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Comparison of quinine and rabeprazole with quinine monotherapy in the treatment of uncomplicated falciparum malaria.

Introduction

Malaria is a protozoan disease caused by infection with parasites of genus Plasmodium (1). Five species responsible for human infection are P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi (recently reported in human infection). At present about 300-500 million new cases are detected each year and 1.1 to 2.7 million deaths are reported annually, mostly due to P. falciparum malaria (1).

Quinine is one of the oldest and very useful drug for the treatment of falciparum malaria and is effective in uncomplicated as well as severe cases. It acts principally on the mature trophozoite stage of parasite development and does not prevent sequestration or further development of circulating ring stages of P. falciparum. It also has effect on the pre-erythrocytic stages of malaria parasites (2). To reduce the onset of resistance and increase the patient compliance, quinine is used in combination with an antibiotic, usually doxycycline, tetracycline, clindamycin or azithromycin (2). Over dosage of quinine may cause oculotoxicity, including blindness from direct retinal toxicity, and cardiotoxicity, which can also be fatal (3). Multi drug resistant P. falciparum is an important public health problem in many areas where malaria is endemic, and in last few years the declining efficacy of important antimalarial drugs has left us with an increasingly limited choice of effective antimalarial drugs (4,5).

Proton pump inhibitors (PPIs) have antiparasitic and antibacterial properties. Omeprazole inhibits the growth of Leishmania donovani (6) and is also effective against the bovine pathogen Tritrichomonas foetus. PPIs also have antibacterial activity against Helicobacter pylori and rabeprazole is the most effective amongst different PPIs.

Earlier study on the efficacy of four PPIs, viz. omeprazole, lansoprazole, rabeprazole and pantoprazole against P. falciparum in vitro has shown definite action against three different isolates of P. falciparum (7). Earlier an in vitro study also found combination of quinine and omeprazole to be significantly synergistic (8), similarly another in vitro study found rabeprazole and lansoprazole to be the most effective antimalarial agents amongst the available PPI (7). Thus, we decided to study its synergistic efficacy in the treatment of uncomplicated falciparum malaria.

Material & Methods

This study was conducted between July and November 2007 on 50 adult hospitalized patients of uncomplicated P. falciparum malaria. The diagnosis was confirmed by microscopic examination of Giemsa stained peripheral blood smear. Patients of P. falciparum mono infection with density of 1000-100,000 asexual parasite/fil were included in the study. Other inclusion requirements were documented fever (axillary temperature >37.5[degrees]C) in the past 48 h in absence of another obvious cause of fever, willing to participate in the study, willing to stay in hospital up to one week and to come for follow-up visits up to 28 days.

These patients were randomly divided into two groups. They were allocated in accordance with a randomization chart. Group 1 (25 patients) received quinine with placebo [Q+P; Quinine (10 mg/kg bw) 8 h orally + Placebo (BD) orally for 7 days] and the Group 2 (25 patients) received quinine with rabeprazole [Q+R; Quinine (10 mg/kg bw) 8 hourly orally + Rabeprazole (20 mg BD) orally] for 7 days. Identical appearing capsule filled with inert substances were used as placebo. Patients of both the groups received 45 mg of primaquine in a single dose on 3rd day. Temperature was recorded every 6 h. Laboratory investigations were performed on all patients in the beginning, and later if considered necessary. Blood smears were taken six hourly till it became negative for two consecutive times. Since all patients were hospitalized, compliance was ensured. All patients were followed on Day 7, 14, 21, 28. On every visit a complete physical examination was done and peripheral blood smear was studied for the evidence of parasite. Patients who withdrew before receiving at least one dose of the study drugs and patients lost to follow-up after randomization, were excluded and their records were deleted from the database. All the end points and adverse effects were recorded before the randomization. SPSS 12.0 software and strata 9.0 were used for data management and statistical analysis. For all statistical analysis p<0.05 was considered to be statistically significant.

Results

Out of 50 patients enrolled only 40 could complete the study. The demographic profile and symptomatology of two groups were almost similar and described in Table 1. Therapeutic response to drug regimen was classified as per WHO criteria. Early treatment failure (ETF), late clinical failure (LCF), late parasitological failure (LPF) and adequate clinical response (ACR) were taken as primary outcome measures. Fever clearance time (FCT) and parasite clearance time (PCT) were taken as secondary outcome measures. The details of response in two groups are shown in Table 2. The FCT of both the groups was almost same having 52.8 and 51.3 h and was not statistically significant. The mean PCT of Group 1 and Group 2 were 60.30 and 51.9 h respectively which was statistically significant (p <0.05) (Table 3). These were secondary outcome measures.

Discussion

Quinine is an important drug for the treatment of P. falciparum malaria, however, the mono therapy decrease the selection pressure and ultimately leads to development of resistance. Thus, quinine is used with antibiotic like doxycycline, tetracycline or azithromycin to overcome this phenomenon5. PPI is another group of drugs with well-proved anti-malarial activity and also helpful in overcoming commonly observed gastrointestinal side-effects like nausea and vomiting. Rabeprazole is considered to be the most potent PPI amongst the other commonly available drugs9 and based on these observations we planned this observational study to see the synergistic effect of these two drugs.

The important clinical observation of this study was evidence of ETF in three out of the 20 patients receiving Q+P, 2 out of these 3 patients had parasitaemia on Day 2 higher than Day 0 count, irrespective of axillary temperature and one patient had parasitaemia on Day 3 with axillary temperature [greater than or equal to]37.5. ETF was not observed in any patient of Q+R group. However, the difference was not statistically significant. None of the patients in either group experienced LCF or LPF. The Q+P group showed 85% ACR while the Q+R group showed 100%. However, the difference was not statistically significant (p >0.05), which may be because of less number of cases.

The difference in ETF rate of the two groups can be due to the antimalarial activity of rabeprazole or the increased susceptibility of the malarial parasites to quinine in the presence of rabeprazole. Nevertheless, the cure rate was 100% in both the groups, suggesting that even if it is due to declining susceptibility of P. falciparum to quinine, it is still a very effective antimalarial agent in this region, although the cure rate may be different at different places (10).

In spite of the observation of no significant difference in the cure rates of the two groups, the significant difference in the PCT of the two groups was evident (60.3 h vs 51.9 h, p <0.05). A study from Thailand observed the mean PCT of patients treated with quinine mono therapy to be 82.1 h (11) whereas another study from Vietnam reported it to be 62 h (12). This significant difference in the PCT of the two groups can certainly be attributed to the synergistic antimalarial activity of rabeprazole. This observation suggests that addition of rabeprazole to quinine facilitate the parasite elimination rate, and it may be helpful in reducing the duration of the quinine therapy, thereby decreasing the side-effects and increasing the patient compliance.

The PPIs are known to have antiparasitic and antibacterial activities. Omeprazole inhibits Leishmania donovani by inhibiting the P type [K.sup.+][H.sup.+] ATPase on its surface membrane (13). An in vitro study demonstrated that omeprazole inhibits the growth of metronidazole resistant bovine pathogen Tritrichomonas foetus by inhibiting the enzyme Pyruvate decarboxylase of the parasite (14). Certain in vitro studies have also shown a significant activity of PPIs against P. falciparum (7,15). The precise mode of action of PPIs against P. falciparum is unknown, but they may have mechanisms distinct from those of the conventional drugs (7). The PPIs are metabolized by hepatic CYPs and, therefore, may interfere with the metabolism of other drugs eliminated by this route. This effect may cause increase in the serum quinine concentration. PPIs may inhibit the growth of P. falciparum by inhibiting parasite ATPase activity, which in turn increases the pH of the acidic food vacuole. There is evidence that quinine also inhibits membrane ATPase in the same way as PPIs (16).

Another in vitro study reported the combination of omeprazole and quinine to be significantly synergistic against P. falciparum (8). It was also having effective action against all of the P. falciparum clones tested at lower concentrations than omeprazole and pantoprazole. According to these studies for potent activity, the drug should have both hydrogen bond acceptor and hydrogen bond donor sites along with two aromatic hydrophobic sites. The hydrogen bond acceptor feature is totally absent in the mapping for pantoprazole. We used rabeprazole because of the fact that although all PPIs were found to be active against H. pylori in an in vitro study but rabeprazole had shown greater antibacterial properties against 8 strains of H. pylori than omeprazole and lansoprazole (17). It was also better found than omeprazole and lansoprazole in inhibiting the urease activity of H. pylori (18) and suppressing the motility of H. pylori, Campylobacter jejuni and C. coli (19).

There was statistically significant difference in ETF or ACR in the two groups, which definitely indicates the antimalarial activity of rabeprazole. This observation is further supported by the significant difference in the PCT of the two groups. These results strongly suggest that addition of rabeprazole to quinine results in an increase in the parasite elimination rate and it may be helpful in reducing the duration of the quinine therapy, thereby decreasing the side-effects of quinine and increasing patient compliance. Our results showed that a rabeprazole-quinine combination could be a safe combination for Pf malaria. Moreover, a larger study or a randomized controlled trial can conclusively prove the antimalarial activity of rabeprazole and its use in management of malaria.

Received: 17 September 2009

Accepted in revised form: 12 May 2010

References

(1.) Park K. Park's textbook of preventive and social medicine. XVIII edn. Jabalpur: M/s. Banarsidas Bhanot 2005; p. 201.

(2.) Guidelines for treatment of malaria. Geneva: World Health Organization 2006; pp. 32, 43, 108-10, 170.

(3.) Boland ME, Roper SM, Henry JA. Complications of quinine poisoning. Lancet 1985; 1: 384-5.

(4.) Pukrittayakamee S, White NJ. Combination therapy: making the best use of existing drugs. Pharm News 8: 21-5.

(5.) White NJ. Delaying antimalarial drug resistance with combination chemotherapy. Parasitologia 1999; 41: 301-8.

(6.) Kochar DK, Saini G, Kochar SK, Bumb RA, Mehta RD, Sirohi P, Purohit SK. A double blind randomized placebo controlled trial of rifampicin with omeprazole in the treatment of human cutaneous leishmaniasis. J Vector Borne Dis 2006; 43(4): 161-7.

(7.) Riel MA, Kyle DE, Bhattacharjee AK, Milhous WK. Efficacy of proton pump inhibitor drugs against P. falciparum in vitro and their probable pharmacophores. Antimicrob Agent Chemother 2002; 46: 2627-32.

(8.) Skinner-Adams TS, Davis TM. Synergistic in vitro antimalarial activity of omeprazole and quinine. Antimicrob Agent Chemother 1999; 43: 1304-6.

(9.) Tsuchiya M, Imamura L, Park JB, Kobashi K. Helicobacter pylori urease inhibition by Rabeprazole, a proton pump inhibitor. Biol Pharm Bull 1995; 18: 1053-6.

(10.) Pukrittayakamee S, Chantra A, Vanijanonta S, Clemens R, Looaresuwan S, White NJ. Therapeutic responses to quinine and clindamycin in multidrug resistant falciparum malaria. Antimicrob Agents Chemother 2000; 44: 2395-8.

(11.) Pukrittayakamee S, Prokongpan S, Wanwimolruk S, Clemens R, Looaresuwan S, White NJ. Adverse effect of Rifampin on quinine efficacy in uncomplicated falciparum malaria. Antimicrob Agents Chemother 2003; 47(5): 1509-13.

(12.) Peter J de Vries, Nguyen Ngoc Bich, Huynh Van Thien, Le Ngoc Hung, Trin Kim Anh, Piet A, Kager, Siem H Heisterkamp. Combination of artemisinin and quinine for uncomplicated falciparum malaria: efficacy and pharmacodynamics. Antimicrob Agents Chemother 2000; 44: 1302-8.

(13.) Jiang S, Meadows J, Anderson SA, Mukkada AJ. anti-leishmanial activity of antiulcer agent omeprazole. Antimicrob Agents Chemother 2002; 46(8): 2569-74.

(14.) Sutac R, Tachezy J, Kulda J, Hrdy I. Pyruvate decarboxylase, the target for omeprazole in metronidazole resistant and iron restricted Tritrichomonas foetus in vitro. Antimicrob Agents Chemother 2004; 48(6): 2185-9.

(15.) Skinner-Adams TS, Davis ME, Manning LS, Johnston WA. The efficacy of benzimidazole drugs against Plasmodium falciparum in vitro. Trans R Soc Trop Med Hyg 1997; 91: 580-4.

(16.) Choi I, Mego L. Purification of Plasmodium falciparum digestive vacuoles and partial characterization of the vacuolar membrane ATPase. Mol Bichem Parasitol 1988; 31: 71-8

(17.) Hirai MH, Azuma T, Ite S, Kato T, Kohli Y. A proton pump inhibitor, E 3810, has antibacterial activity through binding to Helicobacter pylori. J Gastroenterol 1995; 30: 461-4.

(18.) Tsuchiya M, Imamura L, Park JB, Kobashi K. Helicobacter pylori urease inhibition by Rabeprazole, a proton pump inhibitor. Biol Pharm Bull 1995; 18: 1053-6.

(19.) Tsutsui N, Taneike I, Ohara T, Goshi S, Kojio S, Iwakura N, Matsumaru H, Wakisaku Saito N, Zhan HM, Yamamoto T. A novel action of the proton pump inhibitor Rabeprazole and its thioether derivative against the motility of Helicobacter pylori. Antimicrob Agents Chemother 2000 ; 44: 3069-73.

Corresponding author: Dr D.K. Kochar, C-54, Sadul Ganj, Bikaner-334 003, India. E-mail: drdkkochar@indiatimes.com; drdkkochar@yahoo.com

Dhanpat K. Kochar [a], Vikas Gupta [b], Abhishek Kochar [b], Jyoti Acharya [b], Sheetal Middha [b], Parminder Sirohi [b] & Sanjay K. Kochar [b]

[a] Kothari Medical & Research Institute, Bikaner, [b] Department of Medicine, S.P. Medical College, Bikaner, India
Table 1. Clinical characteristics of patients with
P. falciparum malaria

Characteristics                        Group 1     Group 2      Total
                                        (Q+P)       (Q+R)     patients
                                       (n=20)      (n=20)      (n=40)
Age
Mean                                    26.05       35.1       30.575
SD                                     10.555      18.352      15.471

Sex
Male                                     10          16       24 (60)
Female                                   10           4       16 (40)

Clinical symptoms
Fever                                    20          20       40 (100)
Chills and Rigors                        13          14       27 (67.5)
Nausea and Vomiting 14                               16       30 (75)
Abdominal pain                            2           4        6 (15)
Dizziness                                 2           3        5 (12.5)
Diarrhea                                  1           2        3 (7.5)
Headache                                 13          12       25 (62.5)
Bodyache                                 11          10       21 (52.5)

Parasite density in the beginning
[less than or equal to] 20,000            8          10       18 (45)
20,001-40,000                             9          10       19 (47.5)
40,001-60,000                             1           0        1 (2.5)
60,001-80,000                             1           1        2 (5)

Figures in parentheses indicate percentage.

Table 2. Details of primary efficacy variables

Parameters      Group 1       Group 2        Total
                 (Q+P)         (Q+R)       patients
                (n=20)        (n=20)        (n=40)
                No. (%)       No. (%)       No. (%)

ETF              3 (15)       0 (0)         3 (7.5)
LCF              0 (0)        0 (0)         0 (0)
LPF              0 (0)        0 (0)         0 (0)
ACR             17 (85)      20 (100)      37 (92.5)

Parameters       [chi         p-value
                square]

ETF              3.243         >0.05
LCF
LPF
ACR              3.243         >0.05

ETF--Early treatment failure; LCF--Late clinical failure;
LPF--Late parasitological failure; ACR--Adequate clinical
response.

Table 3. Changes in secondary efficacy variables

Parameter                        Group 1 (n=20)

                      Mean            SD             SE

FCT                   52.8            20            4.47
PCT                   60.3          12.07           2.70

Parameter                        Group 2 (n=20)

                      Mean            SD             SE

FCT                   51.3          16.68           3.73
PCT                   51.9           9.18           2.05

Parameter           t-value        p-value

FCT                  -0.283         0.780
PCT                  -2.424         0.026

FCT--Fever clearance time; PCT--Parasite clearance time.
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Article Details
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Author:Kochar, Dhanpat K.; Gupta, Vikas; Kochar, Abhishek; Acharya, Jyoti; Middha, Sheetal; Sirohi, Parmind
Publication:Journal of Vector Borne Diseases
Article Type:Clinical report
Geographic Code:9INDI
Date:Sep 1, 2010
Words:2587
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