Udomsak Silachamroon

Randomized Trial of 3-Dose Regimens of Tafenoquine (WR238605) versus Low-Dose Primaquine for Preventing Plasmodium vivax Malaria Relapse

BACKGROUND Tafenoquine is an 8-aminoquinoline developed as a more effective replacement for primaquine. In a previous dose-ranging study in Thailand, 3 tafenoquine regimens with total doses ranging from 500 mg to 3000 mg prevented relapse of Plasmodium vivax malaria in most patients when administered 2 days after receipt of a blood schizonticidal dose of chloroquine. METHODS To improve convenience and to begin comparison of tafenoquine with primaquine, 80 patients with P. vivax infection were randomized to receive 1 of the following 5 treatments 1 day after receiving a blood schizonticidal dose of chloroquine: (A) tafenoquine, 300 mg per day for 7 days (n=18); (B) tafenoquine, 600 mg per day for 3 days (n=19); (C) tafenoquine, 600 mg as a single dose (n=18); (D) no further treatment (n=13); or (E) primaquine base, 15 mg per day for 14 days (n=12). The minimum duration of protocol follow-up was 8 weeks, with additional follow-up to 24 weeks. RESULTS Forty-six of 55 tafenoquine recipients, 10 of 13 recipients of chloroquine only, and 12 of 12 recipients of chloroquine plus primaquine completed at least 8 weeks of follow-up (or had relapse). There was 1 relapse among recipients of chloroquine plus tafenoquine, 8 among recipients of chloroquine only, and 3 among recipients of chloroquine plus primaquine. The rate of protective efficacy (determined on the basis of reduction in incidence density) for all recipients of chloroquine plus tafenoquine, compared with recipients of chloroquine plus primaquine, was 92.6% (95% confidence interval, 7.3%-99.9%; P=.042, by Fishers exact test). CONCLUSIONS Tafenoquine doses as low as a single 600-mg dose may be useful for prevention of relapse of P. vivax malaria in Thailand.

Pharmacokinetics of High-Dose Oseltamivir in Healthy Volunteers

ABSTRACT The effects of loading doses and probenecid coadministration on oseltamivir pharmacokinetics at four increasing dose levels in groups of eight healthy adult Thai volunteers (125 individual series) were evaluated. Doses of up to 675 mg were well-tolerated. The pharmacokinetics were dose linear. Oseltamivir phosphate (OS) was rapidly and completely absorbed and converted (median conversion level, 93%) to the active carboxylate metabolite. Median elimination half-lives (and 95% confidence intervals [CI]) were 1.0 h (0.9 to 1.1 h) for OS and 5.1 h (4.7 to 5.7 h) for oseltamivir carboxylate (OC). One subject repeatedly showed markedly reduced OS-to-OC conversion, indicating constitutionally impaired carboxylesterase activity. The coadministration of probenecid resulted in a mean contraction in the apparent volume of distribution of OC of 40% (95% CI, 37 to 44%) and a reduction in the renal elimination of OC of 61% (95% CI, 58 to 62%), thereby increasing the median area under the concentration-time curve (AUC) for OC by 154% (range, 71 to 278%). The AUC increase for OC in saliva was approximately three times less than the AUC increase for OC in plasma. A loading dose 1.25 times the maintenance dose should be given for severe influenza pneumonia. Probenecid coadministration may allow considerable dose saving for oseltamivir, but more information on OC penetration into respiratory secretions is needed to devise appropriate dose regimens.

Azithromycin Combination Therapy with Artesunate or Quinine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Adults: A Randomized, Phase 2 Clinical Trial in Thailand

BACKGROUND Because antimalarial drug resistance is spreading, there is an urgent need for new combination treatments for malaria, which kills >1 million people every year. Azithromycin is a macrolide antibiotic that is particularly attractive as an antimalarial because of its safety in children and the extensive experience with its use during pregnancy. METHODS We undertook a randomized, controlled, 28-day inpatient trial involving patients with acute, uncomplicated Plasmodium falciparum malaria. We compared the safety and efficacy of 2 azithromycin-artesunate combinations and 2 azithromycin-quinine regimens in adults with malaria. Treatments were as follows: cohort 1 received 3 days of azithromycin (750 mg twice daily) plus artesunate (100 mg twice daily), cohort 2 received 3 days of azithromycin (1000 mg once daily) plus artesunate (200 mg once daily), cohort 3 received 3 days of azithromycin (750 mg twice daily) plus quinine (10 mg/kg twice daily), and cohort 4 received 3 days of azithromycin (500 mg 3 times daily) plus quinine (10 mg/kg 3 times daily). The enrollment target was 25 evaluable subjects per group. RESULTS The 28-day cure rates were similarly high in the artesunate and the standard-dose quinine cohorts: 92.0% (95% confidence interval [CI], 74.0%-99.0%), 88.9% (95% CI, 70.8%-97.6%), and 92.0% (95% CI, 74.0%-99.0%), for cohorts 1, 2, and 4, respectively. Late R1 treatment failures were seen in each of the artesunate and the standard-dose quinine cohorts. The cure rate for cohort 3 was 73.3% (95% CI, 44.9%-92.2%). In this cohort, 3 early treatment failures led to the termination of enrollment after 16 subjects had been enrolled. With mean parasite and fever clearance times (+/-SD) of 34+/-13 h and 20+/-20 h, the artesunate combinations were found to have led to a significantly (P<.001) faster clinical and parasitological improvement than occurred in the quinine cohorts (74+/-32 h and 43+/-37 h, respectively). Treatment-related adverse events were significantly more common in the quinine cohorts (P<.001). No deaths or drug-related serious adverse events were observed. In vitro results suggest that the treatment failures--particularly in the low-dose quinine cohort--were associated with decreased susceptibility to quinine, as well as with mefloquine cross-resistance. CONCLUSIONS These data suggest that azithromycin-artesunate, even when given only once daily for 3 days, and azithromycin-quinine, given 3 times daily, are safe and efficacious combination treatments for uncomplicated falciparum malaria, and they deserve additional study in special patient populations.

Decreased hemoglobin concentrations, hyperparasitemia, and severe malaria are associated with increased Plasmodium falciparum gametocyte carriage.

To determine factors influencing gametocyte carriage, a cross-sectional study was conducted among 512 patients admitted for Plasmodium falciparum malaria. After adjustments for potential confounders, hemoglobin concentrations were lower in gametocyte carriers 10.5 (±2.5) than in patients without gametocytes 12.5 (±2.3) (P < 0.0001). Hemoglobin concentrations were negatively correlated with peak gametocyte counts (Spearmans ρ = −0.37, P < 0.0001) and gametocyte carriage durations (Spearmans ρ = −0.30, P < 0.0001). Adjustments for the duration of the malaria episode and other potential confounders did not alter the association (P < 0.0001). After adjustment for potential confounders, the median asexual parasitemia was higher in patients with gametocytes than in patients without gametocytes (P = 0.003). Severe malaria cases were more likely to have gametocytes (65%) than malaria with hyperparasitemia (38%) or mild malaria (31%) (P = 0.0001). These findings suggest that events surrounding anemia and tissue hypoxia stimulate Plasmodium falciparum gametocytogenesis.

Efficacy of DB289 in Thai Patients with Plasmodium vivax or Acute, Uncomplicated Plasmodium falciparum Infections

BACKGROUND DB289 is the orally active prodrug of the diamidine DB75, which was developed for the treatment of human African trypanosomiasis. METHODS We tested the safety and efficacy of DB289 for the treatment of Plasmodium vivax and acute, uncomplicated P. falciparum infections in an open-label pilot study at the Hospital for Tropical Diseases in Bangkok. Nine patients with P. vivax infections and 23 patients with P. falciparum infections were admitted and treated with 100 mg of DB289 given orally twice a day for 5 days and were followed for 28 days. Patients with P. vivax infections were also treated with primaquine on days 10-23. RESULTS All patients cleared parasites by day 7, with a mean+/-SD clearance time of 43+/-41 h. One patient with a P. vivax infection had a recurrence of parasitemia on day 9. Of the 23 patients with P. falciparum infections, 3 had recurrences of parasitemia caused by P. vivax and 2 had recurrences of parasitemia caused by P. falciparum. In only 1 of 2 recurrences of parasitemia caused by P. falciparum were the parasites genotypically distinct from the infecting parasites the patient had at enrollment, which means there was a 96% cure rate. CONCLUSIONS DB289 is a promising new antimalarial compound that could become an important component of new antimalarial combinations.

Regional Variation in Travel-related Illness acquired in Africa, March 1997-May 2011

To understand geographic variation in travel-related illness acquired in distinct African regions, we used the GeoSentinel Surveillance Network database to analyze records for 16,893 ill travelers returning from Africa over a 14-year period. Travelers to northern Africa most commonly reported gastrointestinal illnesses and dog bites. Febrile illnesses were more common in travelers returning from sub-Saharan countries. Eleven travelers died, 9 of malaria; these deaths occurred mainly among male business travelers to sub-Saharan Africa. The profile of illness varied substantially by region: malaria predominated in travelers returning from Central and Western Africa; schistosomiasis, strongyloidiasis, and dengue from Eastern and Western Africa; and loaisis from Central Africa. There were few reports of vaccine-preventable infections, HIV infection, and tuberculosis. Geographic profiling of illness acquired during travel to Africa guides targeted pretravel advice, expedites diagnosis in ill returning travelers, and may influence destination choices in tourism.

Relationship between reactive nitrogen intermediates and total immunoglobulin E, soluble CD21 and soluble CD23: comparison between cerebral malaria and nonsevere malaria.

To search for evidence of a protective role of the CD23/NO pathway against cerebral malaria, concentrations of reactive nitrogen intermediates (RNI) and sCD21, total immunoglobulin (Ig)E and sCD23 were compared between 17 cases of cerebral malaria and 33 controls. The geometric mean of sCD23 concentration was higher among cerebral malaria cases than among controls (optical density 2643/1495, P = 0·01). The ratio between sCD21 and sCD23 was significantly lower in cerebral malaria cases than in controls (0·67 ± 0·02 versus 0·77 ± 0·02, respectively, P = 0·009). Multiple linear regression analysis showed that, among cerebral malaria cases, there was a clear correlation between RNI and both IgE (P = 0·007) and sCD21 (P < 0·0001). Among controls, there was a strong negative correlation between RNI and sCD23 concentrations (r = −0·61, P < 0·0001). However, multivariate analysis unmasked the fact that, in controls, there was also a positive correlation between RNI and IgE (P = 0·045). Logistic regression showed that increased RNI concentrations were associated with a cerebral malaria adjusted odds ratio of 1·05 per unit increase [95% confidence interval (CI) 1·006–1·1, P = 0·02] and that an increased ratio between sCD21 and sCD23 was associated with protection from cerebral malaria (adjusted OR = 0·00001 per unit increase (95% CI 0–0·03, P = 0·005). These different immunological profiles suggest that, among controls, the CD23/NO pathway was chronically stimulated whereas, in cerebral malaria, its stimulation was acute, which could explain why some patients developed cerebral malaria and others did not.

Presence of autoimmune antibody in chikungunya infection.

Chikungunya infection has recently re-emerged as an important arthropod-borne disease in Thailand. Recently, Southern Thailand was identified as a potentially endemic area for the chikungunya virus. Here, we report a case of severe musculoskeletal complication, presenting with muscle weakness and swelling of the limbs. During the investigation to exclude autoimmune muscular inflammation, high titers of antinuclear antibody were detected. This is the report of autoimmunity detection associated with an arbovirus infection. The symptoms can mimic autoimmune polymyositis disease, and the condition requires close monitoring before deciding to embark upon prolonged specific treatment with immunomodulators.

Frequency of pruritus in Plasmodium vivax malaria patients treated with chloroquine in Thailand.

Chloroquine-induced itch in black-skinned African malaria patients is common and frequently leads to poor compliance or treatment defaulting. To assess the frequency and severity of chloroquine-induced pruritus in an Asian population, we reviewed case records of 1189 Plasmodium vivax malaria patients treated with chloroquine (25 mg/kg over 3days) at the Bangkok Hospital for Tropical Diseases from 1992 through 1997. The majority of patients were Thais or ethnic Burmese (light brown skin), referred from the western border of Thailand. Overall, there were 23 patients (1.9%) with complaints of pruritus during chloroquine therapy. Of these, 12 (52%) had palm and sole involvement, eight (35%) had generalized pruritus including the palms and soles, and three (13%) had palm itching only. One patient developed pruritus on the palms and soles on two consecutive admissions. The pruritus did not interfere with daily activity, was reduced in intensity by anti-histamine therapy, and did not affect the patients willingness to complete the chloroquine regimen. Therapeutic responses in the 23 patients with chloroquine itch was similar to those without itch. Among the itch patients, there was no association with gender or level of parasitaemias. Our findings indicate that the frequency of chloroquine-induced pruritus in Asian patients treated with chloroquine for P. vivax malaria is low in comparison with black-skinned Africans. This may be related to pharmacogenetic factors, the infective Plasmodium species, drug metabolism or drug-parasite interactions, or a lower affinity of chloroquine for less pigmented skin.

Comparison of Artesunate and Chloroquine Activities against Plasmodium vivax Gametocytes

ABSTRACT The gametocidal activities of chloroquine and artesunate were compared. The relative risk (RR) of having detectable gametocytes appear after treatment initiation was lower in artesunate-treated patients (n = 792) than in chloroquine-treated patients (n = 695) (RR = 0.29; 95% CI = 0.2 to 0.40; P < 0.0001). The duration and magnitude of gametocyte carriage were also lower for artesunate than chloroquine. By reducing the transmission of Plasmodium vivax to the vector, artesunate could therefore reduce the incidence of P. vivax malaria.