A clinical and molecular study of artesunate + sulphadoxine-pyrimethamine in three districts of central and eastern India.

BACKGROUND: Artesunate + sulphadoxine-pyrimethamine (AS + SP) is recommended throughout India as the first-line treatment for uncomplicated falciparum malaria. Due to the presence of several eco-epidemiological zones of malaria and variable drug pressure, it is necessary to evaluate the efficacy of this combination in different regions of India. The objective of this study was to use clinical and molecular methods to monitor the efficacy of AS + SP in three diverse sites. METHODS: The study was undertaken in three high endemic sites of central and eastern India. Patients with uncomplicated falciparum malaria were enrolled and followed for 28 days. Molecular genotyping was conducted for merozoite surface protein (msp1 and msp2) to differentiate between re-infection and recrudescence and for the dhfr and dhps genes to monitor antifolate drug resistance. RESULTS: In all, 149 patients were enrolled at the three sites. The crude cure rates were 95.9%, 100%, and 100% in Ranchi, Keonjhar, and West Garo Hills respectively. PCR-corrected cure rates were 100% at all sites. In dhfr, 27% of isolates had triple mutations, while 46% isolates were double-mutants. The most prevalent mutation was S108N followed by C59R. 164 L mutation was observed in 43/126 (34%) isolates. In dhps, most (76%) of the isolates were wild-type. Only 2.5% (2/80) isolates showed double mutation. dhfr-dhps two locus mutation were observed in 16% (13/80) isolates. Parasite clearance time was not related with antifolate mutations. CONCLUSIONS: AS + SP combination therapy remained effective against falciparum malaria despite common mutations promoting resistance to antifolate drugs. Although the prevalence of double and triple mutations in dhfr was high, the prevalence of dhfr-dhps two locus mutations were low. Even isolates with dhfr triple and dhfr-dhps two locus mutations achieved adequate clinical and parasitological response.

Artesunate-amodiaquine fixed dose combination for the treatment of Plasmodium falciparum malaria in India.

BACKGROUND: Artemisinin-based combination therapy (ACT) has been recommended for the treatment of falciparum malaria by the World Health Organization. Though India has already switched to ACT for treating falciparum malaria, there is need to have multiple options of alternative forms of ACT. A randomized trial was conducted to assess the safety and efficacy of the fixed dose combination of artesunate-amodiaquine (ASAQ) and amodiaquine (AQ) for the treatment of uncomplicated falciparum malaria for the first time in India. The study sites are located in malaria-endemic, chloroquine-resistant areas. METHODS: This was an open label, randomized trial conducted at two sites in India from January 2007 to January 2008. Patients between six months and 60 years of age having Plasmodium falciparum mono-infection were randomly allocated to ASAQ and AQ arms. The primary endpoint was 28-day PCR-corrected parasitological cure rate. RESULTS: Three hundred patients were enrolled at two participating centres, Ranchi, Jharkhand and Rourkela, Odisha. Two patients in AQ arm had early treatment failure while there was no early treatment failure in ASAQ arm. Late treatment failures were seen in 13 and 12 patients in ASAQ and AQ arms, respectively. The PCR-corrected cure rates in intent-to-treat population were 97.51% (94.6-99.1%) in ASAQ and 88.65% (81.3-93.9%) in AQ arms. In per-protocol population, they were 97.47% (94.2-99.2%) and 88.30% (80-94%) in ASAQ and AQ arms respectively. Seven serious adverse events (SAEs) were reported in five patients, of which two were reported as related to the treatment. All SAEs resolved without sequel. CONCLUSION: The fixed dose combination of ASAQ was found to be efficacious and safe treatment for P. falciparum malaria. Amodiaquine also showed acceptable efficacy, making it a suitable partner of artesunate. The combination could prove to be a viable option in case India opts for fixed dose combination ACT. CLINICAL TRIAL REGISTRY: ISRCTN84408319.

Efficacy of artemether-lumefantrine in area of high malaria endemicity in India and its correlation with blood concentration of lumefantrine.

This study was conducted to correlate blood concentrations of lumefantrine with treatment outcome for patients with Plasmodium falciparum malaria when the drug was given without specific instructions for administration with food. Patients with P. falciparum malaria in the highly endemic state of Orissa, India, were enrolled during 2008 and followed-up for 28 days after admistration of artemether-lumefantrine for three days according to a World Health Organization protocol. Drug concentration in whole blood was determined by using blood spots placed on filter paper on day 7. The technology is suitable for field studies. One hundred percent of the patients had an adequate clinical and parasitological response. These results confirm the efficacy of artemether-lumefantrine in persons from poor tribal communities when given without specific instructions regarding co-administration with food, despite high inter-individual variability in blood concentrations of lumefantrine.

Identification of IgE-mediated food allergy and allergens in older children and adults with asthma and allergic rhinitis.

BACKGROUND AND OBJECTIVE: Prevalence of immunoglobulin (Ig) E-mediated food allergy is primarily reported for certain pediatric populations and adults. The present study was aimed to investigate the relative prevalence of food allergy and allergens in older children and adults with asthma and allergic rhinitis. METHODS: Patients (12-62 years) were screened using standard questionnaire and skin prick-test (SPT) with common foods and aeroallergens. Specific IgE level was determined by enzyme linked immunosorbent assay (ELISA) and allergy was established by blinded food challenges. RESULTS: Of 1860 patients screened, 1097 (58.9%) gave history of food allergy. Of the history positive patients skin tested (n=470), 138 (29.3%) showed a marked positive reaction to food extracts. Rice elicited positive SPT reaction in maximum number of cases 29 (6.2%) followed by blackgram 28 (5.9%), lentil 26 (5.5%), citrus fruits 25 (5.3%), pea 18 (3.8%), maize 18 (3.8%) and banana 17 (3.6%). The SPT positive patients showed elevated specific IgE levels (range: 0.8-79 IU/mL) against respective food allergens than normal controls (0.73 IU/mL, mean +/- 2 SD). Food allergy was confirmed in 21/45 (46.6%) of the patients by blinded controlled food challenges. The prevalence of food allergy was estimated to be 4.5% (2.6%-6.34%) at 95% confidence interval (95% CI) in test population (n=470). Sensitisation to food was significantly associated with asthma (p = 0.0065) while aeroallergens were strongly related to rhinitis (p < 0.01). CONCLUSIONS: Food allergy is estimated to be 4.5% in adolescents and adults with asthma, rhinitis or both. Rice, citrus fruits, blackgram and banana are identified as major allergens for inducing allergic symptoms.

Therapeutic efficacy of artemether-lumefantrine in uncomplicated falciparum malaria in India.

BACKGROUND: Artemisinin-based combination therapy (ACT) is the treatment of choice for uncomplicated falciparum malaria. Artemether-lumefantrine (AL), a fixed dose co-formulation, has recently been approved for marketing in India, although it is not included in the National Drug Policy for treatment of malaria. Efficacy of short course regimen (4 x 4 tablets of 20 mg artemether plus 120 mg lumefantrine over 48 h) was demonstrated in India in the year 2000. However, low cure rates in Thailand and better plasma lumefantrine concentration profile with a six-dose regimen over three days, led to the recommendation of higher dose globally. This is the first report on the therapeutic efficacy of the six-dose regimen of AL in Indian uncomplicated falciparum malaria patients. The data generated will help in keeping the alternative ACT ready for use in the National Programme as and when required. METHODS: One hundred and twenty four subjects between two and fifty-five years of age living in two highly endemic areas of the country (Assam and Orissa) were enrolled for single arm, open label prospective study. The standard six-dose regimen of AL was administered over three days and was followed-up with clinical and parasitological evaluations over 28 days. Molecular markers msp-1 and msp-2 were used to differentiate the recrudescence and reinfection among the study subjects. In addition, polymorphism in pfmdr1 was also carried out in the samples obtained from patients before and after the treatment. RESULTS: The PCR corrected cure rates were high at both the sites viz. 100% (n = 53) in Assam and 98.6% (n = 71) in Orissa. The only treatment failure case on D7 was a malnourished child. The drug was well tolerated with no adverse events. Patients had pre-treatment carriage of wild type codons at positions 86 (41.7%, n = 91) and 184 (91.3%, n = 91) of pfmdr1 gene. CONCLUSION: AL is safe and effective drug for the treatment of acute uncomplicated falciparum malaria in India. The polymorphism in pfmdr1 gene is not co-related with clinical outcome. However, treatment failure can also occur due to incomplete absorption of the drug as is suspected in one case of failure at D7 in the study. AL can be a viable alternative of artesunate plus sulphadoxine/pyrimethamine (AS + SP), however, the drug should be used rationally and efficacy needs to be monitored periodically.

Rice (Oryza sativa) allergy in rhinitis and asthma patients: a clinico-immunological study.

Sensitization to foods varies in different countries reflecting a possible interaction of genetic factors, cultural and dietary habits. Rice is a major food consumed world wide and needs evaluation for IgE mediated reactions. The present study was carried out to identify rice allergy in patients of rhinitis and asthma and identify the allergenic proteins in raw and cooked rice. Of 1200 patients screened using standard questionnaire, 165 presented with history of rice allergy. Of these, 20 (12.1%) patients demonstrated marked positive skin prick test (SPT) and 13 showed significantly raised specific IgE to rice compared to normal controls. Double blind placebo controlled food challenge (DBPCFC) confirmed rice allergy in 6/10 patients. Immunoblot with hypersensitive individual patients' sera showed 14-16, 33, 56 and 60 kDa proteins as major IgE-binding components in rice. Boiled rice retained four IgE reactive proteins of 16, 23, 33 and 53 kDa. In summary, IgE-mediated rice allergy affects 0.8% [(0.42-1.58) at 95% CI] of asthma and rhinitis cases. The subjects with severe SPT reactions (4 mm or above) and specific IgE, 6.9 ng/ml to rice demonstrated positive blinded food challenge with clinical symptoms.

Relevance of serum IgE estimation in allergic bronchial asthma with special reference to food allergy.

Studies suggest the importance of serum total and specific IgE in clinical evaluation of allergic manifestations. Such studies are lacking in Indian subcontinent, though a large population suffer from bronchial asthma. Here relevance of serum total and specific IgE was investigated in asthmatics with food sensitization. A total of 216 consecutive patients (mean age 31.9 years, S.D. 11.8) were screened by various diagnostic testing. Out of 216 patients, 172 were with elevated serum total IgE (201 to > 800 IU/ml). Rice elicited marked positive skin prick test reactions (SPT) in 24 (11%) asthma patients followed by black gram 22 (10%), lentil 21 (9.7%) and citrus fruits 20 (9.2%). Serum total IgE and specific IgE showed significant correlation, p = 0.005 and p = 0.001, respectively, with positive skin tests. Blinded food challenges (DBPCFC) with rice and or black gram confirmed food sensitization in 28-37% of cases. In summary, serum total IgE of 265 IU/ml or more with marked positive SPT (4 mm or more) can serve as marker for atopy and food sensitization. Specific IgE, three times of normal controls correlates well with positive DBPCFC and offers evidence for the cases of food allergy.