Efficacy of Cymelarsan and Diminasan against Trypanosoma equiperdum infections in mice and horses.

Trypanocidal sensitivity studies were conducted to assess the efficacy of Diminazene diaceturate (Diminasan) and Bis (aminoethylthio) 4-melaminophenylarsine dihydrochloride (Cymelarsan) against Trypanosoma equiperdum (isolated from two mares with chronic cases of dourine) 713/943 and 834/940 Dodola strains in experimentally infected mice and horses. Diminasan at doses from 3.5 mg/kg to 28 mg/kg and Cymelarsan at doses of 0.25 mg/kg and 0.5 mg/kg body weight failed to cure any of the mice, indicating a clear dose dependent relationship in the mean time of relapse observed in mice. Indeed, mice treated with lower doses relapsed after a shorter time than mice treated with higher doses. However, mice treated with Cymelarsan at doses of 1.0 mg/kg and 2.0 mg/kg body weight were cured and no parasitemia was observed for 60 days. The efficacy of Cymelarsan was also tested in horses. Two groups of horses containing two animals each were infected with T. equiperdum 834/940 Dodola strain and treated with Cymelarsan at a dose rate of 0.25 mg/kg and 0.5 mg/kg, respectively. Cymelarsan at 0.25 mg/kg and 0.5 mg/kg body weight cleared parasitemia within 24 h post treatment and none of the animals were found to show relapse throughout the 320 days of observation. The sensitivity of the particular trypanosome strain to Cymelarsan was also supported by the relative improvement in the mean PCV levels of horses following treatment. A statistically significant difference (p<0.01) in the mean PCV levels of horses treated with Cymelarsan was observed between day 20 at peak parasitemia and days 40 as well as 60 of observation. The mean PCV levels of horses in the control group progressively decreased within the first 60 days of post infection. Two of the horses in the control group developed chronic form of dourine manifested by genital as well as nervous signs with progressive loss of body condition within 320 days post infection. The efficacy of Cymelarsan against the chronic form of dourine was confirmed after treatment of one of the control horses with Cymelarsan at a dose rate of 0.25 mg/kg body weight at day 282 post infection. It was noted that the treated horse improved overall body condition and clinical signs such as incoordination of hind legs, weakness and ventral oedema disappeared within 10 days of treatment. Thus, Cymelarsan was found to be quite effective in curing horses in acute as well as chronic form of dourine. The results obtained from the present study will be important for designing effective control measures against dourine.

Seroepidemiological survey of trypanozoon infection in horses in the suspected dourine-infected Bale highlands of the Oromia region, Ethiopia.

This paper presents the results of a seroepidemiological survey of trypanozoon infection in horses carried out between September 2007 and June 2008. The survey was conducted to determine the seroprevalence of anti-trypanozoon antibodies in 880 serum samples collected randomly from selected horse-breeding districts of the Bale highlands of Ethiopia. The seroprevalence of trypanozoon infection was found to be 173 (19.66%) and 140 (15.91%) for the CATT/T. evansi and LATEX/T. evansi tests, respectively. The high seroprevalence of trypanozoon infection strongly indicates that the infection is endemic. Neither test can differentiate between anti-trypanozoon antibodies caused by infection with T. equiperdum (the causative agent of dourine) and those of T. evansi (the causative agent of surra). The findings of the present study suggest that field-applicable screening serological tests such as the CATT/T. evansi and LATEX/T. evansi could be useful for epidemiological studies and the control of trypanozoon infection.

Echinococcosis/hydatidosis: its prevalence, economic and public health significance in Tigray region, North Ethiopia.

A cross sectional study was carried out to assess the prevalence, economic and public health significance of echinococcosis/hydatidosis in Tigray Regional State, north Ethiopia. Out of 18 stray dogs euthanized and examined, three of them were found harboring the adult parasite Echinococcus granulosus in their small intestine. From 5,194 cattle examined at slaughter houses, 1146 (22.1%) of them were found harboring hydatid cyst. The majority of the infected cattle had hydatid cyst in both liver and lungs. The hydatid cyst infection in the lung, liver, kidney, heart and spleen were found to be 13%, 8.1%, 0.5%, 0.4%, and 0.1%, respectively. The estimated total annual loss from bovine hydatidosis due to offal condemnation (lungs and liver) and carcass weight loss was 25,608 Ethiopian (Eth.) Birr. The present human hydatidosis survey conducted in all six zonal hospitals of Tigray Regional State disclosed one active clinical case in Mekelle hospital during the study period. While, the retrospective data analyses of the six zonal hospitals indicated that eight cases of human hydatidosis were diagnosed since 2000. Thus echinococcosis/hydatidosis is considerably prevalent disease in cattle and it is a serious public health concern in Tigray region.

Prevalence of bovine trypanosomosis and trypanocidal drug sensitivity studies on Trypanosoma congolense in Wolyta and Dawero zones of southern Ethiopia.

Cross-sectional studies were conducted in tsetse and non-tsetse-controlled areas of the Southern Nation Nationalities and Peoples Regional State (SNNPRS) of Ethiopia to determine the prevalence of bovine trypanosomosis as well as drug sensitivity tests on Trypanosoma congolense in both naturally and experimentally infected cattle and mice, respectively. A total trypanosome prevalence of 4.8% (95% CI: 1.8-7.5) and 20.4% (95% CI: 14-26.8) were recorded in the tsetse-controlled study area of Humbo district and the non-tsetse-controlled area of Mareka district, respectively, indicated statistically significant difference between the two areas (P<0.001). The mean PCV value for Humbo and Mareka was 26.2 (95%: 25.7-26.7) and 22.7 (95% CI: 22.1-23.3), respectively, which were also statistically significant (P<0.001). The prophylactic activity of isometamidium chloride (ISMM) was observed in Humbo on nine naturally positive zebu cattle. Breakthrough infections were recorded in (6/9) 66.7% of the cases in less than 5 weeks. A qualitative assay on mice was conducted on two T. congolense isolates obtained from the breakthrough cases with ranges of doses of ISMM and diminazene diaceturate (DA). Thereafter the mice were followed for relapse infection. ISMM at doses 0.5-4 mg/kg body weight (bw) and DA at doses of 3.5-28 mg/kg bw failed completely to cure T. congolense infections in any of the mice. A quantitative assay on mice was conducted on four T. congolense isolates obtained from Mareka. The four isolates were pooled into two pools (Pool-1 and Pool-2) for the quantitative assay on mice. The pooled isolates were tested with the same trypanocidal drugs and ranges of doses as it was used for the qualitative assay on mice. The minimum curative dose (MCD) of ISMM that cleared T. congolense infected mice was 4 and 2mg/kg bw for Pool-1 and Pool-2, respectively, whereas MCD of DA was 28 and 14 mg/kg bw, in Pool-1 and Pool-2, respectively. Although cloned populations were not used to prove whether the observed resistance was at the individual level or not, the results show that there is resistance to both ISMM and DA; failure of the "sanative pair".

Selective transport of a new class of purine antimetabolites by the protozoan parasite Trypanosoma brucei.

Purine antimetabolites have been very successful therapeutic agents against a host of infectious diseases and malignancies. Success of the treatment relies as much on the efficient accumulation by the target cell or organism as it does on selective action on a vital biochemical pathway of the target cell. Here we compare the ability of a new class of tricyclic purine antimetabolites to interact with transporters from human erythrocytes or Trypanosoma brucei. We show that these compounds display a remarkable selectivity for the parasite's transporters. The adenine analogue showed greater trypanocidal activity than the hypoxanthine or guanine analogues in vitro.

"Fleximers". Design and synthesis of two novel split nucleosides.

[structure: see text] A new class of shape-modified nucleosides is introduced. The purine heterobases of adenosine and guanosine have been split into their imidazole and pyrimidine components, thereby introducing flexibility while retaining the elements necessary for recognition. As a consequence, these novel "fleximers" should find use as bioprobes for investigating enzyme-coenzyme binding sites as well as nucleic acid and protein interactions. Their design and synthesis is described.

Synthesis and antitumor activity of thieno-separated tricyclic purines.

The purine ring system is undoubtedly one of the most ubiquitous heterocyclic ring systems in nature as it has the distinction of being the parent ring in countless derivatives of biological relevance. It is not surprising then that modified purines possess the potential to impact several areas, including a better understanding of the biological effects of DNA damaging agents, enzyme/substrate interactions, and in the development of more potent medicinal agents. One focus for our research at Georgia Tech has centered around the design and synthesis of a series of extended purine analogues containing a heterocyclic spacer ring, with sites set on investigations into their use as (i) potential anticancer and antiviral agents, (ii) dimensional probes for enzyme and coenzyme binding sites, and (iii) structural probes of the minor groove of DNA. The synthesis and preliminary antitumor activity of two thieno-separated purine analogues are described herein. Tricyclic 1 was synthesized in 12 steps from tribromoimidazole and with an overall yield of 7%. Tricyclic 2 was synthesized in 9 steps with an overall yield of 13%. Both 1 and 2 exhibited growth inhibitory effects on HCT116 colorectal cancer cells in vitro.