, but conferred some resistance to samorin. Our findings validate the significance of the TevAT1 adenosine transporter-1 gene in mediating the trypanocidal effect of diamidines in T. evansi. Further, we show for the first time that RNAi gene silencing in T. evansi can be induced using plasmids designed for T. brucei. We also demonstrate the usefulness of real-time PCR in rapidly quantifying mRNA levels in trypanosomes.

Animals↗
PubMed2005

Diminazene aceturate resistance on the virulence of Trypanosoma brucei for rats.

Four groups (A, B, C and D) of 10 naïve rats were used to compare the virulence of isolates of a strain of Trypanosoma brucei before and after the development of diminazene aceturate resistance. Group A rats were uninfected (controls). Group B rats were infected with a trypanosome isolate unexposed to the drug, while groups C and D rats were infected with two different drug-resistant isolates of the same strain. Rats in the three infected groups each received 10(6) trypanosomes intraperitoneally. Prepatent periods were longer (P<0.05) in groups C and D than in group B. The parasitaemic periods in groups B, C and D were similar, but group C and D rats differed from group B rats in surviving longer, and in showing lower degrees of parasitaemia, anaemia and hepatomegaly. No differences were noted between group C and D rats. Thus, diminazene aceturate resistance appeared to reduce the virulence of T. brucei.

Animals↗
PubMed1983

Studies in rabbits on the disposition and trypanocidal activity of the anti-trypanosomal drug, diminazene aceturate (Berenil).

After intramuscular injection of 3.5 mg kg-1 to rabbits, diminazene aceturate shows biphasic pharmacokinetics with maximum blood and interstitial fluid concentrations occurring after 15 min and 3 h respectively. Seven days after treatment, 40-50% of the dose had been excreted in the urine and 8-20% in faeces. Highest diminazene residues were determined in liver: 7 days after dosage, residues of 40.53 +/- 4.00 micrograms g-1 were present, corresponding to 35-50% of the dose. The recommended dose of 3.5 mg kg-1 was not curative for Trypanosoma congolense infections of rabbit but did cause the parasitaemia to become subpatent. A limited prophylactic effect was observed.

Amidines↗
PubMed1997

The effect of diminazene aceturate on cholinesterase activity in dogs with canine babesiosis.

A clinical trial was designed to evaluate the effects of diminazene aceturate and its stabiliser antipyrine on serum pseudocholinesterase (PChE) and red blood cell acetylcholinesterase (RBC AChE) in dogs with babesiosis. The trial was conducted on naturally occurring, uncomplicated cases of babesiosis (n = 20) that were randomly allocated to groups receiving a standard therapeutic dose of diminazene aceturate with antipyrine stabiliser (n = 10) or antipyrine alone (n = 10). Blood was drawn immediately before and every 15 minutes for 1 hour after treatment. Plasma PChE showed a 4% decrease between 0 and 60 min within the treatment group (p < 0.05). No statistically significant differences were found between the treatment and control groups at any of the time intervals for PChE. There was an increase in RBC AChE activity at 15 min in the treatment group (p < 0.05). No significant differences were found between the treatment and control groups at any time interval for RBC AChE. In view of the difference in PChE, samples from additional, new cases (n = 10) of canine babesiosis were collected to identify the affect of the drug over 12 hours. No significant depression was identified over this time interval. The results suggests that the underlying mechanism in producing side-effects, when they do occur, is unlikely to be through cholinesterase depression.

Acetylcholinesterase↗
PubMed2003

The effects of diminazene aceturate on systemic blood pressure in clinically healthy adult dogs.

Diminazene aceturate is a commonly used antibabesial agent. It has been postulated that diminazine may induce a decrease in blood pressure and exacerbate the hypotension presented in dogs with babesiosis. This study was undertaken to assess the effect of diminazine aceturate on the blood pressure of healthy dogs. Six healthy German shepherd dogs between 18 and 24 months of age with a mean weight of 30.4 +/- 2.75 kg were used. Blood pressure was directly measured at the following time intervals: -5, 0, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 90 and 120 minutes after treatment with diminazine aceturate (4.2 mg/kg) intramuscularly. No statistical difference (P > 0.05) was found in blood pressure between any of the time intervals. An increase in heart rate was seen 5 minutes after the administration of diminazine aceturate but no change in blood pressure was evident. This study concluded that diminazene aceturate in its current formulation with antipyrine does not alter blood pressure in healthy adult dogs.

Animals↗
PubMed2005

The susceptibility of Trypanosoma congolense isolated in Zambézia Province, Mozambique, to isometamidium chloride, diminazene aceturate and homidium chloride.

Resistance to trypanocidal drugs has been detected in various African countries and is a serious impediment to the control of livestock trypanosomosis. To determine whether drug resistant trypanosome strains are present in the Zambézia Province of Mozambique a study was initiated. To assess the effect of the farming system and the drug-use regimen on the development of drug resistance, trypanosome isolates were collected from cattle from subsistence and commercial livestock production systems. The susceptibility of seven isolates against isometamidium chloride, diminazene aceturate and homidium chloride was tested in mice using a multiple-dose test. In four of the seven isolates high levels of drug resistance to diminazene aceturate and isometamidium chloride were detected. In most cases the observed levels of drug resistance correlated with the drug-use practices in the particular livestock production system.

Animals↗
PubMed1979

Neurologic complications following the treatment of human Babesia microti infection with diminazene aceturate.

A 65-year-old man infected with Babesia microti failed to respond to therapy with oral chloroquine phosphate. He was then successfully dreated with diminazene aceturate, an experimental anti-protozoal agent. After his recovery from babesiosis, the patient developed acute idiopathic polyneuritis (Landry-Guillain-Barré Syndrome), which was probably related to his diminazene therapy.

Aged↗
PubMed1991

Efficacy of combination of DFMO and diminazene aceturate in the treatment of late stage Trypanosoma brucei brucei infection in rats.

The therapeutic activity of difluoromethylornithine and diminazene aceturate alone and in combination was investigated in albino rats with late stage Trypanosoma brucei brucei infection. The criteria used in the assessment of the trypanocidal effect of the compounds include the degree of parasitaemia, and frequency of relapse and death. DFMO (4 percent administered in drinking water for 6 days) and diminazene aceturate (10 mg per kg intraperitoneal) produced an intermittent aparasitaemia with relapse occurring in the two groups. A combination of the two agents produced a permanent cure. The combination of the two agents appear to act synergistically in the treatment of T.b. brucei C.N.S. infection in rats.

Animals↗
PubMed1988

Berenil (diminazene aceturate)-resistant Trypanosoma congolense in cattle under natural tsetse challenge at Kibaha, Tanzania.

Twenty-nine cattle, naturally infected with Trypanosoma congolense Kibaha, were subjected to chemotherapy with diminazene aceturate (Berenil, Hoechst) at 3.5 to 14.0 mg/kg. Fourteen animals recovered while six were refractory to treatment at 7.0 to 14.0 mg/kg. Further treatment of the Berenil-resistant isolates with isometamidium chloride (Samorin, May and Baker) at 1.0 mg/kg, effected cure. Corresponding chemotherapeutic trials in mice showed that the isolates were resistant to diminazene aceturate at 56.0 mg/kg and sensitive to Samorin at 20.0 mg/kg. It is noted, that T. congolense infections that do not respond to treatment with Berenil at 7.0 mg/kg may indicate development of resistance; the use of Samorin at 1.0 mg/kg or Homidium may be the alternative. The paper calls for judicious use of Berenil and Samorin, as they are the only sanative pairs available for the chemotherapy of bovine trypanosomiasis.

Amidines↗
PubMed1989

Effect of in vitro cultivation on the stability of resistance of Trypanosoma brucei brucei to diminazene, isometamidium, quinapyramine, and Mel B.

A Trypanosoma brucei brucei stock resistant to diminazene aceturate, isometamidium chloride, quinapyramine sulfate, and Mel B was grown in vitro and its response to these drugs compared to that of a drug-sensitive trypanosome stock. There was little if any change of drug sensitivity after in vitro propagation as bloodstream forms for 120, 177, and 275 days and after in vitro transformation of bloodstream forms into procyclic, epimastigote, and finally metacyclic forms. Drug resistance was stable during in vitro maintenance in the absence of drugs in both culture systems. The response of resistant and sensitive T. b. brucei to diminazene in vitro correlated with their sensitivity pattern in vivo. Thus, in vitro techniques can be used to study drug resistance in trypanosomes.

Animals↗