Disease relevance of DIMINAZENE

• Subcurative treatment with diminazene aceturate, which did not clear parasites from the central nervous system, resulted in a post-treatment meningoencephalitis similar to that seen in man [1].
• The binding of berenil to Escherichia coli ribosome [2].
• All animals were treated with diminazene aceturate (7 mg/kg of body weight) 2 weeks before the start of the experiment and were tested monthly by the buffy coat technique for a period of 8 months [3].
• Resistance to diminazene aceturate (Berenil) is a severe problem in the control of African trypanosomiasis in domestic animals [4].
• Hypergammaglobulinemia was also induced in relapsing T. equiperdum-infected mice treated with Berenil [5].

High impact information on DIMINAZENE

• Berenil (4,4'-diazoamino-bis-benzamidine), a parabolic competitive inhibitor of beta-trypsin, was a hyperbolic competitive inhibitor of azo-beta-trypsin [6].
• After Berenil treatment of terminally infected mice immunocompetence was restored gradually, first to the lymph node cells and subsequently to the spleen cell population [7].
• We observe that the binding of berenil induces characteristic responses in different helical parameters for the base-pairs around the binding site [8].
• The technique has been applied to analyse the binding of berenil to the minor groove of a 60 base-pair sequence derived from the tyrT promoter; the results are compared with those obtained by DNAse I and hydroxyl radical footprinting on the same sequence [8].
• Interaction of berenil with the tyrT DNA sequence studied by footprinting and molecular modelling. Implications for the design of sequence-specific DNA recognition agents [8].

Chemical compound and disease context of DIMINAZENE

• On the other hand, Berenil, Antrycide and suramin, used against African trypanosomiasis, inhibited protein biosynthesis in vitro but did not affect ribosomal distribution, probably due to low permeability to the drugs [9].
• The activities of the N-acetyltransferase from O. volvulus and A. suum were potently inhibited by the drug berenil; the type of inhibition was competitive with respect to putrescine [10].
• When infected mice were treated on the second day of detectable parasitaemia, there was complete cure with Berenil at 10 mg/kg, Novidium at 4 mg/kg and Samorin at 0.2 mg/kg body weight respectively [11].
• Relapses in dogs experimentally infected with Trypanosoma brucei and treated with diminazene aceturate or isometamidium chloride [12].
• Primaquine is active only against 'L. infantum LV9'. All three parasites in mice respond to Berenil, but not to pentamidine which is used in the treatment of kala-azar [13].

Biological context of DIMINAZENE

• Since there is evidence that Berenil binds preferentially to AT-rich DNA and seems to be involved in inhibition of DNA replication, the following hypothetical model can be proposed [14].
• The replication of the circular kDNA molecules is discontinuous and involves the synthesis of RNA primers; when Berenil is bound to the AT-rich regions, synthesis of new RNA primers is inhibited and replication is blocked at these points, leading to the accumulation of replicating intermediates with defined branch lengths [14].
• On binding with berenil, the ribosome is degraded faster by RNase I especially at low Mg++ concentration and its capacity to inhibit RNase I catalysed hydrolysis of ribopolymers is decreased [2].
• Comparative pharmacokinetics of diminazene in noninfected Boran (Bos indicus) cattle and Boran cattle infected with Trypanosoma congolense [15].
• (v) Berenil binding unwinds negative supercoils in the pBR322 plasmid, an observation consistent with an intercalative mode of binding to duplex DNA [16].

Anatomical context of DIMINAZENE

• There is positive cooperativity in the binding of berenil to the ribosome as demonstrated by the equilibrium dialysis [2].
• Berenil treatment abolished the immune depression against sheep erythrocytes, but did not cure the animals, which relapsed with the development of a new state of immune depression [5].
• We also used localized spectroscopy to monitor the uptake of diminazene acturate, an antitrypanosomal agent, into compartments of a single living oocyte [17].
• BALB/c mice infected with Trypanosoma brucei and treated seven days after inoculation with Diminazene aceturate develop polyclonal B-cell stimulation, including production of antibodies to known nephritogenic autoantigens and glomerular disease associated with severe albuminuria [18].
• In the lymphocytes of heterozygous carriers of the rare autosomal fragile site (16)(q22) an exceptionally high frequency of sister chromatid exchanges was demonstrated at the induced fragile site by means of simultaneous berenil and BrdU treatment of the cultures [19].

Associations of DIMINAZENE with other chemical compounds

• A theoretical study of the nonintercalative binding of berenil and stilbamidine to double-stranded (dA-dT)n oligomers [20].
• This arrangement is distinct from that previously found for berenil with the sequence d(CGCGAATTCGCG)2, which has the drug bound to the sequencing 5'-ATT via hydrogen bonds to adenine N-3 atoms with the involvement of a bridging water molecule at one end of the binding site [21].
• One agent, CGP 40215A, a bicyclic analog of MGBG which also resembles the diamidines diminazene (Berenil) and pentamidine, was curative of infections by 19 isolates of Trypanosoma brucei subspecies as well as a Trypanosoma congolense isolate [22].
• Guanine alkylation by duocarmycin A was not observed with berenil, Hoechst 33258, or DAPI [23].
• We have studied a number of petite [rho-] mutants of Saccharomyces cerevisiae induced in a wild-type strain of mitochondrial genotype [ome- CHL(R) ERY(S) OLI(S) (1, 2, 3) PAR(S)] by Berenil and ethidium bromide, all of which have retained two mitochondrial genetic markers, [CHL(R)] and [ERY(S)], but have lost all other known markers [24].

Gene context of DIMINAZENE

• We document two unrelated normal individuals who are homozygotes for the rare fragile site FRA16B and record the patterns of induction of this fragile site with berenil [25].
• Treatment of mice on day 21 with a subcurative dose of diminazene aceturate (Berenil), a procedure known to induce a mild PTRE, cleared the parasite from the circulation with plasma APP and liver expression of mRNA for IL-6 and TNFalpha returning to the levels in the controls [26].
• Berenil does not bind within the triplex target sequence, and only one berenil binding sequence downstream of the triplex motif was present within the c-Ki-ras promoter fragment [27].
• The amidine protons on berenil are also close to the H2 proton of both adenines [28].
• Competitive electrophoretic mobility shift assays were used to show that berenil, distamycin, and mithramycin, all of which bind in the minor groove, compete with MBP-1 for binding to the MPB-1 binding site [29].

Analytical, diagnostic and therapeutic context of DIMINAZENE

• The binding of the nonintercalating dye berenil to the 70S ribosome of Escherichia coli has been demonstrated by spectrophotometric measurements and gel filtration through Biogel P100 column [2].
• In cattle infected with T. congolense, simultaneous Berenil treatment at the time of vaccination abolished the suppression of immune response to L. biflexa, and lessened but did not abrogate the suppression of immune response to B. abortus [30].
• Suppression of antibody response to Leptospira biflexa and Brucella abortus and recovery from immunosuppression after Berenil treatment [30].
• 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 [31].
• Four weeks after infection, the goats were treated with 10 mg/kg diminazene aceturate (Berenil, Hoechst A.G.). Three weeks after treatment, 3 goats in each group were challenged intradermally with 10(4) homologous metacyclics derived from culture [32].

References