J. A. Sánchez

Primaquine Prophylaxis against Malaria in Nonimmune Colombian Soldiers: Efficacy and Toxicity: A Randomized, Double-Blind, Placebo-Controlled Trial

Malaria prophylaxis is required for nonimmune persons who enter malaria-endemic regions. Although mefloquine and doxycycline are highly effective for malaria prophylaxis [1], the actual or perceived toxicities of these drugs and the possibility of mefloquine resistance have prompted the evaluation of other prophylactic regimens. Fryauff and colleagues [2] investigated primaquine, a drug normally used to clear latent stages of Plasmodium vivax from the liver. In a 52-week study of persons who had recently immigrated to an endemic area of Indonesia, these investigators found that approximately 30 mg of primaquine per day was 95% protective against P. falciparum infection and 90% protective against P. vivax infection [2]. Because the indication for prophylaxis is to prevent disease in nonimmune travelers to all endemic regions, trials should be performed in persons in several regions of the world who are completely inexperienced with (that is, are not immune to) malaria. The clinical end point should be malaria (parasitemia plus symptoms) rather than parasitemia alone. We performed a randomized, double-blind, placebo-controlled clinical trial of primaquine prophylaxis against clinical malaria in nonimmune Colombian soldiers on patrol in a region in which P. falciparum and P. vivax malaria is endemic. Methods The study was performed between 18 April and 19 September 1997 in the province of Uraba, Colombia. Participants were 176 soldiers in the Colombian army. On specific questioning, all participants denied previous exposure to a malaria-endemic area. Eligible participants were male; were 18 to 42 years of age; did not have important medical problems as determined by history, physical examination, and routine laboratory tests (complete blood count and measurement of blood urea nitrogen, glutamic oxalacetic aminotransferase, and methemoglobin); and were not G6PD deficient (G6PDH Diagnostic Test, Sigma, St. Louis, Missouri). The study was conducted according to the regulations of the Colombian Army and was approved by the institutional review board of the Universidad Militar Nueva Granada. Written informed consent was required from all participants. Drug Administration Patients were randomly allocated to receive prophylaxis with primaquine diphosphate (two tablets of 15-mg base each, for a total of 30 mg/d) or matching placebo (two tablets) in a 2:1 allocation. Primaquine (Parmamed, Ltd., Malta) and placebo (Sanofi-Winthrop, New York, New York) were identical-looking brown-orange tablets obtained by the Colombian Ministry of Health. Investigators and participants were unaware of the randomization code and remained blinded to treatment group assignment throughout the study. On 16 May 1997, participants began 15 weeks of patrol in Mutapa, a malaria-endemic region of Uraba province, after which they returned to barracks duty in Carepa, a nonmalarial area. Prophylaxis (two tablets) was taken daily from 15 May, the day before patrol, during the 15 weeks of patrol, and for 7 days after the return to Carepa. Colombian soldiers on patrol have access only to items issued by their commanders and therefore could not acquire or take unauthorized antimalarial agents. Each day, immediately before a breakfast of coffee, bread, and, sometimes, an egg, the senior sergeant personally gave two tablets to each soldier from a bag labeled with the soldiers patient number and watched the soldier swallow the tablets. At the end of each week, the number of pills remaining in the bags was counted and recorded. Determination of Infection During the 15 weeks of exposure and for 4 weeks after the soldiers returned to the barracks, thick and thin smears were obtained weekly or sooner if participants had symptoms compatible with malaria infection. Giemsa-stained smears were read by a microscopist blinded to the symptom status of the participant. A smear was considered negative if no parasites were found in 200 fields of x1000 magnification. All positive smears were combined with two negative smears and were reread by a second microscopist blinded to participant status. Discordant readings were resolved by a third blinded reader in Bogota. There were no discordant readings for smears that resulted in study end points. Diagnosis of Malaria A participant was considered to have malaria if he had parasitemia of at least 1500 Plasmodia organisms/L or lesser parasitemia with at least two symptoms compatible with malaria (fever, headache, myalgia, nausea, vomiting, diarrhea, or icterus). Determination of Drug Toxicity Each day, participants were asked, Do you feel at all sick? Do you have any complaints? If the answer was no, questioning was stopped. If the answer was yes, the complaints were recorded. Toxicity was graded as severe if the side effects of the drug caused the participant to withdraw from the trial, moderate if the complaints resulted in some impairment of normal duty, and mild if duty was not impaired. Laboratory tests other than G6PD were repeated during 2 to 4 weeks of follow-up. End Points Study end points were prophylaxis failure, indicated by P. falciparum or P. vivax malaria, and withdrawal from the study because of severe drug toxicity, other medical reasons, or noncompliance (defined as missing more than 2 days of drug administration in any 2-week period). All end points and toxicity grades were assigned before the code was broken. Statistical Analysis Protective efficacy was based on the rate of disease. This rate was calculated by dividing the total number of cases by the total number of weeks during which the drug was administered (primaquine group, 2137 weeks; placebo group, 709 weeks). For each participant, the number of weeks of drug administration was the week of the study in which an end point was reached or the week just before an end point was reached. Protective efficacy was defined as 1 [(rate in primaquine group)/(rate in placebo group)]. Values are expressed as the estimate of efficacy with 95% CIs (calculated by using the method of Ederer and Mantel [3]). On the basis of assumptions of 50% incidence of malaria in the placebo group, 90% prophylactic efficacy of primaquine, a desired lower limit of confidence of the prophylactic efficacy of 70%, and a 2:1 allocation ratio, the sample size was approximately 120 participants in the primaquine group and 60 participants in the placebo group. Results Patient Characteristics One hundred seventy-nine volunteers were screened for this study. Because 3 volunteers declined to participate, 176 persons (mean age, 23.6 years) were enrolled. One hundred twenty-two (69%) participants were randomly allocated to the primaquine group and 54 (31%) were randomly allocated to the placebo group. Compliance and Withdrawal Of the 16 821 doses intended to be administered, 16 789 doses (99.8%) were observed by the senior sergeant to have been swallowed. A total of 32 pills were not taken by a total of 6 participants. Ten participants withdrew (Table 1). Table 1. Efficacy and Toxicity of Primaquine and Placebo* Efficacy The protective efficacy, based on the rate of all malaria, was 89% (95% CI, 75% to 96%). All patients had fever (temperature 38.3 C) and two to four of the other six symptoms of malaria (chills, headache, myalgia, nausea, vomiting, and icterus). The protective efficacy for P. falciparum infection was 94% (CI, 78% to 99%). Two participants in the primaquine group became parasitemic in week 6. Eleven participants who received placebo became parasitemic (2 in week 5, 1 in week 7, 2 in week 8, 1 in week 10, 3 in week 12, 1 in week 13, and 1 in week 14. The protective efficacy of primaquine against P. vivax infection was 85% (CI, 57% to 95%). Six participants in the primaquine group became parasitemic (2 in week 5, 2 in week 7, 1 in week 8, and 1 in week 17). Among participants who received placebo, 13 became parasitemic (3 in week 4, 2 in week 5, 1 in week 6, 1 in week 7, 1 in week 8, 2 in week 9, 1 in week 10, 1 in week 13, and 1 in week 18). Toxicity Three participants in the primaquine group (2.5% [CI, 0.2% to 5.2%]) had epigastric pain, abdominal pain, or vomiting of sufficient severity that they had to withdraw from the study. Six other participants in the primaquine group (5.0% [CI, 1.0% to 9.0%]) had mild or moderate gastrointestinal symptoms. In contrast, only one placebo recipient (2.0% [CI, 3.0% to 7.0%]) had mild gastrointestinal symptoms. Discussion Prophylaxis with primaquine, 30 mg/d, or placebo was administered to nonimmune Colombian soldiers on patrol in a malaria-endemic area. The treatments were begun 1 day before the start of patrol, were administered during the 15 weeks of patrol, and were continued for 1 week after return to base camp. Participants were followed for parasitemia and symptoms for the 16 weeks of drug administration and for 3 more weeks at base camp. The protective efficacy of primaquine was 89% against all types of malaria, 94% against P. falciparum malaria, and 85% against P. vivax malaria. Members of the military are tightly supervised. Troops that patrol malaria-endemic regions often come from malaria-free regions. Using participants in the military made it possible to fulfill our aims of conducting the trial according to exacting protocol conditions, adopting the clinically relevant criterion of disease as the end point, and performing the study in nonimmune persons who reflect the population requiring prophylaxis. Although primaquine was administered immediately before a modest breakfast, moderate gastrointestinal toxicity occurred. Our results contrast with the lack of increased gastrointestinal distress due to primaquine seen in other studies [2]. Other side effects of this regimen that are listed in the literature but were not evaluated in this study are an increase in methemoglobin value to a mean of 0.06% (range, 0.01% to 0.13%) without clinical manifestations [2] and, rarely, cases of leukopenia and arrhythmias [4]. Acute intravascular

Dormancy and germination in Talipariti elatum seeds

The dormancy in fresh seeds of Talipariti elatum (Sw.) Fryxell from moist evergreen forest and secondary vegetation was determined. Structural and germinative variables of the seeds were studied, and water absorption dynamics of intact and scarified seeds was determined. In seeds from both ecosystems, the dry weight of seed coats was higher than the food storage weight. Intact seeds absorbed water but lacked the triphasic pattern of absorption shown by scarified seeds. 88% intact seeds were hydrated in contact with water, though 30% ± were scarcely hydrated (up to 30% humidity) and over 50% showed hydration values surpassing 30%. Germination in intact seeds was poor and erratic, contrary to coatless seeds. Results show that fresh seeds do not have exogenous dormancy as the only impediment for avoiding germination, but a mechanical dormancy in combination with a certain degree of seed coat impermeability to water which prevent germination.

Caracterización de semillas de un bosque siempreverde tropical del oeste de Cuba: Correlaciones ecológicas entre rasgos

Seed traits are determined in 50 species from an evergreen forest in Sierra del Rosario, Cuba. These traits were analyzed at their community level, according...

Variabilidad seminal entre las especies de un bosque siempreverde tropical de la Sierra del Rosario, Cuba

Se describe el tipo de embrion (forma y tamano, relacion embrion:semilla) en semillas de 85 especies, que comprenden arboles, arbustos y trepadoras procedentes de un bosque siempreverde de la Sierra del Rosario, Cuba. Se detallan ademas rasgos morfologicos tales como: tipo de fruto, forma de la semilla, presencia de indumentos y superficie de la testa, y la relacion entre el tipo de semilla y la dormancia seminal descrita por otros autores para estas especies. Se comprobo el predominio de cuatro categorias carpologicas (bayas, drupas, capsulas y legumbres) que en su conjunto contienen a 78 especies. Se demostro el polimorfismo existente en las semillas y la presencia de indumentos en la testa independientemente de la forma de vida de la planta. En especies arboreas predominaron el arilo, mucilago y cilios mientras en trepadoras y arbustivas se destacan los tricomas y vilanos. Se confirmo la presencia de embriones no desarrollados, de tipo rudimentario, lineal o capitado en las plantas arboreas Dendropanax arboreus, Oxandra lanceolata y Schoepfia didyma, y las trepadoras Smilax laurifolia, Smilax mollis y Dioscorea tamoidea, lo cual implica la presencia de dormancia morfologica o morfofisiologica en las semillas. Mientras tanto, el resto de las especies presentaron embriones desarrollados espatulado, lineal, plegado, doblado e invertido, donde la dormancia seminal en caso que este presente puede ser fisica, fisiologica o la combinacion de ambas. Estos resultados corroboran que la distribucion de clases de dormancia establecida para estas especies se corresponde con el tipo de embrion que presentan las semillas.