RI Resistance Research Articles

Immunocytochemical characteristics ofthyrocytes in radioiodine refractory metastases ofpapillary thyroid cancer.

The ICC research was carried out on a fine needle aspiration biopsy material of 104metastases that were found after thyroidectomy and RI therapy, i.e. in postoperative period (79- radioiodine-refractory metastases, 25- radioiodine-uptake metastases). The ICC analysis of TPO and Tg expression in PTC was performed with the use of monoclonal antibodies against TPO and Tg. RI-refractory (RIRM) and RI-uptake metastases of PTC significantly differ by the percentage of cells expressing TPO and Tg (p < 0.05, and p < 0.05respectively). The effectiveness of RI therapy was different for patients with different percentages of TPO-positive cells. A statistically significant difference was demonstrated in the expression of TPO in a punctates of RI-resistant and RI-sensitive metastatic TPC, based on which a new method for preoperative prediction of RI resistance and RI therapy efficiency was developed. It was shown that ICC determination of Tg expression in metastases is effective in preoperative monitoring of RI resistance of PTC if the part of Tg-positive cells in punctates is lower than 56%. The comprehensive study of the ICC profile of thyrocytes in RI-uptake metastases punctates allows us to develop a personified approach to prediction, monitoring and therapy of patients with PTC.

Synthesis, β-haematin inhibition, and in vitro antimalarial testing of isocryptolepine analogues: SAR study of indolo[3,2-c]quinolines with various substituents at C2, C6, and N11

A series of indolo[3,2-c]quinolines were synthesized by modifying the side chains of the ω-aminoalkylamines at the C6 position and introducing substituents at the C2 position, such as F, Cl, Br, Me, MeO and NO2, and a methyl group at the N11 position for an SAR study. The in vitro antiplasmodial activities of the derivative agents against two different strains (CQS: NF54 and CQR: K1) and the cytotoxic activity against normal L6 cells were evaluated. The test results showed that compounds 6k and 6l containing the branched methyl groups of 3-aminopropylamino at C6 with a Cl atom at C2 exhibited a very low cytotoxicity with IC50 values above 4000 nM, high antimalarial activities with IC50 values of about 11 nM for CQS (NF54), IC50 values of about 17 nM for CQR (K1), and RI resistance indices of 1.6. Furthermore, the compounds were tested for β-haematic inhibition, and QSAR revealed an interesting linear correlation between the biological activity of CQS (NF54) and three contributing factors, namely solubility, hydrophilic surface area, and β-haematin inhibition for this series. In vivo testing of 6l showed a reduction in parasitaemia on day 4 with an activity of 38%.

Chloroquine-Resistant Plasmodium falciparum Local Strain in Taiz Governorate, Republic of Yemen

Background: The emergence of Plasmodium falciparum resistance to widely used antimalarial drugs such as chloroquine has made malaria control and treatment much more difficult. In Yemen, 60% of the total population live in malarious areas. The problem of chloroquine resistance in Yemen is gradually worsening since the detection of first indigenous cases of P. falciparum resistance to chloroquine in 1989. Methods: In a cross-sectional malariometric parasitic survey, 447 Yemeni children were enrolled from two selected districts (Hethran and Al-mafatch) representing Taiz Governorate. Duplicate thin and thick blood smears were prepared, stained with Giemsa stain and examined microscopically. Fifty-six students satisfied all criteria of the WHO for the assessment of P. falciparum response to chloroquine using a 7-day in vivo test. Results: Out of 447 examined slides, 83 cases (100%) were found with falciparum malaria. The overall malaria parasite rate in Taiz Governorate was 18.6%, a prevalently mesoendemic condition. The obtained results of the 7-day in vivo study revealed that out of 83 P. falciparum cases who completed the study period, 56 cases did not respond to the standard dose of chloroquine, i.e. the overall resistance rate was 16.1%. The prevalence of chloroquine resistance was higher in the Hethran district (19.4%) compared with 10.0% in the Al-mafatch district. The majority had an RI resistance level. Conclusion: Chloroquine resistance of the local strain of P. falciparum was recorded in all studied districts in Taiz Governorate. This calls for an urgent revision of the current malaria treatment policy which still considers chloroquine as the first-line drug for treatment of uncomplicated P. falciparum malaria. To assess the magnitude of the problem, these districts could be the basis of future sentinel posts for continuous monitoring of chloroquine resistance in the whole country.

COMPARISON OF SULFADOXINE-PYRIMETHAMINE WITH AND WITHOUT CHLOROQUINE FOR UNCOMPLICATED MALARIA IN NIGERIA

While resistance to older antimalarials is increasingly common, newer antimalarials are still not widely available or affordable in much of Africa. Older antimalarials used in combination might be adequately effective in treating uncomplicated malaria. The objective of this study was to determine whether the combination of sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) is superior to SP alone in the treatment of uncomplicated Plasmodium falciparum malaria in Nigerian patients. We recruited subjects with malaria, defined as the presence of fever and parasitemia > 2,000/microL, from the outpatient department of a Nigerian teaching hospital. We alternately assigned 280 subjects to receive SP with or without CQ. We assessed clinical and parasitologic responses on days 1, 2, 3, 7, and 14. A total of 114 in the SP + CQ group and 116 in the SP group completed the study. By day 3, 97 (75%) in the SP + CQ group and 52 (42%) in the SP group had cleared their parasitemia (P < 0.001); by day 14, 112 (98%) and 67 (58%), respectively, had cleared their parasitemia (P < 0.001). By day 3, 82 (63%) in the SP + CQ group and 20 (16%) in the SP group were symptom free (P < 0.001). When a modified World Health Organization clinical classification system was used, adequate clinical response occurred in 99 (87%) and 61 (53%) of those in the SP + CQ and SP groups, respectively. RI, RII, and RIII resistance to SP + CQ was 7.9%, 3.5%, and 1.8%, respectively, whereas resistance to SP was 23%, 17%, and 5%, respectively. Combined SP + CQ is superior to SP alone for treatment of uncomplicated malaria in Nigerian patients and may prolong the usefulness of these readily available and affordable drugs.

COMPARISON OF THE PARASITOLOGIC EFFICACY OF AMODIAQUINE AND SULFADOXINE-PYRIMETHAMINE IN THE TREATMENT OF PLASMODIUM FALCIPARUM MALARIA IN THE BUNGOMA DISTRICT OF WESTERN KENYA

The efficacy of amodiaquine (AQ) and sulfadoxine-pyrimethamine (SP) was assessed in 310 symptomatic children from western Kenya with uncomplicated Plasmodium falciparum malaria. A non-blinded, randomized, 14-day study was performed and parasitologic criteria were used. Of 310 patients included, 238 (77%) completed the study: 120 received AQ and 118 received SP. In those treated with AQ, there were sensitive (S) infections in 107 patients (89.2%, 95% confidence interval [CI] = 82.2, 94.1%), RI resistance in 10 (8.3%, 95% CI = 4.1, 14.8%), RII resistance in 1 (0.8%, 95% CI = 0, 4.6%), and RIII resistance in 2 (1.7%, 95% CI = 0.2, 5.9%). In those treated with SP, there were S infections in 74 patients (62.7%, 95% CI = 53.3, 71.4%), RI resistance in 21 (17.8%, 95% CI = 11.4, 25.9%), RII resistance in 11 (9.3%, 95% CI = 4.7, 16.1%), and RIII resistance in 12 (10.2%, 95% CI = 5.4, 17.1%). Resistance rates were consistently higher in the SP-treated patients (P < 0.001). Resistance to SP in this area has reached such levels that it should no longer be the first-line treatment. Alternative treatment, such as SP plus AQ combination treatment or artemisinin combination treatment, is urgently needed.

Efficacies of chloroquine, sulfadoxine–pyrimethamine and quinine in the treatment of uncomplicated,Plasmodium falciparummalaria in eastern Sudan

The efficacies of several antimalarial drugs in the treatment of uncomplicated Plasmodium falciparum malaria were compared, during an open, randomized trial, in New Halfa, eastern Sudan. The 96 patients who completed the 28 days of follow-up were treated with chloroquine (N = 26), sulfadoxine-pyrimethamine (N = 38) or quinine (N = 32). No treatment failures were observed among the patients given sulfadoxine-pyrimethamine. Only 23.1% of the patients given chloroquine showed adequate clinical response, however, the rest showing early (15.4%) or, more frequently, late (61.5%) treatment failure. In terms of parasitological failure, 54.1% of the patients given chloroquine showed early RI resistance, 7.7% showed late RI, and 15.1% showed RIII. Most (90.6%) of the patients treated with quinine had adequate treatment responses, the rest having late treatment failures (and late RI). The frequency of treatment failure was significantly higher, however, among the patients given chloroquine than in the quinine-treatment arm. The present results and those of earlier investigations indicate that the problem of chloroquine resistance is worsening in eastern Sudan, and that the use of chloroquine as the first-line drug for the treatment of uncomplicated malaria in this area is now compromised. The response to quinine may also be faltering.

Application of a multi-faceted approach for the assessment of treatment response in falciparum malaria: a study from Malaysian Borneo

Thirty-two patients reporting to the Lundu District Hospital, Sarawak, Malaysian Borneo, with uncomplicated falciparum malaria were recruited into a multifaceted study to assess treatment response. Following combined chloroquine and sulphadoxine/pyrimethamine treatment the patients were followed for 28 days according to the World Health Organisation in vivo drug response protocol. The in vivo study revealed that 13 (41%) of the patients had a sensitive response to treatment, five (16%) cleared asexual stage parasites but had persistent gametocytes, 11 (34%) had RI type resistance and three (9%) had RII type resistance requiring quinine intervention before day 7 for parasite clearance. Although clinically insignificant, patients with persistent gametocytes, surviving chloroquine and sulphadoxine/pyrimethamine treatment during maturation, were placed in the reduced response to treatment group for analysis. Allelic typing detected 100% prevalence of the pfcrt K76T marker associated with chloroquine resistance and 78% prevalence of the pfdhfr NRNL haplotype associated with sulphadoxine/pyrimethamine treatment failure. High serum chloroquine levels and pfdhfr haplotypes with <or=2 point mutations were independently associated with a sensitive response to treatment. However four patients in the sensitive response group had both low serum chloroquine levels and the pfdhfr NRNL haplotype. A degree of immunity, consistent with malaria endemicity, may account for the apparently paradoxical presence of markers of drug resistance in the sensitive group.

The drug sensitivity and transmission dynamics of human malaria on Nias Island, North Sumatra, Indonesia.

Nias Island, off the north-western coast of Sumatra, Indonesia, was one of the first locations in which chloroquine-resistant Plasmodium vivax malaria was reported. This resistance is of particular concern because its ancient megalithic culture and the outstanding surfing conditions make the island a popular tourist destination. International travel to and from the island could rapidly spread chloroquine-resistant strains of P. vivax across the planet. The threat posed by such strains, locally and internationally, has led to the routine and periodic re-assessment of the efficacy of antimalarial drugs and transmission potential on the island. Active case detection identified malaria in 124 (17%) of 710 local residents whereas passive case detection, at the central health clinic, confirmed malaria in 77 (44%) of 173 cases of presumed 'clinical malaria'. Informed consenting volunteers who had malarial parasitaemias were treated, according to the Indonesian Ministry of Health's recommendations, with sulfadoxine-pyrimethamine (SP) on day 0 (for P. falciparum) or with chloroquine (CQ) on days 0, 1 and 2 (for P. vivax). Each volunteer was then monitored for clinical and parasite response until day 28. Recurrent parasitaemia by day 28 treatment was seen in 29 (83%) of the 35 P. falciparum cases given SP (14, 11 and four cases showing RI, RII and RIII resistance, respectively). Recurrent parasitaemia was also observed, between day 11 and day 21, in six (21%) of the 28 P. vivax cases given CQ. Although the results of quantitative analysis confirmed only low prevalences of CQ-resistant P. vivax malaria, the prevalence of SP resistance among the P. falciparum cases was among the highest seen in Indonesia. When the parasites present in the volunteers with P. falciparum infections were genotyped, mutations associated with pyrimethamine resistance were found at high frequency in the dhfr gene but there was no evidence of selection for sulfadoxine resistance in the dhps gene. Night-biting mosquitoes were surveyed by human landing collections and tested for sporozoite infection. Among the five species of human-biting anophelines collected, Anopheles sundaicus was dominant (68%) and the only species found to be infective--two (1.2%) of 167 females being found carrying P. vivax sporozoites. The risk of malarial infection for humans on Nias was considered high because of the abundance of asymptomatic carriers, the reduced effectiveness of the available antimalarial drugs, and the biting and infection 'rates' of the local An. sundaicus.

Plasmodium vivax clinically resistant to chloroquine in Colombia.

Chloroquine-resistant Plasmodium vivax has been the subject of numerous case reports and prospective studies from Oceania and Asia. In contrast, only case reports exist from the Americas. We performed a prospective study with 28-day follow-up of clinical responses to chloroquine in 2 P. vivax-endemic regions of Colombia. Three (11%) of 27 patients failed to respond to treatment with the standard regimen of chloroquine (1,500 mg of base over 3 days). One patient demonstrated RI resistance on Day 26; one patient demonstrated RI resistance due to recrudescence of blood stages on Day 11; and one patient demonstrated RII resistance of blood stages by never displaying clearing of peripheral parasitemia. All patients were successfully treated with primaquine, which has some blood stage efficacy against P. vivax, combined with a second course of chloroquine. Clinical resistance of P. vivax to chloroquine is present in Colombia and should be monitored in the Americas.

Molecular analysis of DHFR and DHPS genes in P. falciparum clinical isolates from the Haut–Ogooué region in Gabon

The main objective of this work was to determine the prevalence of mutations in genes coding for the dihydropteroate synthase (DHPS) and the dihydrofolate reductase (DHFR) enzymes which are implicated in resistance of P. falciparum to antifolate (pyrimethamine-sulfadoxine (P/S)). In this study, 117 human blood samples were collected at Franceville located in the region of Haut-Ogooué (South-eastern Gabon). In this area, a relatively low level of sensitivity of Plasmodium falciparum to P/S has been reported with 18.2% of RII and 12.1% of RI resistance. A nested polymerase chain reaction was used to amplify a fragment of the DHFR gene containing codon 108, where a point mutation causing a Serine (wild type) to Asparagine or to a Threonine (resistant types) change occurs in pyrimethamine resistant parasites. Eleven DHFR fragments were sequenced and mutations occurring at codons 51, 59 and 108 were analysed. The DHPS gene was amplified by polymerase chain reaction (PCR) and sequenced directly or after cloning. Variant amino acid residues 436, 437, 540, 581, 613 associated with sulfadoxine resistance were analysed. The analysis of codon 108 of the DHFR gene was undertaken for 81 isolates. More than one DHFR P. falciparum genotype was present in 64% of the samples. We showed that 47% of 141 DHFR gene PCR products had Serine (wild phenotype), and 52% had Asparagine. We found one isolate with the Thr-108 confirmed by sequencing of the PCR product. Triple, double and single DHFR mutant at positions 51, 59 and 108 were found. Only codons 436 and 437 of the 38 analysed sequences of the DHPS gene revealed point mutations. These results have been compared with those reported from different sites in Africa, Asia or South-America.

Mutations in the pfmdr1, dhfr and dhps genes of Plasmodium falciparum are associated with in-vivo drug resistance in West Papua, Indonesia

This study (conducted in 1996-99) examines the association of mutations in pfmdr1, dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes of Plasmodium falciparum with in-vivo drug resistance in West Papua, Indonesia. Initially, 85 patients infected with P. falciparum were treated with chloroquine, of whom 21 were cleared of parasites, 49 had parasitaemias classified as RI, RII or RIII resistance and 1 patient had recrudescent parasitaemia. Fansidar (pyrimethamine-sulfadoxine) was the second-line treatment and 18 patients were cleared of parasites and 31 had continuing infections classified as RI, RII or RIII resistance and 1 patient had recrudescent parasitaemia. The pfmdr1, dhfr and dhps genes were examined for mutations previously shown to be associated with resistance to these drugs. In this study, mutations in pfmdr1 were associated with chloroquine resistance and mutations in both dhfr and dhps were associated with Fansidar resistance in vivo. Interestingly, Gly-437 in dhps along with Arg-59/Asn-108 in dhfr were associated with RI, RII and RIII resistance whereas Glu-540 was highly associated with only RII and RIII Fansidar resistance. This finding supports the hypothesis that the molecular basis of RI, RII and RIII Fansidar resistance involves an accumulation of mutations in both dhfr and dhps. These results suggest that mutations in both dhfr and dhps genes are a good predictor of potential Fansidar treatment failure.

Resistance of Plasmodium falciparum malaria to chloroquine is widespread in eastern Afghanistan.

After two decades of war and conflict in Afghanistan, the public-health system is in disarray and malaria has re-emerged as a major disease, with Plasmodium falciparum malaria becoming increasingly common. The limited healthcare services that are available are mainly delivered by non-governmental organizations in collaboration with the Ministry of Health. Although chloroquine (CQ) remains the official first-line treatment against P. falciparum malaria, there is little information on the severity or distribution of resistance to this drug in Afghanistan. In-vivo surveys, co-ordinated by the Malaria Reference Centre in Jalalabad, were therefore performed to determine the frequency and grades of CQ resistance in the three eastern provinces of Kunar, Nangarhar and Laghman. Of the 142 cases enrolled in the study, only 47 (33%) were sensitive. Most of the cases (55%) showed RI resistance but RII/RIII resistance was not uncommon (11%). The prevalence of resistance appeared similar in children and adults, in males and females, and in each of the three provinces investigated. Gametocyte carriage post-treatment was elevated in the resistant cases. As in neighbouring Pakistan, the resurgence of P. falciparum in Afghanistan is probably associated with the transmission and spread of chloroquine-resistant strains. The first-line therapy used against P. falciparum malaria must be changed in order to reverse this trend.

Resistance ofPlasmodium falciparummalaria to chloroquine is widespread in eastern Afghanistan

After two decades of war and conflict in Afghanistan, the public-health system is in disarray and malaria has re-emerged as a major disease, with Plasmodium falciparum malaria becoming increasingly common. The limited healthcare services that are available are mainly delivered by non-governmental organizations in collaboration with the Ministry of Health. Although chloroquine (CQ) remains the official first-line treatment against P. falciparum malaria, there is little information on the severity or distribution of resistance to this drug in Afghanistan. In-vivo surveys, co-ordinated by the Malaria Reference Centre in Jalalabad, were therefore performed to determine the frequency and grades of CQ resistance in the three eastern provinces of Kunar, Nangarhar and Laghman. Of the 142 cases enrolled in the study, only 47 (33%) were sensitive. Most of the cases (55%) showed RI resistance but RII/RIII resistance was not uncommon (11%). The prevalence of resistance appeared similar in children and adults, in males and females, and in each of the three provinces investigated. Gametocyte carriage post-treatment was elevated in the resistant cases. As in neighbouring Pakistan, the resurgence of P. falciparum in Afghanistan is probably associated with the transmission and spread of chloroquine-resistant strains. The first-line therapy used against P. falciparum malaria must be changed in order to reverse this trend.

Towards an Understanding of the Mechanism of Pyrimethamine-Sulfadoxine Resistance in Plasmodium falciparum : Genotyping of Dihydrofolate Reductase and Dihydropteroate Synthase of Kenyan Parasites

The antifolate combination of pyrimethamine (PM) and sulfadoxine (SD) is the last affordable drug combination available for wide-scale treatment of falciparum malaria in Africa. Wherever this combination has been used, drug-resistant parasites have been selected rapidly. A study of PM-SD effectiveness carried out between 1997 and 1999 at Kilifi on the Kenyan coast has shown the emergence of RI and RII resistance to PM-SD (residual parasitemia 7 days after treatment) in 39 out of 240 (16.25%) patients. To understand the mechanism that underlies resistance to PM-SD, we have analyzed the dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes of 81 patients. Fifty-one samples were obtained, before treatment, from patients who remained parasite free for at least 7 days after treatment. For a further 20 patients, samples were obtained before treatment and again when they returned to the clinic with parasites 7 days after PM-SD treatment. Ten additional isolates were obtained from patients who were parasitemic 7 days after treatment but who were not sampled before treatment. More than 65% of the isolates (30 of 46) in the initial group had wild-type or double mutant DHFR alleles, and all but 7 of the 47 (85%) had wild-type DHPS alleles. In the paired (before and after treatment) samples, the predominant combinations of DHFR and DHPS alleles before treatment were of triple mutant DHFR and double mutant DHPS (41% [7 of 17]) and of double mutant DHFR and double mutant DHPS (29% [5 of 17]). All except one of the posttreatment isolates had triple mutations in DHFR, and most of these were "pure" triple mutants. In these isolates, the combination of a triple mutant DHFR and wild-type DHPS was detected in 6 of 29 cases (20.7%), the combination of a triple mutant DHFR and a single mutant (A437G) DHPS was detected in 4 of 29 cases (13.8%), and the combination of a triple mutant DHFR and a double mutant (A437G, L540E) DHPS was detected in 16 of 29 cases (55.2%). These results demonstrate that the triply mutated allele of DHFR with or without mutant DHPS alleles is associated with RI and RII resistance to PM-SD. The prevalence of the triple mutant DHFR-double mutant DHPS combination may be an operationally useful marker for predicting the effectiveness of PM-SD as a new malaria treatment.

Pyrimethamine-sulfadoxine efficacy and selection for mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase in Mali.

To assess pyrimethamine-sulfadoxine (PS) efficacy in Mali, and the role of mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) in in vivo PS resistance, 190 patients with uncomplicated P. falciparum malaria were treated with PS and monitored for 56 days. Mutation-specific polymerase chain reactions and digestion with restriction endonucleases were used to detect DHFR and DHPS mutations on filter paper blood samples from pretreatment and post-treatment infections. Only one case each of RI and RII level resistance and no cases of RIII resistance or therapeutic failure were observed. Post-PS treatment infections had significantly higher rates of DHFR mutations at codons 108 and 59. No significant selection for DHPS mutations was seen. Pyrimethamine-sulfadoxine is highly efficacious in Mali, and while the low level of resistance precludes assessing the utility of molecular assays for in vivo PS resistance, rapid selection of DHFR mutations supports their role in PS failure.

Molecular assays for surveillance of antifolate-resistant malaria

to detect all known DHFR and DHPSmutations, and correlations were determined betweenDHFR and DHPS genotypes and therapeutic responsedefined as sensitive (S), RI, RII, or RIII resistance.A genotype defined by DHFR mutations Asn-108, Ile-51,and Leu-164 combined with DHPS mutations Gly-437,Glu-540, and Gly-581 was detected in 7/8 cases (87·5%) ofRIII resistance, 9/13 cases (69·2%) of RII resistance, 5/13cases (38·5%) of RI resistance, and 0/11 sensitive cases(0·0%) (figure). The Bolivia repeat mutation at codon 30,

Chloroquine resistance in Pakistan and the upsurge of falciparum malaria in Pakistani and Afghan refugee populations.

Surveys conducted in Pakistan during the last decade show that falciparum malaria has become resistant to chloroquine in Pakistani and Afghan refugee populations throughout the country. Although RI resistance is common everywhere (with a frequency of 30%-84%), RII is rarer (2%-36%), and RIII resistance has yet to be detected. The national policy is to prescribe chloroquine as first-line treatment of malaria. A repeated in-vivo survey in a sentinel village indicated that prescription of chloroquine can lead to a 15% increase in the frequency of resistance in a single year, and similar trends were observed in other districts. Coinciding with the spread of resistance is a 6-fold increase in the number of falciparum cases recorded nationally between 1982 and 1992 and a parallel, 5-fold increase in the number of cases recorded in the Afghan refugee population. Resistance contributes to this trend in various ways. Firstly, patients with resistant malaria make repeated visits to health centres. In the sentinel village, for example, where resistance was measured at 71%, recrudescent infections inflated by 66% the genuine incidence of new infections recorded at the health centre. Secondly, owing to ineffective treatment, resistant infections are often still patent during the post-transmission season. This may enlarge the 'overwintering' parasite reservoir, leading to a surge of new cases when transmission resumes. Other factors potentially contributing to the upsurge in falciparum include the decrease availability of insecticide for indoor spraying. Despite the problems posed by resistance for case management, the evidence from the vector-control programme among the refugees is that malaria control through well-targeted campaigns of insecticide spraying is still able to reduce the incidence of falciparum malaria to a level that existed before the advent of resistance.

Chloroquine resistance in Pakistan and the upsurge of falciparum malaria in Pakistani and Afghan refugee populations

Surveys conducted in Pakistan during the last decade show that falciparum malaria has become resistant to chloroquine in Pakistani and Afghan refugee populations throughout the country. Although RI resistance is common everywhere (with a frequency of 30%–84%), RII is rarer (2%–36%), and RIII resistance has yet to be detected. The national policy is to prescribe chloroquine as first-line treatment of malaria. A repeated in-vivo survey in a sentinel village indicated that prescription of chloroquine can lead to a 15% increase in the frequency of resistance in a single year, and similar trends were observed in other districts.Coinciding with the spread of resistance is a 6-fold increase in the number of falciparum cases recorded nationally between 1982 and 1992 and a parallel, 5-fold increase in the number of cases recorded in the Afghan refugee population. Resistance contributes to this trend in various ways. Firstly, patients with resistant malaria make repeated visits to health centres. In the sentinel village, for example, where resistance was measured at 71%, recrudescent infections inflated by 66% the genuine incidence of new infections recorded at the health centre. Secondly, owing to ineffective treatment, resistant infections are often still patent during the post-transmission season. This may enlarge the ‘overwintering’ parasite reservoir, leading to a surge of new cases when transmission resumes. Other factors potentially contributing to the upsurge in falciparum include the decreased availability of insecticide for indoor spraying.Despite the problems posed by resistance for case management, the evidence from the vector-control programme among the refugees is that malaria control through well-targeted campaigns of insecticide spraying is still able to reduce the incidence of falciparum malaria to a level that existed before the advent of resistance.

STUDY OF CHLOROQUINE RESISTANCE IN Plasmodium falciparum INFECTION IN NORTH EAST INDIA

During the period April 1993 to July 1993, a total of 410 patients with pyrexia were screened for malarial parasite and 109 (26.5%) cases were found positive for malarial parasite. Of these 109 cases, 91 were positive for Plasmodium falciparum. Of these 91 cases, 43 patients fulfilled the study criteria as per WHO's extended field trial and were included in the analysis. These patients were treated with standard doses of chloroquine. Seven patients each (16.3%) showed RI and RII resistance and 2 patients (4.7%) showed RIII levels of chloroquine resistance.

Short report: gametocytes, chloroquine pressure, and the relative parasite survival advantage of resistant strains of falciparum malaria in west Africa.

Patients with Plasmodium falciparum infections were selected with an in vivo chloroquine sensitivity assay. Fourteen days after treatment, the gametocytes were studied in relation to asexual parasite responses classified as drug-sensitive or showing RI or RII resistance. Gametocyte prevalence and density appeared significantly higher in RII than RI strains and higher in RI than in sensitive strains. This finding on gametocyte variation in vivo may explain why the RII type of chloroquine resistance has became more prevalent than RI everywhere in tropical Africa in the short time since its emergence. The biological and epidemiologic advantage of chloroquine-resistant malaria mediated through gametocytes is discussed in the context of the present drug pressure in Africa.