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Biomedical subjects

C Burri

Publications and source records attributed to C Burri.

At least 19 recordsLinked to original sources
PubMed2002

Treatment of late stage sleeping sickness caused by T.b. gambiense: a new approach to the use of an old drug.

Melarsoprol is the standard treatment of late stage trypanosomiasis. The development of treatment schedules was previously purely empirical. Generally melarsoprol is given in 3 series of three to four consecutive injections, given every 24 hours, with an interval of about one week between the series. Based on pharmacokinetic analysis, computer simulations and extensive literature research covering all schedules previously used and tested, a new schedule, consisting of ten daily consecutive doses of 2.16 mg/kg of the drug was suggested. The pharmacokinetic model was validated in uninfected vervet monkeys. No unexpected drug accumulation and no systemic toxic effects were observed. In a pilot clinical trial in Congo RDC a small group of T. b. gambiense patients (n = 11) was treated successfully with the new schedule. In an open randomised clinical trial conducted in 500 patients in Angola the clinical efficacy and safety of this new concise treatment were compared to those of standard protocol treatment. Parasitological cure 24 hours after treatment was 100% in both groups. Statistical analysis yielded no significant differences for adverse events between the two treatment protocols. The new schedule reduces the amount and cost for the drug by about one third, and those for hospitalisation by about half.

Animals↗
PubMed2001

New drugs for the treatment of human African trypanosomiasis: research and development.

Chemotherapy of human African trypanosomiasis is problematic because of the high frequency of severe adverse events, the long duration and high cost of treatment, and an increasing number of treatment-refractory cases. New cost-efficient, easy-to-use drugs are urgently needed. Whereas basic research on potential drug targets is anchored in academia, the complex, highly regulated and very expensive process of preclinical and clinical drug development is almost exclusively in the hands of pharmaceutical companies. Jennifer Keiser, August Stich and Christian Burri here review, from the angle of industrial drug research and development, the past ten years of research activities at different stages of the development of trypanocidal drugs, and assess future prospects. The absence of compounds in clinical development Phases I-III indicates no new drugs will become available in the next few years.

Animals↗
PubMed2001

Clinical description of encephalopathic syndromes and risk factors for their occurrence and outcome during melarsoprol treatment of human African trypanosomiasis.

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.

Adult↗
PubMed2001

Evaluation of quinolone derivatives for antitrypanosomal activity.

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.

Animals↗
PubMed2001

Pharmacokinetic investigations in patients from northern Angola refractory to melarsoprol treatment.

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.

Adolescent↗
PubMed2001

The story of CGP 40 215: studies on its efficacy and pharmacokinetics in African green monkey infected with Trypanosoma brucei rhodesiense.

CGP 40 215 is an inhibitor of S-adenosylmethionine decarboxylase, a key enzyme in trypanosomal polyamine biosynthesis. It is highly active against Trypanosoma brucei rhodesiense and T. b. gambiense in vitro and in the corresponding rodent models, and therefore was a promising candidate for further development as a new drug against human African trypanosomiasis. We conducted initial pharmacokinetic and efficacy studies in African green monkeys: based on two dose-finding studies, an infection-treatment and a pharmacokinetic study in eight monkeys infected with T. b. rhodesiense in the 1st stage of infection. PK analysis revealed curative drug levels in the serum but complete absence of the drug in the cerebrospinal fluid. No adverse effects of the drug were observed, although in rats CGP 40 215 had caused hypotension. The following PK parameters were calculated using a two-compartment model: t1/2=1.8 h, VSS/f=0.4 l/kg, CL/f=3.0 ml/min x kg and AUC=21 900 ng x h/ml. Six of the eight monkeys were cured, one animal relapsed on day 222 and one animal died of unknown reasons, but was aparasitaemic. The study confirmed the curative potential of CGP 40 215 for 1st stage T. b. rhodesiense infection. Unfortunately, it was also found that the compound did not pass the blood-brain barrier, a pre-requisite for cure of 2nd stage (CNS) infection. As the majority of sleeping sickness patients seeking treatment are in the 2nd stage of the disease, further development of the compound was stopped.

Adenosylmethionine Decarboxylase↗
PubMed2001

The phenomenon of treatment failures in Human African Trypanosomiasis.

Treatment of Human African Trypanosomiasis (HAT or sleeping sickness) relies on a few drugs which are old, toxic and expensive. The most important drug for the treatment of second stage infection is melarsoprol. During the last 50 years treatment failures with melarsoprol were not a major problem in Trypanosoma brucei gambiense patients. Commonly a relapse rate of 5-8% was reported, but in recent years it has increased dramatically in some important foci of T. b. gambiense sleeping sickness. Treatment failures for T. b. rhodesiense are much less of a problem apart from some reports between 1960 and 1985 of refractoriness in T. b. rhodesiense patients in East Africa. Analysis of those isolates revealed that their in vitro sensitivity to melarsoprol was one-tenth that of sensitive isolates, and complete failure to cure the infection in the acute mouse model with melarsoprol levels comparable with those in human patients. There was very little indication of resistance in T. b. gambiense isolates from Côte d'Ivoire and NW Uganda. The in vitro melarsoprol sensitivities for populations from relapsing and from curable patients were in the same range. Melarsoprol concentrations in the plasma and cerebrospinal fluid of patients 24 h after treatment did not show any difference between patients who relapsed and those who could be cured. The reason for relapses in the recent T. b. gambiense epidemics are not known. Other parasite-related factors might be involved, e.g. affinity to extravascular sites other than the CNS which are less accessible to the drug. In conclusion, a combination of factors rather than a single one may be responsible for the phenomenon of melarsoprol treatment failures in T. b. gambiense patients.

Africa, Eastern↗
PubMed2000

Efficacy of new, concise schedule for melarsoprol in treatment of sleeping sickness caused by Trypanosoma brucei gambiense: a randomised trial.

BACKGROUND: African trypanosomiasis is a fatal disease caused by protozoan parasites of the species Trypanosoma brucei. The disease has reached epidemic dimensions in various countries of central Africa. Treatment of the second stage is long and complicated, and is hampered by severe adverse reactions to the first-line drug, melarsoprol. Despite these problems, melarsoprol is likely to remain the drug of choice for the next decade. We therefore did a randomised trial comparing the standard treatment schedule with a new, concise regimen. METHODS: The safety and efficacy of the new schedule were assessed in patients presenting to a hospital in Kwanza Norte, Angola with sleeping sickness. The control group followed the 26-day standard Angolan schedule of three series of four daily injections of melarsoprol at doses increasing from 1.2 to 3.6 mg/kg within each series, with a 7-day interval between series. The new treatment schedule comprised 10 daily injections of 2.2 mg/kg. Primary outcomes assessed were elimination of parasites, deaths attributed to treatment, and rate of encephalopathy. Analysis was by intention to treat. FINDINGS: Of 767 patients with second-stage disease, 500 were enrolled: 250 were assigned the standard schedule, and 250 the new schedule. 40 patients on the standard schedule and 47 on the new schedule had adverse events which resulted in treatment disruption or withdrawal. 50 patients on the standard regimen deviated or withdrew from treatment, compared with two on the new regimen. Parasitological cure 24 h after treatment was 100% in both groups; there were six deaths (all due to encephalopathy) 30 days after treatment in each group. The number of patients with encephalopathic syndromes was also the same in each group (14). Skin reactions were more common with the new treatment, but all could be resolved by additional medication or withdrawal of treatment. INTERPRETATION: Considering the economic and practical advantages of the new 10-day schedule over the standard 26-day treatment schedule, and the similarity of treatment outcome, the new schedule is a useful alternative to the present standard, especially in epidemic situations and in locations with limited resources.

Adult↗
PubMed2000

An automated biological assay to determine levels of the trypanocidal drug melarsoprol in biological fluids.

For the investigation of the pharmacokinetic properties of a drug, methods for sensitive and precise quantification are a prerequisite. Only few functional methods exist for the determination of the trypanocidal drug melarsoprol in biological fluids: A bioassay which requires microscopical evaluation and two HPLC methods, which require sample extraction and are difficult to automatize due to the drug's properties. We report the development of an automated biological assay, based on the fluorescent dye Alamar blue. To validate the assay for melarsoprol, 108 serum and 37 cerebrospinal fluid (CSF) samples were spiked with melarsoprol at concentrations of 17-92 ng/ml for CSF and 17 ng/ml-2.2 microg/ml for serum. The precision (repeatability) expressed as the interday average coefficient of variation was 9.9% for serum and 18.8% for CSF samples over the respective concentration range. The accuracy (measurement for the systematic error) of the test was 99.4% for serum and 96.4% for CSF. The assay's limit of quantitation with the use of the trypanosome stock STI 704 BABA was 4 ng/ml for both serum and CSF samples.

Animals↗
PubMed2000

Investigations of the metabolites of the trypanocidal drug melarsoprol.

BACKGROUND: Melarsoprol remains the first-choice drug for trypanosomiasis (human African sleeping sickness). To contribute to the sparse pharmacologic data and to better understand the cause of the frequent serious adverse reactions, we investigated the metabolism of this 50-year-old organoarsenic compound. RESULTS: The half-life of melarsoprol determined by HPLC was <1 hour compared with 35 hours determined by bioassay and atomic absorption spectroscopy, indicating the existence of active metabolites. One metabolite, melarsen oxide, was identified by ultraviolet HPLC after incubation of melarsoprol with microsomes. The maximum plasma concentration of melarsenoxide was reached 15 minutes after administration; the clearance was 21.5 mL/min/kg and the half-life of free melarsen oxide was 3.9 hours. Either melarsen oxide or a yet-undiscovered active metabolite is irreversibly bound to proteins, as shown by ultrafiltration, precipitation experiments, and atomic absorption spectroscopy. Because of the poor pharmaceutical properties of melarsoprol, the therapeutic potential of melarsen oxide was investigated. In a rodent model of acute infection, 20 of 20 mice were cured (0.1 to 1 mg/kg intravenously or 2.2 mg/kg intraperitoneally). In a rodent model of central nervous system infection, five of six mice survived for more than 180 days (5 mg/kg intravenously), indicating a sufficient melarsen oxide penetration across the blood-brain barrier. CONCLUSION: The prospects for the future of trypanosomiasis treatment are deplorable. Investigations on the improvement of the use of the old drugs are therefore required. The results of this study may build a basis for further research on the cause of severe adverse reactions.

Adult↗
PubMed1999

Antitrypanosomal activity of fluoroquinolones.

Six fluoroquinolones presently in clinical use and four investigational tetracyclic fluoroquinolones were tested for in vitro activity against bloodstream-form Trypanosoma brucei brucei. All compounds had measurable activity, but the tetracyclic analogs were most potent, with 50% effective concentrations in the low micromolar range. In general, trypanosomes were more susceptible than L1210 leukemia cells. Consistent with the notion that they target type II topoisomerase in trypanosomes, the fluoroquinolones promote the formation of protein-DNA covalent complexes.

Animals↗
PubMed1998

Discrepancy in plasma melarsoprol concentrations between HPLC and bioassay methods in patients with T. gambiense sleeping sickness indicates that melarsoprol is metabolized.

OBJECTIVE: With the use of a specific high-performance liquid chromatography (HPLC) method and a bioassay which determines trypanocidal activity, concentrations of melarsoprol were assessed in plasma, urine and cerebrospinal fluid (CSF) from 8 patients with late-stage Trypanosoma gambiense sleeping sickness. The aim was to unravel to what extent the bioassay codetermines biologically active metabolites of melarsoprol. METHODS: Subjects were given one dose of melarsoprol i.v. per day for 4 days (1.2, 2.4, 3.0-3.6, 3.0-3.6 mg per kg b.w., respectively). Plasma samples were obtained before the first melarsoprol injection, immediately after and at 1 h, 24 h and 5 days after the 4th injection. Urine was collected before melarsoprol therapy and at 24 h after the 4th injection. CSF samples were taken once before treatment and at 24 h after the 4th injection. RESULTS: HPLC analyses showed that plasma concentrations immediately after the 4th injection varied from 2200 to 15,900 nmol/l; dropping to 0-1800 nmol/l at 1 h; and to undetectable levels at 24 h. In urine small amounts of melarsoprol were recovered. Melarsoprol could not be detected in CSF by HPLC. Immediately after injection, bioassay analyses showed plasma concentrations of the same magnitude as HPLC assays but at 1 h they were 4-65-fold higher than the levels assessed by HPLC. Even 24 h and 5 days after the 4th injection there was significant but decreasing activity. Urine levels were 40-260-fold higher than the measured HPLC concentrations, whereas there was low but detectable activity in CSF. CONCLUSION: Results indicate that melarsoprol is rapidly eliminated from plasma. The significant trypanocidal activity determined by bioassay and simultaneous low or undetectable levels of melarsoprol assayed by HPLC indicate that the compound is transformed into metabolites with parasiticidal activity.

Adolescent↗
PubMed1996

Topoisomerases in kinetoplastids.

Topoisomerases are enzymes that mediate topological changes in DNA that are essential for nucleic acid biosynthesis and for cell survival. The kinetoplastid protozoa, which include pathogenic trypanosomes and Leishmania, have yielded an interesting variety of purified topoisomerase activities as well as several topoisomerase genes. In these parasites, topoisomerases are involved in the metabolism of both nuclear and mitochondrial (kinetoplast) DNA. In this review, Christian Burri, Armette Bodley and Theresa Shapiro summarize what is known about topoisomerases in kinetoplastids, and consider the intriguing possibility that these enzymes may act as valuable antiparasite drug targets.

Journal Article↗
PubMed1995

Alternative application of melarsoprol for treatment of T. B. gambiense sleeping sickness. Preliminary results.

The protocols for treatment of human African trypanosomiasis (sleeping sickness) with the organoarsenical drug melarsoprol are based on empirical observations. Therapy is often accompanied by serious side effects and relapses. Additionally, the duration of treatment, which is up to forty days, is a major drawback in African countries. Based on pharmacokinetic investigations an alternative therapy protocol for T. gambiense sleeping sickness has recently been proposed which consists of ten consecutive injections of 2.2 mg/kg melarsoprol given at intervals of 24 hours. In a preliminary study, eleven patients were treated in Vanga, Zaire following this alternative protocol which reduces the duration of the treatment to ten days. The results indicate that the alternative schedule was as effective as the traditional protocol, showed similar adverse reactions but required a much shorter treatment period.

Adolescent↗
PubMed1994

Pharmacokinetics of melarsoprol in uninfected vervet monkeys.

The level of the trypanocidal drug melarsoprol was determined in serum and cerebrospinal fluid (CSF) of six healthy vervet monkeys after intravenous application of the drug following a standard treatment schedule and a recently suggested alternative protocol. The maximum serum levels measured were about 3 micrograms/ml. A three-compartment model was used to analyze the serum data. The mean residence time calculated for melarsoprol in serum was 18 h, the volume of distribution was 3.6 l/kg and the clearance was 3.5 ml/min*kg. In the CSF the drug levels were generally very low, not exceeding 55 ng/ml, and the adaptation of the drug levels was found to be very low. The comparison of the drug concentrations required to eliminate trypanosomes in vitro and the drug concentrations reached in the CSF during treatment revealed that the latter might be insufficient in some cases to eliminate all trypanosomes from this site. The peak serum levels during alternative application of the drug were lower compared to those during empirical treatment. No evidence for drug cumulation in the body was found. The results of this study are compared with recent pharmacokinetic data from human patients, and discussed in the context of the problem of relapses and reactive encephalopathy occurring after treatment of sleeping sickness.

Animals↗
PubMed1994

Antiparasitic activity of diallyl trisulfide (Dasuansu) on human and animal pathogenic protozoa (Trypanosoma sp., Entamoeba histolytica and Giardia lamblia) in vitro.

Garlic (Allium sativum L.) and one of its major components, allicin, have been known to have antibacterial and antifungal activity for a long time. Diallyl trisulfide is a chemically stable final transformation product of allicin which was synthesized in 1981 in China and used for treatment of bacterial, fungal and parasitic infections in man. The activity of diallyl trisulfide was investigated in several important protozoan parasites in vitro. The IC50 (concentration which inhibits metabolism or growth of parasites by 50%) for Trypanosoma brucei brucei, T.b. rhodesiense, T.b. gambiense, T. evansi, T. congolense and T. equiperdum was in the range of 0.8-5.5 micrograms/ml. IC50 values were 59 micrograms/ml for Entamoeba histolytica and 14 micrograms/ml for Giardia lamblia. The cytotoxicity of the compound was evaluated on two fibroblast cell lines (MASEF, Mastomys natalensis embryo fibroblast and HEFL-12, human embryo fibroblast) in vitro. The maximum tolerated concentration for both cell lines was 25 micrograms/ml. The results indicate that the compound has potential to be used for treatment of several human and animal parasitic diseases.

Allyl Compounds↗