Evaluation of quinolone derivatives for antitrypanosomal activity.
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About 160 fluoroquinolones and derivatives were tested for antitrypanosomal activity in a drug sensitivity assay followed by fluorometric evaluation. The most active quinolone compounds had IC50 values in the range from 100 to 900 ng/ml, while several derivatives were not active at a concentration of 100 microg/ml. In a structure activity relationship study, modification of the quinolones at position R1, R2, R3 and R8 did not influence trypanocidal activity. An exchange of the fluor at position 6 may contribute to an increase in activity but does not entirely control it. Pyrrolidine substituents at position R7 generally were more active than other substituents at this position. Tetracyclic quinolone derivatives were amongst the most active compounds with IC50 values in the range of 0.3-8.8 microg/ml. The in vitro cytotoxicity on HT-29 cells was determined for active compounds with IC50 values below 1 microg/ml. In addition, six drugs with an IC50 below 1 microg/ml and a selectivity index of more than 10 were chosen for in vivo experiments. Dose escalation experiments with a maximum dose of 100 mg/kg/bid were performed in a mouse model without central nervous system involvement. For unknown reasons the in vitro effect of the drugs could not be confirmed in vivo, but the class of compound remains of interest for their mode of action, the low toxicity, pharmacological properties and the availability of a large number of synthesized compounds. (+info)
Clinical description of encephalopathic syndromes and risk factors for their occurrence and outcome during melarsoprol treatment of human African trypanosomiasis.
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Encephalopathies are the most feared complications of sleeping sickness treatment with melarsoprol. To investigate the existence of risk factors, the incidence of encephalopathic syndromes and the relationship between the development of different types of encephalopathies and the clinical outcome was studied in a clinical trial with 588 patients under treatment with melarsoprol. The 38 encephalopathy cases were classified into three types according to the leading clinical picture: coma type, convulsion type and psychotic reactions. Nine patients were attributed to the convulsion type, defined as a transient event of short duration with convulsions followed by a post-ictal phase, without signs of a generalized disease. None of these patients died from the reaction. Febrile reactions in the 48 h preceding the reaction were generally not observed in this group. Twenty-five patients were attributed to the coma type, which is a progredient coma lasting several days. Those patients often had signs of a generalized disease such as fever (84%), headache (72%) or bullous skin (8%) reactions. The risk of mortality was high in this group (52%). About 14/16 patients with encephalopathic syndrome of the coma type were infected with malaria. Patients with psychotic reactions or abnormal psychiatric behaviour (3/38) and one patient who died after alcohol intake were excluded from the analysis. The overall rate of encephalopathic syndromes in the cases analysed (n=34) was 5.8%, of which 38.2% died. We did not find any parameters of predictive value for the risk of developing an encephalopathic syndrome based on the symptoms and signs before treatment initiation. The appearance during treatment of febrile reactions (RR 11.5), headache (RR 2.5), bullous eruptions (RR 4.5) and systolic hypotension (RR 2.6) were associated with an increased risk for the occurrence of encephalopathic syndromes especially of the coma type. (+info)
Melarsoprol refractory T. b. gambiense from Omugo, north-western Uganda.
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Culture adapted T. b. gambiense isolated from Northwest Uganda were exposed to 0.001-0.14 microg/ml melarsoprol or 1.56-100 microg/ml DL-alpha-difluoromethylornithine (DFMO). Minimum inhibitory concentrations (MICs) of each drug were scored for each isolate after a period of 10 days drug exposure. The results indicate that T. b. gambiense isolates from Northwest Uganda had elevated MIC values for melarsoprol ranging from 0.009 to 0.072 microg/ml as compared with T. b. gambiense isolates from Cote d'Ivoire with MIC values ranging from 0.001 to 0.018 microg/ml or with T. b. rhodesiense from Southeast Uganda with MIC values from 0.001 to 0.009 microg/ml. All MIC values obtained fell below expected peak melarsoprol concentrations in serum of treated patients. However, it may not be possible to maintain constant drug concentrations in serum of patients as was the case in our in vitro experiments. Importantly, the MIC of 0.072 microg/ml exhibited by one of the isolates from Northwest Uganda was above levels attainable in CSF indicating that this isolate would probably not be eliminated from CSF of treated patients. PCR amplification of the gene encoding the P2-like adenosine transporter followed by restriction digestion with Sfa NI enzyme revealed presence of fragments previously observed in a trypanosome clone with laboratory-induced arsenic resistance. From our findings it appears that reduced drug susceptibility may be one factor for the frequent relapses of sleeping sickness after melarsoprol treatment occurring in Northwest Uganda. (+info)
Pharmacokinetic investigations in patients from northern Angola refractory to melarsoprol treatment.
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Melarsoprol, an organo-arsenical drug, has been the drug of choice for late-stage trypanosomiasis for 50 years. Because of the lack of alternatives any abatement of this medication will have a dramatic negative impact on the perspectives for patients. As a large number of patients refractory to melarsoprol treatment was recently reported from northern Uganda and northern Angola, we investigated in northern Angola whether interpatient pharmacokinetic differences influence the outcome of melarsoprol treatment. Drug levels were determined by a biological assay in serum and cerebrospinal fluid (CSF) of 22 patients. Nine patients could be successfully treated, eight were refractory and the outcome was unclear or no adequate follow-up information was available for five patients. No differences in the pharmacokinetic parameters (maximum serum concentration Cmax, half-life t1/2 beta, total clearance CL and the volume of distribution Vss) could be detected between the groups. Serum and CSF concentrations for all patients were in the expected range. This result indicates that other underlying factors are responsible for treatment failures. (+info)
Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 20). Testicular toxicity of nitrofurazone after 2 and 4 weeks.
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Nitrofurazone (NF) has been previously demonstrated to induce testicular toxicity with 4 weeks of oral administration in rats. In the present study, rats were administered NF to assess whether testicular toxicity becomes evident with a 2-week administration period. Male Sprague-Dawley rats were administered oral doses of NF at 50 mg/kg for 2 or 4 weeks. Another group was administered NF at 100 mg/kg for 2 weeks. The control animals received the vehicle (0.5% methylcellulose) for 4 weeks. Organ weights of the testis and epididymis were significantly decreased in all NF-administered animals, and seminiferous tubules were severely atrophied, due to a total absence of spermatids and degeneration and desquamation of spermatocytes. In the epididymis, decreased numbers of spermatozoa were evident in the ducts. In rats that were administered NF at 50 mg/kg, the changes in the epididymis in the 2-week group were less prominent than those in the 4-week group. In the testis, however, the changes were similar in both groups. Thus it was demonstrated that NF-induced testicular toxicity comparable to that observed after 4 weeks of administration is also detectable after 2 weeks. (+info)
Trypanosoma brucei CTP synthetase: a target for the treatment of African sleeping sickness.
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The drugs in clinical use against African sleeping sickness are toxic, costly, or inefficient. We show that Trypanosoma brucei, which causes this disease, has very low levels of CTP, which are due to a limited capacity for de novo synthesis and the lack of salvage pathways. The CTP synthetase inhibitors 6-diazo-5-oxo-l-norleucine (DON) and alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin) reduced the parasite CTP levels even further and inhibited trypanosome proliferation in vitro and in T. brucei-infected mice. In mammalian cells, DON mainly inhibits de novo purine biosynthesis, a pathway lacking in trypanosomes. We could rescue DON-treated human and mouse fibroblasts by the addition of the purine base hypoxanthine to the growth medium. For treatment of sleeping sickness, we propose the use of CTP synthetase inhibitors alone or in combination with appropriate nucleosides or bases. (+info)
Progressive chronic Chagas heart disease ten years after treatment with anti-Trypanosoma cruzi nitroderivatives.
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A randomized ten-year follow-up study involving 91 Chagas patients and 41 uninfected controls was undertaken to determine the effectiveness of nitroderivative therapy. Anti-Trypanosoma cruzi antibodies were consistently lower one year after treatment than 10 years thereafter (P < 0.001). The blood of all treated and 93.7% of untreated Chagas patients yielded polymerase chain reaction (PCR) product from probes annealing to T. cruzi nuclear DNA, indicating active infection. Competitive PCR showed means +/- standard deviations of 20.1+/-22.6 T. cruzi/ml of blood from untreated and 13.8+/-14.9 from treated Chagas patients, but the differences between means were not statistically significant (P > 0.05). Electrocardiograms recorded a gamut of alterations several-fold more frequent in Chagas patients, regardless of treatment, than in uninfected controls (P < 0.001). These results show that nitroderivative therapy for T. cruzi infections is unsatisfactory and cannot be recommended since it fails to eradicate the parasite or change the progression of heart disease in chronic Chagas patients. (+info)
Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of Trypanosomatidae via structure-based drug design.
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In our continuation of the structure-based design of anti-trypanosomatid drugs, parasite-selective adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Crystal structures of Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, and human GAPDH's provided details of how the adenosyl moiety of NAD(+) interacts with the proteins, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various GAPDH's. From exploration of modifications of the naphthalenemethyl and benzamide substituents of a lead compound, N(6)-(1-naphthalenemethyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine (6e), N(6)-(substituted-naphthalenemethyl)-2'-deoxy-2'-(substituted-benzamido)adenosine analogues were investigated. N(6)-(1-Naphthalenemethyl)-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (6m), N(6)-[1-(3-hydroxynaphthalene)methyl]-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosi ne (7m), N(6)-[1-(3-methoxynaphthalene)methyl]-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosi ne (9m), N(6)-(2-naphthalenemethyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine (11e), and N(6)-(2-naphthalenemethyl)-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (11m) demonstrated a 2- to 3-fold improvement over 6e and a 7100- to 25000-fold improvement over the adenosine template. IC(50)'s of these compounds were in the range 2-12 microM for T. brucei, T. cruzi, and L. mexicana GAPDH's, and these compounds did not inhibit mammalian GAPDH when tested at their solubility limit. To explore more thoroughly the structure-activity relationships of this class of compounds, a library of 240 N(6)-(substituted)-2'-deoxy-2'-(amido)adenosine analogues was generated using parallel solution-phase synthesis with N(6) and C2' substituents chosen on the basis of computational docking scores. This resulted in the identification of 40 additional compounds that inhibit parasite GAPDH's in the low micromolar range. We also explored adenosine analogues containing 5'-amido substituents and found that 2',5'-dideoxy-2'-(3,5-dimethoxybenzamido)-5'-(diphenylacetamido)adenosine (49) displays an IC(50) of 60-100 microM against the three parasite GAPDH's. (+info)