A comparative trial of the combination of mefloquine or MSP with tetracycline was carried out in fifty-one adult Thai male patients with acute falciparum malaria. The patients were randomized to receive eitherthe combination of tetracycline (250 mg qid for 7 days) with mefloquine 4 tablets (1,000 mg) or with MSP 4 tablets (one tablet contains 250 mg mefloquine, 500 mg sulfadoxine and 25 mg pyrimetha­ mine). Fifty patients had a complete 28-day follow-up period. Both regimens produced similar efficacy with no difference in adverse effects. In the mefloquine plus tetracycline group, the cure rate was 72% (18125). One patient had an Rill response, the others showed initial response to the treatment with FCT and PCT of40.7 ± 27.4 and 76.2 ± 34.2 hours (mean ± SD) respectively. However, 6 patients developed recrudes­ cence between days 17 and 29 (RI), 3 of these had vomiting. In the MSP plus tetracycline group, the cure rate was 76% (19125). The means (± SD) of FCT and PCT were 44.7 ± 38.0 and 80.6 ± 25.0 hours, respectively. Six patients had recrudescence between days 17 and 31 (RI), 2 of these had vomiting. Although the addition of tetracycline improved the cure rate of mefloquine when compared with standard dose of mefloquine alone (3 tablets), these combinations seem to be useful in areas where altema­ ative drugs are not available.

A 5-day course of oral artesunate at total doses of 1200, 600, 650 mg and intramuscular artemether 480 mg proved effective (90-100% cured) in the treatment of multidrug resistant falciparum malaria in Thailand. Shorter courses yielded high recrudescence rates. The fever clearance and parasite clearance times were short. The side effects were mild and transient including occasional abnormal electrocardiograms and pain at the injection site. Slight reduction of neutrophil leucocytes and reticulocytes was observed. Further studies of artesunate and artemether should be carried out to find the optimum dosage regimen and to clarify the hematological effects.

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.

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.

Eleven cases of imported cutaneous leishmaniasis are described based on clinical features such as sex, age, occupation, country visited prior to consultation, sites and numbers of lesions, duration of illness, treatment and outcomes. Ketoconazole was shown to be effective against imported cutaneous leishmaniasis. With the increasing numbers of cutaneous leishmaniasis due to exchange workers going to the endemic areas and the presence of vectors in some localities in Thailand, primary transmission of the disease in this country is possible if feeding habits of the vectors change.

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.

To determine the prevalence of Sarcocystis and other intestinal parasites in Thai laborers who were going abroad for work, stool examinations of 362 asymptomatic laborers were studied. The four most frequently parasites found in stool were Sarcocystis sp (23.2%), Opisthorchis viverini (40.3%), hookworm (21.5%), and Strongyloides stercoralis (14.1%). Giardia intestinalis (5.2%), Entamoeba coli (1.7%), Endolimax nana (2.5%), Blastocystis hominis (4.1%), Echinostoma sp (3.6%), Trichuris trichiura (0.3%), Taenia sp (1.7%), Hymenolepis nana (0.6%), and Enterobius vermicularis (0.3%) were present at low rates. Sarcocystis were frequently found in male laborers (83.3%) (p < .01). The laborers from northeastern Thailand (n = 278) had a higher prevalence (26.6%) of Sarcocystis infection (p < .01). This study shows that Thai laborers, particularly from northeastern Thailand, are commonly infected with intestinal parasites. The high prevalence rates of Sarcocystis and other intestinal parasites in this study were indicative of the local habit of eating raw beef and pork, poor living conditions, and low levels of hygiene in Thai laborers. Sarcocystosis could be a significant food-borne zoonotic infection in Thailand.

Serum concentrations of laminin and basic fibroblast growth factor (FGF) were measured in 20 patients suffering from complicatedPlasmodium falciparum malaria in Bangkok. Significant higher mean serum concentrations of laminin were determined prior to treatment (1973 ng/ml) and 7 days after starting medication (1025 ng/ml) in comparison to the control (412 ng/ml). The values remained numerically higher for at least 21 days. With regard to serum basic FGF concentrations, a peak was found 7 day after starting treatment (35.61 pg/ml). In addition, a significant correlation was found for parasite clearance time and basic FGF concentration on day 7 (P < 0.01). These increased values of laminin and basic FGF may be the consequence of endothelial and basement membrane damage induced by sequestration of the parasites. Furthermore, basic FGF might play a role in endothelial repair mechanisms after the clearance of the parasites.

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.

One-hundred thirteen men (mean age, 23 years) who presented with inguinal buboes to a government-operated hospital for sexually transmitted diseases (STDs) in Bangkok were studied between February 1987 and February 1989, The median duration of preceding symptoms was 7 days (range, 1-62 days), The majority of patients (74; 65%) had received treatment previously; 31 (27%) were febrile, 13 (12%) had extrainguinal lymphadenopathy, and 31 (27%) had concurrent active genital ulcers, There was no history of genital ulceration in 66 (58%) of the patients, Pus was obtained from 51 of the 110 buboes aspirated for culture; 21 (41%) of these cultures yielded Haemophilus ducreyi, and 2 (3.9%) were positive for Chlamydia trachomatis on immunofluorescence microscopy, Saline (1 mt) was injected and reaspirated from the buboes of 35 of the other 59 patients; 3 buboes yielded H. ducreyi and 9 were positive for C. trachomatis. All cultures for other aerobic and anaerobic bacteria and viruses in intact buboes were negative, Syphilis serology was positive in only one case, Patients attending STD clinics in this region who have large, fluctuant, edematous inguinal buboes containing pus should receive presumptive treatment for chancroid, If there is no pus, then the bubo is more likely to be caused by lymphogranuloma venereum.

Clinical studies have shown atovaquone (ATQ), a new blood schizontocidal drug, in combination with proguanil (PROG) to be very effective in the treatment of acute multidrug-resistant falciparum malaria. The multiple dose pharmacokinetics of PROG were determined in Thai patients with acute falciparum malaria given PROG alone (200 mg PROG twice a day for 3 days, n = 4) and concurrently PROG and ATQ (200 mg PROG and 500 mg ATQ twice a day for 3 days, n = 12). There were no statistical differences (p > 0.05) in the area under the plasma drug concentration-time curve (AUC), apparent oral clearance (CL/F) and elimination half-life (t1/2) of PROG between patients given PROG alone and PROG/ ATQ. The median (range) kinetic values of PROG in patients given PROG alone and PROG/ATQ were respectively: CL/F = 1.25 l/h/kg (0.99-1.45) and 0.95 (0.73-1.32) l/h/kg, and t1/2 = 14.2 hours (9.3-16.8) and 13.6 hours (9.1-17.6). The CL/F and t1/2 of PROG in the Thai patients treated with the 2 treatment regimens were also comparable to values reported in healthy Thai volunteers given a standard prophylactic dose (200 mg PROG). The results of this preliminary study suggest that ATQ is unlikely to affect the pharmacokinetics of PROG to a clinically important extent at an ATQ dosage of 500 mg twice a day for 3 days in malaria infected patients.

A clinical trial of oral dihydroartemisinin for the treatment of acute, uncomplicated, falciparum malaria involved 53 adult patients in Thailand. Each received a total dose of 480 mg over 7 days (120 mg given immediately, followed by 60 mg/day) after being admitted to the Hospital for Tropical Diseases in Bangkok for 28 days. Most (92%) completed the 28-day follow-up but four patients left the hospital early, for reasons unrelated to their treatment. Most patients showed clinical improvement 1-3 days after starting treatment and none suffered from serious adverse reactions. The cure rate was 90% (44/49). The mean (S.D.) parasite-clearance time was 40.4 (14.1) h and the mean fever-clearance time was 37.0 (30.2) h. Seven patients had a brief increase in parasitaemia after initiation of treatment but subsequent counts declined dramatically. Five patients who failed treatment (RI response) were successfully treated with quinine plus tetracycline for 7 days. No RII or RIII responses were observed. These findings indicate that treatment with oral dihydroartemisinin is effective and well tolerated, and that dihydroartemisinin may be suitable as an alternative treatment for acute, uncomplicated, falciparum malaria. Comparisons with other conventional antimalarial drugs in a large, double-blind, randomized trial and studies of dihydroartemisinin in combination with other, long-acting antimalarials are needed.

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.

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.

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.

In a prospective study of cerebral malaria, 24 adults with this disease underwent magnetic resonance imaging (MRI) of the brain. Four patients died. Two of these patients (nos. 17 and 24) had breathing abnormalities requiring ventilatory support followed by clinical signs of brain death. Four days later MRI of patient 17 showed gross swelling of the brain, and 5 hours later MRI of patient 24 showed foramen magnum herniation. Twenty-two patients had no evidence of cerebral edema, but MRI revealed that brain volume during acute cerebral malaria was slightly greater than that during the convalescent phase of the disease. This difference was attributed to an increase in the volume of intracerebral blood. The cerebral volume was lower during early convalescence than several months later. The volume of the brain in patients with cerebral malaria is increased. This increased volume probably results from sequestration of parasitized erythrocytes and compensatory vasodilatation rather than from edema. Brain stem herniation may occur, but its temporal relation to brain death in cases of cerebral malaria remains uncertain.

Thirty patients with severe falciparum malaria were each given a total of 1600-mg artesunate suppository over three consecutive days followed by 1250 mg mefloquine per os, divided into two doses which were given 12 h apart. All patients were admitted for 28 days to the Bangkok Hospital for Tropical Diseases, so that the efficacy and tolerability of the treatment could be assessed. All the patients showed clinical improvement, with mean (S.D.) parasite and fever clearance times of 50.4 (13.0) and 70.7 (44.9) h, respectively. Two patients with unrousable coma (Glasgow coma score < or = 8) on admittance regained consciousness 46 and 48 h post-treatment. One other patient had acute renal failure and required dialysis. Most patients (80%) were initially hyperparasitaemic, with a mean density of 184,344 parasites/microliters blood. No deaths occurred. Efficacy was evaluated in 25 of the patients. The cure rate 28 days post-treatment was 92%. None of the patients had major adverse effects although two had tenesmus and passed stools immediately after each suppository was administered. A fresh suppository had to be inserted when this occurred. The results indicate that artesunate suppositories followed by oral mefloquine constitute a well-tolerated regimen with a high cure rate. The combination is suitable as an alternative treatment for severe malaria, particularly in children. Further, large-scale studies are required.

To assess cellular immune function in malaria, 61 patients admitted to the Bangkok Hospital for Tropical Diseases with Plasmodium falciparum (PF) or Plasmodium vivax malaria were examined with the MULTITEST CMI system (Merieux Institute, Florida) to evaluate delayed-type hypersensitivity (DTH) during and after acute disease over 4 weeks. All patients demonstrated significantly decreased responsiveness to seven commonly encountered recall antigens. This deficit was most severe immediately upon admission (prior to therapy). Uncomplicated Pf cases demonstrated significant hyporesponsiveness only during Week 1. Responses in moderate/severe falciparum and all vivax patients gradually increased in Weeks 2 and 3 but remained significantly below control values. This study confirms functional cell-mediated immune deficits in falciparum malaria and, for the first time, shows hyporesponsiveness in vivax malaria. We conclude that malaria causes a pronounced CMI deficit that is still detectable in some individuals for 3-4 weeks after treatment of acute infection. These changes in DTH should be a consideration in future vaccine development and in evaluation of immune status in endemic areas.

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.

The antimalarial effects of rifampin in 60 adults with Plasmodium vivax malaria were assessed. There were three treatment groups: rifampin (20 and 15 mg/kg of body weight per day for 1 and 4 days, respectively; n = 5); rifampin followed by primaquine (15 mg of base per day for 14 days; n = 25), and chloroquine (25 mg of base per kg over 3 days) followed by primaquine (n = 30). All patients were hospitalized till clearance of fever and parasites, and 45 patients stayed in the hospital for 1 month. Despite initial clearance of fever in all patients and a > or = 6-fold reduction in parasitemia per 48-h life cycle, rifampin alone was not effective: all five patients had subsequent R2-like parasitological responses. All patients treated with rifampin-primaquine cleared both fever and parasitemia, but the therapeutic responses were slower than those following treatment with chloroquine-primaquine. Final fever clearance times were significantly longer (mean [standard deviation] = 43 [35] versus 27 [19] h; P = 0.046), and the parasite clearance times (to 50 and 90% of admission parasite counts and to a level undetectable in a peripheral blood smear) were also significantly greater (P = 0.053 to < 0.001). However, reappearance of infection occurred in only one patient treated with rifampin-primaquine. The results of this study suggest that rifampin at the usual therapeutic doses has partial activity against blood stages of P. vivax in humans but that used alone it is insufficient for cure. Rifampin might therefore be of value in combination antimalarial therapy.