Efficacy and Tolerability of Antimalarials and Molecular Resistance Markers of Falciparum Malaria in Jimma Region, Ethiopia [Elektronische Ressource] / Teferi Eshetu. Betreuer: Thomas Löscher

Teferi Eshetu

Description

Aus der Abteilung für Infektions- und Tropenmedizin der Medizinischen Poliklinik – Innenstadt der Ludwig – Maximilians – Universität München Leiter: Univ. Prof. Dr. Thomas Löscher Efficacy and Tolerability of Antimalarials and Molecular Resistance Markers of Falciparum Malaria in Jimma Region, Ethiopia Dissertation zum Erwerb des Doktorgrades der Humanbiologie an der Medizinischen Fakultät der Ludwig-Maximilians-Universität zu München vorgelegt von Teferi Eshetu aus Jimma, Äthiopien Jahr 2011 Mit Genehmigung der Medizinischen Fakultät der Universität München Berichterstatter: Prof. Dr. Thomas Löscher Mitberichterstatter: Priv. Doz. Dr. Sören Schubert Prof. Dr. Peter Stingl Mitbetreuung durch den Dr. med. Nicole Berens-Riha promovierten Mitarbeiter: Dekan: Prof. Dr. med. Dr. h.c. M. Reiser, FACR, FRCR Tag der mündlichen Prüfung: 19. 10. 2011 Table of Contents Table of Contents Table of Contents................................................................................................................I List of Publications............................................................................................................III Summary..........................................................................................................................IV Introduction..................................................................................

Sujets

• Gesundheit

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2011
• Nombre de lectures: 25
• Langue: Deutsch
• Poids de l'ouvrage: 1 Mo

Extrait

 

Aus der Abteilung für Infektions- und Tropenmedizin der Medizinischen Poliklinik–Innenstadt der Ludwig–Maximilians–Universität München   Leiter: Univ. Prof. Dr. Thomas Löscher

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    Efficacy and Tolerability of Antimalarials and Molecular Resistance Markers of Falciparum Malaria in Jimma Region, Ethiopia      

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Dissertation   zum Erwerb des Doktorgrades der Humanbiologie an der Medizinischen Fakultät der Ludwig-Maximilians-Universität zu München vorgelegt von Teferi Eshetu aus Jimma, Äthiopien Jahr 2011  

Mit Genehmigung der Medizinischen Fakultät der Universität München

 

Berichterstatter:  

Mitberichterstatter:  

Mitbetreuung durch den

promovierten Mitarbeiter:

Dekan:

Tag der mündlichen Prüfung:

 

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Prof. Dr. Thomas Löscher

Priv. Doz. Dr. Sören Schubert

Prof. Dr. Peter Stingl

 

Dr. med. Nicole Berens-Riha

Prof. Dr. med. Dr. h.c. M. Reiser, FACR, FRCR

19. 10. 2011

Table of Contents

Table of Contents   Table of Contents................................................................................................................I ListofPublications............................................................................................................III Summary..........................................................................................................................IV Introduction.......................................................................................................................1

1. Life Cycle and Development of the Parasite....................................................................1

2. Aetiology and Pathogenesis of Malaria...........................................................................2

 2.1. Uncomplicated Falciparum Malaria.........................................................................4

 2.2. Sever Falciparum Malaria........................................................................................4

3. Overview of Molecular Biology.......................................................................................4

4.Epidemiology..................................................................................................................6

5. Antimalarial Treatment and Resistance..........................................................................7

5.1.Atovaquone-ProguanilTreatment..........................................................................10

5.2.QuinineTreatment.................................................................................................10

 5.3. Artemisinin-Based Combination Therapy (ACT) Treatment.....................................11

5.3.1.MechanismofAction......................................................................................12

 5.3.2. Efficacy and Resistance with ACT....................................................................13

 5.3.3. Safety/Tolerability/Toxicity of ACT............................................................... ..15

6.AimoftheThesis..........................................................................................................17

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I

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Table of Contents

7.OverviewofStudyOutcomes......................................................................................18

 7.1. Review of Antimalarials Tolerability and Ototoxicity Study...................................18

 7.2. Review of Antimalarials Efficacy and Molecular Markers Study............................20

8.References..................................................................................................................22

9.OriginalArticles..........................................................................................................33

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II

List of Publications

  List of Publications     This thesis is based on the following publications:     1.   Gürkov R,Eshetu T, Barreto Miranda I, Berens-Riha N, Mamo Y, Girma T, Krause1 E, Schmidt M, Hempel J, Löscher T: artemether/lumefantrine in theOtotoxicity of treatment of   falciparum malaria: a randomized trial.Malaria Journal2008,7:179.           2.   Eshetu T, Berens-Riha N, Fekadu S, Tadesse Z, Gürkov R, Hölscher M, Löscher T, Barreto Miranda I:Different mutation patterns ofPlasmodium falciparum among patients in Jimma University   Hospital, Ethiopia.Malaria Journal2010,9:226.  

 

 

     

   

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Summary

Summary Ethiopia as one of the malaria endemic countries has adopted artemisinin-based combination therapy (ACT) in the form of Artemether-Lumefantrine (AL) as first-line treatment for uncomplicated falciparum malaria in 2004. The broad introduction of the drug was achieved in 2006 including our study area Jimma, where we conducted a prospective open-label randomized trial by comparing AL to Quinine (Q) and Atovaquone-Proguanil (AP) to address the controversial reports concerning neuro-ototoxicity and resulting hearing loss due to artemisinin based treatments of uncomplicated falciparum malaria. In addition, the clinical and parasitological efficacy of the study drugs were evaluated and underlying molecular markers correlated with resistance were determined in the parasite isolates.

Patients > 5 years of age and eligible for complete audio-vestibular evaluations with uncomplicated falciparum malaria were recruited from April to August 2006 in Jimma and the patients were randomized to receive either AL (n=30) or Q (n=35) or AP (n=32). Tolerability assessments and comprehensive audio-vestibular evaluations were also performed after chemotherapy on follow-up days 7, 28, and 90. Clinical assessments included otoscopy, Rinne and Weber tests, neurological examinations (Romberg, Unterberger’s stepping, gait, finger-to- nose, nystagmus, Halmagyi test); neuro-otologic evaluation was performed by transitory evoked otoacoustic emissions (TEOAE), distortion product otoacoustic emissions (DPOAE), pure tone audiometry (PTA), and brainstem evoked response audiometry (BERA).

On the other hand, genotyping of the isolates by molecular analysis of the surface antigensmsp-1  andmsp-2 genes was performed to determine clonality and to distinguish between reinfection and recrudescence (resistance) if parasitaemia occurred after day 7. Molecular markers associated with drug resistance were determined by sequencing ofpfsercaandpfcytbgenes; and by amplification and enzyme digestion (RFLP) ofpfmdr1andpfdhfrgenes.

Tolerability was good, no severe adverse effects were observed related to the drugs upon malaria treatment and as a result patient compliance was high. All malaria symptoms were resolved by day 7 except few patients with headache in all groups. As expected, a significant proportion of patients complained perceived hearing problem in the Q group, but not in the AL or AP group. Tinnitus was experienced with some patients in all groups from day 0 through 7, significantly

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