Doses Of Amodiaquine Research Articles

Pharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria

BackgroundAccurate measurement of anti-malarial drug concentrations in therapeutic efficacy studies is essential to distinguish between inadequate drug exposure and anti-malarial drug resistance, and to inform optimal anti-malarial dosing in key target population groups.MethodsA sensitive and selective LC–MS/MS method was developed and validated for the simultaneous determination of amodiaquine and its active metabolite, desethylamodiaquine, and used to describe their pharmacokinetic parameters in Ghanaian patients with uncomplicated falciparum malaria treated with the fixed-dose combination, artesunate-amodiaquine.ResultsThe day-28 genotype-adjusted adequate clinical and parasitological response rate in 308 patients studied was > 97% by both intention-to-treat and per-protocol analysis. After excluding 64 patients with quantifiable amodiaquine concentrations pre-treatment and 17 with too few quantifiable concentrations, the pharmacokinetic analysis included 227 patients (9 infants, 127 aged 1–4 years, 91 aged ≥ 5 years). Increased median day-3 amodiaquine concentrations were associated with a lower risk of treatment failure [HR 0.87 (95% CI 0.78–0.98), p = 0.021]. Amodiaquine exposure (median AUC0-∞) was significantly higher in infants (4201 ng h/mL) and children aged 1–5 years (1994 ng h/mL) compared to older children and adults (875 ng h/mL, p = 0.001), even though infants received a lower mg/kg amodiaquine dose (median 25.3 versus 33.8 mg/kg in older patients). Desethylamodiaquine AUC0-∞ was not significantly associated with age. No significant safety concerns were identified.ConclusionsEfficacy of artesunate-amodiaquine at currently recommended dosage regimens was high across all age groups. Reassuringly, amodiaquine and desethylamodiaquine exposure was not reduced in underweight-for-age young children or those with high parasitaemia, two of the most vulnerable target populations. A larger pharmacokinetic study with close monitoring of safety, including full blood counts and liver function tests, is needed to confirm the higher amodiaquine exposure in infants, understand any safety implications and assess whether dose optimization in this vulnerable, understudied population is needed.

Influence of MAMA decoction, an Herbal Antimalarial, on the Pharmacokinetics of Amodiaquine in Mice.

MAMA decoction (MD) is an antimalarial product prepared from the leaves of Mangifera indica L. (Anacardiaceae), Alstonia boonei De Wild (Apocynaceae), Morinda lucida Benth (Rubiaceae) and Azadirachta indica A. Juss (Meliaceae). A previous report showed that MD enhanced the efficacy of amodiaquine (AQ) in malaria-infected mice, thus suggesting a herb-drug interaction. The present study hence evaluated the effect of MD on the disposition of AQ in mice with a view to investigating a possible pharmacokinetic interaction. In a 3-period study design, three groups of mice (n = 72) were administered oral doses of AQ (10mg/kg/day) alone, concurrently with MD (120mg/kg/day), and in the 3rd period, mice were given AQ after a 3-day pre-treatment with MD. Blood samples were collected between 0 and 96h for quantification of AQ and its major metabolite, desethylamodiaquine, by a validated high-performance liquid chromatography method. Maximum concentrations of AQ increased by 12% with the concurrent dosing of MD and by 85% in the group of mice pre-treated with MD. The exposure and half-life of desethylamodiaquine increased by approximately 11% and 21%, respectively, with concurrent administration. Corresponding increases of approximately 20% and 33% of desethylamodiaquine were also observed in mice pre-treated with MD. MD influenced the pharmacokinetics of AQ and desethylamodiaquine, its major metabolite. The increase in the half-life and systemic exposure of AQ following its co-administration with MD may provide a basis for the enhanced pharmacological effect of the combination in an earlier study in Plasmodium-infected mice.

Adherence to intermittent preventive treatment for malaria in Papua New Guinean infants: A pharmacological study alongside the randomized controlled trial.

BackgroundThe intermittent preventive treatment in infants (IPTi) trial that took place in Papua New Guinea showed an overall reduction of 29% of the risk of malaria when delivering single-dose sulfadoxine-pyrimethamine (SP) associated to 3 days of amodiaquine (AQ) every three months to children during the first year of life. The aim of the present study was to assess if the last two doses of AQ were truly administered as prescribed by the parents at home based on drug level measurement and PK modelling, which is a good proxy of medication adherence. It provides also important information to discuss the efficacy of the intervention and on feasibility of self-administered preventive malaria treatment.Methods and findingsDuring the three-arm randomized double-blinded IPTi trial, each child was prescribed one dose of SP (day 0) and 3 doses of either AQ or artesunate (AS) at day 0, 1 & 2 adjusted to weight or placebo. Treatments were given at 3, 6, 9 and 12 months of age. The first day of treatment was delivered by nursing staff (initiation under directly observed treatment (DOT)) and the two last doses of AQ or AS by parents at home without supervision. For this cross-sectional study, 206 consecutive children already involved in the IPTi trial were enrolled over a 2-month period. At the time of the survey, allocation of the children to one of the three arms was not known. Blood samples for drug level measurement were collected from finger pricks one day after the planned last third dose intake. Only children allocated to the SP-AQ arm were included in the present analysis. Indeed, the half-life of AS is too short to assess if drugs were given on not. Because of the short half-life of AQ, desethyl-AQ (metabolite of AQ (DAQ)) measurements were used to investigate AQ medication adherence. Two PK (PK) models from previously published studies in paediatric populations were applied to the dataset using non-linear mixed effect modelling (NONMEM) to estimate the number of doses really given by the parents. The study nurse reported the administration time for the first AQ dose while it was estimated by the parents for the remaining two doses. Out of 206 children, 64 were in the SP-AQ arm. The adjusted dosing history for each individual was identified as the one with the lowest difference between observed and individual predicted concentrations estimated by the two PK models for all the possible adherence schemes. The median (range) blood concentration AQ in AQ arm was 9.3 ng/mL (0–1427.8 ng/mL), (Quartiles 1–3: 2.4 ng/mL -22.2 ng/mL). The median (range) for DAQ was 162.0 ng/mL (0–712 ng/mL), (Quartiles 1–3: 80.4 ng/mL-267.7 ng/mL). Under the assumption of full adherence for all participants, a marked underprediction of concentrations was observed using both PK models. Our results suggest that only 39–50% of children received the three scheduled doses of AQ as prescribed, 33–37% two doses and 17–24% received only the first dose administered by the study nurse. Both models were highly congruent to classify adherence patterns.ConclusionsConsidering the IPTi intervention, our results seem to indicate that medication adherence is low in the ideal trial research setting and is likely to be even lower if given in day-to-day practice, questioning the real impact that this intervention might have. More generally, the estimation of the number of doses truly administered, a proxy measure of adherence and an assessment of the feasibility of the mode of administration, should be more thoroughly studied when discussing the efficacy of the interventions in trials investigating self-administered malaria preventive treatments.

Bidirectional Pharmacokinetic Interaction Between Amodiaquine and Pioglitazone in Healthy Subjects.

Amodiaquine (AQ) and pioglitazone (PGZ) are both metabolized by CYP2C8, an enzyme also inhibited by PGZ. These drugs are likely to be administered in instances of comorbidity of malaria with type 2 diabetes. This study, hence, evaluated the possibility of a drug interaction resulting from the concurrent use of both drugs. A 3-period crossover design in 10 healthy subjects, that assessed the disposition of AQ and PGZ alone and when coadministered, was implemented with the administration of single oral doses of AQ and PGZ. Whole-blood samples collected between 0 and 24hours on protein saver cards across the study periods were processed and analyzed for AQ and PGZ contents. Pharmacokinetic parameters were derived by a noncompartmental analysis. Geometric mean ratios for the Cmax , area under the concentration-time curve for 24 hours (AUC0-24h ), and AUC0-∞ , alongside their corresponding 90%CIs, were compared across the study periods to infer clinically significant changes in disposition. The coadministration of AQ and PGZ resulted in decreases of about 38% and 54% in the Cmax and AUC0-24h of AQ, respectively. For PGZ, the Cmax increased by about 50%, and AUC0-24 rose by 48%. The 90%CIs of geometric mean ratios for the Cmax , AUC0-24h , and AUC0-∞ were all outside the expected bioequivalence interval of 80% to 125% for both drugs, implying significant interactions. These findings suggest that a bidirectional interaction between AQ and PGZ, with likely implications for the therapy and toxicity of both drugs, may occur in the event of their coadministration.

Effect of Seasonal Malaria Chemoprevention (SMC) with SulfadoxinePyrimethamine (SP) and Amodiaquine (AQ) on the Acquisition of antiAMA1 and anti-MSP1_42 Antibodies among Children under 10 Years Living in the Southern part of Senegal (Velingara)

Background: In developing countries, malaria is still a leading cause of morbidity and mortality and children are the most affected individuals. In order to strengthen malaria control, new intervention such as Seasonal Malaria Chemoprevention (SMC) has been developed. This strategy is very effective in preventing malaria clinical episodes but its effect on children’s immunity is not well documented. This study aimed to evaluate the effects of SMC on the acquisition of anti-AMA1 and anti-MSP1_42 antibodies among children fewer than 10 years living in the southern part of Senegal (Velingara). Patients and methods: The study was nested in a cluster randomized trial assessing the impact of SMC with a single dose of Sulfadoxine-Pyrimethamine (SP) and 3 doses of Amodiaquine (AQ). Two cross-sectional surveys were carried out (October 2010) and (September 2011) to assess the effect of SMC on children’s immunity. Thick and thin blood smears were performed to assess malaria parasiteamia prevalence. Blood was collected on filter paper for serological measurement by ELISA to measure IgG anti-MSP1_42 and anti-AMA1. Logistic regression analysis was performed to assess factors associated with the production of antibodies. Results: A total number of 1611 children under 10 years old were included in two surveys (866 children in 2010 and 745 children in 2011). Malaria prevalence was 10.39% at baseline (2010) and 5.03% one year after intervention (2011). The seroprevalence of anti-MSP1_42 anti-AMA1 antibodies was higher in 2010 compared to 2011 providing a significant reduction of IgG production at 11.4 AU (95%CI ⦋8.3-14.4⦌) for MSP1_42 and 7.2 AU (95%CI ⦋4.5-9.9⦌) for AMA1. Seroprevalence increased with age and Plasmodium falciparum carriage while it decreased according to the area and study period. Conclusion: SMC is an effective strategy for malaria prevention in children under 10 years. The strategy can as well induce a decrease of IgG anti-AMA1 and anti-MSP1_42 which are protective against malaria. Consequently, this strategy needs to be renewed each year in areas where malaria is highly seasonal to avoid a resurgence of malaria, while promoting the use of other antimalarial interventions.

Impact of combining intermittent preventive treatment with home management of malaria in children less than 10 years in a rural area of Senegal: a cluster randomized trial

BackgroundCurrent malaria control strategies recommend (i) early case detection using rapid diagnostic tests (RDT) and treatment with artemisinin combination therapy (ACT), (ii) pre-referral rectal artesunate, (iii) intermittent preventive treatment and (iv) impregnated bed nets. However, these individual malaria control interventions provide only partial protection in most epidemiological situations. Therefore, there is a need to investigate the potential benefits of integrating several malaria interventions to reduce malaria prevalence and morbidity.MethodsA randomized controlled trial was carried out to assess the impact of combining seasonal intermittent preventive treatment in children (IPTc) with home-based management of malaria (HMM) by community health workers (CHWs) in Senegal. Eight CHWs in eight villages covered by the Bonconto health post, (South Eastern part of Senegal) were trained to diagnose malaria using RDT, provide prompt treatment with artemether-lumefantrine for uncomplicated malaria cases and pre-referral rectal artesunate for complicated malaria occurring in children under 10 years. Four CHWs were randomized to also administer monthly IPTc as single dose of sulphadoxine-pyrimethamine (SP) plus three doses of amodiaquine (AQ) in the malaria transmission season, October and November 2010. Primary end point was incidence of single episode of malaria attacks over 8 weeks of follow up. Secondary end points included prevalence of malaria parasitaemia, and prevalence of anaemia at the end of the transmission season. Primary analysis was by intention to treat. The study protocol was approved by the Senegalese National Ethical Committee (approval 0027/MSP/DS/CNRS, 18/03/2010).ResultsA total of 1,000 children were enrolled. The incidence of malaria episodes was 7.1/100 child months at risk [95% CI (3.7-13.7)] in communities with IPTc + HMM compared to 35.6/100 child months at risk [95% CI (26.7-47.4)] in communities with only HMM (aOR = 0.20; 95% CI 0.09-0.41; p = 0.04). At the end of the transmission season, malaria parasitaemia prevalence was lower in communities with IPTc + HMM (2.05% versus 4.6% p = 0.03). Adjusted for age groups, sex, Plasmodium falciparum carriage and prevalence of malnutrition, IPTc + HMM showed a significant protective effect against anaemia (aOR = 0.59; 95% CI 0.42-0.82; p = 0.02).ConclusionCombining IPTc and HMM can provide significant additional benefit in preventing clinical episodes of malaria as well as anaemia among children in Senegal.

Two Strategies for the Delivery of IPTc in an Area of Seasonal Malaria Transmission in The Gambia: A Randomised Controlled Trial

The Expanded Programme on Immunisation (EPI) provides an effective way of delivering intermittent preventive treatment for malaria (IPT) to infants. However, it is uncertain how IPT can be delivered most effectively to older children. Therefore, we have compared two approaches to the delivery of IPT to Gambian children: distribution by village health workers (VHWs) or through reproductive and child health (RCH) trekking teams. In rural areas, RCH trekking teams provide most of the health care to children under the age of 5 years in the Infant Welfare Clinic, and provide antenatal care for pregnant women. During the 2006 malaria transmission season, the catchment populations of 26 RCH trekking clinics in The Gambia, each with 400-500 children 6 years of age and under, were randomly allocated to receive IPT from an RCH trekking team or from a VHW. Treatment with a single dose of sulfadoxine pyrimethamine (SP) plus three doses of amodiaquine (AQ) were given at monthly intervals during the malaria transmission season. Morbidity from malaria was monitored passively throughout the malaria transmission season in all children, and a random sample of study children from each cluster was examined at the end of the malaria transmission season. The primary study endpoint was the incidence of malaria. Secondary endpoints included coverage of IPTc, mean haemoglobin (Hb) concentration, and the prevalence of asexual malaria parasitaemia at the end of malaria transmission period. Financial and economic costs associated with the two delivery strategies were collected and incremental cost and effects were compared. A nested case-control study was used to estimate efficacy of IPT treatment courses. Treatment with SP plus AQ was safe and well tolerated. There were 49 cases of malaria with parasitaemia above 5,000/µl in the areas where IPT was delivered through RCH clinics and 21 cases in the areas where IPT was delivered by VHWs, (incidence rates 2.8 and 1.2 per 1,000 child months, respectively, rate difference 1.6 [95% confidence interval (CI) -0.24 to 3.5]). Delivery through VHWs achieved a substantially higher coverage level of three courses of IPT than delivery by RCH trekking teams (74% versus 48%, a difference of 27% [95% CI 16%-38%]). For both methods of delivery, coverage was unrelated to indices of wealth, with similar coverage being achieved in the poorest and wealthiest groups. The prevalence of anaemia was low in both arms of the trial at the end of the transmission season. Efficacy of IPTc against malaria during the month after each treatment course was 87% (95% CI 54%-96%). Delivery of IPTc by VHWs was less costly in both economic and financial terms than delivery through RCH trekking teams, resulting in incremental savings of US$872 and US$1,244 respectively. The annual economic cost of delivering at least the first dose of each course of IPTc was US$3.47 and US$1.63 per child using trekking team and VHWs respectively. In this setting in The Gambia, delivery of IPTc to children 6 years of age and under by VHWs is more effective and less costly than delivery through RCH trekking clinics. ClinicalTrials.gov NCT00376155. Please see later in the article for the Editors' Summary.

A trial of intermittent preventive treatment and home-based management of malaria in a rural area of The Gambia

BackgroundIndividual malaria interventions provide only partial protection in most epidemiological situations. Thus, there is a need to investigate whether combining interventions provides added benefit in reducing mortality and morbidity from malaria. The potential benefits of combining IPT in children (IPTc) with home management of malaria (HMM) was investigated.MethodsDuring the 2008 malaria transmission season, 1,277 children under five years of age resident in villages within the rural Farafenni demographic surveillance system (DSS) in North Bank Region, The Gambia were randomized to receive monthly IPTc with a single dose of sulphadoxine/pyrimethamine (SP) plus three doses of amodiaquine (AQ) or SP and AQ placebos given by village health workers (VHWs) on three occasions during the months of September, October and November, in a double-blind trial. Children in all study villages who developed an acute febrile illness suggestive of malaria were treated by VHWs who had been taught how to manage malaria with artemether-lumefantrine (Coartem™). The primary aims of the project were to determine whether IPTc added significant benefit to HMM and whether VHWs could effectively combine the delivery of both interventions.ResultsThe incidence of clinical attacks of malaria was very low in both study groups. The incidence rate of malaria in children who received IPTc was 0.44 clinical attacks per 1,000 child months at risk while that for control children was 1.32 per 1,000 child months at risk, a protective efficacy of 66% (95% CI -23% to 96%; p = 0.35). The mean (standard deviation) haemoglobin concentration at the end of the malaria transmission season was similar in the two treatment groups: 10.2 (1.6) g/dL in the IPTc group compared to 10.3 (1.5) g/dL in the placebo group. Coverage with IPTc was high, with 94% of children receiving all three treatments during the study period.ConclusionDue to the very low incidence of malaria, no firm conclusion can be drawn on the added benefit of IPTc in preventing clinical episodes of malaria among children who had access to HMM in The Gambia. However, the study showed that VHWs can successfully combine provision of HMM with provision of IPTc.Trial RegistrationClinicalTrials.gov NCT00944840

Amodiaquine-associated adverse effects after inadvertent overdose and after a standard therapeutic dose

A case of an acute dystonic reaction in a child presumptively treated for malaria with amodiaquine, and a case of persistent asymptomatic bradycardia in another child with mild pulmonary stenosis treated with a standard dose of amodiaquine for parasitologically confirmed uncomplicated malaria, is reported. Both subjects were homozygous for the wild type allele of cytochrome P450 2C8, the main enzyme responsible for amodiaquine metabolism. In both subjects, plasma concentrations of N-desethylamodiaquine and N-bis-desethylamodiaquine, the main metabolites of amodiaquine, were normal. No other drugs were detectable in the plasma of these two subjects after further toxicological screening. These observations, which suggest altered metabolism in the subject with an acute dystonic reaction, support the assertion that amodiaquine-associated dystonia is an idiosyncratic reaction. However, the occurrence of bradycardia after a standard dose of amodiaquine, which coincided with the time of expected peak concentrations of the active metabolite of amodiaquine, suggests a direct drug effect. These less reported adverse effects are likely to increase in parallel with the increased use of amodiaquine as a partner drug for combination therapy of malaria in Ghana. Further studies aimed at elucidating the mechanisms underlying these effects are, therefore, required.

Population pharmacokinetics of artesunate and amodiaquine in African children.

BackgroundPharmacokinetic (PK) data on amodiaquine (AQ) and artesunate (AS) are limited in children, an important risk group for malaria. The aim of this study was to evaluate the PK properties of a newly developed and registered fixed dose combination (FDC) of artesunate and amodiaquine.MethodsA prospective population pharmacokinetic study of AS and AQ was conducted in children aged six months to five years. Participants were randomized to receive the new artesunate and amodiaquine FDC or the same drugs given in separate tablets. Children were divided into two groups of 70 (35 in each treatment arm) to evaluate the pharmacokinetic properties of AS and AQ, respectively. Population pharmacokinetic models for dihydroartemisinin (DHA) and desethylamodiaquine (DeAq), the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity, defined as the sum of the molar equivalent plasma concentrations of DHA and artesunate, were constructed using the non-linear mixed effects approach. Relative bioavailability between products was compared by estimating the ratios (and 95% CI) between the areas under the plasma concentration-time curves (AUC).ResultsThe two regimens had similar PK properties in young children with acute malaria. The ratio of loose formulation to fixed co-formulation AUCs, was estimated as 1.043 (95% CI: 0.956 to 1.138) for DeAq. For DHA and total anti-malarial activity AUCs were estimated to be the same. Artesunate was rapidly absorbed, hydrolysed to DHA, and eliminated. Plasma concentrations were significantly higher following the first dose, when patients were acutely ill, than after subsequent doses when patients were usually afebrile and clinically improved. Amodiaquine was converted rapidly to DeAq, which was then eliminated with an estimated median (range) elimination half-life of 9 (7 to 12) days. Efficacy was similar in the two treatments groups, with cure rates of 0.946 (95% CI: 0.840–0.982) in the AS+AQ group and 0.892 (95% CI: 0.787 – 0.947) in the AS/AQ group. Four out of five patients with PCR confirmed recrudescences received AQ doses < 10 mg/kg. Both regimens were well tolerated. No child developed severe, post treatment neutropaenia (<1,000/μL). There was no evidence of AQ dose related hepatotoxicity, but one patient developed an asymptomatic rise in liver enzymes that was resolving by Day-28.ConclusionThe bioavailability of the co-formulated AS-AQ FDC was similar to that of the separate tablets for desethylamodiaquine, DHA and the total anti-malarial activity. These data support the use this new AS-AQ FDC in children with acute uncomplicated falciparum malaria.

The Effect Of Amodiaquine On The Histomorphology Of The Spleen Of Wistar Rats

This study was to ascertain the effect of the administration of amodiaquine (AQ) on the histomorphology of the spleen of Wistar rats. Twenty adult Wistar rats weighing between 150-180g were divided into four groups (A, B, C and D) of eight animals each. Group A served as the control and the animals received distilled water, while groups B, C and D were the experimental groups. The drug was administered as 17.50mg/kg, 8.75mg/kg and 8.75mg/kg for groups B, C and D respectively. The administration lasted three days for groups B and C, while group D administration lasted six days. Histomorphological sections showed increased size of the white pulp, hypertrophied and hyperplastic red pulp parenchymal cells in group C, while groups B and D showed decreased white pulp sizes, and hypertrophied red pulp parenchymal cells. This is an indication of lymphocyte destruction. Thus, these results suggest that over-dose and chronic doses of AQ is detrimental to the spleen, therefore excess dosage should not be taken especially as a prophylactic. The study was carried out in the Laboratory of Anatomy Department, Faculty of Basic Medical Sciences University of Calabar, Calabar-Nigeria

Different doses of amodiaquine and chloroquine for treatment of uncomplicated malaria in children in Guinea-Bissau: implications for future treatment recommendations

The aim of the present study was to compare different doses of chloroquine (CQ) and amodiaquine (AQ) for the treatment of falciparum malaria in children. Children with Plasmodium falciparum monoinfection were allocated by block randomisation to treatment with CQ 50/kg mg or 25 mg/kg or AQ 15 mg/kg or 30 mg/kg. The main outcomes were the cumulative adequate clinical and parasitological response (ACPR) rates and the number of true recrudescences as determined by PCR. A total of 729 children were included. In an evaluability analysis, the PCR-uncorrected cumulative ACPR rates on Day 28 for the treatment groups CQ 50/kg mg or 25 mg/kg and AQ 15 mg/kg or 30 mg/kg were 90%, 76%, 92% and 94%, respectively; the PCR-adjusted ACPR rates on Day 28 were 92%, 80%, 94% and 94%, respectively. No differences in adverse effects were observed. AQ has a high cure rate given as 30 mg/kg and 15 mg/kg, although it is not superior to treatment with CQ 50 mg/kg. However, 25 mg/kg of CQ is less efficient. As an interim option, Guinea-Bissau could change the recommended first-line treatment of uncomplicated malaria to CQ 50 mg/kg, reserving AQ as a partner drug for a future combination therapy.

Eficacia de amodiaquina y sulfadoxina/pirimetamina en el tratamiento de malaria no complicada por Plasmodium falciparum en Nariño, Colombia, 1999-2002.

The resurgence and spread of antimalarial drug resistance is one of the causes of the worldwide increase of malaria. In Colombia, uncomplicated Plasmodium falciparum malaria has been treated with a combination of amodiaquine (AQ) and sulfadoxine/pyrimethamine (SP) since 2000. The efficacy of these two antimalarials was evaluated after the implementation of the new malaria treatment scheme. In the municipalities of El Charco and Tumaco (Nariño) on the Pacific Coast region, the standard PAHO protocol was used to evaluate antimalarial efficacy in areas of low to moderate malaria transmission. Patients were randomly allocated to treatment regime in two cities of Nariño, El Charco (n = 48) and Tumaco (n = 50). After 14 days none of El Charco patients presented therapeutic failure to either antimalarial. However, in Tumaco after 28 days, 12 of 24 (95% CI: 30.6-69.4) patients presented AQ treatment failure while 4 of 26 (95% CI: 5.1-33.1) patients had SP treatment failure. The high level of AQ treatment failure in Tumaco was unexpected because it had been introduced only recently as an antimalarial treatment in Colombia. The results suggest that the use of the current dose of AQ in combination with SP will be therapeutically useful for less time than expected. Use of combined therapies is a key strategy to delay antimalarial resistance. Unfortunately, its success depends on the efficacy of antimalarial drugs individually.

Immunogenicity of Amodiaquine in the Rat

Amodiaquine is an antimalarial drug that has been associated with adverse reactions which may be immune mediated. Specific IgG anti-amodiaquine antibodies were detected after administration of the drug to rats (269 mumols/kg for 4 days), using an enzyme-linked immunosorbent assay employing amodiaquine conjugated to metallothionein as an antigen. A positive immune response was observed regardless of the route of administration, but the magnitude of the response in terms of antibody titre was in the order intraperitoneal administration greater than intramuscular administration greater than oral administration. Hapten inhibition experiments with structurally related drugs defined the specificity of the antibody which appears to recognize a conjugate of amodiaquine quinone imine and cysteine residues present in protein. Amodiaquine was converted to a protein-reactive species by activated human polymorphonuclear leucocytes in vitro, and this may provide a mechanism for immunogen formation in vivo. A humoral immune response was observed with doses of amodiaquine that did not produce either direct hepatotoxicity or leucopenia. Thus an animal model has been developed with which to investigate the toxicological consequences of amodiaquine immunogenicity.

Effect of amodiaquine on gastric histamine methyltransferase and on histamine-stimulated gastric secretion.

1 Amodiaquine was found to be a potent inhibitor in vitro of gastric histamine methyltransferase from human and canine corpus and from pig antrum. The ID50 for the enzyme, purified from pig antrum mucosa by ultracentrifugation and chromatography on DEAE-cellulose, was 2.5 muM. 2 In six dogs with Heidenhanin pouches the maximum secretory response to histamine (40 mug/kg i.m.) was augmented by i.m. injection of amodiaquine. The augmentation depended on the dose of amodiaquine, the optimum effect (40% increase in volume of gastric juice, 80% in acid output) being achieved with 2 mg/kg. The maximum secretory response to betazole was also enhanced by amodiaquine. 3 It was suggested that amodiaquine may enhance the histamine and betazole stimulated gastric secretion by an inhibition of gastric histamine methyltransferase in vivo.