Therapeutic Efficacy Of Chloroquine Research Articles

Molecular profile of Pfatpase-6 gene from Plasmodium falciparum isolates in Nigeria

Anti-malarial drug resistance is one of the biggest public health burdens confronting global malaria control programmes. The emergence of P. falciparum chloroquine resistance transporter and multi-drug resistance mutant genes had devastating effects on the therapeutic efficacy of chloroquine when it was the drug of choice for malaria treatment. The artemisinins have proven to be an excellent therapeutic alternative to fill the void in chemotherapeutic options left by resistance mechanisms. The sarco/endoplasmic reticulum Ca2+-ATPase ortholog of P. falciparum (PfATPase-6) has been suggested as one of the targets of the artemisinins. Consequently, Pfatpase-6 gene polymorphisms are being investigated as markers of artemisinin resistance elsewhere. The present study assessed the molecular profile of the current prevalence of four P. falciparum candidate artemisinin resistance biomarkers L263E, E431K, A623E, and S769N in the Pfatpase-6 gene in 113 samples of P. falciparum isolates collected from Ibadan, Oyo State, Nigeria between 2017 and 2018. The frequency of occurrence of E431K mutation was 17% from collected samples. No A623E, L263E and S769N were detected. The result suggests that resistance to artemisinin has either not yet been selected in Nigeria or other genes mutations might be responsible for such, if at all

Efficacy Study of Chloroquine to Plasmodium vivax Malaria in Darimu and Bure Districts, Southwest Ethiopia.

BackgroundChloroquine (CQ) is the first line treatment for vivax malaria in Ethiopia. However, the therapeutic efficacy of the drug is now declining. Several reports from different areas of the country showed CQ-vivax treatment failure increasing. This study therefore aimed to provide additional data on the therapeutic efficacy of CQ against Plasmodium vivax malaria from two districts of Southwestern Ethiopia.MethodsAn observational prospective study among P. vivax malaria infected individuals was conducted in two districts of Southwest Ethiopia for a period of 28 follow-up days. Study participants were treated with 25 mg/kg of standard CQ for 3 consecutive days according to the procedure. Microscopic blood film examinations and other clinical assessments were measured within the follow-up period on a weekly basis.ResultsA total of 115 patients were enrolled in the study. Sixty-five were from Darimu and 50 were from Bure districts. The majority (67%) of study participants were male and 86.1% (99/115) were below 35 years old. The study revealed that CQ treatment was able to clear vivax malaria parasites and febrile within a week. During the follow-up study period, recurrence of vivax parasitemia was not recorded. However, there was a marked heterogeneity with respect to fever clearance time, parasitemia load, and carriage of parasite gametocyte within 72 hours of post-treatment between the two study areas.ConclusionThe present study revealed that CQ has good clinical and parasitological response to vivax malaria in the study areas. Thus, it can be continued as the first line P. vivax malaria treatment. However, further monitoring and evaluation of the drug should be considered.

Pattern of anti-malarial drugs and artemether combination therapy adherence in an institution based medical centre, Nigeria

The change in policy guidelines for treating uncomplicated malaria became necessary because the therapeutic efficacy of chloroquine and SP had deteriorated. Hence compliance is a necessity to enable effective check on malaria. This work was carried out to evaluate antimalaria drug prescription and to update its usage in line with WHO guideline on Artemeter Combination therapy in a university based medical center. We utilized descriptive, cross-sectional, retrospective study of antimalaria prescriptions purposely carried out among male and female outpatients with mean age of 22.4±2.8 at a University health facility. This comprised all outpatients prescriptions that contained at least one antimalarial drug filed from October 2018 to September 2019. Systematic sampling was used to select the prescriptions. Based on the total number of 1250 prescriptions containing at least one antimalarial drug, a sampling interval of 5 was calculated and simple balloting was used for the first pick. A total number of two hundred and fifty (250) prescriptions containing at least one antimalarial drug were selected for the study. Out of 250 antimalaria prescriptions, usage of ACT class of Artemeter lumefantrine, Artemeter Amodiaquine and Artemeter Piparaqiune were recorded at 45.6%, 10.4% and 9.6% respectively. Triple combination Artemeter lumefantrine and Sulphadoxine-Pyrimethamine was recorded at 20.4% while Sulphadoxine-Pyrimethamine was recorded at 4%. Combination of antimalarial drugs with antibiotics was recorded at 31.2%. This study showed compliance with National Antimalarial Treatment Guideline for the treatment of malaria infection as it regards the use of artemisinin-based combination therapy. The frequency usage of artemeter lumefantrine was proceeding among other ACTs. The frequency in co-prescription of antibiotics with anti-malaria should be guarded to comply with WHO recommendation.

Evaluation of Efficacy of Chloroquine for Plasmodium Vivax Infection Using Parasite Clearance Times: A 10-Year Study and Systematic Review

Chloroquine, in combination with primaquine, is used as the firstline treatment for uncomplicated P. vivax malaria in Thailand. In view of the declining efficacy of chloroquine in many P. vivax endemic areas, the possibility of emergence of chloroquine- resistant P. vivax in Thailand is a concern. The aim of this study was to assess the trends in therapeutic efficacy of chloroquine and primaquine for the treatment of uncomplicated P. vivax malaria and to assess the utility of parasite clearance times as a measure of efficacy. This study consisted of: 1) review of medical records of patients who were hospitalised for a period during their treatment for uncomplicated P. vivax malaria at the Hospital for Tropical Diseases, Bangkok, Thailand between 2004 and 2013. Treatment consisted of chloroquine (1500 mg base administered over 3 days) or chloroquine (as before) plus primaquine (15 to 30 mg base/daily for 14 days from day 2); and 2) systematic review of the literature in English to assess current standards in the reporting of parasite clearance times. The 28-day cure rate was 99.1%. The range of median parasite clearance time over the 10-year period was 46 to 59 hours, and there was statistical evidence for an increasing trend in parasite clearance times between 2009 and 2013. Heterogeneity was noted among previous chloroquine efficacy studies in the measurement and reporting of parasite clearance. The treatment of P. vivax infection with a combination of chloroquine and primaquine has remained efficacious in Thailand. Increasing rates of parasite clearance in a population over time may be a useful early warning mechanism for the emergence of chloroquine resistance. The utility of monitoring time-trends in parasite clearance to detect resistance may be enhanced if parasite clearance measurements are standardised.

Pharmacological and Genetic Inhibition of Autophagy Decreases the Secretion of High Molecular Weight Von Willebrand Factor from Endothelial Cells in Vitro and in Vivo

The regulation of von Willebrand factor (VWF) processing, packaging, and secretion is important for primary hemostasis. Recently, autophagy has been implicated in modulating VWF maturation and Weibel-Palade body (WPB) morphology. Additionally, treatment of mice and humans with chloroquine (CQ), an anti-malarial agent and pharmacological inhibitor of autophagy, is shown to increase bleeding time. Therefore, we hypothesize that targeting autophagic flux may be therapeutic for arterial thrombotic disorders such as thrombotic thrombocytopenic purpura (TTP). To test this hypothesis, we first treated human umbilical vein endothelial cells (HUVECs) with CQ in culture and showed that CQ dose-dependently decreased VWF antigen levels and multimer sizes in the conditioned medium of histamine-stimulated cells (not shown). Knockdown of an autophagy-related protein (Atg7) with shRNA in HUVECs had similar effect to CQ treatment in VWF secretion and multimer distribution (not shown). More interestingly, daily injections (i.p.) of CQ at 60 mg/kg into Adamts13-/- mice (CAST/Ei strain) for 7 days reduced plasma VWF concentration by more than 60% compared to vehicle control (Fig. 1). Interestingly, VWF secreted from CQ-treated mice remained functional as collagen binding activity/antigen ratio was comparable to vehicle control mice. However, multimer analysis demonstrated the selective lack of ultra large VWF in plasma of Adamts13-/- mice treated with CQ as compared with those treated with vehicle alone (Fig. 2). These results indicate that targeting autophagy pathway with a pharmacological agent, such as CQ, may modulate VWF secretion and, thereby, arterial thrombosis. Our ongoing experiments are to determine the therapeutic efficacy of CQ and other autophagy inhibitors in murine models of arterial thrombosis and TTP. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Effectiveness of Chloroquine and Inflammatory Cytokine Response in Patients With Early Persistent Musculoskeletal Pain and Arthritis Following Chikungunya Virus Infection

To evaluate whether chloroquine (CQ) is more effective than meloxicam for treating early musculoskeletal pain and arthritis following acute chikungunya (CHIK) virus infection. During the 2006 CHIK epidemic, 509 rural community cases of acute CHIK virus infection were identified in the district of Sholapur in India. Seventy consenting adult patients (seropositive for IgM/IgG anti-CHIK antibody) with early persistent musculoskeletal pain and arthritis were randomized into a 24-week, 2-arm, parallel efficacy trial of CQ (250 mg/day) and meloxicam (7.5 mg/day). Assessors completed a rheumatology evaluation in a blinded manner and collected blood samples in the patients' homes, as per protocol. Laboratory parameters included serum cytokine assay (interleukin-6 [IL-6], interferon-γ [IFNγ], tumor necrosis factor α, CXCL10/IFNγ-inducible protein 10, and IL-13). Twenty-two patients who failed to meet the eligibility criteria (low pain cohort) were also followed up with similar evaluations. An intent-to-treat analysis was completed. At baseline, the 2 groups (38 patients randomized to receive CQ and 32 patients randomized to receive meloxicam) were well matched. There were no significant efficacy differences between the meloxicam group and the CQ group (mean changes in the visual analog scale score for pain -3.9 and -4.2, respectively). Patients improved significantly. Cytokine levels remained several-fold increased, were disproportionate to the clinical response, and were not different from those in the low pain cohort. Seven patients withdrew. Adverse events were mild and infrequent. This exploratory community intervention trial failed to identify an advantage of CQ over meloxicam to treat early musculoskeletal pain and arthritis following acute CHIK virus infection, but therapeutic efficacy of CQ was not ruled out. The inflammatory cytokine response was intense and was not consistent with clinical status.

In Vivo Therapeutic Efficacy of Chloroquine Alone or in Combination with Primaquine against Vivax Malaria in Kolkata, West Bengal, India, and Polymorphism in pvmdr1 and pvcrt-o Genes

Plasmodium vivax malaria, though benign, has now become a matter of concern due to recent reports of life-threatening severity and development of parasite resistance to different antimalarial drugs. The magnitude of the problem is still undetermined. The present study was undertaken to determine the in vivo efficacy of chloroquine (CQ) and chloroquine plus primaquine in P. vivax malaria in Kolkata and polymorphisms in the pvmdr1 and pvcrt-o genes. A total of 250 patients with P. vivax monoinfection were recruited and randomized into two groups, A and B; treated with chloroquine and chloroquine plus primaquine, respectively; and followed up for 42 days according to the WHO protocol of 2009. Data were analyzed using per-protocol analyses. We assessed polymorphisms of the pvmdr1 and pvcrt-o genes by a DNA-sequencing method. Out of the 250 patients recruited, 204 completed a 42-day follow-up period, 101 in group A and 103 in group B. In group A, the non-PCR-corrected efficacy of CQ was 99% (95% confidence interval [CI], 0.944 to 1.00), and in group B, all cases were classified as adequate clinical and parasitological response (ACPR). Day 3 positivity was observed in 11 (5.3%) cases. No specific mutation pattern was recorded in the pvcrt-o gene. Eight nonsynonymous mutations were found in the pvmdr1 gene, three of which were new. The Y976F mutation was not detected in any isolate. Chloroquine, either alone or in combination with primaquine, is still effective against P. vivax malaria in the study area. (The study protocol was registered in CTRI [Clinical Trial Registry-India] of the Indian council of Medical Research under registration no. CTRI/2011/09/002031.).

English

A total of 101 P. falciparum positive patients were enrolled from urban population of Kolkata, India to determine the therapeutic efficacy of chloroquine as per 28 days follow-up schedule of WHO, 2003. All parasite strains were analyzed for P. falciparum chloroquine resistance transporter (pfcrt) haplotypes using DNA sequencing methodology. The PCR corrected chloroquine resistant P. falciparum was very high (76.3%, 95% CI 0.642 – 0.832) of which early treatment failure was (10%), and late treatment failure was (66.3%). K76T mutation was found in all parasite strains irrespective of therapeutic outcomes. Both the Venezuelan (SVMNT) and Southeast Asian (CVIET) haplotypes were prevalent in the study population with predominance of South East Asian haplotype (87.1%). The present study showed that incidence of CQ resistant P. falciparum malaria in Kolkata was very high and well above the WHO recommended cut-off level for change of drug policy. Recently introduced Artimisinine Combination Therapy by the Government of India to treat all P. falciparum cases is an appropriate step.

Chikungunya disease and chloroquine treatment

In a recent issue of the Journal of Medical Virology, Khan et al. [2010] presented an “assessment of in vitro prophylactic and therapeutic efficacy of chloroquine against Chikungunya virus in Vero cells.” This article mentions the fact that chloroquine, a well-known drug developed for the treatment of malaria in the 1930s, was considered previously as a potent antiviral drug in a number of viral diseases (HIV, HBV, influenza A virus, SARS, and others) but makes no reference to previous studies of the antiviral activity of chloroquine against alphaviruses (and more specifically Chikungunya virus) suggesting that the authors had identified a new and promising field of investigation. Their presentation deserves significant qualification. First, the in vitro antiviral effect of chloroquine is not a recent discovery. It was first reported some 40 years ago [Inglot, 1969; Shimizu et al., 1972]. A clinical antiviral application of the molecule has been assessed over time for a number of viral pathogens, and the concrete benefits or risks of such treatment is still debated [Boelaert et al., 1999; Seth et al., 1999; Fredericksen et al., 2002; Savarino et al., 2006]. Regarding alphaviruses, in cellulo inhibition of Sindbis and Semliki Forest virus replication was reported 30 years ago [Coombs et al., 1981; Helenius et al., 1982], but these results were balanced by those obtained from a mouse model, which suggested that chloroquine may enhance viral replication in vivo and aggravate the disease [Maheshwari et al., 1991]. Soon after the beginning of the Chikungunya outbreak in 2005, in the Indian Ocean, the question of the possible use of chloroquine was raised. It is a matter of fact that, in many tropical areas, chloroquine is used as a symptomatic treatment of febrile illnesses and thus, the health authorities had to face its actual—non-evaluated—use during the acute phase of Chikungunya disease. The (confusing) reasons why a part of the local population utilized chloroquine also possibly included the fact that immunomodulatory effects of chloroquine have been used for a long time in autoimmune and rheumatological diseases [Cooper and Magwere, 2008], including chronic Chikungunya arthritis [Brighton, 1984]. Early studies of the emerging Indian Ocean Chikungunya virus (CHIKV) variant demonstrated in vitro inhibition of virus replication by chloroquine [Charrel, 2006; de Lamballerie et al., 2008, 2009; Gould et al., 2010]. Sourisseau et al. [2007] reported that chloroquine inhibited potently the appearance of CHIKV-positive cells and CHIKV-associated cytopathic effect and noted that the therapeutic (antiviral) index of chloroquine in cell cultures is rather narrow and thus, one should be cautious when proposing the use of chloroquine as an antiviral treatment in infected individuals. These early results led to the careful design of a clinical trial in the French Reunion Island (Indian Ocean) (CuraChik, http://clinicaltrials.gov/ct/show/NCT00391313), which was performed at the end of the 2006 outbreak [de Lamballerie et al., 2008]. In this double-blind placebo-controlled randomized trial, 27 patients (diagnosed within <48 hr) received chloroquine and 27 other patients received a placebo treatment. The chloroquine treatment consisted of 600 mg at day 1, 600 mg at days 2 and 3, and 300 mg at days 4 and 5 (and not 250 mg daily as reported by Savarino et al. [2007]). The results did not provide justification for the use of chloroquine to treat acute Chikungunya infections. In conclusion, the issue of chloroquine treatment of Chikungunya virus infection has been examined for years. Whilst in vitro inhibition of CHIKV replication is strongly established, the narrow therapeutic index and the absence of obvious biological or clinical improvement during a clinical trial do not argue in favor of a curative use in non-complicated cases. Whether chloroquine may be useful as a prophylactic treatment, or in the case of severe, sustained Chikungunya infections deserves further investigations that could take advantage of the availability of a relevant non-human primate animal model [Labadie et al., 2010].

Assessment of in vitro prophylactic and therapeutic efficacy of chloroquine against chikungunya virus in vero cells

The resurgence of Chikungunya virus (CHIKV) in the form of unprecedented and explosive epidemics in India and the Indian Ocean islands after a gap of 32 years is a major public health concern. Currently, there is no specific therapy available to treat CHIKV infection. In the present study, the in vitro prophylactic and therapeutic effects of chloroquine on CHIKV replication in Vero cells were investigated. Inhibitory effects were observed when chloroquine was administered pre‐infection, post‐infection, and concurrent with infection, suggesting that chloroquine has prophylactic and therapeutic potential. The inhibitory effects were confirmed by performing a plaque reduction neutralization test (PRNT), real‐time reverse transcriptase (RT)‐PCR analysis of viral RNA levels, and cell viability assays. Chloroquine diminished CHIKV infection in a dose‐dependent manner, with an effective concentration range of 5–20 µM. Concurrent addition of drug with virus, or treatment of cells prior to infection drastically reduced virus infectivity and viral genome copy number by ≥99.99%. The maximum inhibitory effect of chloroquine was observed within 1–3 hr post‐infection (hpi), and treatment was ineffective once the virus successfully passed through the early stages of infection. The mechanism of inhibition of virus activity by chloroquine involved impaired endosomal‐mediated virus entry during early stages of virus replication, most likely through the prevention of endocytosis and/or endosomal acidification, based on a comparative evaluation using ammonium chloride, a known lysosomotropic agent. J. Med. Virol. 82: 817–824, 2010. © 2010 Wiley‐Liss, Inc.

Monitoring of failure of chloroquine treatment for Plasmodium vivax using polymerase chain reaction in Sanliurfa province, Turkey

Malaria is a complex disease that varies widely in epidemiology and clinical manifestation in the southeastern part of Turkey. In many regions of the world, chloroquine (CQ) has been the standard treatment for Plasmodium vivax. However, the resistance of the Plasmodium species to antimalarial drugs has become an increasing problem and a concern worldwide. Our target was to determine the Plasmodium species in the southeast region of Turkey and the therapeutic efficacy of CQ used in the treatment of malaria. Blood samples were collected from 180 patients infected with malaria before and after CQ treatment and were subjected to DNA isolation. The isolated DNA was amplified by a seminested multiplex polymerase chain reaction (SnM-PCR) including primers selected on Plasmodium small subunit ribosomal RNA (ssrRNA) genes for identification of the malaria species. The SnM-PCR results showed that only P. vivax exists in this province. It was also determined that there is a therapeutic failure to CQ in 9.5% of patients. These were the second report on identification of P. vivax and the third report on determination of the therapeutic failure in patients who used CQ to cure human malaria in the southeastern region of Turkey. Our results demonstrate that the SnM-PCR is a sensitive, specific, and a rapid tool for the differentiation of malaria species.

Therapeutic efficacy of chloroquine and sequence variation inpfcrtgene among patients withfalciparummalaria in central India

To assess the therapeutic efficacy of chloroquine (CQ) treatment against uncomplicated Plasmodium falciparum infections in a tribal population of central India (Madhya Pradesh) and to investigate the prevalence of mutant P. falciparum chloroquine-resistant transporter (pfcrt) gene in the parasite population. Clinical and parasitological response was determined by in-vivo testing. For molecular testing, the parasite DNA was extracted from blood samples and used to amplify and sequence parts of the pfcrt (44-177 codons), MSP1 (block 2) and MSP2 (central repeat region) genes. Of 463 patients presenting fever, 137 tested positive for P. falciparum. They were treated with CQ. Of these, 58% participated in the study. Overall, treatment failure occurred in 53% of participants. Children under 5 years of age showed significantly more CQ resistance than adults. Mutant genotype S(72)V(73)M(74)N(75)T(76) was prevalent among both CQ responders (61.29%) and non-responders (66.7%). Interestingly, several patients from the CQ non-responder group (33.3%, n = 39) were harbouring parasite with wild type C(72)V(73)M(74)N(75)K(76) genotype of the pfcrt gene. Microsatellite sequences downstream of exon 2 varied widely among both wild type and mutant pfcrt haplotypes. The high rate of treatment failure in the present study clearly indicates the need to reassess the use of CQ as first-line antimalarial therapy in central India. This is supported by the presence of mutant pfcrt genotype among majority of the parasite population of the CQ non-responder group of patients. However, the presence of wild type amino acid at codon 76 of the pfcrt gene among several patients with CQ non-responders requires further investigations.

Therapeutic efficacy of chloroquine and chloroquine plus primaquine for the treatment of Plasmodium vivax in Ethiopia

Plasmodium vivax is the second most important cause of morbidity in Ethiopia. There is, however, little information on P. vivax resistance to chloroquine and chloroquine plus primaquine treatment although these drugs have been used as the first line treatment for over 50 years. We assessed the efficacy of standard chloroquine and chloroquine plus primaquine treatment for P. vivax infections in a randomized open-label comparative study in Debre Zeit and Nazareth in East Shoa, Ethiopia. A total of 290 patients with microscopically confirmed P. vivax malaria who presented to the outpatient settings of the two laboratory centers were enrolled: 145 patients were randomized to receive CQ and 145 to receive CQ + PQ treatment. Participants were followed-up for 28–157 days according to the WHO procedures. There were 12 (6.5%) lost to follow-up patients and 9 (3.1%) withdrawals. In all, 96% (277/290) of patients were analysed at day 28. Baseline characteristics were similar in all treatment groups. In all, 98.6% (275/277) of patients had cleared their parasitemia on day 3 with no difference in mean parasite clearance time between regimens (48.34 ± 17.68, 50.67 ± 15.70 h for the CQ and CQ + PQ group, respectively, P = 0.25). The cumulative incidence of therapeutic failure at day 28 by a life-table analysis method was 5.76% (95% CI: 2.2–14.61) and 0.75% (95% CI: 0.11–5.2%) in the CQ and CQ + PQ group, respectively ( P = 0.19). The relapse rate was 8% (9/108) for the CQ group and 3% (4/132) for the comparison group ( P = 0.07). The cumulative risk of relapse at day 157 by a life-table method was 61.8% (95% CI: 20.1–98.4%) in the CQ group, compared with 26.3% (95% CI: 7.5–29.4%) in the CQ + PQ group ( P = 0.0038). The study confirms the emergence of CQ and PQ resistance/treatment failure in P. vivax malaria in Ethiopia. Although treatment failures were detected, they were similar between the treatment groups. We recommend regular monitoring and periodic evaluation of the efficacy of these antimalarial drugs in systematically selected sentinel sites to detect further development of resistance and to make timely national antimalarial drug policy changes.

Efficacy of monotherapies and artesunate-based combination therapies in children with uncomplicated malaria in Somalia

In order to guide the antimalarial treatment policy of Somalia, we conducted therapeutic efficacy studies of routinely used antimalarial monotherapies as well as artemisinin-based combination therapies (ACTs) for uncomplicated malaria in three sentinel sites during 2003–2006. Therapeutic efficacy of chloroquine (CQ), amodiaquine (AQ) and sulfadoxine/pyrimetahmine (SP) monotherapies, and artesunate plus SP (AS + SP) or AQ (AS + AQ) were evaluated in children 6 months to 10 years old with uncomplicated malaria. For the assessment of the monotherapies, 2003 WHO protocol with 14-day follow-up was used while the 2005 WHO protocol with 28-day follow-up was used for testing the ACTs. Of the monotherapies, CQ performed very poorly with treatment failures varying from 76.5% to 88% between the sites. AQ treatment failure was low except for Janale site with treatment failure of 23.4% compared to 2.8% and 8% in Jamame and Jowhar, respectively. For SP, treatment failures from 7.8% to 12.2% were observed. A 28-day test of artemisinin-based combinations, AS + SP and AS + AQ, proved to be highly efficacious with cure rates of 98–100% supporting the choice of AS + SP combination as first line treatment for uncomplicated malaria for Somalia.

Therapeutic responses ofPlasmodium vivaxandP. falciparumto chloroquine, in an area of western India whereP. vivaxpredominates

In 2003-2005, following an increase in the local incidence of human malaria, the therapeutic efficacy of chloroquine (CQ) in the treatment of Plasmodium vivax and P. falciparum malaria was evaluated in the Anand district of Gujarat state, in western India. After oral administration of CQ, clinical and parasitological responses were measured over a follow-up period of 28 days, following the standard protocol of the World Health Organization. Most of the recurrent infections were checked, by genotyping, to see whether they were the result of treatment failure or re-infection during the follow-up. At the primary health centre (PHC) in Deva, all 57 P. vivax cases included in the study responded to CQ within 3 days. At the Pansora PHC, however, only 59 [90.8%, with a 95% confidence interval (CI) of 83.7%-97.8%] of the 65 P. vivax cases appeared to respond completely, recurrent infections being observed in the other six cases (9.2%; CI=2.2%-16.3%). Of the four recurrent infections checked by genotyping, however, only two appeared to be the result of true treatment failure. Twenty-seven (81.8%; CI=67.2%-94.4%) of the 33 P. falciparum cases who were enrolled in the study, all from Pansora PHC also showed apparent treatment failure, with one early failure, 17 late clinical failures and nine late parasitological failures. All 23 P. falciparum cases that showed apparent treatment failure and were investigated by genotyping appeared to be true cases of failure, none showing any evidence of re-infection during follow-up. The mean parasite-clearance times for those infected with P. falciparum, both those considered CQ-sensitive and the treatment failures, exceeded 2 days. These results indicate the presence of CQ-resistant P. vivax and P. falciparum in Anand district. The high frequency of CQ failure against P. falciparum observed in this study led to a change in the drug policy at the Pansora PHC, with artemisinin-based combination therapy now being used for the first-line treatment of P. falciparum malaria. Chloroquine remains the recommended first-line treatment for P. vivax infections in the area but the treatment failure seen in at least two P. vivax cases indicates a need for further monitoring of the therapeutic efficacy of CQ against such infections, in central Gujarat and elsewhere.

Assessment of the therapeutic efficacy of chloroquine in the treatment of uncomplicated Plasmodium falciparum malaria in a tribal block of the Kalahandi district of Orissa, India

The study on therapeutic efficacy of chloroquine was carried out in a tribal dominated block of Kalahandi district of Orissa, India. It revealed 94% treatment failure with standard dose of chloroquine in the treatment of uncomplicated P. falciparum malaria cases. The study warrants the change to alternate antimalarials in this region.

Chloroquine resistant Plasmodium falciparum malaria in Osogbo Nigeria: efficacy of amodiaquine + sulfadoxine-pyrimethamine and chloroquine + chlorpheniramine for treatment

Chloroquine (CQ) resistance in Plasmodium falciparum contributes to increasing malaria-attributable morbidity and mortality in Sub-Saharan Africa. Despite a change in drug policy, continued prescription of CQ did not abate. Therefore the therapeutic efficacy of CQ in uncomplicated falciparum malaria patients was assessed in a standard 28-day protocol in 116 children aged between six and 120 months in Osogbo, Southwest Nigeria. Parasitological and clinical assessments of response to treatment showed that 72 (62.1%) of the patients were cured and 44 (37.9%) failed the CQ treatment. High initial parasite density and young age were independent predictors for early treatment failure. Out of the 44 patients that failed CQ, 24 received amodiaquine + sulphadoxine/pyrimethamine (AQ+SP) and 20 received chlorpheniramine + chloroquine (CH+CQ) combinations. Mean fever clearance time in those treated with AQ+SP was not significantly different from those treated with CH+CQ (p = 0.05). There was no significant difference in the mean parasite density of the two groups. The cure rate for AQ+SP group was 92% while those of CH+CQ was 85%. There was a significant difference in parasite clearance time (p = 0.01) between the two groups. The 38% treatment failure for CQ reported in this study is higher than the 10% recommended by World Health Organization in other to effect change in antimalarial treatment policy. Hence we conclude that CQ can no more be solely relied upon for the treatment of falciparum malaria in Osogbo, Nigeria. AQ+SP and CH+CQ are effective in the treatment of acute uncomplicated malaria and may be considered as useful alternative drugs in the absence of artemisinin-based combination therapies.

Prevalence and Chloroquine Sensitivity of Plasmodium malariae in Madagascar

We report the results of clinical studies carried out at six sites in Madagascar, between January and October 2006. The aims were (i) to update our knowledge of the burden of Plasmodium malariae infection and (ii) to assess the therapeutic efficacy of chloroquine for uncomplicated quartan malaria. Our findings confirm that P. malariae is the third leading cause of malaria, accounting for 1.1% of all malarial infections. They also demonstrate that chloroquine-currently recommended for the home management of presumed malaria in children under the age of five years and commonly used by adults-remains highly effective in patients with uncomplicated P. malariae infection.

UNUSUAL PATTERN OF PLASMODIUM FALCIPARUM DRUG RESISTANCE IN THE NORTHWESTERN PERUVIAN AMAZON REGION

High levels of Plasmodium falciparum resistance to both chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) have been documented throughout the Amazon Basin of South America. Because of reports about the persistent efficacy of both of these drugs in the northwestern Peruvian Amazon region, we carried out an evaluation of the therapeutic efficacy of chloroquine (25 mg/kg) and SP (25 mg/kg of the sulfadoxine component) for the treatment of uncomplicated P. falciparum infections at two sites: Ullpayacu and Pampa Hermoza/Alianza. A total of 111 patients were enrolled. Only 5 (14.3%) of the 35 patients who received CQ had an adequate clinical and parasitologic response (ACPR). Six subjects (17%) had early treatment failure, 1 (2.9%) had late clinical failure, and 23 (65.7%) had late parasitologic failure (LPF). Of the subjects treated with SP, 92.3% had ACPR and 7.7% had LPF. Based on these findings, it is clear that there are at least limited areas within the Peruvian Amazon region where P. falciparum strains continue to be sensitive to SP.

Therapeutic efficacy of sulphadoxine-pyrimethamine and chloroquine for the treatment of uncomplicated malaria in pregnancy in Burkina Faso.

BackgroundA reduction in the therapeutic efficacy of chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) has recently been observed in Burkina Faso. As these two drugs are used in pregnancy, their efficacy in pregnant women was studied to directly assess the level of drug resistance in this specific population, rather than to extrapolate results of studies conducted in children < 5 years of age.MethodsDuring the malaria transmission season of 2003 in Ouagadougou, the clinical efficacy of SP and CQ, using the WHO 28-day protocol, was assessed in primigravidae and secundigravidae presenting with uncomplicated malaria.ResultsPCR-corrected results by day 28 showed that among 62 women treated with SP, eight (12.9%) experienced late parasitological failure, but no clinical failures. Among 60 women treated with CQ, the overall failure rate was 46.7% including 1.7% early treatment failures, 5% late clinical failures and 40% late parasitological failures. SP induced a haemoglobin gain of 0.3 g/dL by day 14 and 0.9 g/dL by day 28. Treatment responses were independent of gravidity, gestational age and prior antenatal care visits.ConclusionWhile CQ should no longer be used, the efficacy of SP is still compatible with use for intermittent preventive treatment (IPT) in pregnancy. However, given the possible spread of resistance, the drug should be restricted in its use.