Serum laminin in malaria.

AIM: To determine serum laminin concentrations in patients with uncomplicated Plasmodium falciparum malaria. METHODS: An enzyme linked immunosorbent assay (ELISA) was used to determine serum laminin concentrations in 54 patients with acute uncomplicated P falciparum malaria during and after treatment, and in 17 control subjects in Bangkok, Thailand. RESULTS: Raised concentrations of soluble laminin were observed in patients (mean (SD) concentration 628 (225) ng/ml), compared with normal controls (490 (116) ng/ml), during the acute phase of the disease. During treatment, serum laminin concentrations decreased and returned to normal within three days. Serum laminin concentrations were correlated with parasite counts before treatment, and with the serum concentration of soluble intercellular adhesion molecule-1 (ICAM-1), soluble E-selectin, and soluble tumour necrosis factor receptor at 55 kilodaltons. CONCLUSIONS: These findings are compatible with an increased production or release of laminin in P falciparum malaria, which could indicate a role for the subendothelial basement membrane in the pathogenesis of the disease.

Randomized trial of mefloquine-doxycycline, and artesunate-doxycycline for treatment of acute uncomplicated falciparum malaria.

One hundred nine adult patients with acute uncomplicated falciparum malaria were randomly selected to receive combinations of either doxycycline plus mefloquine or doxycycline plus artesunate. Fifty-four patients received mefloquine (1,250 mg divided between two doses of 750 and 500 mg six hours apart) with doxycycline and 55 patients received artesunate (300 mg total for 2.5 days; 100 mg followed by 50 mg every 12 hr for 2.5 days) with doxycycline. Doxycycline was administered in doses of 200 mg once a day for seven days. All patients were admitted to the hospital for 28 days to exclude reinfection. Ninety-seven patients completed the study; 12 patients left prior to completion of follow-up for reasons unrelated to their treatment. Cure rates for the two groups were 96% (46 of 48) for mefloquine plus doxycycline and 80% (39 of 49) for artesunate plus doxycycline. Mean fever and parasite clearance times were significantly shorter in the group that received artesunate plus doxycycline (38.7 and 41.3 hr) than mefloquine plus doxycycline (64.3 and 69.0 hr), respectively. In vitro drug sensitivity testing of selected isolates obtained prior to treatment indicated that eight of nine admission isolates were resistant to mefloquine; all isolates were susceptible to artesunate. Recrudescent isolates failed to show a pattern of decreased sensitivity to the drugs to which the parasites had been exposed during treatment; the studies showed decreased sensitivity to doxycycline in only two of eight isolates tested.(ABSTRACT TRUNCATED AT 250 WORDS)

ELISA confirmation of acute and past envenoming by the monocellate Thai cobra (Naja kaouthia).

The monocellate Thai cobra (Naja kaouthia) is a major cause of snake bite mortality and morbidity throughout Thailand, but neither the local nor the systemic effects of its venom are diagnostic. Species diagnosis is important because only monospecific antivenoms are available for treatment in Thailand. We tested the ability of the ELISA technique to detect venom antigen in the sera of 58 acute snake bite cases including 4 fatalities, and venom antibody in 51 patients bitten between 1 month and 19 years previously. N. kaouthia venom antigen was found in 8 of 33 patients with only local envenoming and in 14 of 20 with local plus systemic (neurotoxic) envenoming, but the mean venom concentration was 33 times greater in the latter group. The serum of 1 fatal case contained banded krait (Bungarus fasciatus) but no cobra venom antigen. N. kaouthia venom antibody was present in sera of patients bitten between 1 month and 7 years previously. Antibody was found in 6 of 8 patients who had had local envenoming alone but in only 19 of 41 who had had systemic envenoming treated by antivenom. The titer of antibody declined with an approximate half time of 2-3 years. One patient had a significant titer of B. fasciatus venom antibody. This study confirms the value of ELISA-immunodiagnosis and the predominance of N. kaouthia as a cause of neurotoxic envenoming in the Bang Phli area. However, the attribution of 1 fatal case to B. fasciatus bite suggests that patients with neurotoxic signs should be given B. fasciatus antivenom if they fail to respond to cobra antivenom.

Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand.

The therapy of Plasmodium falciparum malaria continues to be a problem in many parts of Southeast Asia because of multidrug resistance to nearly all existing antimalarial drugs. Atovaquone is a novel hydroxynaphthoquinone with broad spectrum anti-protozoal activity. We recently evaluated the antimalarial activity of atovaquone in a series of dose-ranging studies in 317 patients with malaria at the Bangkok Hospital for Tropical Diseases. Originally, the drug was administered alone. Using atovaquone alone resulted in satisfactory, initial clinical responses in all patients; the mean parasite and fever clearance times were 62 and 53 hr, respectively. However, irrespective of the duration of therapy, overall cure rates were approximately 67%. In vitro sensitivity studies on parasites taken from patients prior to treatment and at the time of recrudescence showed a marked decrease in susceptibility to atovaquone in the recrudescent parasites. To improve cure rates, atovaquone was administered in combination with other drugs with antimalarial activity. Proguanil and tetracycline were chosen due to laboratory evidence of potentiation; doxycycline was selected because it has a longer half-life than tetracycline. Although pyrimethamine did not show laboratory evidence of potentiation with atovaquone, it was chosen as an alternative inhibitor of dihydrofolic acid reductase with a longer half-life than proguanil. The clinical studies with these drug combinations confirmed the laboratory results with marked improvement in cure rates for proguanil, tetracycline, and doxycycline; pyrimethamine showed only minimal improvement. Proguanil was subsequently selected as the preferred drug partner because of its long record of safety and the ability to use the drug in pregnant women and children. Of the 104 patients with falciparum malaria treated with atovaquone plus proguanil for 3-7 days, 101 were cured and had virtually no adverse side effects. The combination of atovaquone and proguanil also was effective in eliminating erythrocytic forms of P. vivax, but parasitemia recurred in most patients.

Clinical study of pyronaridine for the treatment of acute uncomplicated falciparum malaria in Thailand.

One hundred one adult patients with acute uncomplicated falciparum malaria were treated with pyronaridine. All patients were admitted to the Bangkok Hospital for Tropical Diseases for 28 days to exclude reinfection. Sixty-nine patients (Group I) received pyronaridine 1,200 mg over a three-day period and 32 patients (Group II) received 1,800 mg pyronaridine over a five-day period. Cure rates for the two groups were 63% (38 of 60) for Group I and 88% (23 of 26) for Group II (P<0.05). No RII or RIII type response was seen. Mean fever and parasite clearance times were not significantly different in the two groups. The drug was well-tolerated. In vitro drug sensitivity tests of the paired parasite isolates obtained prior to treatment and after recrudescence indicated that the Plasmodium falciparum isolates of the successfully treated patients had a lower mean concentration for 50% inhibition of growth (IC50) and a much narrower range of the individual IC50 values (15.69 +or- 3.82 ng per ml (mean +or- SD)) as compared with those from the recrudescence cases (22.98 +or- 12.05 ng per ml). Nevertheless, there was no evidence of an increase of the IC50 and IC95 values after recrudescence. The results of the study show that pyronaridine alone at a total dose of 1,800 mg given over five days is well-tolerated in patients suffering from acute uncomplicated malaria and has evident activity against multidrug-resistant falciparum malaria. However, it cannot be recommended for use in Thailand as long as the recrudescence rate is as high as 12%. Further studies of its combinations with other antimalarial drugs are needed.

Comparative clinical trial of artesunate followed by mefloquine in the treatment of acute uncomplicated falciparum malaria: two- and three-day regimens.

The difficulties in treating drug-resistant falciparum malaria in Thailand are compounded by the necessity of giving antimalarials over long periods of time. The resultant decrease in patient compliance not only lowers cure rates but also predisposes to the further spread of drug resistance. We compared the efficacy of two sequential treatment regimens given over two and three days in 111 patients with acute uncomplicated falciparum malaria. Sixty-seven patients received two 400-mg doses of artesunate (total dose = 800 mg) followed by two doses of mefloquine (750 mg given immediately and 500 mg 12 hr later; total dose = 1,250 mg) in Group 1. Forty-four patients (Group II) received four 200-mg doses of artesunate (total dose = 800 mg) given 12 hr apart followed by a mefloquine regimen similar to that for Group I. All patients were admitted to hospital in Bangkok for 28 days to preclude reinfection. Ninety-six patients completed the study. Cure rates for the two groups were 84% (49 of 58) for Group I and 100% (38 of 38) for Group II. The mean parasite clearance time and fever clearance time were significantly shorter in Group II (P < 0.02). There were no serious adverse reactions. All nine of the treatment failures in Group I were of the RI types. The results indicate that the sequential treatment with artesunate followed by mefloquine given over three days is effective and well-tolerated in patients with acute, uncomplicated falciparum malaria and suitable as an alternative treatment for multidrug-resistant falciparum malaria.

Open randomized trial of oral artemether alone and a sequential combination with mefloquine for acute uncomplicated falciparum malaria.

One hundred fifty-one patients with acute uncomplicated falciparum malaria were enrolled in a randomized, open-label study of oral artemether given alone for five or seven days or a sequential treatment of oral artemether followed by mefloquine. Forty patients received oral artemether, 100 mg initially, then 50 mg every 12 hr for a total dose of 500 mg over a five-day period: Group I. Fifty-eight patients received oral artemether, 100 mg initially, then 50 mg every 12 hr for a total dose of 750 mg over a seven-day period: Group II. Fifty-three patients received oral artemether, 200 mg every 8 hr for a total dose of 600 mg, followed 8 hr later with mefloquine (1,250 mg divided into two doses given 6 hr apart: Group III. All patients were admitted to the hospital for 28 days to exclude reinfection and 131 patients remained through the 28-day follow-up. Only two, nine, and nine patients in Groups I, II, and III, respectively, left the hospital prior to study completion for reasons unrelated to their treatment. Cure rates for the three groups were 74% (28 of 38) for Group I, 98% (48 of 49) for Group II, and 98% (43 of 44) for Group III. Mean fever and parasite clearance times were not significantly different (32.8, 27.5, and 31.4 hr for fever clearance times and 40.2, 40.6, and 36.7 hr for parasite clearance times of Groups I, II, and III, respectively) nor were any adverse effects seen. In vitro drug susceptibility testing of admission and recrudescent parasite isolates was conducted for 10 patients. These data showed no decreased response to artemether or dihydroartemisinin in recrudescent isolates when compared with admission isolates. The results of this study suggest that sequential treatment for two days with oral artemether (600 mg) followed by mefloquine (1,250 mg) is effective and well-tolerated in patients with acute uncomplicated falciparum malaria and may be an alternative treatment for multidrug-resistant falciparum malaria, particularly useful for treating patients in rural areas where the period of admission to the hospital should be as short as possible. A seven-day regimen of artemether alone (750 mg) is also very effective, yet requires prolonged administration of drug after malaria symptoms disappear.

Clinical significance of venom antigen levels in patients envenomed by the Malayan pit viper (Calloselasma rhodostoma).

Serial venom antigen levels were measured by enzyme-linked immunosorbent assay (ELISA) in 46 patients with systemic envenoming by the Malayan pit viper (Calloselasma rhodostoma), a major cause of snake bite in Southeast Asia. The principal effects of the venom are defibrination, hemorrhage and local tissue necrosis. Admission venom levels, which varied between 0 and 595 ng/ml, correlated with the incidence of spontaneous systemic bleeding, blood incoagulability and concentrations of plasma fibrinogen and serum fibrin degradation products. The presence or absence of nonclotting blood also correlated with the time elapsed between the bite and hospital admission. The development of nonclotting blood may be delayed by up to 72 hr after the bite even though circulating venom and raised FDP may be detected at presentation. This is probably explained by a temporary equilibrium between synthesis and consumption of fibrinogen. Venom antigenemia recurred in 12 patients (26%) suggesting continuous absorption of venom from the wound or saturation of extravascular binding sites. Admission venom levels also correlated with the extent of local swelling and the occurrence of tissue necrosis at the site of the bite. Venom was detected in 87% of wound aspirates and 88% of urine specimens taken on admission. Tourniquets, of the type used in rural Thailand, did not delay the absorption of venom into the circulation.

Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in southern Thailand: clinical and laboratory correlations.

Three monospecific antivenoms for Malayan pit viper (MPV) (Calloselasma rhodostoma) were compared in Southern Thailand, where this species is the most common cause of snake bite morbidity. Forty-six patients with proved MPV bites and incoagulable blood, indicating systemic envenoming, were randomly allocated for treatment with Thai Red Cross (TRC), Thai Government Pharmaceutical Organization (GPO), or Twyford Pharmaceutical monospecific antivenoms. Both GPO and Twyford antivenoms produced rapid and permanent restoration of blood coagulability, but TRC antivenom failed in 2/15 cases. Patients in the GPO group showed the greatest increase in plasma fibrinogen concentration during the first 24 hr and had fewer early anaphylactic reactions (6/15) compared with Twyford 8/16 and with TRC 13/15. Pyrogenic reactions occurred more frequently after TRC antivenom (8/15) than GPO (1/15) or Twyford (0/16). Patients requiring more than one dose of antivenom were identifiably more severely envenomed on admission. In an accompanying laboratory study the antivenoms were assessed in rodents using five WHO standard tests of neutralizing activity. Compared with the other two antivenoms TRC was significantly inferior in anti-lethal potency, GPO was superior in anti-hemorrhagic and anti-necrotic potency and Twyford was superior in anti-procoagulant and anti-defibrinogenating potency. The clinical efficacy of these antivenoms against local necrosis remains equivocal. GPO and Twyford antivenoms are recommended for the treatment of systemic envenoming by MPV in an initial dose of 5 ampoules.

Opisthorchis viverrini infection in Thailand: studies on the morbidity of the infection and resolution following praziquantel treatment.

A community study on opisthorchiasis was conducted in Prachinburi Province in eastern Thailand during 1990-1992. The morbidity from opisthorchiasis in the community and reversibility of biliary pathology following treatment with praziquantel at a single dose of 40 mg/kg were assessed by longitudinal investigations of clinical, laboratory, and ultrasonographic changes. A total of 913 voluntary subjects infected with Opisthorchis viverrini were randomly selected for longitudinal study, and 579 subjects without liver fluke infection were recruited as controls. The majority of the study group suffered from mild and moderate infections that were associated with nonspecific gastrointestinal symptoms. Grade I and II ultrasonographic changes, which indicated chronic inflammation of the biliary tract and gallbladder, were detected in 32% of the infected individuals. Clinical symptoms and ultrasonographic changes were common in subjects 21-40 years of age and older. Satisfactory resolution of morbidity was observed during two years follow-up on days 0, 60, 180, 360, and 720, as shown by significant clinical improvement, normalization of laboratory parameters, and downgrading of ultrasonographic abnormalities. Portable ultrasonography has proved to be a reliable noninvasive technique in the evaluation of the morbidity due to opisthorchiasis in rural areas.

Treatment of patients with recrudescent falciparum malaria with a sequential combination of artesunate and mefloquine.

A sequential combination of artesunate followed by mefloquine was evaluated prospectively in 24 patients with acute recrudescent falciparum malaria. The sequential combination was used to minimize possible side effects and to take advantage of the ability of artesunate to rapidly clear parasitemia and the prolonged effect of mefloquine to clear residual parasites. All patients had experienced one or more treatment failures with one or more courses of the following drugs (administered alone or in combination): quinine, tetracycline, mefloquine, artesunate, and sulfadoxine/pyrimethamine. Sequential treatment with artesunate (600 mg over five days) followed by mefloquine (750 mg and 500 mg six hours apart) cured all 24 patients. Each patient was followed for 28 days and 10 were observed for at least 35 days without clinical or parasitologic evidence of recrudescence. Fever and parasite clearance times after treatment with the sequential combination were 32.8 +/- 19.3 hr (mean +/- SD) and 40.0 +/- 16.2 hr, respectively. Susceptibility testing of selected parasite isolates indicated that all of the isolates tested were resistant to one or more antimalarial drugs. These results suggest that sequential treatment with artesunate followed by mefloquine is effective and well-tolerated in patients with recrudescent falciparum malaria.

Serum levels of erythropoietin in acute Plasmodium falciparum malaria.

The pathophysiologic backgrounds of anemia in malaria are complex and multifactorial. The purpose of the present study was to measure serum concentrations of erythropoietin (EPO) and to evaluate the adequacy of EPO production in patients suffering from acute Plasmodium falciparum malaria. Fifteen patients with complicated malaria were included in the study. Serum samples were taken on the day of admission, and days 7, 14, 21 and 28. Serum EPO concentrations were measured using an enzyme-linked immunosorbent assay. The median serum EPO concentration was 15.6 mU/ml on the day of admission (range 0.5-567) mU/ml, 10.6 mU/ml (1.2-863) on day 7, 11.8 mU/ml (0.5-72.8) on day 14, 10 mU/ml (0.5-74.6) on day 21, and 8.3 mU/ml (2.2-61.6) on day 28. Inadequate EPO production was found in 46.6% of the patients on the day of admission, which increased to 67% and 68% on days 7 and 14, and reached a maximum of 80% on day 21. Almost 54% of patients had inadequate EPO production on day 28. Our data indicate inadequate EPO production in patients suffering from acute P. falciparum malaria, which might contribute to the prolonged anemia observed in these patients.

Factors contributing to fatal snake bite in the rural tropics: analysis of 46 cases in Thailand.

Records of 46 cases of fatal bites by identified snakes from 15 provincial hospitals throughout Thailand contained sufficient information for detailed analysis. Bungarus candidus and Calloselasma rhodostoma were each responsible for 13 deaths, Naja kaouthia for 12, Vipera russelli for 7 and B. fasciatus for one. Major causes of death among elapid victims were respiratory failure (26) and complications of prolonged mechanical ventilation (10), and among viper victims shock (12), intracranial haemorrhage (9), complications of local wound necrosis (7) including tetanus (2), and renal failure (2). Factors contributing to fatal outcome included inadequate dose of antivenom (15 cases), misidentification of the snake leading to use of the wrong antivenom (12), problems associated with mechanical ventilation (10), and delayed arrival in hospital after traditional (herbal) treatment (10). Similar problems have been identified in other tropical countries. Education of medical staff and the patient population at highest risk could reduce snake bite mortality.

Opisthorchis viverrini infection in Thailand: symptoms and signs of infection--a population-based study.

A population-based study of the clinical, laboratory and ultrasonographic findings in patients suffering from mild or moderate opisthorchiasis in Prachinburi province, Thailand was conducted in 1990-1992. The effectiveness of treatment with praziquantel at 40 mg/kg body weight was evaluated. After treatment, a long-lasting, marked improvement in the well-being of the study group was observed. Symptoms common in opisthorchiasis infection decreased in intensity and the clinical response showed total or partial remission in 98% of all cases studied. Total and direct bilirubin concentrations decreased significantly and remained low up to the end of the follow-up period of 2 years, indicating a reduction in cholestasis. Also, white blood cell counts decreased initially, which can be interpreted as a reduction in inflammation intensity. No relationship was found between intensity of infection and age or clinical findings. Population-based treatment of opisthorchiasis appears to have had a significant impact on public health in north-east Thailand. However, it is also evident that drug therapy alone will not solve the opisthorchiasis problem, as indicated by the reinfection rate of almost 10% at the end of the study.

Antibody response to suckling mouse brain rabies vaccines for post exposure treatment.

A new suckling mouse brain vaccine (SMBV) against rabies, produced by the Thai Red Cross Society, was compared with the well established Institut Pasteur SMBV in patients with very low risk rabies contact. The 4 regimens used were the standard daily injections with booster doses of Thai Red Cross vaccine (TRCV) and Institut Pasteur Vaccine (IPV), and a reduced dose scheme of 6 injections as used for tissue culture vaccines. The effect of 20 IU/kg of human rabies immune globulin (HRIG) was tested on each regimen, making 8 groups, a total of 122 patients. Blood samples taken on days 0, 7, 14, 28 and 91 were tested for neutralizing antibody. Only the standard IPV regimen produced antibody in every patient; all had levels greater than 0.5 IU at some stage. Two people (13%) given the standard TRCV produced no detectable antibody (less than or equal to 0.1 IU) throughout the study. The reduced dose regimens gave very low antibody levels. 7% of the IPV and 76% of the TRCV groups failed to produce antibody on any occasion. The antibody response was significantly suppressed by the administration of HRIG. Compared to the original South American SMBV, the vaccines tested induced low levels of short lived antibody. No reduction in the dosage of SMBV should be considered unless the potency of the product is adequate.

Arboreal green pit vipers (genus Trimeresurus) of South-East Asia: bites by T. albolabris and T. macrops in Thailand and a review of the literature.

In Thailand 29 patients were proved to have been bitten by arboreal green pit vipers: 24 by Trimeresurus albolabris and 5 by T. macrops. They were studied in order to define the clinical effects of envenoming, to characterize the haemostatic abnormalities and assess the efficacy of Thai Red Cross antivenom. T. macrops caused only local painful swelling, neutrophil leucocytosis and thrombocytopenia. T. albolabris caused more severe envenoming with local blistering and necrosis, shock, spontaneous systemic bleeding, defibrination, thrombocytopenia and leucocytosis. There was no evidence of disseminated intravascular coagulation, but fibrinolytic activity was increased. Platelet function was normal. The product of admission venom antigen concentration and the delay between bite and admission was significantly higher in defibrinated patients than in those without severe coagulopathy. Antivenom (5 ampoules intravenously) restored blood coagulability, but there was persistent venom antigenaemia, associated in some cases with recurrent coagulopathy. The literature on bites by south Asian green pit vipers of the genus Trimeresurus is reviewed; these bites are common medical problems and causes of morbidity. The identification of individual species is difficult, but may be important if antivenom is to be improved and used appropriately.

A national hospital-based survey of snakes responsible for bites in Thailand.

Snakes which had been killed and brought to hospital with the patients they had bitten were collected in 80 district and provincial hospitals throughout 67 provinces in Thailand in order to establish the geographical distribution and relative medical importance of the venomous species. Of the 1631 snakes collected, 1145 were venomous: Malayan pit vipers (Calloselasma rhodostoma), green pit vipers (Trimeresurus albolabris) and Russell's vipers (Daboia russelii) were the most numerous, while T. albolabris, C. rhodostoma and spitting cobras ('Naja atra') were the most widely distributed. In 22 cases, non-venomous species were mistaken for venomous ones and antivenom was used unnecessarily. The Malayan krait (Bungarus candidus) was confused with B. fasciatus in 5 cases and B. fasciatus antivenom was used inappropriately. The study extended the known ranges of most of the medically-important venomous species in Thailand. Correct identification of venomous snakes is especially important in Thailand because the locally-produced antivenoms are monospecific. The technique of hospital-based collection, labelling and preservation of dead snakes brought by bitten patients is recommended when rapid assessment of a country's medically important herpetofauna is required.

Plasmodicidal effect of desferrioxamine B in human vivax or falciparum malaria from Thailand.

Desferrioxamine B (DFO, Desferal), an iron chelator, was earlier shown to be active against Plasmodium falciparum in vitro and in vivo. The present open pilot study served to assess its clinical tolerability and efficacy in human malaria under hospital conditions. Continuous intravenous DFO was administered to 28 Thai males at a dose of 100 mg/kg over 24 h for 3 consecutive days. No other antimalarial therapy was administered unless recrudescence had occurred. The first 14 patients had symptomatic Plasmodium vivax (P.v.) malaria, while the other 14 patients were suffering from uncomplicated Plasmodium falciparum malaria (P.f.). Both groups were treated in Bangkok, where malaria transmission does not take place, and followed up, on the ward, for 3 weeks (P.v. group) or 4 weeks (P.f. group) after the start of therapy. In both groups DFO reduced the parasitaemia to zero within 106 and 57 h respectively. The fever clearance time was 55 and 60 h, respectively. The overall tolerability of DFO was good but 4 P.v. and 5 P.f. patients had transient visual blurring. Recrudescences were observed on average 15, respectively 10 days after the start of therapy. Only 2 P.v. patients and none of the P.f. patients remained free of recrudescences during the observation period. There was no apparent gametocytocidal effect of DFO on P.f.

Randomised trial of mefloquine-tetracycline and quinine-tetracycline for acute uncomplicated falciparum malaria.

The combination of mefloquine plus tetracycline was compared with quinine plus tetracycline in a randomised therapeutic trial in 102 patients with acute uncomplicated falciparum malaria in Thailand. Quinine plus tetracycline is considered the standard treatment for the highly drug-resistant strains of P. falciparum found in this area. Fifty patients received mefloquine (750 mg given immediately, followed by 500 mg 6 h later) with tetracycline and 52 patients received quinine (600 mg every 8 h for seven days) with tetracycline. Tetracycline was administered to both groups in doses of 250 mg four times daily. All patients were admitted to the hospital for 28 days to exclude re-infection. Ninety-three patients completed the study; nine patients left prior to completion of follow-up for reasons unrelated to their treatment. Cure rates for the two groups were 94% (44/47) for mefloquine plus tetracycline and 98% (45/46) for quinine plus tetracycline. Parasite and fever clearance times were shorter for the group treated with mefloquine but the differences were not statistically significant. Nearly all patients (94%) treated with quinine developed cinchonism compared with only 12% treated with mefloquine; all other symptoms following treatment were similar. Thirteen patients (26%) treated with quinine also developed delayed primary attacks of P. vivax during the follow-up period; none developed in the patients treated with mefloquine. These results support the contention that the combination of mefloquine plus tetracycline is equally effective and less toxic than quinine plus tetracycline for treatment of acute uncomplicated falciparum malaria in areas requiring combination therapy for drug resistance.

SPf66 malaria vaccine is safe and immunogenic in malaria naive adults in Thailand.

In preparation for an efficacy trial of malaria vaccine SPf66 in Thailand, a series of overlapping Phase I trials were conducted of US-manufactured SPf66. Here, two clinical lots were evaluated for safety and immunogenicity in a combined open-label trial. Eleven healthy, malaria naive, 18-44 year-old Thai men and women received three doses by subcutaneous injection in alternate arms at 0, 1 and 6 months. Safety was assessed by monitoring local and systemic reactogenicity and laboratory parameters. Common side effects were mild erythema, induration and tenderness at the site of injection which resolved within 24-48 h. At third immunization, two volunteers developed acute bilateral reactions with induration, erythema and pruritus limited to the sites of the second and third immunizations. Eight of 11 volunteers sero-converted by ELISA, six of whom would be classified as high responders by Colombian standards. Eight of 11 volunteers developed a lymphoproliferative response to the SPf66 antigen. Side effects were more common and antibody and lymphoproliferative responses greatest, among the four female volunteers. This initial study of SPf66 malaria vaccine in Asia constitutes an essential link between the initial Phase I study in the US and subsequent field studies in a semi-immune population in a malaria endemic area of Thailand. This study further establishes comparability of US-manufactured SPf66 with that of Colombian provenance and substantiates the validity of the subsequent negative efficacy results of SPf66 in a field trial in Thailand.