ascorbic-acid and Malaria

Indoloquinoline (IQ) is an important class of naturally occurring antimalarial alkaloids, mainly represented by cryptolepine, isocryptolepine, and neocryptolepine. The IQ structural framework consists of four isomeric ring systems differing via the linkage of indole with quinoline as [3,2-b], [3,2-c], [2,3-c], and [2,3-b]. Structurally, IQs are planar and thus they bind strongly to the DNA which largely contributes to their biological properties. The structural rigidity and associated nonspecific cellular toxicity is a key shortcoming of the IQ structural framework for preclinical development. Thus, the lead optimization efforts were aimed at improving the therapeutic window and ADME properties of IQs. The structural modifications mainly involved attaching the basic aminoalkyl chains that positively modulates the vital physicochemical and topological parameters, thereby improves biological activity. Our analysis has found that the aminoalkylation consistently improved the selectivity index and provided acceptable in-vivo antimalarial/anticancer activity. Herein, we critically review the role of aminoalkylation in deciphering the antimalarial and cytotoxic activity of IQs.

Topics: Alkaloids; Antimalarials; Antineoplastic Agents; Cell Proliferation; Indoles; Malaria; Molecular Structure; Neoplasms; Quinolines

Oxidative damage is one of the most important pathological consequences of malarial infections. It affects vital organs of the body manifesting in changes such as splenomegaly, hepatomegaly, endothelial and cognitive damages. The currently used antimalarials often leave traces of these damages after therapy, as evident in memory impairment after cerebral malaria. Hence, some research investigations have focused attention on the use of antioxidants, alone or in combination with antimalarials, as a viable therapeutic strategy aimed at alleviating plasmodium-induced oxidative stress and its associated complications. However, the practical application of this approach often yields conflicting outcomes because some antimalarials specifically act via induction of oxidative stress. This article critically reviews most of the studies conducted on the potential role of antioxidant therapy in malarial infections. The most frequently investigated antioxidants are vitamins C and E, N-acetylcystein, folate and desferroxamine. Some of the investigations measured the effects of direct administration of the antioxidants on the plasmodium parasites while others performed an adjunctive therapy with standard antimalarials. The therapeutic application of each of the antioxidants in malaria management depends on the targeted aspect of malarial pathology. It is hoped that this article will provide an informed basis for future research activities on the therapeutic role of antioxidants on malarial pathogenesis.

Topics: Acetylcysteine; Antimalarials; Antioxidants; Ascorbic Acid; Deferoxamine; Folic Acid; Humans; Malaria; Oxidative Stress; Plasmodium; Vitamin E

Pathogenic organism can be considered as pro-oxidant agents because they produce cell death and tissue damage. In addition organism can be eliminated by specific cell defense mechanism which utilize in part, reactive oxygen radicals formed by oxidative stress responses. The cause of the necessarily defense process results in cell damage thereby leading to development of inflammation, a characteristic oxidative stress situation. This fact shows the duality of oxidative stress in infections and inflammation: oxygen free radicals protect against microorganism attack and can produce tissue damage during this protection to trigger inflammation. Iron, a transition metal which participates generating oxygen free radicals, displays also this duality in infection. We suggest also that different infectious pathologies, such as sickle cell anemia/malaria and AIDS, may display in part this duality. In addition, it should be noted that oxidative damage observed in infectious diseases is mostly due the inflammatory response than to the oxidative potential of the pathogenic agent, this last point is exemplified in cases of respiratory distress and in glomerulonephritis. This review analyzes these controversial facts of infectious pathology in relation with oxidative stress.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anemia, Sickle Cell; Animals; Antioxidants; Arachidonic Acid; Ascorbic Acid; Cells, Cultured; Child; Endotoxins; Fetus; Free Radicals; Glomerulonephritis; Humans; Infections; Inflammation; Iron; Malaria; Mice; Oxidative Stress; Phagocytosis; Rabbits; Respiratory Distress Syndrome; Sheep

This paper presents several mechanisms/pathways by which oxidative stress could cause damage to the parasites. During developmental stages of plasmodia profound alterations of the structure and function of host erythrocytes take place, in order to support the development and/or survival of the parasite. In addition an oxidant stress is also induced by the parasite. There is also an increased production of reactive oxygen species (ROS) by the parasite. This may deplete the erythrocyte of its defense mechanisms namely, superoxide dismutase (SOD), catalase, glutathione peroxidase, NADPH, NADH, glutathione (GSH) and glutathione reductase etc. Thus oxidative stress may be exerted by the growing parasite in red blood cells which are highly sensitive to such a challenge. These enhanced alterations may result in a retarded development of the parasite. Thus, the coexistence of both parasite and erythrocyte is a matter of a delicate balance. However, one cannot rule out the role of external modulations (immune pressure) inhibiting the vitality of the parasites.

Topics: Animals; Ascorbic Acid; Erythrocytes; Glutathione; Humans; Hydrogen Peroxide; Leukocytes; Malaria; Membrane Lipids; Oxidants; Oxidative Stress; Plasmodium; Superoxides

Susceptibility to oxidative stress is a well-established feature of the malarial parasite. Pharmacologists have taken advantage of this property to design highly effective pro-oxidant antimalarial drugs. Less well appreciated is the fact that nutritional manipulation of host oxidative stress status by dietary means can have a profound effect on the growth of the parasite. In particular, rapid induction of vitamin E deficiency in mice by feeding highly unsaturated fatty acids (fish oil) strongly suppresses plasmodial growth. Likewise, the status of other antioxidant nutrients (e.g., riboflavin or vitamin C) may also influence the course of malarial infection under certain conditions. A combined nutritional pharmacology approach may offer some promise in controlling malaria.

Topics: Animals; Antimalarials; Antioxidants; Artemisinins; Ascorbic Acid; Dietary Fats; Drug Interactions; Malaria; Male; Mice; Nutritional Status; Oxidation-Reduction; Plasmodium; Rats; Riboflavin; Sesquiterpenes; Vitamin E Deficiency

Nutritional anemia is a public health problem among Ghanaian schoolchildren. There is need to employ dietary modification strategies to solve this problem through school and household feeding programs.. To evaluate the effectiveness of cowpea-based food containing fish meal served with vitamin C-rich drink to improve iron stores and hemoglobin concentrations in Ghanaian schoolchildren.. The study involved cross-sectional baseline and nutrition intervention phases. There were 150 participants of age 6 to 12 years. They were randomly assigned to 3 groups, fish meal -vitamin C (n = 50), vitamin C (n = 50), and control (n = 50), and given different cowpea-based diets for a 6-month period. Height and weight measurements were done according to the standard procedures, dietary data were obtained by 24-hour recall and food frequency questionnaire, hemoglobin concentrations were determined by Hemocue Hemoglobinometer, and serum ferritin and complement-reactive protein (CRP) were determined by enzyme-linked immunosorbent assay. Participants' blood samples were examined for malaria parasitemia and stools for helminthes using Giemsa stain and Kato-Katz techniques, respectively.. Mean ferritin concentration was not significantly different among groups. End line mean or change in hemoglobin concentrations between fish meal-vitamin C group (128.4 ± 7.2/8.3 ± 10.6 g/L) and control (123.1 ± 6.6/4.2 ± 10.4 g/L) were different, P < .05. Change in prevalence of anemia in fish meal-vitamin C group (19.5%) was different compared to those of vitamin C group (9.3%) and the control (12.2%). Levels of malaria parasitemia and high CRP among study participants at baseline and end line were 58% and 80% then 55% and 79%, respectively. Level of hookworm infestation was 13%.. Cowpea-based food containing 3% fish meal and served with vitamin C-rich drink improved hemoglobin concentration and minimized the prevalence of anemia among the study participants.

Topics: Anemia, Iron-Deficiency; Animals; Ascorbic Acid; Beverages; C-Reactive Protein; Child; Cross-Sectional Studies; Female; Ferritins; Fishes; Food, Fortified; Ghana; Hemoglobins; Humans; Malaria; Male; School Health Services; Surveys and Questionnaires; Treatment Outcome; Vegetables

The effect of a combined supplement of iron, thiamine, riboflavin and vitamin C on malarial incidence in 5 to 14-year-old children was tested in a malnourished rural community in a region of The Gambia noted for high prevalence of malaria during the rainy season. 190 children, divided into 2 matched groups, received either the supplement or a matching placebo for 3 months. No significant difference in malarial incidence was observed between the 2 groups, despite a major improvement in biochemical indices of nutrient status in the supplemented group, especially for riboflavin and vitamin C. Severity of episodes was also similar between groups, but in subjects who developed parasitaemias there was a trend towards higher parasite counts in those receiving the active supplement. Nutritional interventions in malarious areas may have adverse effects on malaria, and the increase in parasitaemia was compatible with the hypothesis that a small but significant reduction in defences had occurred. However, the absence of increases in the incidence of proven malaria cases and their severity must also be taken into account, in order to make a balanced assessment of the possible increase in risk. Further investigations are needed to measure the risk in benefit rates, and to consider the effects of individual nutrients in isolation.

Topics: Adolescent; Ascorbic Acid; Child; Child, Preschool; Erythrocyte Indices; Female; Ferrous Compounds; Gambia; Humans; Malaria; Male; Nutritional Status; Riboflavin; Rural Population; Thiamine

This study investigated the effects of co-administration of a commercial juice rich in vitamin C (Vit C) on the antimalarial efficacy of artemether-lumefantrine (AL) in Plasmodium berghei-infected mice. Fifty Balb/c mice were infected with Plasmodium berghei NK65 strain from a donor mouse. Parasitemia was established after 72 h. Animals were grouped into 6 (n = 10) and treated daily for 3 days with normal saline, chloroquine, artemether-lumefantrine (AL), AL plus 50% commercial juice (CJ), and AL plus 50% Vit C supplementation in drinks ad libitum, respectively. Body weight, parasitemia levels, and mean survival time were determined. Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), nitrite, malondialdehyde, reduced glutathione (GSH), catalase, and superoxide dismutase (SOD) were determined in the serum and liver tissues. Spleen histopathological changes were determined by H&E staining. Parasitemia was cleared by administration of AL and was not affected by Vit C and CJ supplementation. Vit C significantly prevented body weight reduction in AL-treated mice. CJ and Vit C supplementation to AL-treated mice significantly improved survival proportion compared with AL alone animals. Vit C and CJ supplementation significantly improved reduction of TNF-α, IL-6, and malondialdehyde, and increased GSH, CAT, and SOD in AL-treated mice. Spleen cell degeneration and presence of malaria pigment were reduced in AL-treated animals. The results suggest that ad libitum co-administration of commercial juice and vitamin C with artemether-lumefantrine does not impair its antimalarial efficacy but rather improved antioxidant and anti-inflammatory effects in mice.

Topics: Animals; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Ascorbic Acid; Interleukin-6; Malaria; Malondialdehyde; Mice; Parasitemia; Plasmodium berghei; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Vitamin C (ascorbate) is maintained at high levels in most immune cells and can affect many aspects of the immune response. Here, we evaluated the effect of vitamin C supplementation on the immune response to Plasmodium yoelii 17XL (P. yoelii 17XL) infection in BALB/c mice. Two orally administered doses (25 mg/kg/day and 250 mg/kg/day) of vitamin C significantly reduced levels of parasitemia during the early stages of P. yoelii 17XL infection. The numbers of activated Th1 cells and macrophages in the groups receiving vitamin C supplementation were both higher than those in the untreated group. Meanwhile, vitamin C administration reduced the levels of tumor necrosis factor α secreted by splenocytes. Vitamin C also regulated the protective anti-malarial immune response by increasing the number of plasmacytoid dendritic cells, as well as the expression of dendritic cell maturation markers, such as major histocompatibility complex class II and cluster of differentiation 86. In conclusion, the doses of vitamin C (25 mg/kg/day, 250 mg/kg/day) during the early stages of malaria infection may better enhance host protective immunity, but have no dose dependence.

Topics: Animals; Antimalarials; Ascorbic Acid; Cell Differentiation; Cells, Cultured; Dendritic Cells; Dietary Supplements; Drug Dosage Calculations; Female; Humans; Immunity, Cellular; Lymphocyte Activation; Malaria; Mice; Mice, Inbred BALB C; Plasmodium yoelii; Th1 Cells

Sulphonamides and carboxamides have shown large number of pharmacological properties against different types of diseases among which is malaria. Twenty four new carboxamide derivatives bearing benzenesulphonamoyl alkanamides were synthesized and investigated for their in silico and in vitro antimalarial and antioxidant properties. The substituted benzenesulphonyl chlorides (1a-c) were treated with various amino acids (2a-h) to obtain the benzenesulphonamoyl alkanamides (3a-x) which were subsequently treated with benzoyl chloride to obtain the N-benzoylated derivatives (5a-f, i-n and q-v). Further reactions of the N-benzoylated derivatives or proline derivatives with 4-aminoacetophenone (6) using boric acid as a catalyst gave the sulphonamide carboxamide derivatives (7a-x) in excellent yields. The in vitro antimalarial studies showed that all synthesized compounds had antimalarial property. Compound 7k, 7c, 7l, 7s, and 7j had mean MIC value of 0.02, 0.03, 0.05, 0.06 and 0.08 μM respectively comparable with chloroquine 0.06 μM. Compound 7c was the most potent antioxidant agent with IC

Topics: Antimalarials; Dose-Response Relationship, Drug; Malaria; Molecular Docking Simulation; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium falciparum; Structure-Activity Relationship; Sulfonamides

In this paper, the design, synthesis and biological evaluation of a set of quinazoline-2,4,6-triamine derivatives (1-9) as trypanocidal, antileishmanial and antiplasmodial agents are explained. The compounds were rationalized basing on docking studies of the dihydrofolate reductase (DHFR from Trypanosoma cruzi, Leishmania major and Plasmodium vivax) and pteridin reductase (PTR from T. cruzi and L. major) structures. All compounds were in vitro screened against both bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and promatigotes of Leishmania mexicana (MHOM/BZ/61/M379 strain), and also for cytotoxicity using Vero cell line. Against T. cruzi, three compounds (5, 6 and 8) were the most effective showing a better activity profile than nifurtimox and benznidazole (reference drugs). Against L. mexicana, four compounds (5, 6, 8, and 9) exhibited the highest activity, even than glucantime (reference drug). In the cytotoxicity assay, protozoa were more susceptible than Vero cells. In vivo Plasmodium berghei assay (ANKA strain), the compounds 1, 5, 6 and 8 showed a more comparable activity than chloroquine and pyrimethamine (reference drugs) when they were administrated by the oral route. The antiprotozoal activity of these substances, endowed with redox properties, represented a good starting point for a medicinal chemistry program aiming for chemotherapy of Chagas' disease, leishmaniosis and malaria.

Topics: Administration, Oral; Animals; Antimalarials; Antiprotozoal Agents; Chlorocebus aethiops; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Female; Leishmania major; Malaria; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium vivax; Quinazolines; Structure-Activity Relationship; Trypanosoma cruzi; Vero Cells

Anaemia among children is a public health issue in Ghana. The Ghana School Feeding Programme (GSFP) was instituted on pilot basis in an effort to provide nutritious lunch to school children. Evidence on the nutritional status of pupils is needed to inform the expansion of GSFP. This study sought to assess anaemia among Ghanaian pupils.. This cross-sectional study involved a random sample of 143 pupils aged 6 to 12 years. Blood samples were collected and analysed for serum-ferritin (SF), C-reactive protein (CRP), haemoglobin and malaria-parasitaemia (MP). Stool samples were examined for soil-transmitted helminths. Dietary data were collected using the 24 hour-recall method on three non-consecutive days and a food frequency questionnaire. The Student's t-test was used to compare mean values between sexes. Binary logistic regression was performed to identify factors associated with anaemia. Statistical significance was set at p < 0.05.. SF and haemoglobin concentrations were 23.9 ± 15 ng/ml and 120 ± 11 g/L respectively. The prevalence of anaemia was 30.8%. More females (41.5%) than males (21.8%) had anaemia (p < 0.005). Seventy-one percent of pupils had low SF levels. MP prevalence was 67.8%. Hookworm infestation was only observed in males (18.0%). Dietary iron and vitamin C intakes were 18.98 ± 8.8 mg and 23.7 ± 6.7 mg, respectively. Child's sex, SF and MP were associated with anaemia. Males had a lower likelihood of being anaemic (OR = 0.2, CI 0.1-0.5, p = 0.002).. The study findings underscore the need for multi-pronged approaches that address both malaria control and nutrition in order to reduce anaemia among pupils.

Topics: Anemia; Ascorbic Acid; C-Reactive Protein; Child; Cross-Sectional Studies; Female; Ferritins; Ghana; Hemoglobins; Hookworm Infections; Humans; Iron, Dietary; Logistic Models; Malaria; Male; Nutritional Status; Prevalence; Sex Factors

Fifty cases of severe malaria were studied for their oxidant and antioxidant status. Severe anemia (54%) was the most common presentation followed by hyperpyrexia, cerebral malaria and jaundice. Plasma malondialdehyde, protein carbonyl, nitrite, ascorbic acid and copper levels were significantly raised in cases as compared with controls (p < 0.001). Plasma ceruloplasmin, glutathione and superoxide dismutase levels were significantly decreased in children with severe malaria (p < 0.001). Plasma zinc was increased in cases but difference is not statistically significant. Significantly decreased level of nitrites and increased value of glutathione was found in patients with hemoglobinuria and jaundice, respectively. The significantly elevated malondialdehyde and protein carbonyl levels reflect the increased oxidative stress, whereas decreased levels of glutathione and superoxide dismutase point toward utilization of the antioxidants in severe malaria. Thus, changes in oxidants and antioxidants observed suggest the production of reactive oxygen species and their possible role in pathogenesis of severe malaria.

Topics: Adolescent; Antioxidants; Ascorbic Acid; Ceruloplasmin; Child; Child, Preschool; Copper; Female; Glutathione; Glutathione Peroxidase; Humans; Infant; Malaria; Male; Malondialdehyde; Nitrites; Oxidants; Oxidative Stress; Prospective Studies; Reactive Oxygen Species; Superoxide Dismutase; Zinc

This work studied the effect of malaria infection and antimalarial drugs on oxidative stress in 259 pregnant and nonpregnant women at Ade-Oyo hospital, Ibadan, Nigeria. Oxidative stress was determined by measuring serum lipid peroxidation, ascorbic acid, and reduced glutathione (GSH) levels using spectrophotometer. The results showed that mean lipid peroxidation was significantly higher (p < 0.05) in malaria positive than malaria negative women, while GSH and ascorbic acid levels were significantly (p < 0.05) reduced. The parasite density was significantly reduced in patients who had taken antimalarial drugs relative to those without. While mean ascorbic acid and GSH levels were significantly reduced in those who had taken drugs as compared with those without drugs, the lipid peroxidation level was significantly higher in them. The increase in lipid peroxidation and decrease in GSH and ascorbic acid levels in women who were malaria positive and in those who had taken drugs is indicative of oxidative stress.

Topics: Adolescent; Adult; Antimalarials; Ascorbic Acid; Chi-Square Distribution; Female; Glutathione; Humans; Lipid Peroxidation; Malaria; Nigeria; Oxidative Stress; Pregnancy; Pregnancy Complications, Infectious

To our knowledge, the impact of a nutrition education program combined with an increase in bioavailable dietary iron to treat iron-deficiency anemia has never been studied in adolescent girls.. To evaluate the impact of an intensive dietary program for the treatment of iron-deficiency anemia in 34 intervention and 34 control boarding-school girls aged 12 to 17 years from Benin.. A quasi-experimental design consisting of 4 weeks of nutrition education combined with an increase in the content and bioavailability of dietary iron for 22 weeks was implemented in the intervention school, but not in the control school. Data were obtained from both groups from a nutrition knowledge questionnaire, 24-hour dietary recalls, anthropometric measurements, measurement of iron status indices, and screening for malarial and intestinal parasitic infections.. Nutrition knowledge scores and mean intakes of nutrients, including dietary iron, absorbable iron, and vitamin C, were significantly higher in the intervention group (p < .05) than in the control group after 26 weeks. Mean hemoglobin and serum ferritin values were also significantly higher in the intervention group than in the control group (122 vs. 112 g/L [p = .0002] and 32 vs. 19 microg/L [p = .04], respectively), whereas the prevalence of anemia (32% vs. 85% [p = .005] and iron-deficiency anemia (26% vs. 56% [p = .04]) was significantly lower in the intervention group than in the control group. No significant differences between the groups were observed in intestinal parasitic infections or malaria status postintervention.. A multidietary strategy aiming to improve available dietary iron can reduce iron-deficiency anemia in adolescent girls.

Topics: Adolescent; Anemia, Iron-Deficiency; Ascorbic Acid; Benin; Biological Availability; Child; Diet; Diet Surveys; Energy Intake; Female; Ferritins; Health Education; Health Knowledge, Attitudes, Practice; Hemoglobins; Humans; Iron; Iron, Dietary; Malaria; Micronutrients; Trace Elements; Treatment Outcome; Vitamins

Malaria remains a major cause of human morbidity and mortality worldwide. Plasmodium falciparum, the most virulent of the 4 human Plasmodium species causing malaria, is potentially life threatening, is increasing in prevalence and is becoming even more resistant to in-use drugs. In light of the growing problem of multi-drug resistance to malarial parasites, the development of new drugs or the use of a combination therapy is of primary importance. A previous report describes a remarkable synergistic antimalarial interaction between 2 structurally similar compounds, rufigallol, an anthraquinone derivative and exifone, a benzophenone derivative, in vitro. The synergistic antimalarial activity of exifone and vitamin C was also reported. To extend the same analogy to other ketones, we carried out antimalarial testing of 20 benzophenone derivatives, individually, in combination with rufigallol, and also in combination with vitamin C, in mice infected with Plasmodium berghei. Five ketones, out of 20, showed good antimalarial activity, in vivo, when tested individually. Nine ketones, out of 20, showed good antimalarial activity, in vivo, when tested in combination with rufigallol, indicating the synergism between them. However, synergism between ketones and vitamin C was not satisfactory since only 2 ketones showed good antimalarial activity when tested in combination with vitamin C.

Topics: Animals; Anthraquinones; Antimalarials; Antioxidants; Ascorbic Acid; Benzophenones; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Humans; Ketones; Malaria; Malaria, Falciparum; Mice; Parasitic Sensitivity Tests; Plasmodium berghei; Treatment Outcome

Copper/zinc superoxide dismutase (CuZnSOD) catalyses the conversion of O2.- into H2O2. Constitutive overexpression of CuZnSOD in cells and animals creates an indigenous oxidative stress that predisposes them to added insults. In this study, we used transgenic CuZnSOD (Tg-CuZnSOD) mice with elevated levels of CuZnSOD to determine whether overexpression of CuZnSOD affected the susceptibility of these mice to plasmodium infection. Acute malaria is associated with oxidative stress, mediated by redox-active iron released from the infected RBC. Two independently derived Tg-CuZnSOD lines showed higher sensitivity than control mice to infection by Plasmodium berghei (P. berghei), reflected by an earlier onset and increased rate of mortality. Nevertheless, while Tg-CuZnSOD mice were more vulnerable than control mice, the levels of parasitemia were comparable in both strains. Moreover, treatment of infected red blood cells (RBC) with oxidative stress inducers, such as ascorbate or paraquat, reduced the viability of parasites equally in both transgenic and control RBC. This further confirms that increased CuZnSOD does not support plasmodia development. The data are consistent with the possibility that the combination of increased redox-active iron and elevated H2O2 in the plasmodium-infected Tg-CuZnSOD mice, led to an enhanced Fenton's reaction-mediated HO. production, and the resulting oxidative injury renders the transgenic mice more vulnerable to parasite infection.

Topics: Animals; Ascorbic Acid; Enzyme Activation; Erythrocytes; Female; Genetic Predisposition to Disease; Humans; Hypoxanthine; Malaria; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Oxidative Stress; Plasmodium berghei; Reactive Oxygen Species; Superoxide Dismutase

It has been suggested that the host antimalarial response depends in part on phagocyte-derived oxidants and that the parasite itself exerts an oxidative stress on its erythrocytic environment. Intraerythrocytic malaria parasites are particularly susceptible to being damaged by oxidative drugs, several of which are under development as chemotherapeutic agents. Thus the antioxidant status and associated regulatory mechanisms of the blood during malaria infection are of great interest. The important antioxidant ascorbate (AH-) and isoascorbate (IAH-), an isomer that does not occur naturally in animals, were found to have similar redox properties. We therefore assessed the usefulness of IAH- as a marker for studies of AH- handling in vivo and in vitro under normal conditions and in murine malaria infection. DHIA added to whole blood from normal or Plasmodium vinckei-infected mice in vitro was rapidly taken up into blood cells and reduced to IAH-. Intracellular IAH- derived from the exogenous DHIA was released into the plasma by blood cells from malaria-infected mice but not those from normal mice. Uptake and reduction of DHIA had no effect on plasma or cellular levels of AH- under these conditions. IAH- injected i.v. into either normal or P. vinckei-infected mice was rapidly cleared in both cases and led to an increase in plasma levels of AH-; this suggested displacement of the latter from some intracellular site, presumably not associated with blood cells. DHIA administered as an intravascular bolus into either normal or malaria-infected mice was rapidly reduced. However, in contrast to the in vitro situation, the concentration of plasma IAH- derived from the injected DHIA was approximately the same in both the infected and control animals. The IAH- so formed disappeared quickly from the plasma. Intravenous injection of DHIA into malaria-infected mice caused a rapid, prolonged increase in the proportion of plasma vitamin C in the form of DHA, whereas in uninfected mice there was a transient decrease in plasma DHA followed by normalisation. The changes in plasma AH- and DHA following IV injection of a single dose of DHA closely paralleled those seen after DHIA administration. These observations indicate that: (i) blood cells from normal and malaria-infected mice take up and reduce DHIA in a similar fashion, but they have different ways of handling the resulting IAH-; (ii) cells other than blood cells are important in the reduction of plasma DHIA and DHA in vi

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Dehydroascorbic Acid; Erythrocytes; Female; Free Radicals; In Vitro Techniques; Malaria; Mice; Mice, Inbred CBA; Oxidation-Reduction; Reactive Oxygen Species; Stereoisomerism

Intraerythrocytic malaria parasites ingest the cytosol of their host cell and digest it inside their acid food vacuoles. Acidified (pH 4-5.5, 37 degrees C) human red blood cell lysates were used to simulate this process, measuring the denaturation of hemoglobin (Hb) and the release of iron, in the absence or presence of exogenous protease. Spontaneous Hb denaturation and appearance of non-heme iron were observed upon lysate acidification, its rate decreasing with increasing pH, and increasing in presence of protease. Although the pH- and proteolysis-dependent release of iron paralleled Hb denaturation, released iron accounted for only a few percent of degraded Hb. Superoxide dismutase, catalase, and various scavengers of oxidative radicals had no effect on either process, consistent with the involvement of Fe(IV) intermediates in iron release from heme. Histidine and imidazole inhibited iron release, probably by binding directly to heme. Ascorbate enhanced iron release considerably but marginally enhanced the denaturation of Hb, suggesting that redox cycling of lysate free iron accelerated further release from heme. These processes could account for the endogenous supply of iron to the malarial parasite.

Topics: Ascorbic Acid; Catalase; Cathepsin D; Cytosol; Dose-Response Relationship, Drug; Endopeptidases; Erythrocytes; Free Radical Scavengers; Hemoglobins; Hemolysis; Humans; Hydrogen-Ion Concentration; Iron; Malaria; Protease Inhibitors; Superoxide Dismutase; Time Factors

As oxidative mechanisms have been suggested to be part of the host immune reaction against malarial parasites, we investigated the redox metabolism of the antioxidant vitamin C in the blood of control and malaria-infected mice. At the peak of infection (day 6) with the malaria parasite P. vinckei, plasma levels of ascorbate (AH-) were 10.8 +/- 0.9 micrograms/ml compared to 5.7 +/- 0.7 micrograms/ml in control mice, though no significant change was observed in the plasma concentration of dehydroascorbate (DHA). The plasma redox ratio of vitamin C, [AH-]:[DHA], was 7.4 in control mice and 18.5 in infected mice on day 6 post-inoculation. The increased AH- level in plasma of P. vinckei-infected mice was not due to differences in stabilities of either AH- or DHA in plasmas from control or P. vinckei-infected mice. DHA added to plasma was lost rapidly. In contrast, when added to whole blood. DHA was rapidly taken up and reduced to AH by blood cells from both normal mice and P. vinckei-infected mice. Most of the intracellular AH- derived from the exogenously added DHA was released into the plasma by blood cells from the infected but not normal mice. The observed release of AH- into the plasma by blood cells from infected mice was not caused by a plasma factor. Depletion of leukocytes from erythrocytes had no effect on the uptake and reduction of DHA by red blood cells, but the subsequent release of intracellular AH- occurred more rapidly.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Ascorbic Acid; Dehydroascorbic Acid; Erythrocytes; Female; Leukocytes; Malaria; Mice; Mice, Inbred CBA; Oxidation-Reduction

A young women was treated with intravenous quinine and chloramphenicol for suspected severe malaria and/or typhoid fever. On the second day of quinine therapy (after 2.25 g of quinine) she suddenly developed total bilateral loss of vision. Both drugs were stopped and cyclandelate therapy was started. She showed slight improvement in vision but on referral her visual acuity was limited to seeing waving hand movement only; visual fields were constricted and colour vision was absent. Both pupils were fixed and dilated. The fundi showed macular oedema and attenuated retinal arteries. She was treated with dexamethasone, cyclandelate, vitamin B complex and vitamin C. Colour vision was completely recovered after 5 days of treatment. Full recovery of the direct light reflex occurred after 10 days. Visual acuity improved slowly over a period of one month to 6/15 vision in both eyes. At this time macular oedema and retinal arteriolar attenuation were still present but less severe. In the context of this case report the condition of quinine blindness is briefly reviewed and the management discussed.

Topics: Adult; Ascorbic Acid; Blindness; Chloramphenicol; Cyclandelate; Dexamethasone; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Malaria; Ophthalmoscopy; Quinine; Referral and Consultation; Typhoid Fever; Visual Acuity; Vitamin B Complex

Red blood cell (RBC) antioxidant defense was investigated in eight individuals with hemoglobin E (Six EE and two E-B(+) thalassemia) and compared to that in six individuals with thalassemia and ten normal subjects. Individuals with hemoglobin E had increased incubated Heinz body formation (68% +/- 18%; p less than 0.001) compared to normal and thalassemic RBC (10% +/- 2% and 11% +/- 5%, respectively). Stimulated pentose phosphate shunt activity was increased in the thalassemic and decreased in the hemoglobin E RBC as compared to normal. The 2,3-diphosphoglycerate (DPG) content of the EE RBC was increased to 5.59 +/- 0.69 mumol/ml RBC as compared to normal (4.51 +/- 0.77; p less than 0.001). In the EE RBC, there was a direct correlation between Heinz body formation and DPG content (r = 0.73). Ascorbic and dehydroascorbic acid (0.1 and 1.0 mM) were able to decrease the degree of Heinz body formation in the hemoglobin E RBC. Ascorbic acid (0.1 mM) prolonged the response of the pentose shunt. Thus impaired antioxidant defense may account for the persistence of the hemoglobin E gene in areas where malaria is endemic. Oxidant medications should be used with caution in individuals of Southeast Asian origin.

Topics: 2,3-Diphosphoglycerate; Antioxidants; Ascorbic Acid; Diphosphoglyceric Acids; Erythrocytes; Glutathione; Heinz Bodies; Hemoglobin A; Hemoglobin E; Hemoglobins, Abnormal; Humans; Malaria; Pentose Phosphate Pathway; Thalassemia

The in vitro growth of Plasmodium falciparum in red cells containing haemoglobin E (HbE) was studied at oxygen concentration of 5 to 20%, with and without antioxidants. Under all conditions, parasite growth decreased as the concentration of HbE increased as compared with growth in red cells containing only HbA. The decreases were proportionately greatest at the highest oxygen concentration. The antioxidant vitamin C partially reversed the decreases in growth observed in HbE-containing cells at 20% oxygen. South-east Asian refugees with HbAE or HbEE had high antimalarial IFA titres, indicative of exposure to malaria more frequently than did refugees with HbAA. The decreased growth of P. falciparum in HbE-containing red cells may reduce the severity of malaria infections, conferring a survival advantage and thus increasing the numbers of individuals with HbE in local areas of South-east Asia with high incidences of malaria.

Topics: Antibodies; Ascorbic Acid; Erythrocytes; Hemoglobin E; Hemoglobins, Abnormal; Humans; Malaria; Oxygen; Plasmodium falciparum

The possible mechanisms underlying the acquisition of an increased ascorbic acid content by mouse erythrocytes containing the malarial parasite Plasmodium vinckei were investigated. Ascorbic acid was taken up readily by parasitized red blood cells but not by controls, whilst its partly oxidized form, dehydroascorbic acid, entered both. The uptake of both ascorbic acid and dehydroascorbic acid into erythrocytes was increased as a result of malarial infection. Lysates prepared from parasitized red blood cells reduced exogenous dehydroascorbic acid to ascorbic acid at a higher rate than control red blood cell lysates; this difference was abolished following dialysis of the lysates, a process which removes endogenous reduced glutathione (GSH). The rates of chemical and enzymatic reduction of dehydroascorbic acid to ascorbic acid by GSH were of similar magnitude, thus calling into question the existence of a specific dehydroascorbate reductase in erythrocytes and parasites. These observations suggest that the increased uptake of dehydroascorbic acid into parasitized red blood cells may be a result of enhanced dehydroascorbate-reducing capacity, whilst the presence of the parasite induces a selective increase in the permeability of the erythrocyte plasma membrane to ascorbic acid. The endogenous ascorbic acid content of livers obtained from infected mice was 55% below the normal concentration and its relative rate of destruction during incubation in vitro was enhanced in comparison with that of control livers. Furthermore, the capacity of liver homogenates to synthesize ascorbic acid from glucuronic acid was greatly reduced in infected mice. Therefore it is unlikely that the increase in ascorbic acid content of parasitized red blood cells is a consequence of increased biosynthesis and release of ascorbic acid by the host liver. We have not been able to exclude the possibility that the malarial parasite itself may be capable of de novo synthesis of ascorbic acid.

Topics: Animals; Ascorbic Acid; Carbon Radioisotopes; Erythrocytes; Kinetics; Liver; Malaria; Male; Mice; Mice, Inbred CBA; Organ Size; Plasmodium

The late stage of infection of mice with the malarial parasite Plasmodium vinckei was accompanied by significant changes in the content of most antioxidants within plasma. The plasma concentrations of uric acid and vitamin C increased, in contrast to those of vitamin E and total plasma proteins, whilst the activity of superoxide dismutase did not change significantly. In contrast to the situation within erythrocytes, the ratio of partly oxidized forms of vitamin C (dehydroascorbate and diketogulonic acid) to reduced ascorbic acid failed to decrease as a result of malarial infection. These results are consistent with earlier findings and add to the idea that malarial infection may result in oxidative tissue damage.

Topics: Animals; Antioxidants; Ascorbic Acid; Dehydroascorbic Acid; Malaria; Male; Mice; Mice, Inbred CBA; Superoxide Dismutase; Uric Acid; Vitamin E

Erythrocytes isolated from mice at a late stage of infection with the malarial parasite Plasmodium vinckei contained increased levels of vitamin E, but neither control nor infected erythrocytes contained detectable levels of alpha-tocopherolquinone, an oxidation product of vitamin E. Total levels of the antioxidant, vitamin C, were more than doubled in the same populations of highly parasitized erythrocytes. These observations, and the lower ratio of oxidized to reduced forms of ascorbic acid in parasitized compared to nonparasitized erythrocytes, raise the possibility that increased redox-cycling between the two vitamins may account for the failure to detect alpha-tocopherolquinone. Thus, late in infection of mice with the lethal parasite P. vinckei, the content and redox state of erythrocytic ascorbic acid is altered so that it protects vitamin E, and presumably the parasitized red cell and its contents, from oxidative damage.

Topics: Animals; Ascorbic Acid; Chromatography, High Pressure Liquid; Erythrocytes; Kinetics; Malaria; Male; Mice; Mice, Inbred Strains; Oxidation-Reduction; Plasmodium; Vitamin E

It is proposed that the loss of ability by humans to synthesize ascorbic aicd may have markedly enhanced the survival opportunities of early man living in a malarial infested environment. This hypothesis is based on biomedical evidence which indicates that glucose-6-phosphate dehydrogenase (G-6-PD) deficient individuals display enhanced sensitivity to ascorbic acid induced hemolysis which has been fatal at sufficiently high doses and that the G-6-PD deficient trait has been selected for in malarial environments.

Topics: Ascorbic Acid; Biological Evolution; Genetics, Population; Glucosephosphate Dehydrogenase Deficiency; Hemolysis; Humans; Malaria; Species Specificity

Topics: Anemia, Macrocytic; Ascorbic Acid; Drug Stability; Erythropoiesis; Female; Folic Acid; Humans; Malaria; Nigeria; Plasmodium falciparum; Postpartum Period; Pregnancy; Pregnancy Complications, Hematologic; Temperature

Topics: Anemia; Anemia, Sickle Cell; Ascorbic Acid; Counseling; Eugenics; Galactosemias; Genetics, Medical; Humans; Immunity; Malaria; Metabolism, Inborn Errors; Phenylketonurias; Preventive Medicine

Topics: Anemia; Ascorbic Acid; Humans; Iron; Malaria

Topics: Animals; Ascorbic Acid; Haplorhini; Malaria; Parasites; Plasmodium; Plasmodium knowlesi

Topics: Ascorbic Acid; Female; Fetus; Humans; Malaria; Placenta; Pregnancy; Vitamins