Therapeutic Efficacy Of Combined Antimalarials In Malaria Biology Essay

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Artemether-lumefantrine (AL) is a co-formulation of artemether and lumefantrine. Multidrug resistance of Plasmodium falciparum is spreading throughout Asia and is impeding efforts to control malaria. The emergence of drug resistance in Plasmodium falciparum has significantly undermined malaria control programs in countries where it is endemic3. To ensure high cure rates and to combat this threat, the World Health Organization (WHO) has recommended the use of artemisinin combination therapy4. Artemisinin or Qinghaosu is an extract of the medical plant Qinghao (Artemisia annua), which together with its derivatives, artesunate and artemether are the most active antimalarial compounds to date5. Artemether-lumefantrine is approved for the treatment of uncomplicated malaria in infants, children, adults and nonimmune travelers returning from malarious areas6. Both artemether and lumefantrine are blood schizonticides with complementary pharmacokinetics and dissimilar modes of action, and hence provide synergistic anti-malarial activity. Artemether is rapidly eliminated from plasma with a half-life of two to three hours, whereas lumefantrine is eliminated more slowly with a half-life of three to six days and provides a high long-term cure rate after a short treatment course7.

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The fixed dose regimen ensures that malaria parasites always encounter artemether and metabolites in the presence of lumefantrine and provides protection against the emergence of resistance to both components, but absorption of the lipophilic lumefantrine is erratic, and the drug needs to be administered twice per day8. Therapeutic levels are more reliably achieved by coadministration with a fatty meal and by extending the treatment course from 4 to 6 doses9, 10 .The trial presented here was conducted to monitor the efficacy of the six-dose regimen of artemether-lumefantrine combination given over three days for the treatment of uncomplicated P. falciparum infections children .

Patients & Methods

It is open label in vivo drug study to determine the efficacy of combination antimalarial therapy in terms of therapeutic efficacy, in uncomplicated plasmodium Falciparum infections. The study included 75 patients during a period of six months from July 2009-to December 2009, at children hospital larkana & children hospital Ghulam Muhammad Mahar medical college Sukkur.

Inclusion criteria :

Male or female, 1year to 12year of age.

Weight > 10 kg.

Diagnosis of uncomplicated acute plasmodium Falciparum malaria parasitemia with history of fever & vegetative forms of falciparum malaria .

Exclusion criteria:

Has received anti-malarial treatment in the past 7 days.

Severely ill (based on WHO Criteria for severe malaria) or if patient is considered in the opinion of investigator or designee, to have moderately severe malaria ( e.g repeated vomiting, dehydrated ).

Has received cotrimoxazole or chloramphenicol in the past 7 days.

Has a history of allergy to study drug i.e Gen M ( Artemther-Lumefantrine) .

Patients with microscopically confirmed P. Falciparum malaria (vegetative forms) with fever were enrolled at clinic. 75 children 1- 12years of both sexes who gave voluntary consent was assigned to enter the study.

After obtaining the written consent from parents, medical history including presenting symptoms, current medications (single or combined) antimalarials were obtained. Case record form containing clinical history, examination & investigations were filled for each patient. Blood was collected for L.F.T, & Complete blood counts.

Patients were given standard six doses of artemther â€"Lumefantrine (Gen M 40/240 ) .

Treatment was discontinued in patients who developed vomiting either due to disease or drug.

Follow-up

All the patients were followed-up on days 1, 2 & 3. On each day, in addition to physical examination they were also enquired for adverse effects of drug.

Results

Before treatment

Age of patients

Ages of patients were between 1-12 years as shown below.

1-4 years 25 patients 34.67%

5-8 years 22 patients 29.33%

9-12 years 26 patients 36.0%

Table 1 Clinical presentation of malarial patients.

Clinical presentation

No of pts

% of pts

Fever

75

100%

Chills

54

72%

Vomiting

52

69%

Splenomegaly

50

66%

Hepatomegaly

40

53%

Malaise

38

50%

Investigation 1 CBC

1. Level of hemoglobin

Was normal in 7 patients (9.3%).

< 6 g/dl in 16 patients (21%).

6-9 g/dl in 40 patients (53%).

9-12 g/dl in 12 patients (16%).

2. Platelet count

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Platelet count was normal in 62 patients (82%) but was low in 13 patients ( 17%) as shown

Table 2

Frequency

Percent

Normal

62

82.7

Low

13

17.3

Total

75

100.0

II. L.F.T

1. Serum bilirubin

Serum bilirubin was elevated in 8 patients (10.67%) as shown in table

Table 3

Bilirubin

Frequency

Percent

Normal

67

89.33

Raised

8

10.67

Total

75

100

2. SGPT was normal in all patients .

After treatment

The key criterion used to assess the efficacy of an anti-malarial agent is the elimination of malaria parasites, which in turn leads to resolution of symptoms such as fever.

I. Parasite and fever clearance

After taking standard 6 doses of Artemther-Lumefantrine, fever subsided (defined as a temperature of < 37.5 oC) on day 1 was found in 15 patients (20%), fever disappeared on day 2 in 42 patients (56%), on day 3 in 12 patients (16%).

II. Regression of clinical features; After start of treatment fever relieved in 69 patients (92%) while fever persisted in 6(8%) patients. Chills disappear in 50 patients (93%) but remained in 4 patients (7%). 47 patients (90%) out of 52 patients got relief from nausea and vomiting after completion of therapy. Spleen size regressed in 48 patients (96%) out of 50 patients (66%). Liver size Regressed in 34 patients (85%) out of 40 patients (53%). 34 patients (89%) got relief from malaise as shown in figure 1.

FEVER CHILLS

VOMITING SPLEENOMEGALY

HEPATOMEGALY MALAISE

Figure 1 Clinical features before and after treatment

D. Adverse effects

No any other adverse effect was seen except vomiting which can be either due to drug or disease.

Discussion

The loss of affordable effective antimalarial drugs to resistance represents a major threat to the people of malaria endemic countries 11. Using ineffective drugs with high failure rates kills many and is unacceptable. The rising threat of Plasmodium falciparum resistance to monotherapies prompted the World Health Organization (WHO) 2006 guidelines for the treatment of malaria to recommend that combinations of antimalarials be used to treat malaria caused by P. falciparum [4]. The combination of artemether (an artemisinin derivative) and lumefantrine in a 1:6 ratio was the first fixed-dose ACT to meet the WHO's prequalification criteria for efficacy, safety and quality12 Artemisinin derivatives have the most potent and rapid onset of anti-parasitic activity of any anti-malarial drug available today and are active against all Plasmodium species that infect humans. Importantly, they allow more parasite clearance than any other anti-malarial drug (parasite numbers can be reduced by a factor of 105 per asexual cycle, compared with 102-103 with other anti-malarial drugs)13. When combined with efficacious anti-malarials with slower elimination rates, such as lumefantrine, shorter courses of treatment (three days) become effective13.

Our results showed a high cure rate for Artemether-lumefantrine and are consistent with efficacy results reported from several sub-Saharan African countries14-15, indicating a high overall cure rate with these regimens in the short (28-day) term. Adequate clinical and parasitological response was 98.6% in Indian study6 and 96.3% in South African study16 as shown in table 4.

Table 4. Therapeutic efficacy of artemether-lumefantrine in uncomplicated plasmodium falciparum in various studies.

Our study

South African study

Indian's study

92%

96.3 %

98.6%

In contrast to our study, comparative study of combined antimalarials shows that Artesunate plus Amodiaquine treatment is associated with more rapid clearance of parasites and fever as compared to Artemether-lumefantrine17. Another comparative study shows that both treatments were effective in clearing the current infection, but in terms of people being parasite free at day 28, artemetherâ€"lumefantrine was more effective than artesunate plus amodiaquine in some trials18. Results of one study were matching to our study in which parasite clearance time was short and most patients cleared their parasites by day 2 19.

Conclusion

Current study proved the excellent therapeutic efficacy of Artemether-Lumefantrine, which is 92%- associated with rapid fever and parasite clearance, safe and cost effective strategy.

Recommendation

Malaria in children should be treated according to standard guidelines i.e. with Artimisinin combination rather than alone avoid the development of resistance.