vitamin-b-12 and Malaria--Falciparum

We have explored the possibility of using organometallic derivatives of cobalamin as a scaffold for the delivery of the same antimalarial drug to both erythro- and hepatocytes. This hybrid molecule approach, intended as a possible tool for the development of multi-stage antimalarial agents, pivots on the preparation of azide-functionalized drugs which, after coupling to the vitamin, are released with a 4-(4-ethynylphenyl)-triazole functionality. Three chloroquine and one imidazolopiperazine derivative (based on the KAF156 structure) were selected as model drugs. One hybrid chloroquine conjugate was extensively studied via fluorescent labelling for in vitro and in vivo bio-distribution studies and gave proof-of-concept for the design. It showed no toxicity in vivo (zebrafish model) as well as no hepatotoxicity, no cardiotoxicity or developmental toxicity of the embryos. All 4-(4-ethynylphenyl)-triazole derivatives of chloroquine were equally active against chloroquine-resistant (CQR) and chloroquine-sensitive (CQS)

Topics: Antimalarials; Chloroquine; Drug Resistance; Humans; Malaria, Falciparum; Molecular Structure; Organometallic Compounds; Plasmodium falciparum; Triazoles; Vitamin B 12

Elevated blood lead levels (BLL) and malaria carry an important burden of disease in West Africa. Both diseases might cause anemia and they might entail long-term consequences for the development and the health status of the child. Albeit the significant impact of malaria on lead levels described in Nigeria, no evaluation of the effect of elevated BLL on malaria risk has been investigated so far.. Between 2010 and 2012, blood lead levels of 203 Beninese infants from Allada, a semi-rural area 50km North from Cotonou, were assessed at 12 months of age. To assess lead levels, blood samples were analyzed by mass spectrometry. In parallel, clinical, microbiological and hematological data were collected. More precisely, hemoglobin, serum ferritin, CRP, vitamin B12, folate levels, and Plasmodium falciparum parasitemia were assessed and stool samples were also analyzed.. At 12 months, the mean BLL of infants was 7.41 μg/dL (CI: 65.2; 83), and 128 infants (63%) had elevated blood lead levels, defined by the CDC as BLL>5 μg/dL. Lead poisoning, defined as BLL>10 μg/dL, was found in 39 infants (19%). Twenty-five infants (12.5%) had a positive blood smear at 12 months and 144 infants were anemic (71%, hemoglobin<110 g/L). Elevated blood lead levels were significantly associated with reduced risk of a positive blood smear (AOR = 0.38, P-value = 0.048) and P. falciparum parasite density (beta-estimate = -1.42, P-value = 0.03) in logistic and negative binomial regression multivariate models, respectively, adjusted on clinical and environmental indicators.. Our study shows for the first time that BLL are negatively associated with malarial risk considering other risk factors. Malaria is one of the main causes of morbidity and mortality in infants under 5 years worldwide, and lead poisoning is the 6th most important contributor to the global burden of diseases measured in disability adjusted life years (DALYs) according to the Institute of Health Metrics. In conclusion, due to the high prevalence of elevated BLL, health interventions should look forward to minimize the exposure to lead to better protect the population in West Africa.

Topics: Anemia; Benin; C-Reactive Protein; Cross-Sectional Studies; Feces; Female; Ferritins; Folic Acid; Hemoglobins; Humans; Infant; Lead Poisoning; Malaria, Falciparum; Male; Mass Spectrometry; Multivariate Analysis; Plasmodium falciparum; Risk Factors; Rural Population; Vitamin B 12

Anemia is a common complication in malarial infection. Direct destruction and ineffective erythropoesis does not adequately explain the cause of anemia in malaria. We present a case with refractory megaloblastic anemia with asymptomatic falciparum malaria. We hypothesize that promoter variants in the inducible nitric oxide synthase gene might be the cause of severe refractory megaloblastic anemia and pancytopenia in our patient. Malaria should always be kept in mind as a cause of anemia especially in endemic areas even if the child is asymptomatic or there is no demonstrable parasite on routine smear examination.

Topics: Anemia, Megaloblastic; Antimalarials; Artemisinins; Artesunate; Child; Drug Therapy, Combination; Erythrocyte Transfusion; Fatal Outcome; Folic Acid; Humans; Malaria, Falciparum; Male; Nitric Oxide Synthase Type II; Pancytopenia; Plasmodium falciparum; Platelet Transfusion; Vitamin B 12; Vitamin B Complex

Anemia is a common complication of human malaria. Since micronutrient deficiencies are highly prevalent in malaria-endemic areas and appear to contribute to anemia etiology, we conducted a cross-sectional study in Tumaco, Colombia, to examine the associations between plasma vitamin B12 or erythrocyte folate concentrations and hemoglobin (Hb) among 96 adults with predominantly Plasmodium falciparum malaria. Prevalence of folate and vitamin B12 deficiencies was 26.0 and 26.6%, respectively. There was an inverse, linear relation between folate and Hb concentrations. Adjusted difference in Hb between lowest and highest folate quartiles was 1g/dL (p=0.04; p, test for trend=0.01). Vitamin B12 was not associated with Hb concentrations and did not modify the associations between folate and Hb. Incidentally, body mass index (BMI) was inversely associated with parasitemia and risk of clinical malaria. Future longitudinal studies are warranted to determine the potential pathophysiological role of folate in malaria-related anemia.

Topics: Adolescent; Adult; Anemia; Animals; Colombia; Cross-Sectional Studies; Female; Folic Acid; Hemoglobins; Humans; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Plasmodium falciparum; Vitamin B 12; Young Adult

The acquisition of resistance by malaria parasites towards existing antimalarials has necessitated the development of new chemotherapeutic agents. The effect of vitamin B(12) derivatives on the formation of beta-haematin (synthetic haemozoin) was determined under conditions similar to those in the parasitic food vacuole (using chloroquine, a known inhibitor of haemozoin formation for comparison). Adenosylcobalamin (Ado-cbl), methylcobalamin (CH(3)-cbl) and aquocobalamin (H(2)O-cbl) were approximately forty times more effective inhibitors of beta-haematin formation than chloroquine, cyanocobalamin (CN-cbl) was slightly more inhibitory than chloroquine, while dicyanocobinamide had no effect. It is proposed that the cobalamins exert their inhibitory effect on beta-haematin formation by pi-interactions of their corrin ring with the Fe(III)-protoporphyrin ring and by hydrogen-bonding using their 5,6-dimethylbenzimidazole/ribose/sugar side-chain. The antimalarial activity for the cobalamins (Ado-cbl>CH(3)-cbl>H(2)O-cbl>CN-cbl) was found to be less than that for chloroquine or quinine. Ado-cbl, CH(3)-cbl and CN-cbl do not accumulate in the parasite food vacuole by pH trapping, but H(2)O-cbl does. Unlike humans, the malaria parasite has only one enzyme that uses cobalamin as a cofactor, namely methionine synthase, which is important for growth and metabolism. Thus cobalamins in very small amounts are necessary for Plasmodium falciparum growth but in larger amounts they display antimalarial properties.

Topics: Animals; Antimalarials; Hemeproteins; Humans; Malaria, Falciparum; Plasmodium falciparum; Tetrazolium Salts; Thiazoles; Vitamin B 12

Vitamin B12 and its binding proteins were measured in the serum and urine of four patients with Plasmodium falciparum who had renal insufficiency. The results showed that these patients had elevated serum transcobalamin II (TCII) levels which decreased to the normal level after recovery from azotaemia. There were direct relationships between serum TCII levels and blood urea-nitrogen or creatinine concentrations. The clearance and urinary excretion of vitamin B12 and TCII were significantly lower in the patients' group than in normal subjects. All these findings indicated that elevated serum TCII could occur in P. falciparum patients with renal insufficiency. This is probably caused by a reduction in renal plasma flow and glomerular filtration rate (GFR), secondary to a low or ineffective blood volume. The reduced GFR, in turn, reduces the TCII-B12 that filters through the glomeruli, resulting in decreased TCII-B12 uptake by the renal tubules, and thus slows down the TCII degradation by lysosomal enzymes. The decreased TCII catabolism therefore prolongs the TCII survival in the circulation and probably stimulates TCII synthesis and secretion in a feedback mechanism.

Topics: Acute Kidney Injury; Adolescent; Adult; Blood Urea Nitrogen; Humans; Malaria, Falciparum; Male; Transcobalamins; Vitamin B 12