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In vitro evaluation of quinidine sensitivity in brazilian Plasmodium falciparum isolates: comparative analysis to quinine and chloroquine

Avaliação da sensibilidade in vitro à quinidina em isolados brasileiros de Plasmodium falciparum: análise comparativa à quinina e à cloroquina

Abstracts

Falciparum malaria represents a serious and an increasing world public health problem due to the acquired parasite's resistance to the most available drugs. In some endemic areas, quinidine, a diastereoisomer of the antimalarial quinine, has been employed for replacing the latter. In order to evaluate the use of quinidine as an alternative to the increasing loss of quinine effectiveness in Brazilian P. falciparum strains, as has been observed in the Amazon area, we have assayed quinidine, quinine and chloroquine. The in vitro microtechnique was employed. All isolates showed to be highly resistant to chloroquine. Resistance to quinine was not noted although high MIC (minimal inhibitory concentration) values have been observed. These data corroborate the decreasing sensitivity to quinine in strains from Brazil. Quinidine showed IC50 from 0.053 to 4.577 mumol/L of blood while IC50 from 0.053 to 8.132 mumol/L of blood was estimated for quinine. Moreover, clearance of the parasitemia was observed in concentrations lower than that used for quinidine in antiarrhythmic therapy, confirming our previous data. The results were similar to African isolate.

Quinidine; Malaria; Quinine; Chloroquine; P. falciparum; Antimalarial resistance


Malária falciparum representa grave e crescente problema de saúde pública mundial, dada a resistência do parasito à maioria dos fármacos disponíveis. Em algumas áreas endêmicas, a quinidina, diastereoisômero do antimalárico quinina, vem sendo empregada em substituição a este último. Com o objetivo de avaliar o emprego da quinidina como alternativa à perda crescente de sensibilidade de cepas brasileiras de P. falciparum à quinina, como o observado na região Amazônica, realizamos ensaio comparativo entre quinidina, quinina e cloroquina. A técnica in vitro do microteste de sensibilidade foi utilizada. Todos os isolados mostraram-se altamente resistentes à cloroquina. Resistência à quinina não foi observada, embora altos valores de CMI (concentração mínima inibitória) tenham sido encontrados. Estes resultados corroboram o decréscimo de suscetibilidade de cepas brasileiras à quinina. Observou-se variação de IC50 de 0,053 a 4,577 mimol/L de sangue para a quinidina, enquanto para a quinina estimou-se IC50 de 0,053 a 8,132 mimol/L de sangue. Ademais, observou-se clareamento da parasitemia em concentrações inferiores à da quinidina quando empregada como fármaco antiarrítmico, confirmando estudo anterior por nós realizado. Resultados semelhantes foram encontrados em isolado oriundo da África.


In vitro EVALUATION OF QUINIDINE SENSITIVITY IN BRAZILIAN Plasmodium falciparum ISOLATES: COMPARATIVE ANALYSIS TO QUININE AND CHLOROQUINE

Carla M. S. MENEZES(1 (1 ) Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brasil. (2 ) Divisão de Programas Especiais, Superintendência de Controle de Endemias (SUCEN), São Paulo, SP, Brasil. (3 ) Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brasil. ), Karin KIRCHGATTER(2 (1 ) Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brasil. (2 ) Divisão de Programas Especiais, Superintendência de Controle de Endemias (SUCEN), São Paulo, SP, Brasil. (3 ) Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brasil. ), Sílvia Maria DI SANTI(2 (1 ) Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brasil. (2 ) Divisão de Programas Especiais, Superintendência de Controle de Endemias (SUCEN), São Paulo, SP, Brasil. (3 ) Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brasil. ), Gilberto A. PAULA(3 (1 ) Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brasil. (2 ) Divisão de Programas Especiais, Superintendência de Controle de Endemias (SUCEN), São Paulo, SP, Brasil. (3 ) Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brasil. ) & Elizabeth I. FERREIRA(1 (1 ) Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brasil. (2 ) Divisão de Programas Especiais, Superintendência de Controle de Endemias (SUCEN), São Paulo, SP, Brasil. (3 ) Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brasil. )

SUMMARY

Falciparum malaria represents a serious and an increasing world public health problem due to the acquired parasite's resistance to the most available drugs. In some endemic areas, quinidine, a diastereoisomer of the antimalarial quinine, has been employed for replacing the latter. In order to evaluate the use of quinidine as an alternative to the increasing loss of quinine effectiveness in Brazilian P. falciparum strains, as has been observed in the Amazon area, we have assayed quinidine, quinine and chloroquine. The in vitro microtechnique was employed. All isolates showed to be highly resistant to chloroquine. Resistance to quinine was not noted although high MIC (minimal inhibitory concentration) values have been observed. These data corroborate the decreasing sensitivity to quinine in strains from Brazil. Quinidine showed IC50 from 0.053 to 4.577 mmol/L of blood while IC50 from 0.053 to 8.132 mmol/L of blood was estimated for quinine. Moreover, clearance of the parasitemia was observed in concentrations lower than that used for quinidine in antiarrhythmic therapy, confirming our previous data. The results were similar to African isolate.

KEYWORDS: Quinidine; Malaria; Quinine; Chloroquine; P. falciparum; Antimalarial resistance

INTRODUCTION

Current malaria chemotherapy was considered to start in the middle of the XVII century with the jesuit's discovery of the folkloric use of Cinchona bark as a febrifuge by South American indians. However, Artemisia annua was already known by Chinese population since the beginning of the Christian era13, although the pharmacological studies have started in the 70's .

After its introduction in Europe, Cinchona tree bark powder begun to be extensively employed in the treatment of fevers. In 1820, two alkaloids, quinine (Fig. 1) and cinchonine, were isolated but the antimalarial effect was attributed only to quinine. The pure alkaloid replaced the Cinchona bark and quinine became the only drug in the therapy and prophylaxis of malaria38.


The unavailability of quinine during World Wars I and II led to the advent of the synthetic drugs, from which chloroquine stood out. Considered to be the ideal antimalarial, chloroquine showed to be less toxic, more effective and better to be administered than quinine, therefore, substituting it36.

Plasmodium falciparum strains resistance to chloroquine and to the second-line therapy sulfadoxine-pyrimethamine since the 60's led to the re-introduction of quinine. This alkaloid has been specially used to treat severe or complicated infections and chloroquine or mefloquine resistant malaria. In the later ones, the combination therapy has been recommended for maintaining the antimalarial effectiveness. For instance, tetracycline has been used in combinations with quinine40. Quinine resistant strains were identified in the early stages of the drug usage. Lately, a continuous decreasing in parasite sensitivity has been noted along different endemic areas8,24,27. This has increased the interest in using quinidine (Fig. 1), the dextro-rotatory diastereoisomer of quinine, as an alternative therapy.

Quinidine had its antimalarial activity despised in function of quinine. Recognized as a potent antiarrhythmic agent, quinidine has been mostly employed in the cardiovascular therapy since the 20's29. Nevertheless, in vitro, in vivo and clinical studies have reported quinidine as an effective or even superior to quinine as an antimalarial agent5,7,11,21,22,24,25,32,33,39. For a long time, quinidine has been considered by the Centers for Disease Control (CDC/Drug Service) in USA14,15 to be the drug of choice in the treatment of complicated P. falciparum infection. Since the 80's it has shown to be useful for treating pregnant women with severe falciparum malaria25, since abortifacient properties are alleged to quinine40. Moreover, quinidine, available worldwide, has increasingly been the only useful therapy for severe and complicated malaria since USA stopped the manufacture of quinine25.

With the purpose of facing the challenge of quinine effectiveness decrease in Brazilian P. falciparum strains1,2,8,9,16,26,34,41, we evaluated the in vitro sensitivity of isolates from North Brazilian States to quinidine in comparison to quinine and chloroquine. We were based on previous studies when quinidine showed to exert antimalarial effect in concentrations many times inferior than those used in the cardiovascular therapy23.

MATERIAL AND METHODS

Drugs - The drugs used were quinidine bisulphate dihydrate (Asta Médica Ltda), quinine sulphate (Central de Medicamentos, CEME) and chloroquine diphosphate (Fundação para o Remédio Popular, Furp).

Isolates - Six isolates of P. falciparum were employed: Isolate 1 – 5,760 parasites/mm3; Isolate 2 – 65,280 parasites/mm3; Isolate 3 – 3,240 parasites/mm3 and Isolate 4 – 65,000 parasites/mm3. All these isolates were assayed immediately after blood venum puncture. Isolates 1-3 were obtained from patients infected in Brazilian Northern region and Isolate 4 from a patient infected in Angola. These people had not been submitted to any antimalarial treatment for the previous 28 days10. Blood samples were collected after formal consent from patients. Isolate 5 (SUCEN S20-87) was obtained from a patient infected in Rondonia, Brazil, in 1987. Isolate 6 (Uganda Palo Alto) was used as a reference for chloroquine sensitivity. Isolates 5 and 6 were assayed after synchronization of 10% ring forms parasitemia.

Drug sensitivity assay - The biological assay was the in vitro microtechnique28. 96 flat-bottom wells microplates contained quinidine (at the same concentrations range than quinine), quinine and chloroquine were titrated (Table 1). Each series included the usual antimalarial therapeutic concentrations of quinine (1.14 mmol/L of blood) and chloroquine (6.4 mmol/L of blood) as the medium of the twofold serial dilutions. This procedure was adopted in analogy to the test for the assessment of P. falciparum response to antimalarial drugs as stated by WHO10.

The infected blood was diluted in culture medium to a 10% haematocrit. The plates were incubated at 37 °C for 24-48 hours (depending on schizont maturation) using the candle jar method37. The number of schizonts with three or more nuclei was determined in 200 parasites in thick blood smear stained with Giemsa.

Schizonts growth at 1.6 mmol/L of blood for chloroquine and 51.2 mmol/L of blood for quinine were considered as threshold for in vitro P. falciparum resistance24. The minimal inhibitory concentration (MIC), defined as the lowest concentration that completely inhibited schizont formation, was determined.

Statistical analysis – The parasitemia rate (number of parasites in the different wells in relation to the control) in function of the concentration was analyzed throughout the linear logistic model17 for quinine and quinidine. According to this, coincident, parallel, concurrent (1 intercept) and concurrent (2 intercepts) lines were fitted. The comparisons were made with regard to the simplest model, coincident lines. The goodness-of-fit statistic and the corresponding p-value were computed to assess the adequacy of the model. A significance level of 10% was adopted. Then, the medium inhibitory concentration (IC50) and the correspondent confidence interval (95%) were estimated for each drug.

RESULTS

The in vitro sensitivity of P. falciparum isolates to quinidine and the classical antimalarials quinine and chloroquine is shown in Table 1. Based on MIC, all parasites showed to be resistant to chloroquine, except the Isolate 6. Different susceptibility levels were observed to quinidine and quinine. No resistance to quinine was detected.

The results of the statistical analysis are depicted in Tables 2 and 3 and in Figure 2. For Isolate 1 the best-selected model was the concurrent lines (1 intercept). As the concentration increases, the parasitemia rate decrease is higher for quinidine than for quinine, leading to a lower quinidine IC50 (Table 3). For Isolate 2 parallel lines was the best-fitted model, with the quinine parasitemia rate and consequent IC50 smaller than those of quinidine. Even though none of the proposed models was well fitted for Isolate 3, the concurrent lines model (2 intercepts) indicates that for small and moderate concentrations quinine has a smaller parasitemia rate while an opposite tendency appeares in larger concentrations. Equal IC50 values were estimated. For Isolate 4, the concurrent lines model (2 intercepts) was the selected model. From the fitted lines, small concentrations of quinidine cause lower parasitemia rates while an opposite behavior is observed in high concentrations. Quinidine at 50% inhibition showed to be a worse antiplasmodial agent than quinine. For Isolate 5, coincident lines was the selected model and a common fitted line as well as estimated IC50 values were obtained. For Isolate 6, concurrent lines (1 intercept) was the best-fitted model. In this case, the parasitemia rate of quinine was smaller than the quinidine and the difference increases with the concentration. These results corroborate the estimated IC50 values (Table 3).


DISCUSSION

The loss in P. falciparum sensitivity to quinine in Brazil dated from the beginning of the XX century. A continuous decrease has been reported in special since the 80's when quinine replaced chloroquine and sulfadoxine-pyrimethamine in malaria resistant therapy. Then, tetracycline began to be co-administered with quinine in order to overcome the resistance problem and to reduce its inherent toxicity2,8,9. Quinine is still considered a useful drug for treating non-complicated falciparum malaria8. Nevertheless, a gradual increase in the time to clear the parasitemia followed by an elevation in recurrence frequency were observed in patients from the Eastern Amazon, where quinine was employed during the quadriennial 1983-199426. Moreover, decrease in quinine sensitivity was also evidenced in two recent reports performed with Brazilian samples from Mato Grosso State, Amazon area16,41.

In our study, different susceptibility levels were observed among the isolates in relation to quinine and quinidine. Resistance to quinine was not detected since no schizont maturation was observed at 51.2 mmol/L of blood24. Nevertheless, decreasing in P. falciparum susceptibility to quinine was confirmed, in particular, with Isolate 1 (the highest IC50) and with Isolates 5 and 6, collected for a long time and much more sensitive to quinine. These data corroborated recent evaluations16,26,41, showing a unquestionable and worryingly loss of quinine effectiveness in Brazilian strains. Interestingly, quinine was more effective against the African isolate, Isolate 4. However, opposite data have been obtained with isolates from Gabon24 and Niger35 and, also, out of the African continent, in Thailand32. In addition, all isolates showed to be highly resistant to chloroquine. MIC values were much higher than the considered threshold concentration, 1.6 mmol/L of blood24.

We consider that as observed in former studies 5,7,11,21,22,24,25,32,33,39, quinidine shows a promising activity against Brazilian P. falciparum strains. Quinidine inhibitory effect was observed in concentrations lower (estimated IC50 ranged from 0.053 to 4.577 mmol/L of blood that corresponds to 0.0172 to 1.485 mg/mL) than those employed in antiarrhythmic therapy, 2-6 mg/mL4. These results are in accordance to our previous assay carried out with two North Brazilian P. falciparum isolates23. Although further in vitro, in vivo, and clinical studies should be conducted, the preliminary results here reported are indicative of the possibility of using quinidine in uncomplicated but, especially, in complicated and severe forms of falciparum malaria. This finding assumes greater importance with the increasing loss of quinine efficacy against Brazilian strains. Nevertheless, precautions have been recommended concerning to the intravenous dispensing of quinidine due to its inherent cardiotoxicity6,25,40. In addition, the exchange transfusion after quinidine administration has been recommended for rapidly reducing the parasitemia, lowering the mortality by severe falciparum malaria20.

Notwithstanding, quinidine may also be used in combination with other antimalarial agents as well as with its stereoisomers. Cinchona alkaloid combinations have been successfully used for treating falciparum malaria in endemic areas3,12,18,19,30,31. Quinidine, quinine and cinchonine (QuinimaxÒ) or even quinidine, quinine, cinchonine and chinchonidine have been employed by different administration routes for treating uncomplicated as well as complicated falciparum malaria. These combination regimens allow to reduce the individual doses of the alkaloids, decreasing their inherent toxicities.

RESUMO

Avaliação da sensibilidade in vitro à quinidina em isolados brasileiros de Plasmodium falciparum: análise comparativa à quinina e à cloroquina

Malária falciparum representa grave e crescente problema de saúde pública mundial, dada a resistência do parasito à maioria dos fármacos disponíveis. Em algumas áreas endêmicas, a quinidina, diastereoisômero do antimalárico quinina, vem sendo empregada em substituição a este último. Com o objetivo de avaliar o emprego da quinidina como alternativa à perda crescente de sensibilidade de cepas brasileiras de P. falciparum à quinina, como o observado na região Amazônica, realizamos ensaio comparativo entre quinidina, quinina e cloroquina. A técnica in vitro do microteste de sensibilidade foi utilizada. Todos os isolados mostraram-se altamente resistentes à cloroquina. Resistência à quinina não foi observada, embora altos valores de CMI (concentração mínima inibitória) tenham sido encontrados. Estes resultados corroboram o decréscimo de suscetibilidade de cepas brasileiras à quinina. Observou-se variação de IC50 de 0,053 a 4,577 mmol/L de sangue para a quinidina, enquanto para a quinina estimou-se IC50 de 0,053 a 8,132 mmol/L de sangue. Ademais, observou-se clareamento da parasitemia em concentrações inferiores à da quinidina quando empregada como fármaco antiarrítmico, confirmando estudo anterior por nós realizado. Resultados semelhantes foram encontrados em isolado oriundo da África.

Received: 17 August 2000

Accepted: 16 March 2001

Correspondence to: Dr Elizabeth Igne Ferreira, Faculdade de Ciências Farmacêuticas/USP, Av. Prof. Lineu Prestes 580, Bl 13, 05508-900 São Paulo, SP, Brasil. e-mail: hajudan@usp.br

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  • (1
    ) Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brasil.
    (2
    ) Divisão de Programas Especiais, Superintendência de Controle de Endemias (SUCEN), São Paulo, SP, Brasil.
    (3
    ) Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brasil.
  • Publication Dates

    • Publication in this collection
      06 Sept 2001
    • Date of issue
      Aug 2001

    History

    • Accepted
      16 Mar 2001
    • Received
      17 Aug 2000
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