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MOLECULAR EPIDEMIOLOGY OF MALARIA IN CAMEROON. XIX. QUALITY OF ANTIMALARIAL DRUGS USED FOR SELF-MEDICATION

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  • 1 Unité de Recherche Paludologie Afro-tropicale, Institut de Recherche pour le Développement et Laboratoire de Recherche sur le Paludisme, Organisation de Coordination pour la Lutte Contre les Endémies en Afrique Centrale, Yaoundé, Cameroon

Substandard and counterfeit pharmaceutical products are increasingly circulating and distributed around the world, in particular in less developed countries. These low-quality or counterfeit products often involve drugs that are in high demand for the prevention and treatment of highly prevalent diseases, such as antimalarial drugs in endemic countries. Self-medication for presumed malarial infections with drugs purchased from unofficial drug vendors is a common practice in Africa. The aim of the study was to investigate the quality of chloroquine, quinine, and sulfadoxine-pyrimethamine obtained from illegitimate sector in urban and rural areas in Cameroon and analyze the impact of these drugs on patients. We collected 284 samples of three antimalarial drugs from 132 different sources in 16 villages and cities throughout the country. We also collected antimalarial drugs that were used for self-medication by malaria-infected patients. Drug quality was assessed by a simple color reaction test and semi-quantitative thin-layer chromatography. Fifty (38%) of 133 chloroquine, 52 (74%) of 70 quinine, and 10 (12%) of 81 antifolates had either no active ingredient, an insufficient active ingredient, the wrong ingredient, or unknown ingredient(s). Self-medication with antimalarial drugs purchased from unofficial vendors is not a reliable strategy to diminish morbidity and mortality. These counterfeit drugs contribute to the spread of drug-resistant malaria parasites and may lead to increasing therapeutic failure and medical expense.

INTRODUCTION

Over the past two decades, there has been an increase in public awareness of the existence of counterfeit and substandard drugs.1–4 Increasing international and regional free trade, high demand for curative and preventive drugs and vaccines, proliferation of small pharmaceutical industries, and insufficient regulation of drug manufacture and trade are some of the factors that have contributed to the wide distribution of low-quality medicines, particularly in developing countries. Although practically all types of pharmaceutical products have been shown to be involved, the existing data suggest that anti-infectious agents, in particular antibiotics and anti-parasitic agents, are the most counterfeited products in developing countries.5 The potential risk of counterfeit anti-infectious agents for individual and community health includes clinical aggravation leading to complications and even mortality from either the disease itself or possible toxic components in the product, increased health expenditures to attain cure, and selection of drug-resistant bacteria and parasites. From the epidemiologic viewpoint, ineffective or partially effective counterfeits may lead to biased data on anti-malarial drug efficacy, as well as to discordant results between clinical efficacy and molecular markers. To implement effective countermeasures against counterfeit drugs, there is a need for more data to define the extent of the problem. Many of the previous reports on counterfeit drugs and vaccines have been based on case reports on failure to attain the expected therapeutic or prophylactic effect, chance discovery, or investigation on a small sample of products belonging to different classes of drugs.5–7 Other reports constituting the World Health Organization (WHO) database have remained confidential, unpublished, or published for limited distribution.5

The present nationwide survey was conducted in Cameroon to analyze the situation in the unofficial sector of drug distribution and sale, notably in market places and through street vendors. This illegal market represents the end-product of drug distribution channels that escape government regulation and control. Although these illegitimate health care providers are not authorized to distribute and sell pharmaceutical products, there is an apparent strong population demand that maintains this unofficial sector. From the pragmatic viewpoint, there is a need for an outlet that provides low-cost, effective, good-quality antimalarial drugs for early appropriate home management of presumptive cases of uncomplicated malaria in children.8,9 Self-medication is known to be widely practiced in Africa. While it has many disadvantages from the medical viewpoint, the initial treatment, if correctly administered using a good-quality drug, may contribute to diminution of the risk of a malaria attack progressing towards the potentially fatal, severe, and complicated form, especially in remote areas where access to health centers is difficult.8 Thus, our study also indirectly assessed the reliability of this unofficial sector in combating malaria in Africa. Although a complete survey on counterfeit pharmaceutical products includes identification of the source and manufacturer to evaluate whether packaging is genuine, no attempt was made to trace the actual source of these products in our study.

MATERIALS AND METHODS

Sample collection.

Oral formulations of test samples were obtained from street vendors, who either had a fixed stall in the market place or were ambulatory sellers carrying an assortment of medicines in their bag or basket for sale on the street. None of the test samples was from the official health sectors, including dispensaries, health care centers, hospitals, and authorized pharmacies, which are under government regulation and control. Samples were collected from various sites in Cameroon over a one-year period in 2001–2002. The collection sites included Maroua and Garoua in the Sahelian far north to Sangelima and Djoum in the south, Bamenda and Buea in the west, and Garoua-Boulai in the east. In each locality, a full treatment course of chloroquine, quinine, and/ or sulfadoxine-pyrimethamine was purchased from several different vendors. Since many of the samples had no packaging, each vendor was asked to either write or explain orally the identification of each drug, the quantity of active ingredient in each tablet or capsule, and the way to administer them so that we can identify the drugs later. To avoid suspicion, all transactions were carried out by African nationals in the local dialect, French, or English, depending on the collection site. The purchased drugs were sealed in airtight plastic bags and stored in the dark at room temperature until analysis.

To study the impact of these antimalarial drugs used for home management on population health, febrile patients (fever at the time of consultation or history of fever within the past 48 hours) consulting spontaneously at the Nlongkak Catholic missionary dispensary in Yaounde were requested to provide any remaining drugs that they self-administered before consultation if the presence of Plasmodium falciparum was confirmed by the examination of a Giemsa-stained thick blood smear. Patients with severe and complicated malaria requiring emergency medical treatment were excluded from the study. The presence of quinoline-type antimalarial drugs in urine was screened by the Saker-Solomons test.10 The patients were treated with amodiaquine (30 mg base/kg of body weight in three equally divided daily doses) or quinine (25 mg base/kg of body weight/day for five days) and re-examined on day 3 to ensure parasite clearance. The clinical study was reviewed and approved by the Cameroonian National Ethics Committee and Cameroonian Ministry of Public Health. In vitro response to chloroquine was determined by isotopic microtest if the Saker-Solomons urine test result was negative.11 The threshold value for in vitro chloroquine resistance was set at ≥100 nM.

Reference drugs.

The active principles were obtained from either pharmaceutical companies (chloroquine sulfate; Aventis, Antony, France; sulfadoxine base; Hoffmann-La Roche, Basel, Switzerland) or Sigma Chemical Co. (St. Louis, MO; chloroquine diphosphate, quinine sulfate, pyrimethamine base, sulfamethoxazole, and trimethoprim). The latter two products were included in our assays because three test samples containing one (sulfamethoxazole-pyrimethamine combination), or both of them (sulfamethoxazole-trimethoprim combination), were sold to our surveyors as an equivalent of Fansidar® for malaria treatment. Reference standards were purchased from licensed pharmacies or obtained from European suppliers: chloroquine sulfate (Nivaquine®, 100 mg; Rhône-Poulenc Rorer Specia, France), chloroquine diphosphate (Resochin®, 250 mg, Bayer AG, Leverkusen, Germany), sulfadoxine-pyrimethamine (Fansidar®, sulfadoxine, 500 mg plus pyrimethamine, 25 mg; Roche, Fontenay-sous-Bois, France), generic quinine sulfate (International Dispensary Association, Amsterdam, The Netherlands), and cotrimoxazole or sulfamethoxazole-trimethoprim (Bactrim®, sulfamethoxazole 400 mg plus trimethoprim 80 mg; Roche). The quality of reference tablets was controlled by thin-layer chromatography in respect to the corresponding active principles.

Drug analysis.

The quality of drug samples was evaluated in two steps. First, a color test was performed to screen the tablets and capsules for compatibility with the chemical class to which they belong. For chloroquine and quinine, there is currently no specific color reaction. To simplify screening, the Saker-Solomons test was adapted for the purpose of our study.10 Due to cross-reactivity, this test detects quinoline-type drugs (chloroquine, amodiaquine, quinine, and mefloquine) as well as proguanil, but not sulfonamides. A tablet or capsule was mixed with 1 mL of phosphate buffer (pH 8.0) and 0.5 mL of 0.05% tetrabromophenolphthalein ethyl ester (Sigma Chemical Co.) in chloroform. The latter solution yields a yellow-green color before reaction with test samples. A positive result signifying the presence of quinoline-type drugs is indicated by an immediate change of color to violet. A negative result is denoted by no change in color. The detection limit is 1 μg/mL. If the color test result was negative, no further analysis was done. For sulfonamides, there is a specific color reaction test, which consists of mixing approximately one-fifth to one-tenth of the ground tablet, approximately 10 mg of 4-(dimethylamino)-benzaldehyde, 4 mL of 50% methanol, and 1 drop of 60% sulfuric acid.12 A positive reaction is indicated by the immediate appearance of a bright orange color. The color test can detect < 1 mg/mL of sulfonamides.

Drug samples that passed the color test were further analyzed by the semi-quantitative thin-layer chromatography.13–17 The following technical procedures were kindly provided by Dr. R. W. O. Jähnke (German Pharma Health Fund e. V., Frankfurt, Germany). Chloroquine salt, quinine salt, sulfadoxine-pyrimethamine, and cotrimoxazole reference and test samples were ground to fine powder and diluted to concentrations of 2.5 mg/mL in water, 1.25 mg/mL in 99% methanol, 6.25 mg/mL of sulfadoxine plus 0.312 mg of pyrimethamine in pure methanol, and 6.25 mg/mL of sulfamethoxazole plus 1.25 mg/mL of trimethoprim in pure methanol, respectively. For each solution, 2 μL were spotted onto an aluminium chromatoplate coated with silica gel 60 F254 (stationary phase) (VWR International, Strasbourg, France). The mobile phase consisted of a mixture of methanol/ethylacetate/20% NH4OH solution (v/v/v, 40:10:1) for chloroquine, methanol/20% NH4OH solution (v/v, 40:1) for quinine, and ethylacetate/methanol (v/v, 3:1) for sulfadoxine-pyrimethamine and cotrimoxazole. The spots corresponding to each sample were revealed by exposing the chromatoplate to ultraviolet light (254 nm and/or 365 nm) and staining with iodine. The travel distance of the spots was expressed as the relative retention factor (Rf value), defined as the distance of the spot from the origin divided by the distance covered by the mobile phase. Each test was run against the reference tablets diluted to the standard working solution, defined as the upper limit set at 100% (2.5 mg/mL for chloroquine, 1.25 mg/mL for quinine, and 6.25 mg/mL for sulfadoxine and sulfamethoxazole), and to a lower limit set at 80% (2.0 mg/mL for chloroquine, 1.0 mg/mL for quinine, and 5.0 mg/mL for sulfadoxine and sulfamethoxazole). This range of 80–100% (± 10% possible error due to visual inspection) is considered to be accurate enough to determine the drug quality by thin-layer chromatography.15–17 The lowest detection level of antimalarial drugs by thin-layer chromatography is 0.2 mg/mL.

Data interpretation.

“Counterfeit pharmaceutical product” is defined by the WHO as drugs that are deliberately and fraudulently mislabeled with respect to identity and/or source.18 The definition includes products with correct or wrong ingredients, without active ingredients, with insufficient active ingredients, or with false packaging. The current WHO definition is doubly restrictive due to its legal definition and inclusion of the deliberate intent of a drug manufacturer. Based on a less restrictive and more laboratory-oriented definition, the following samples in our study were considered to be counterfeit or fake: 1) drugs that did not produce the expected color reaction, 2) samples with the expected color reaction but yielding a different spot (i.e., different Rf value) on thin-layer chromatography, and 3) samples with the expected color reaction producing a spot located at the same distance as the reference drug on thin-layer chromatography but with lower intensity, compared with the lower limit set at 80% of the reference tablet. To qualify as a drug with an acceptable quality, we required 1) the Rf value of the spot produced by the test samples to be identical to that of the reference standard (qualitative criterion) and 2) the content of the samples to be within 80–100% of the standard, i.e., the intensity of the spot is at least comparable to that of 80% of the standard (semi-quantitative criterion). Since a large majority of our samples had no packaging and the study did not include a criminal investigation on their sources, the purported intent of the drug producer to fake packaging is unknown. Likewise, none of our samples could qualify as “substandard drug,” which is defined as genuine packaging by authorized pharmaceutical company with incorrect (undeliberate) quantity of ingredient.

RESULTS

A total of 284 test samples were obtained from 132 different vendors (15 from malaria-infected patients) in 16 villages and cities throughout the country. If the bulk container in which drugs were stored is considered as accurate information and taken into account, 118 samples had an identifiable source (61 from the European Union, 6 from an east European country, 39 from Asia, and 12 from Africa), while 166 samples were of unknown origin. If packaging is set as the reliable criterion for country of origin, among 92 samples presented in blisters, there were 48 from Europe, 35 from Asia, and 9 from Africa. In a few cases, it was mentioned that the product was manufactured for a European or African pharmaceutical company, without specifying where it was actually produced.

Based on visual inspection, a wide variety of products sold as chloroquine was obtained (Table 1). The primary screening based on color reaction showed that 42 (32%) of 133 chloroquine samples were counterfeit. These products did not yield any visible spot on thin-layer chromatography, suggesting the absence of active ingredients within the detection limit of thin-layer chromatography. Further analysis by thin-layer chromatography showed that eight (9%) of 91 color-positive samples contained less than 80% of the reference standard.

The color reaction suggested that 63 (90%) of 70 quinine samples contained a quinoline-type drug; the other seven samples were clearly counterfeit with unknown ingredients. However, 45 of 63 color-positive quinine samples yielded spots with considerably lower Rf values (0.58 for genuine quinine and 0.39 for counterfeit quinine). These counterfeit quinine samples produced an intense spot when exposed to ultraviolet radiation source set at 254 nm, which was invisible at 312 nm, unlike the reference standard of quinine. Because primary screening test suggested the presence of a quinoline-type drug and the Rf value for counterfeit quinine using the mobile phase for quinine was similar to that of chloroquine, a second assay was performed for 17 randomly selected counterfeit samples, using the thin-layer chromatography protocol for identifying chloroquine. All of the re-tested samples had Rf values identical to that of the chloroquine reference, and the spot intensity suggested that these counterfeit quinine tablets contained approximately 100 mg of chloroquine (except for one sample with < 80 mg of chloroquine) and no detectable quinine.

Unlike chloroquine and quinine, most (74%) of the sulfadoxine-pyrimethamine samples were sold in packaging under 22 different proprietary names. None of these samples was beyond the expiration date indicated on the package (only one sample expired one month after the purchase date). Four packages contained only two tablets, instead of three tablets required for the standard treatment of adults. These products also contained a notice including a weekly prophylaxis as one of the indications, despite the fact that WHO has officially advised against this indication since the late 1980s. Of 78 sulfadoxine-pyrimethamine samples, 10 (13%) had a negative color reaction. Samples containing sulfamethoxazole-pyrimethamine (n = 2) or sulfamethoxazole-trimethoprim (n = 1) combinations yielded a positive color reaction indistinguishable from the sulfadoxine-pyrimethamine combination. For each of the color-positive samples, thin-layer chromatography revealed two spots corresponding to the correct amount of sulfonamides and antifolates. All 10 counterfeit, color test-negative products yielded a single intense spot with a slightly lower Rf value that did not correspond to that of sulfadoxine or sulfamethoxazole. The identity of these products was not determined.

Chloroquine and quinine used for self-medication were obtained from 15 malaria-infected patients (seven males and eight females, age range = 13–76 years old, mean body temperature at the time of consultation = 38.0°C, range = 36.4–40.5°C) (Table 2). Only six (five with packaging) of 15 drug samples were of acceptable quality. All patients were infected with P. falciparum (one patient with a mixed P. falciparum and P. ovale infection), with parasitemias between 0.1 and 3.0%. Eight patients had a negative urine test result due to self-medication with fake or underdosed antimalarial drugs. One pregnant patient with a negative urine test result did not take the good-quality chloroquine for the past 10 days. An in vitro drug sensitivity assay showed that some of the isolates were chloroquine sensitive (50% inhibitory concentration [IC50] < 100 nM).

DISCUSSION

The present study shows the extent of counterfeit antimalarial drugs circulating throughout the country in the unauthorized sector that, ideally, should be a reliable partner, and not an impediment, for the initial and rapid self-medication administered at home to diminish the risk for the evolution of the disease towards potentially fatal, severe, and complicated malaria. Many of the purchased drugs without packaging were counterfeit, whereas those in packages and blisters were unlikely to be counterfeit. As the immediate step towards informing the concerned local population and combating against counterfeits, it may be suggested that counterfeit drugs in central Africa are unlikely to be presented with packaging if drugs have to be purchased from unofficial vendors (for example, during odd hours and on Sundays and holidays when many of the authorized pharmacies and health care centers are closed). Meanwhile, a more efficient strategy for home management of presumptive malaria cases needs to be developed as an extension of community- and district-level malaria control programs under government regulation.9 Beyond home management of what is presumed to be malarial infection, the population needs to be educated to consult primary and secondary health care centers where correct diagnosis and management can be assured. At the same time, repressive efforts by the government regulatory board are under way with the long-term objective to eradicate unauthorized trade and sales of pharmaceutical products. Moreover, government regulation of drugs entering the country through the official channel needs to be maintained and reinforced.

Previous studies have reported that a considerable proportion of antimalarial drugs obtained from retail outlets in Nigeria, a country bordering Cameroon, as well as in east African countries, is of poor quality.19–21 A follow-up study on drugs purchased from authorized pharmacies in Nigeria and analyzed by high-performance liquid chromatography has shown that a large majority of antimalarial tablets and capsules do not contain the amount of active ingredients within the limits set by British Pharmacopoeia, but they contain slightly higher quantity than the accepted limits.22 In practical terms, drug efficacy is not affected and the risk of toxicity due to slightly higher doses is unlikely if the prescribed number of tablets or capsules are administered. In the unofficial outlet in Cameroon, there was an opposite problem of drugs containing insufficient active principles or different active ingredients, which would obviously affect drug efficacy and possibly expose the patients to risks of toxic effects due to unknown ingredients.

Unlike the study of Taylor and others22 on drugs collected in Nigeria and analyzed in the United Kingdom, all analytical procedures in the present study were carried out with locally available reagents in Cameroon. The relatively simple, rapid, and inexpensive assays used in this study can be performed in moderately equipped laboratories and even in the field in developing countries after initial investment for acquiring ultraviolet source, chromatoplates, and reference drug samples.23 The other sophisticated, costly, labor-intensive techniques, such as analytical chemistry, infrared-absorption spectroscopy, gas chromatography, and high-performance liquid chromatography, have the advantages of allowing a specific identification of an unknown drug substance, determining the exact quantity of active ingredients in the sample, and assessing drug quality according to the specifications established by international pharmacopoeia. Compared with these methods, thin-layer chromatography and color reaction are less sensitive and less specific, but when used together, are reliable screening methods. These latter simple procedures have been recognized by the WHO as appropriate technology for initial screening of a large number of drug samples in developing countries.18

In Cameroon, we have already been exposed to the problem of counterfeit chloroquine in our clinical practice.24 Our study revealed that counterfeit activity may be getting more sophisticated to escape spot controls and minimize the risk of isolated reports on drug treatment failure. This is illustrated by the use of approximately 100 mg of chloroquine in the fake quinine tablet, which was probably calculated to obtain symptomatic relief in patients infected with chloroquine-sensitive malaria parasites. These patients may ingest up to 1.5 g of chloroquine in a five-day fake quinine treatment course (assuming one tablet taken three times a day), which is below the toxic dose, while gaining the benefit of avoiding common side effects of quinine (cinchonism). Our finding that chloroquine is used as a substitute in many counterfeit quinine tablets corroborates our clinical observation that a number of African patients refuse quinine treatment due to their past history of pruritus after “quinine” intake. Pruritus is a well-known side effect after chloroquine intake in dark-skinned patients and has rarely been reported after quinine treatment. Furthermore, medical practitioners encountering “quinine resistance” in Africa usually tend to ascribe it to an inadequate dose due to poor compliance, rather than question drug quality. Likewise, medical practitioners may assume that the absence of clinical improvement after the administration of fake chloroquine may be due to chloroquine resistance, which has become frequent (up to 50%) in southern and central Cameroon.11,25

Recent studies have shown that counterfeits of even new antimalarial drugs, such as artesunate and mefloquine, are circulating in southeast Asia.26,27 In central Africa, new antimalarial drugs (mefloquine, halofantrine, lumefantrine, artemisinin derivatives) are available exclusively through authorized pharmacies. One of the major driving forces that maintains the high demand for drugs sold by unofficial vendors is drug price. The new antimalarial drugs cost > 3,000 Francs de la Communauté Financière Africaine (CFA ) (1 Euro = 656 Francs CFA) in authorized pharmacies. Any desired number of chloroquine tablets can be purchased for 8.33–25 Francs CFA per tablet from street vendors, while in official pharmacies a package containing 20 100-mg chloroquine sulfate tablets costs 1,170 Francs CFA, i.e., 2.3–7 times higher. It is also possible to bargain the drug price in the street. The price of a single quinine tablet varies between 25 and 100 Francs CFA in the streets and markets in Yaounde, while generic quinine in pharmacies is priced between 650 and 1,250 Francs CFA for a package of 10 tablets. A single treatment dose (three tablets) of sulfadoxine-pyrimethamine costs between 400 and 550 Francs CFA in the street and 1,190 Francs CFA in official pharmacies. For low-income families, direct and indirect medical expenditures (transportation, consultation fee, laboratory examinations, drug purchase) in the official sector for a single malarial attack in the family may attain one-tenth of the monthly income. There is clearly a need for more government-supported measures (importation and distribution of good quality generic drugs, repression of counterfeit drugs, training of personnel) so that patients would seek medical care at health centers for rapid and appropriate diagnosis and treatment.

Table 1

Characteristics, types, and number of antimalarial drug samples screened for quality

Active ingredientDosage formPackagingEngraved markingsNumber of samplesPositive color reactionThin-layer chromatography
* One sample with <80% of the reference standard.
† All contained <80% of the reference standard.
‡ Regardless of the salt form (usually sulfate or phosphate, when specified), quinine tablets contain approximately 82% of base. There were seven distinguishable uncoated tablets without any engraved markings, based on visual inspection (color, shape, diameter).
Chloroquine phosphate, 100 mgUncoated tabletsBlisterNone222
NoneCQ363333
Chloroquine111
None888
Coated tabletsNoneNone333
Chloroquine phosphate, 250 mgCapsulesBlisterVarious444
Uncoated tabletBlisterVarious151515
None3 with markings443*
Chloroquine sulfate, 100 mgUncoated tabletsBlister (n = 7)N222
C555
None (n = 49)N4570†
C333
None100
Chloroquine sulfate, 300 mgUncoated tabletsBlisterN 300111
Chloroquine, unknown salt, 100 mgUncoated tabletsNone100111
None222
Quinine salt, 300 mg‡Uncoated tabletsNoneQ666
NoneMD×300100
Coated tabletsNoneNone (7 types)55496
BlisterNone333
NoneNone222
Quinine salt, 250 mgUncoated tabletsNoneQ 250110
Quinine salt, 200 mgUncoated tabletsNoneQ111
None110
Sulfadoxine-pyrimethamine (500 mg/25 mg)Uncoated tabletsBlisterProprietary names474747
None101010
NoneNone201010
CapsuleBlisterProprietary name111
Sulfamethoxazole-pyrimethamine (500 mg/25 mg)Uncoated tabletsBlisterNone222
Sulfamethoxazole-trimethoprim (800 mg/160 mg)Uncoated tabletsBlisterProprietary name111
Table 2

Drugs self-administered by malaria-infected patients before consultation*

No.DrugColor test resultDrug qualityUrine test resultLast intake (no. of days)IC50 (nM)
* The drugs taken by patients no. 1, 2, 6, 9, and 13 were in blisters and originated from France, China, or Cameroon. The other drugs were of unknown origin. Patient no. 1 was pregnant and under weekly chloroquine prophylaxis. Drug quality refers to the results obtained by thin-layer chromatography. Color test and urine test were both performed by the Saker-Solomons method. Threshold for in vitro chloroquine resistance, 50% inhibitory concentration (IC50) ≥ 100 nM. ND = not determined.
1Chloroquine sulfate, 300 mgPositiveAcceptableNegative10217
2Chloroquine phosphate, 100 mgPositiveAcceptablePositive1ND
3Chloroquine sulfate, 100 mgPositiveUnderdosedNegative2114
4Chloroquine sulfate, 100 mgNegativeNo active ingredientNegative122.3
5Chloroquine sulfate, 100 mgNegativeNo active ingredientNegative1Uninterpretable
6Chloroquine sulfate, 100 mgPositiveAcceptablePositive1ND
7Chloroquine sulfate, 100 mgNegativeNo active ingredientNegative<6 hours89.9
8Chloroquine sulfate, 100 mgNegativeNo active ingredientNegative1Uninterpretable
9Chloroquine sulfate, 100 mgPositiveAcceptablePositive1ND
10Chloroquine sulfate, 100 mgNegativeNo active ingredientNegative<6 hours476
11Chloroquine sulfate, 100 mgNegativeNo active ingredientNegative1Uninterpretable
12Quinine sulfate, 300 mgPositiveAcceptablePositive1ND
13Quinine sulfate, 300 mgPositiveAcceptablePositive1ND
14Quinine sulfate, 300 mgPositiveChloroquine, not quininePositive2ND
15Quinine sulfate, 300 mgPositiveChloroquine, not quinineNegative3240

Author’s address: Leonardo K. Basco, Unité de Recherche Paludologie Afro-tropicale, Institut de Recherche pour le Développement, Laboratoire de Recherche sur le Paludisme, Organisation de Coordination pour la Lutte Contre les Endémies en Afrique Centrale, BP 288, Yaoundé, Cameroon, Telephone: 237-223-2232; Fax: 237-223-0061; E-mails: Leonardo.Basco@ibaic.u-psud.fr and lkbasco@yahoo.fr.

Acknowledgments: I thank Dr. Richard W. O. Jähnke (German Pharma Health Fund) for technical advice, the anonymous surveyors for the collection of drug samples, and Sister Marie-Solange Oko, the personnel of the Nlongkak Catholic missionary dispensary, and Delphine Ngo Ndombol for their aid in recruiting patients.

Financial support: This study was supported by the French Ministry of Research (Programme PAL+).

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