DIHYDROArtemisinin-PIPERAQUINE combination therapy in ...dihydroartemisinin-piperaquine combination therapy in uncomplicated falciparum malaria in adults; are there any ecg changes?

DIHYDROARTEMISININ-PIPERAQUINE COMBINATION THERAPY IN UNCOMPLICATED

FALCIPARUM MALARIA IN ADULTS; ARE THERE ANY ECG CHANGES?

Khin Phyu Pyar, Zar Ni Htet Aung, Lay Mg Mg, Nyan Lin Mg, Chan Aye Aung, Soe Win Hlaing, Win Win Myint, Sai Aik Hla &

MarlarThan

Introduction

Malaria - serious global health challange

MDR drug resistance in SEA WHO & National anti-malarial drug policy

recommended ACT in co-formulated tab (ACT – AS/M, AM/L, AS/AM and DHA/P) DHA/P - Artekin /

Artepip/Duocotexin/Piperamisinin/Artequin

• It was reported to have ECG changes especially ventricular arrhythmia and long QT interval in some studies.

Objectives

• To find out the

– therapeutic efficacy,

– safety and tolerability of

Dihydroartemisinin/ Piperaquine compound tablet

• (to detect ECG changes before and after treatment)

Study design

• a hospital based descriptive study

Patients & methods

Inclusion criteria

• Age above 18 year

• mono-infection with P. falciparum detected by microscopy (parasitaemia of 300-100,000/µl asexual forms) presence of axillary ≥ 37.5 °C or history of fever during the past 24 h;

• ability to swallow oral medication.

Exclusion criteria

• signs of severe falciparum malaria • mixed malaria detected by microscopy; • severe malnutrition • febrile conditions other than malaria (e.g. measles, acute

lower respiratory tract infection, severe diarrhoea with dehydration)

• chronic or severe diseases (e.g. cardiac, renal and hepatic diseases, HIV/AIDS);

• regular medication, which may interfere with anti-malarial pharmacokinetics

• history of hypersensitivity reactions • a positive pregnancy test or breastfeeding;

Withdrawal Criteria

• patient's request

• any serious adverse effects to drugs

• serious or repeated non-compliance with protocol specifications

Procedure

• The patients who fulfilled the inclusion criteria were keep in hospital for 28- 42 days. ( 28 days hospital stay till 2010 and 42 days after 2010).

Materials

• Supervised treatment with Dihydroartemisinin and piperaquine phosphate co-formulated tablets (Dihydroartemesinin 40 mg and Piperaquine 375 mg) was given for 3 days.

Procedure

• Clinical, parasitological and biochemical monitoring (full blood count, blood sugar, serum creatinine, liver function test) were done in hospital under the supervision of the physician.

28-days follow-up

Efficacy

Safety

CLINICAL ASSESSMENT

Safety

• Physical examination

• Blood chemistry

• Hematology

• 12-lead ECG

• Serial ECG recordings were done on (Day 0, Day3, Day 7, Day 14, Day 21and Day 28) ( Day 35 and Day 42).

• Interpretations on changes like heart rate, rhythm, PR interval, QRS complexes, QT interval, T wave changes and U waves.

• reviewed by senior physicians.

• Corrected QT interval was calculated.

Correcting the QT interval

• is affected by heart rate

(heart rate increases, the QT interval decreases)

Thus QT interval based on a standard heart rate of 60.

QTc.

( women < 0.46 second , men < 0.45 sec )

(When the QTc is longer than 0.50 sec, torsades de pointes is more likely to

• Develop)

MATERIALS

Artepip(Dihydroartemisinin/Piperaquine)

Nanjing Real Pharmaceutical Co.Ltd, China

Batch No. 060401

Total-8 tablets

Each tab contains 40mg dihydroartemisinin

and 320 mg piperaquine phosphate

Artekin ( Dihydroartemisinin/Piperaquine)

Holleykin Pharmaceutical Co. Ltd.

Guangzhou China

Batch No. 20030302

Total-8 tablets

Each tab contains 40mg dihydroartemisinin

and 320 mg piperaquine phosphate

MATERIALS Piperamisinin (Compound Dihydroartemisinin/Piperaquine)

• Produced from Ministry of Industry (1), Myanmar Pharmaceutical Factory, Myanmar

• Batch No. - 6324 H 9

• Dose - 3 tabs at zero hour, 24 hour and 48 hour

• Total - 400 mg total 9 tabs

• Each tab contains 50mg dihydroartemisinin and 350 mg piperaquine phosphate

Duocotexin

2-2.4/16-19.2 mg/kg once a day for 3 days

Holley-Cotec. Pharmaceutical Co. Ltd.China Dihydroartemisinin (DHA) 40mg + Piperaquine (PPQ) 320mg. (Batch No. -20070302)

Dose -3 tab at 0 hour, 24 hour and 48 hour (Total 9tab)

MATERIALS AND METHOD

MATERIALS Artequine (Compound Dihydroartemisinin/Piperaquine)

• Produced from T P F, Myanmar

• Batch No. -

• Dose - 3 tabs at zero hour, 24 hour and 48 hour

• Total - 400 mg total 9 tabs

• Each tab contains 50mg dihydroartemisinin and 350 mg piperaquine phosphate

Ethical consideration

• The protocol was approved by the Ethical Committee (Research & Development Committee) - Ministry of Defence.

• Written informed consent was obtained from all the patients.

Statistical Evaluation

• EPI-INFO software.

• Categorical data were compared by calculation the chi-square value with Yate's correction. Normally distributed continuous data were compared by the Student's t-test and analysis of variance

Results

• A total of 200 patients were obtained for the study. Follow up was completed for 28-42 days in all patients.

Table 1–Base line characteristic of patients (n=200)

Dihydroartemisinin / Piperaquine combination

therapy

Age [years]

Mean + S.D 29 + 10.77

Body weight [Kg]

Mean+S.D 58 + 4.9

Height [ins]

Mean +S.D 163 + 7.6

Initial Temp. <C

Mean± S.D 37.6 + 0.6

Initial parasitaemia/ul

[range] ( 390 – 187590 )

Table 2.Outcome/cure rate (n=200)

Outcome Number Percent

ETF 0 0

LTF 0 0

ACPR 200 100

Withdrawal 0 0

Loss to follow up 0 0

Total 200 100

Table (3 ) Study drugs, sites & year (n=200)

SR Name of drug Country of

origin

Study site Number of patients Study year

1 Artekin China

Holleykin

Ygn, POL 30 2006

2 Artepip China Ygn, POL, Lashio 30 2007

3 Piperamisinin Myanmar Ygn, POL, Lashio,

Myitkyina, NPT

30 2008- 2010

4 Duocotexin Ygn, Kyaington,

Bokpyin, Ann,

Homalin

95 2010- 2015

5 Artequine Ygn, Bokpyin,

Ann, Homalin

15 2016- 2018

200

Table (4) Cardiovascular side effects (symptoms) (n=200)

symptoms Number Percent

giddiness 10 5

vomiting 5 2.5

palpitation 2 1

Fainting attack 0 0

Chest pain 0 0

Total 200 100

Table (5) Cardiovascular side effects (signs) (n=200)

Parameter Number Percent

Significant BP changes 0 0

Undue tachycardia 0 0

Undue bradycardia 0 0

arrhythmia 0 0

Prolonged corrected QT

interval

0 0

Total 200 100

Table ( 6) QT interval (corrected ) (n=200)

Mean QT interval (corrected)

(sec) SD

Normal QT interval

(sec)

Gender Patients Reference

male 0.45 <0.46

female 0.44 <0.45

Total 200

Discussion

• Multidrug resistant falciparum malaria is an increasing problem in Southeast Asia including Myanmar.

• According to WHO 2010 guideline, artemisinin combination therapy such as Dihydroartemisinin / Piperaquine or Artemether / Lumefantrine or Artesunate / Mefloquine or Artesunate / Amodiaquine is a recommended therapy for treatment of uncomplicated falciparum malaria.

• Artemisinine derivatives are very potent against falciparum malaria leading to rapid decrease of parasitaemia and faster defervescence than other antimalarials.

• The combination of piperaquine with dihydroartemisinin has been used in treatment of falciparum malaria in China, Vietnam, Cambodia and Thailand. The 28-day cure rate is about 95% in the regimen of 8 tablets for 2 to 3 days . (1,2,3,4,5,6)

• The cardiotoxicity of various antimalarial drugs have been problems for long term.(7) There were few reports that the use of quinine, quinidine and halofantrine in treatment of falciparum malaria produced prolong QT interval .( 7,8,9)

• Regarding the newer drug- dihydroartemisinin/ - piperaquine , the data were conflicting. In vitro study done by Franco & group did not show cardiovascular signal They did not display an in vitro signal for a significant pro-arrhythmic risk. They did not appear to induce potential torsadogenic effects in vitro . .(11 )

• Cambodia study revealed cardiac adverse effects. They divided the patients into two groups – two day treatment regimen and three days treatment regimen. They found significant prolongation of QT interval in those receiving two day treatment regimen. Thus, they recommended dihydroartemisinin/ - piperaquine three days treatment regimen. (10 )

• the study done by Boje showed QT prolongation in patients taking piperaquine . (12)

• In this study none of our patients had QT prolongation in serial ECG done on Day 0, Day 3, Day 7, Day 14 and Day 28. No unexplained sudden death.

One report mentioned the cardiac untoward effect was related with meals. They prescribed piperaquine in 3 situations ; • high fat & low calorie meal, • high fat & high calorie meal • and lastly fasting state. They found that QT prolongation was seen in those taking piperaquine on empty stomach.(14) In our study, we did not give particular advice on diet. None of them had severe cardiac side effects.

• According to WHO, there were several precipitating factors for fatal arrhythmia and QT prolongation. They were Risk factors for drug-induced QT/QTc prolongation- female gender, structural heart disease, genetic defects of cardiac ion channels, electrolyte disturbances, bradycardia, hepatic impairment, and concomitant use of medications that prolong the QT/QTc interval or increase drug levels. (6 )

• The concomitant use of medications that prolong the QT/QTc interval was challenging in this study. The patients having nausea or vomiting were prescribed either metoclopramide or odensetron. Even though their ECG did not have long QT interval.

• There were reports on sudden cardiac arrest due to Torsade de pointe. (16)

This study included only 200 patients – supervised treatment by physician.

• QTc was not prolong. • None of them had syncope or sudden death. • Moreover, there were more than 2,000

uncomplicated falciparum malaria patients receiving DHA/P three days treatment regimen in various military hospitals over one decade. There, they did ECG on requirement and no significant changes.

• They did not see syncope or sudden death. • The cure rate was excellent (100%).

• Thus, dihydroartemisinin/ - piperaquine three days treatment regimen was safe and effective

• still the first line pocket therapy for treatment of uncomplicated falciparum malaria in adults in military population.

Conclusion

• Dihydroartemisinin / Piperaquine combination therapy was effective in treatment of uncomplicated falciparum malaria in adults.

• Dihydroartemisinin / Piperaquine combination therapy did not cause prolongation of QT interval or sudden death.

• The adverse effects were tolerable.

Acknowledgement

1)all patients, commanding officer, medical specialists, medical officers, nursing staff, microscopists and medical assistants for their active cooperation in the study.

2) Director, Directorate of Medical Services, Ministry of Defence

References

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• 2.WHO 2010. Treatment guidelines for malaria. 2nd edition. World Health Organization, Geneva. ISBN 978 92 4 154792 5. http://www.who.int/malaria/publications/atoz/978924547925/en/index.html.

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