piperidines and Malaria

Halofuginone is a clinically active derivative of febrifugine that was first isolated from the Chinese herb Dichroa febrifuga. The beneficial biological effects of halofuginone on various diseases including parasitic diseases, cancer, fibrosis, and autoimmune disorders have been investigated. Halofuginone has reduced toxic side effects when compared to febrifugine, an advantage that has led to the commercial availability of halofuginone-based antiparasitic drugs for animal use, and to human clinical trials for the treatment of tumors and fibrosis. This review summarizes advances in determining the mechanism of action of halofuginone, focusing on its antiparasitic role in malaria, cryptosporidiosis, coccidiosis, toxoplasmosis, and leishmaniasis. We discuss mechanistic insights into halofuginone's primary mode of action which involves inhibition of the prolyl-tRNA synthetase enzyme, which is crucial in protein synthesis. Halofuginone exemplifies the untapped wealth of plant-derived compounds in disease therapeutics.

Topics: Animals; Antiprotozoal Agents; Fibrosis; Humans; Malaria; Piperidines; Quinazolinones

At least four doses of quinine followed by a single dose of mefloquine or by a single dose of sulfadoxine-pyrimethamine are two highly effective regimens for chloroquine-resistant falciparum malaria. Mefloquine alone is valuable in ambulant patients. Chloroquine-sensitive falciparum malaria can be treated with a course of chloroquine. Vivax and all other types of malaria should be treated with sequential chloroquine and primaquine. Quinine, by intravenous infusion, is the most effective drug for severe falciparum malaria. The optimum intravenous dose varies between 5 mg/kg and 10 mg/kg administered over four hours. Intravenous or oral quinine should be administered about every 12 hours and the total daily dose of quinine should rarely exceed 20 mg/kg. Intravenous fluid input should be controlled in falciparum malaria to prevent pulmonary oedema. Established renal failure is best treated by dialysis. The value of adrenocortical steroids for falciparum coma has not been established. Fresh blood transfusion may be helpful in small doses for severe anaemia and to replace clotting factors. Anticoagulants, such as heparin, should not be used in falciparum malaria.

Topics: Anemia; Antimalarials; Blackwater Fever; Child; Child, Preschool; Chloroquine; Coma; Drug Combinations; Drug Resistance, Microbial; Hemorrhage; Humans; Kidney Failure, Chronic; Malaria; Piperidines; Plasmodium falciparum; Plasmodium vivax; Primaquine; Pulmonary Edema; Quinine; Quinolines; Sulfadoxine

The public health value of a vector control tool depends on its epidemiological efficacy, but also on its ease of implementation. This study describes an intensive distribution scheme of a topical repellent implemented in 2012 and 2013 for the purpose of a cluster-randomized trial using the existing public health system. The trial aimed to assess the effectiveness of repellents in addition to long-lasting insecticidal nets (LLIN) and occurred in a province of Cambodia. Determinants for accessibility and consumption of this tool were explored.. 135 individuals were appointed to be repellent distributors in 57 villages. A 2-weekly bottle exchange programme was organized. Distributors recorded information regarding the amount of bottles exchanged, repellent leftover, and reasons for not complying in household data sheets. Distributor-household contact rates and average 2-weekly consumption of repellent were calculated. Household and distributors characteristics were obtained using questionnaires, surveying 50 households per cluster and all distributors. Regression models were used to explore associations between contact and consumption rates and determinants such as socio-economic status. Operational costs for repellent and net distribution were obtained from the MalaResT project and the provincial health department.. A fourfold increase in distributor-household contact rates was observed in 2013 compared to 2012 (median2012 = 20 %, median2013 = 88.9 %). Consumption rate tripled over the 2-year study period (median2012 = 20 %, median2013 = 57.89 %). Contact rates were found to associate with district, commune and knowing the distributor, while consumption was associated with district and household head occupation. The annual operational cost per capita for repellent distribution was 31 times more expensive than LLIN distribution (USD 4.33 versus USD 0.14).. After the existing public health system was reinforced with programmatic and logistic support, an intense 2-weekly distribution scheme of a vector control tool over a 2-year period was operated successfully in the field. Lack of associations with socio-economic status suggested that the free distribution strategy resulted in equitable access to repellents. The operational costs for the repellent distribution and exchange programme were much higher than LLIN distribution. Such effort could only be justified in the context of malaria elimination where these interventions are expected to be limited in time.

Topics: Administration, Topical; Adolescent; Adult; Aged; Cambodia; Family Characteristics; Female; Health Services Accessibility; Humans; Insect Repellents; Insecticide-Treated Bednets; Malaria; Male; Middle Aged; Piperidines; Public Health; Rural Health Services; Surveys and Questionnaires; Young Adult

The effect of various dosages of mefloquine hydrochloride (WR 142,490) and sulfadoxine-pyrimethamine in the suppression of malaria infections was studied in an area of northeastern Thailand highly endemic for both chloroquine-resistant Plasmodium falciparum and for P. vivax. Both preparations, in all regimens studied, were effective in greatly reducing the incidence of falciparum infections. Mefloquine was more active in preventing vivax parasitemia than sulfadoxine-pyrimethamine; however, this combination remains the commercially available regimen of choice where both parasites occur and P. falciparum is resistant to chloroquine.

Topics: Adolescent; Adult; Antimalarials; Child; Drug Therapy, Combination; Female; Humans; Malaria; Male; Mefloquine; Piperidines; Plasmodium falciparum; Plasmodium vivax; Pyrimethamine; Quinolines; Sulfadoxine; Thailand

A single oral dose (1.5 g) of mefloquine hydrochloride cured all of 37 patients with falciparum malaria, and a single dose of pyrimethamine (75 mg) plus sulfadoxine (1.5 g) cured 34 of 38 patients. The rates at which parasitaemia and fever abated were similar for the two regimens but mefloquine was associated with a higher incidence of gastrointestinal side effects.

Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Evaluation; Humans; Malaria; Piperidines; Plasmodium falciparum; Pyrimethamine; Quinolines; Sulfadoxine; Sulfanilamides; Tablets

Patients with falciparum malaria were studied in Thailand, an area of known chloroquine resistance. The patients were unselected and some had severe malaria, and they were randomly assigned to one of two sequential regimes. A short course of quinine (average 4 doses, equivalent to 2 g base) followed by a single dose of pyrimethamine-sulfadoxine (Fansidar) cured 92% of patients (36 out of 39), while a short course of quinine followed by a single 1-5-dose of mefloquine cured all of the 35 patients who could be followed up. Gastrointestinal side effects were minimal if at least 12 hours elapsed between the last dose of quinine and the mefloquine. Sequential quinine and mefloquine is the most effective treatment for patients with chloroquine-resistant falciparum malaria, including those with severe or complicated disease. Mefloquine, however, is not commercially available, and the similar regimen using Fansidar is almost as effective.

Topics: Adolescent; Adult; Aged; Antimalarials; Drug Combinations; Drug Therapy, Combination; Humans; Malaria; Male; Middle Aged; Piperidines; Plasmodium falciparum; Pyrimethamine; Quinine; Quinolines; Sulfadoxine; Sulfanilamides

Mefloquine hydrochloride, a new 4-quinolinemethanol, was administered as a single oral dose to 47 volunteers infected with malaria. Treatment resulted in rapid clearence of fever and parasitemia. No recrudescence of parasites was observed after treatment of chloroquine-sensitive infections of Plasmodium falciparum. More significantly, in nonimmune persons with chloroquine-resistant infections, 1 gram of mefloquine cured 10 of 12 patients and 1.5 grams cured all 8 patients who received this dose of the drug. The marked activity of a single dose of mefloquine against chloroquine-resistant strains of Plasmodium falciparum suggests that this agent may be more useful than currently available drugs are for the treatment of drug-resistant malaria.

Topics: Antimalarials; Chloroquine; Clinical Trials as Topic; Drug Resistance; Humans; Malaria; Mutation; Piperidines; Plasmodium falciparum; Quinolines

In preliminary studies with mefloquine (WR 142 490) a single dose exerted prolonged suppressive activity against a drug-resistant strain of Plasmodium falciparum. Development of patent parasitaemia was prevented when nonimmune persons were exposed to infected mosquitos 2 weeks after medication, and it was delayed when exposure occurred 3 weeks after drug administration.

Topics: Antimalarials; Drug Resistance, Microbial; Humans; Malaria; Male; Piperidines; Plasmodium falciparum; Quinolines; Species Specificity

In previous studies, Cassia spectabilis DC leaf has shown a good antiplasmodial activity. Therefore, this study is a follow-up study of the extract of leaf of C. spectabilis DC on its in vitro and in vivo antiplasmodial activity and mechanism as an antimalarial.. The extract was fractionated, sub-fractionated and isolated to obtain the purified compound. In vitro antiplasmodial activity test against Plasmodium falciparum to find out the active compound. In vivo test against P. berghei ANKA-infected mice was conducted to determine prophylactic activity and antiplasmodial activity either alone or in combination with artesunate. The inhibition of heme detoxification test as one of the antimalarial mechanisms was carried out using the Basilico method.. C. spectabilis DC leaf possessed potent antiplasmodial activity and may offer a potential agent for effective and affordable antimalarial phytomedicine.

Topics: Animals; Antimalarials; Artesunate; Cassia; Chloroquine; Heme; Ketones; Malaria; Male; Mice, Inbred BALB C; Phytotherapy; Piperidines; Plant Extracts; Plant Leaves; Plasmodium berghei; Plasmodium falciparum

Insecticide resistance carries the potential to undermine the efficacy of insecticide based malaria vector control strategies. Therefore, there is an urgent need for new insecticidal compounds. Black pepper (dried fruit from the vine, Piper nigrum), used as a food additive and spice, and its principal alkaloid piperine, have previously been shown to have larvicidal properties. The aim of this study was to investigate the larvicidal effects of ground black pepper and piperine against third and fourth instar Anopheles larvae drawn from several laboratory-reared insecticide resistant and susceptible strains of Anopheles arabiensis, An. coluzzii, An. gambiae, An. quadriannulatus and An. funestus.. Larvae were fed with mixtures of standard larval food and either ground black pepper or piperine in different proportions. Mortality was recorded 24 h after black pepper and 48 h after piperine were applied to the larval bowls.. Black pepper and piperine mixtures caused high mortality in the An. gambiae complex strains, with black pepper proving significantly more toxic than piperine. The An. funestus strains were substantially less sensitive to black pepper and piperine which may reflect a marked difference in the feeding habits of this species compared to that of the Gambiae complex or a difference in food metabolism as a consequence of differences in breeding habitat between species.. Insecticide resistant and susceptible strains by species proved equally susceptible to black pepper and piperine. It is concluded that black pepper shows potential as a larvicide for the control of certain malaria vector species.

Topics: Alkaloids; Animals; Anopheles; Benzodioxoles; Insecticide Resistance; Insecticides; Larva; Malaria; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Topics: Animals; Culicidae; Cyclohexane Monoterpenes; DEET; Humans; Insect Bites and Stings; Insect Repellents; Malaria; Menthol; Piperidines; Travel

Scaling up of insecticide treated nets has contributed to a substantial malaria decline. However, some malaria vectors, and most arbovirus vectors, bite outdoors and in the early evening. Therefore, topically applied insect repellents may provide crucial additional protection against mosquito-borne pathogens. Among topical repellents, DEET is the most commonly used, followed by others such as picaridin. The protective efficacy of two formulated picaridin repellents against mosquito bites, including arbovirus and malaria vectors, was evaluated in a field study in Cambodia. Over a period of two years, human landing collections were performed on repellent treated persons, with rotation to account for the effect of collection place, time and individual collector. Based on a total of 4996 mosquitoes collected on negative control persons, the overall five hour protection rate was 97.4% [95%CI: 97.1-97.8%], not decreasing over time. Picaridin 20% performed equally well as DEET 20% and better than picaridin 10%. Repellents performed better against Mansonia and Culex spp. as compared to aedines and anophelines. A lower performance was observed against Aedes albopictus as compared to Aedes aegypti, and against Anopheles barbirostris as compared to several vector species. Parity rates were higher in vectors collected on repellent treated person as compared to control persons. As such, field evaluation shows that repellents can provide additional personal protection against early and outdoor biting malaria and arbovirus vectors, with excellent protection up to five hours after application. The heterogeneity in repellent sensitivity between mosquito genera and vector species could however impact the efficacy of repellents in public health programs. Considering its excellent performance and potential to protect against early and outdoor biting vectors, as well as its higher acceptability as compared to DEET, picaridin is an appropriate product to evaluate the epidemiological impact of large scale use of topical repellents on arthropod borne diseases.

Topics: Animals; Arbovirus Infections; Cambodia; Culicidae; Insect Repellents; Insect Vectors; Insecticide Resistance; Malaria; Piperidines

Febrifugine is an alkaloid isolated from Dichroa febrifuga Lour as the active component against Plasmodium falciparum, but exhibits toxic side effects. In this study novel febrifugine analogues were designed and efficiently synthesized. New compounds underwent efficacy and toxicity evaluation. Some compounds are much less toxic than the natural product febrifugine and existing antimalarial drugs and are expected to possess wide therapeutic windows. In Aotus monkeys infected with the chloroquine resistant FVO strain of P. falciparum, one interesting compound possesses a 50% curative dose of 2mg/kg/day and a 100% curative dose of 8 mg/kg/day. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.

Topics: Animals; Antimalarials; Aotus trivirgatus; Drug Evaluation, Preclinical; Malaria; Piperidines; Plasmodium falciparum; Quinazolines

Malaria is a devastating parasitic disease that afflicts one-third of the world's population. Antimalarial drugs in common use address few targets, and their efficacy is being undermined by parasite resistance. Most therapeutics target blood-stage malaria, whereas only few compounds are active against malaria's liver stage, the first stage of the Plasmodium parasite's life cycle within the human host. The identification of inhibitors active against liver-stage malaria would benefit the development of chemical probes to elucidate the poorly understood biology of this phase of the parasite life cycle and could provide agents to prevent and eliminate the disease. Herein we report the development of a live-cell parasite traversal assay in 384-well format amenable to high-throughput screening that exploits the wounding of liver cells by the parasite. This method identifies small molecules that may inhibit the parasite's actin-myosin motor system. The traversal assay, in addition to established methods, was used to evaluate the activity of halofuginone, a synthetic halogenated derivative of the natural alkaloid febrifugine, against liver-stage Plasmodium berghei parasites. Halofuginone was found to inhibit P. berghei sporozoite load in HepG2 cells with an IC(50) value of 17 nM. While the compound does not affect parasite traversal through human liver cells, an inhibition time course assay indicates that it affects essential processes in both early- and late-stage parasite development.

Topics: Animals; Antimalarials; Cell Line, Tumor; Cytokinesis; High-Throughput Screening Assays; Humans; Inhibitory Concentration 50; Liver; Malaria; Mice; Models, Biological; Piperidines; Plasmodium berghei; Plasmodium falciparum; Quinazolinones; Sporozoites; Structure-Activity Relationship

The compound haliclonacyclamine A was isolated from the Haliclona sponge at Solomon Islands. It acts as a powerful in vitro and in vivo anti-plasmodial agent against the chloroquine-resistant Plasmodium falciparum strain FCB1and Plasmodium vinckei petteri-infected mice, respectively.

Topics: Animals; Cell Line, Tumor; Female; Haliclona; Humans; Macrocyclic Compounds; Magnetic Resonance Spectroscopy; Malaria; Melanesia; Mice; Molecular Structure; Piperidines; Plasmodium; Survival Analysis

Febrifugine is an alkaloid isolated from Dichroa febrifuga Lour as the active component against Plasmodium falciparum. Adverse side effects have precluded febrifugine as a potential clinical drug. In this study novel febrifugine analogues were designed and synthesized. Lower toxicity was achieved by reducing or eliminating the tendency of forming chemically reactive and toxic intermediates and metabolites. Synthesized compounds were evaluated for acute toxicity and in vitro and in vivo antimalarial efficacy. Some compounds are much less toxic than the natural product febrifugine and existing antimalarial drug chloroquine and are expected to possess wide therapeutic windows. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.

Topics: Animals; Antimalarials; Drug Evaluation, Preclinical; Hydrangeaceae; Malaria; Mice; Molecular Structure; Parasitic Sensitivity Tests; Piperidines; Plasmodium falciparum; Quinazolines; Structure-Activity Relationship

The spread of resistance to pyrethroids in the major Afrotropical malaria vectors Anopheles gambiae s.s. necessitates the development of new strategies to control resistant mosquito populations. To test the efficacy of nets treated with repellent and insecticide against susceptible and insecticide-resistant An. gambiae mosquito populations, we impregnated mosquito bed nets with an insect repellent mixed with a low dose of organophosphorous insecticide and tested them in a rice-growing area near Bobo-Dioulasso, Burkina Faso. During the first 2 weeks posttreatment, the mixture was as effective as deltamethrin alone and was more effective at killing An. gambiae that carried knockdown resistance (kdr) or insensitive acetylcholinesterase resistance (Ace1R) genes. The mixture seemed to not kill more susceptible genotypes for the kdr or Ace1R alleles. Mixing repellents and organophosphates on bed nets could be used to control insecticide-resistant malaria vectors if residual activity of the mixture is extended and safety is verified.

Topics: Acetylcholinesterase; Alleles; Animals; Anopheles; Burkina Faso; Cholinesterase Inhibitors; DEET; Female; Genes, Insect; Humans; Insect Repellents; Insect Vectors; Insecticide Resistance; Insecticides; Malaria; Male; Mosquito Control; Nitriles; Organothiophosphorus Compounds; Piperidines; Pyrethrins

Parasitemia patterns, survival and cytokine levels of Plasmodium berghei NK65-infected BALB/c mice, treated orally with the alkaloidal mixture of febrifugine and isofebrifugine at a dose of 1 mg/kg twice a day for 4 consecutive days were monitored. Whereas the untreated mice showed a progressive increase in parasitemia and ultimate death, the alkaloid mixture-treated group showed a transient suppression of parasitemia during the course of treatment. However, the parasitemia increased on discontinuation of treatment, leading to earlier death of mice in the treated group than in the infected but untreated controls. Mice in the infected but untreated group displayed a significant elevation in serum IFN-gammay levels during the first week post-infection (pI) and from Day 14 pI, relative to the levels in the uninfected controls. In contrast, although mice in the alkaloid mixture-treated group displayed no significant elevation in serum IFN-gamma levels during the first week pI, they showed considerable levels on Day 14 pI. There were no significant differences in serum IL-4 levels among the groups. The titers of the parasite-specific IgG1, IgG2a, IgG2b and IgG3 were significantly elevated from Day 11 pI in both the treated and untreated groups. There was a significant difference in survival duration between the IFN-gamma-/- mutant and BALB/c mice. IFN-gamma-/- mutant mice showed a decrease in parasitemia levels while receiving medication, which was significantly lower than those of the treated BALB/c mice. The results of the present study suggest that although IFN-gamma is significant for protective immunity in mice with malaria infection, it may play an adverse role post-medication, causing earlier mortality of treated BALB/c mice.

Topics: Animals; Antibodies, Protozoan; Antigens, Protozoan; Antimalarials; Interferon-gamma; Interleukin-4; Malaria; Male; Mice; Mice, Inbred BALB C; Parasitemia; Piperidines; Plasmodium berghei; Quinazolines

Topics: Animals; Child; Culicidae; DEET; Disease Transmission, Infectious; Europe; Female; Humans; Infection Control; Insect Repellents; Insect Vectors; Insecticides; Malaria; Male; Permethrin; Pest Control; Piperidines; Plant Extracts; Pregnancy; Pyrethrins

Recent studies have proposed curcumin as a potential partner for artemisinin in artemisinin combination therapies to treat malaria infections. The efficacy of curcumin alone and in combination with artemisinin was evaluated on a clone of Plasmodium chabaudi selected for artemisinin resistance in vivo. The addition of piperine as an enhancer of curcumin activity was also tested. Results indicated that curcumin, both alone and in combination with piperine had only a modest antimalarial effect and was not able to reverse the artemisinin-resistant phenotype or significantly affect growth of the tested clone when used in combination with artemisinin. This is in contrast with previous in vivo work and calls for further experimental evaluation of the antimalarial potential of curcumin.

Topics: Administration, Oral; Alkaloids; Animals; Anti-Infective Agents; Artemisinins; Benzodioxoles; Biological Availability; Curcumin; Drug Resistance; Drug Therapy, Combination; Malaria; Male; Mice; Parasitemia; Piperidines; Plasmodium chabaudi; Polyunsaturated Alkamides

Febrifugine (1), a quinazoline alkaloid, isolated from Dichroa febrifuga roots, shows powerful antimalarial activity against Plasmodium falciparum. The use of 1 as an antimalarial drug has been precluded because of side effects, such as diarrhea, vomiting, and liver toxicity. However, the potent antimalarial activity of 1 has stimulated medicinal chemists to pursue compounds derived from 1, which may be valuable leads for novel drugs. In this study, we synthesized a new series of febrifugine derivatives formed by structural modifications at (i) the quinazoline ring, (ii) the linker, or (iii) the piperidine ring. Then, we evaluated their antimalarial activities. Thienopyrimidine analogue 15 exhibited a potent antimalarial activity and a high therapeutic selectivity both in vitro and in vivo, suggesting that 15 is a good antimalarial candidate.

Topics: Animals; Antimalarials; Cell Line; Malaria; Mice; Parasitic Sensitivity Tests; Piperidines; Plasmodium berghei; Plasmodium falciparum; Pyrimidinones; Quinazolines; Stereoisomerism; Structure-Activity Relationship; Thiophenes; Toxicity Tests, Acute

With an aim to identify a dispiro-1,2,4-trioxolane with high oral activity and good physicochemical properties, 27 derivatives of an achiral piperidine trioxolane were synthesized; most were potent antimalarial peroxides with IC(50)s ranging from 0.20 to 7.0 ng/mL. The oral efficacies of two of these were superior to artesunate and comparable to artemether. The attractive chemical simplicity of these compounds is balanced only by an apparent metabolic susceptibility.

Topics: Amines; Animals; Antimalarials; Humans; Malaria; Mice; Microsomes, Liver; Piperidines; Plasmodium berghei; Sulfonamides; Urea

Cytokine and antibody production was investigated during the course of resolution of primary infection in Plasmodium yoelii 17XL-infected BALB/c mice treated with a mixture of febrifugine and isofebrifugine. The infected mice in an untreated control group showed a progressively increasing parasitemia, leading to mouse death. In contrast, infected mice given the mixture orally showed low parasitemia levels during administration. Following a transient increase in parasitemia in the bloodstream of the treated mice, no parasites could be detected by microscopic examination. Analysis of cytokines in plasma showed that the plasma IFN-gamma levels elevated significantly within the first week of infection in both groups. Furthermore, on day 20 the plasma IFN-gamma and IL-4 levels elevated significantly in the treated mice and the production of both cytokines was sustained until at least day 40. The production of both cytokines in the treated mice was coincident with a decrease in parasitemia. The production of parasite-specific antibodies in the course of P. yoelii 17XL infection was also monitored. In the drug-treated mice, the titers of parasite-specific IgG1, IgG2a, IgG2b and IgG3 elevated significantly from day 20; and the production of parasite-specific antibodies was coincident with a decrease in parasite numbers in the bloodstream.

Topics: Animals; Antibodies, Protozoan; Cytokines; Female; Hydrangea; Malaria; Mice; Mice, Inbred BALB C; Phytotherapy; Piperidines; Plant Leaves; Plasmodium yoelii; Quinazolines

Synthetic insect repellents, IR3535 and KBR 3023 (also known as picaridin, or by the trade name Bayrepel, were tested in Burkina Faso against mosquito vectors of disease to compare their relative efficacy and persistence profiles to those of the 'gold standard' DEET. Collection of >49000 mosquitoes (approximately 95% belonging to the Anopheles gambiae complex) showed that after an exposure of 10h, KBR 3023 produced the highest protection against anophelines, followed by DEET, then IR3535. The response of aedines was more variable. By fitting a logistic plane model we estimated 95% effective dosages (ED95) for An. gambiae s.l., as well as a decay constant characterizing the exponential loss of repellent from the skin, with time. The ED95 values for DEET, IR3535, and KBR 3023 were 94.3, 212.4, and 81.8 microg/cm2 respectively. The decay constants were estimated at -0.241, -0.240, and -0.170 h(-1) respectively. The corresponding estimates of half-life were 2.9, 2.9, and 4.1h. Immunoenzymatic detection of the circumsporozoite protein (CSP) of Plasmodium falciparum in 842 An. gambiae s.l. showed that CSP-positive mosquitoes were equally frequent in treated and control subjects, indicating that the repellents could produce a reduction in the number of malaria infectious bites.

Topics: Administration, Topical; Adult; Aedes; Animals; Anopheles; Burkina Faso; DEET; Dose-Response Relationship, Drug; Female; Humans; Insect Repellents; Insect Vectors; Malaria; Male; Piperidines; Propionates; Rural Health; Time Factors; Treatment Outcome

The antimalarial activity of Hydrangea macrophylla var. Otaksa alkaloids was evaluated against Plasmodium yoelii 17XL, P. berghei NK65 and P. chabaudi AS in ICR mice. For trials in P. yoelii 17XL or P. chabaudi AS infections, mice were infected intraperitoneally with 10(5), 10(6) and 10(7) parasitized erythrocytes, respectively, and in P. berghei NK65 infections, mice were infected intraperitoneally with 10(3), 10(4) and 10(5) parasitized erythrocytes, respectively. Three days after injection, mice were orally given febrifugine and isofebrifugine mixture at 1 mg/kg in the treated group and 0.5% cremophor EL solution in the untreated, infected one, respectively, twice a day for 5 consecutive days. In P. yoelii 17XL infections, mice in all the non-treated controls died from 5 to 9 dpi with a gradual body weight loss and increasing parasitemias. In the treated groups, the mouse body weight gradually decreased after the end of administration but turned to increase in several days, and except one mouse in the group given 10(6) parasitized erythrocytes, other mice survived during the experiment. Mice given orally the mixture showed low parasitemia levels during administration. Following a transient recrudescence of malaria parasites in the bloodstream of treated mice, no parasites could be detected by a microscopic examination. In P. berghei NK65 infections, mice in all the non-treated controls died from 7 to 12 dpi with a gradual body weight loss and increasing parasitemias. In the treated groups, the body weight gradually decreased from 11 dpi and all mice died from 12 to 30 dpi. During a mixture administration all mice showed slight suppression of multiplication of malaria parasites. After the end of administration, however, malaria parasites increased in the bloodstream of the treated mice and all mice died. In P. chabaudi AS infections, there were two different patterns in the course of infection; lethal infection or recovery in both the non-treated control and treated groups. In the non-treated and treated groups, mice showed a gradual body weight loss. But the body weights of survivals in both groups turned to increase in several days. Mice in control and treated groups showed as the same profile in the changes of parasitemia. In the non-treated controls, after a transient peak parasitemia malaria parasites in the bloodstream of survivals could not be detected by a microscopic examination. During a mixture administration, all mice showed suppression of m

Topics: Administration, Oral; Animals; Antimalarials; Hydrangea; Malaria; Male; Mice; Mice, Inbred ICR; Parasitic Sensitivity Tests; Phytotherapy; Piperidines; Plant Extracts; Plant Leaves; Plasmodium; Plasmodium berghei; Plasmodium chabaudi; Plasmodium yoelii; Quinazolines

The combination effects of chloroquine with a mixture of febrifugine and isofebrifugine were evaluated against a blood-induced infection with chloroquine-resistant P. berghei NK65 in ICR mice. Mice in the untreated control showed a progressively increasing parasitemia leading to mouse death. A two-day dosage of 20 mg base/kg of chloroquine alone showed little effect against P. berghei NK65 infection, and all mice died from day 13 to 14 with an increasing parasitemia. A four-day dosage of 1 mg/kg of the febrifugine and isofebrifugine mixture alone showed a little antimalarial activity, but all mice died from day 19 to 27 with an increasing parasitemia. On the other hand, mice treated with chloroquine plus alkaloids survived during the experiment. All mice treated with chloroquine alone or the alkaloid mixture alone showed low parasitemia levels during a drug administration and following a few days, but then malaria parasites increased in the bloodstream of the treated mice until death. On the other hand, malaria parasites in the mice given chloroquine plus alkaloids decreased on day 6 and then were not detected by a microscopic examination during observation period.

Topics: Animals; Antimalarials; Chloroquine; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Malaria; Male; Mice; Mice, Inbred ICR; Parasitic Sensitivity Tests; Phytotherapy; Piperidines; Plasmodium berghei; Quinazolines

Although febrifugine (1) and isofebrifugine (2), alkaloids isolated from roots of the Dichroa febrifuga plant, show powerful antimalarial activity against Plasmodium falciparum, strong side effects such as the emetic effect have precluded their clinical use against malaria. However, their antimalarial potency makes them attractive substances as leads for developing new types of chemotherapeutic antimalarial drugs. Thus, we have evaluated the in vitro antimalarial activity of the analogues of febrifugine (1) and isofebrifugine (2). The activities of the analogues derived from Df-1 (3) and Df-2 (4), condensation products of 1 and 2 with acetone, respectively, were also obtained. The 3' '-keto derivative (7, EC(50) = 2.0 x 10(-8) M) of 1 was found to exhibit potential antimalarial activity with high selectivity against P. falciparum in vitro. The in vitro activities of the reduction product (8, EC(50) = 2.0 x 10(-8) M) of 1 at C-2' and its cyclic derivatives 9 and 10 (EC(50) = 3.7 x 10(-9) and 8.6 x 10(-9) M, respectively) were found to be strongly active and selective. Additionally, the Dess-Martin oxidation product of 3 was found to be strongly active with high selectivity against P. falciparum. A structure-activity relationship study (SAR) demonstrates that the essential role played by the 4-quinazolinone ring in the appearance of activity and the presence of a 1' '-amino group and C-2', C-3' ' O-functionalities are crucial in the activity of 1. For 7, 8, and 9, prepared as racemic forms, an in vivo study has also been conducted.

Topics: Animals; Antimalarials; Cell Line; Malaria; Mice; Piperidines; Plasmodium berghei; Plasmodium falciparum; Quinazolines; Structure-Activity Relationship

Febrifugine (1) and isofebrifugine (2), isolated from the roots of Dichroa febrifuga Lour. (Chinese name: Cháng Shan), are active principles against malaria. Adducts of 1 and 2 with acetone, Df-1 (3) and Df-2 (4), respectively, were obtained using silica gel and acetone. They showed high activity against P. falciparum malaria in vitro. Compound 3 was found to be equally effective against P. berghei in vivo as the clinically used drug chloroquine, whereas 4 showed only 1/24 of the activity of 3. Metabolism studies of these compounds revealed that compound 4 is readily metabolized in mouse liver. Accordingly, the dose of 4 must be higher than that of 3 to attain blood levels sufficient for a favorable therapeutic effect.

Topics: Animals; Antimalarials; Drugs, Chinese Herbal; Malaria; Male; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Conformation; Piperidines; Plasmodium berghei; Plasmodium falciparum; Quinazolines; Quinazolinones; Quinolizines

The effect of febrifugine, the main alkaloidal constituent of an antimalarial crude drug, Dichroa febrifuga Lour., on protective immunity in mice infected with erythrocytic stage Plasmodium berghei NK65 was investigated. Febrifugine was administered orally, at a dose of 1 mg/kg/day, to mice before and/or after they were infected intraperitoneally with 2 x 10(6) parasitized red blood cells. Then, mortality and the levels of parasitemia and plasma NO3- [a degradation product of nitric oxide (NO)] were monitored. Febrifugine significantly reduced the mortality and the level of parasitemia. The plasma NO3- concentration began to rise within 2 days after treatment with febrifugine and declined to normal in 2 days when the mice were treated orally with febrifugine once a day for 3 consecutive days before parasite infection. This antimalarial activity of febrifugine was reduced by both N(G)-monomethyl-L-arginine and aminoguanidine. These results indicate that the increased production of NO by febrifugine plays an important role in host defense against malaria infection in mice.

Topics: Animals; Antimalarials; Drug Interactions; Enzyme Inhibitors; Malaria; Male; Mice; Mice, Inbred ICR; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Parasitemia; Piperidines; Plasmodium berghei; Quinazolines

A field experiment was conducted to compare the biting behavior of Plasmodium falciparum-infected and uninfected Anopheles on humans using mosquito repellents. Repellent formulations (5% [wt/vol] N,N-diethyl-3-methylbenzamide [deet] or 5% [wt/vol] AI3-37220, a piperidine compound, both in 100% ethanol, or 100% ethanol alone [as a control]) were applied to the lower legs of 3 collectors in each of 4 houses. Collectors caught mosquitoes over 6 collection nights. Mosquitoes were collected into vials after they initiated probing on the leg of a collector. Infected females made up the same proportion of the Anopheles funestus populations biting either repellent-protected or unprotected individuals. We conclude that repellent formulations are equally effective against Plasmodium-infected and uninfected An. funestus.

Topics: Animals; Anopheles; DEET; Feeding Behavior; Female; Host-Parasite Interactions; Humans; Insect Repellents; Insect Vectors; Malaria; Piperidines; Plasmodium falciparum

Human red cells infected in vitro with Plasmodium falciparum showed a significant increase in the rate of both ouabain-sensitive and ouabain-insensitive 86Rb+ influx. The increase in ouabain-insensitive 86Rb+ influx was due, in part, to increased transport via a bumetanide-sensitive system and, in part to transport via a pathway that was absent (or at least inactive) in uninfected cells. The parasite-induced pathway was inhibited by piperine and had a dose response very similar to that of the Gardos channel of uninfected cells but was less sensitive than the Gardos channel to inhibition by quinine.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Transport; Bumetanide; Dose-Response Relationship, Drug; Erythrocytes; Humans; In Vitro Techniques; Malaria; Ouabain; Piperidines; Polyunsaturated Alkamides; Potassium; Quinine; Rubidium Radioisotopes

Topics: Animals; Antimalarials; Malaria; Mice; Piperidines; Pyrrolidines; Quinazolines

Ornithine decarboxylase activity was inhibited in Plasmodium chabaudi-infected red cells of mice treated with chloroquine, mefloquine, primaquine and floxacrine. In vitro experiments on membrane-bound enzymes performed with intact P. chabaudi-infected red cells and corresponding ghost preparations showed a stimulation of NA+K+-ATP'ase and Ca2+Mg2+-ATP'ase activity in the presence of chloroquine, mefloquine and floxacrine.

Topics: Acridines; Animals; Antimalarials; Carboxy-Lyases; Chloroquine; Enzyme Repression; Erythrocyte Membrane; Malaria; Mefloquine; Mice; Ornithine Decarboxylase Inhibitors; Piperidines; Plasmodium; Primaquine; Quinolines

Topics: China; Drug Resistance, Microbial; Humans; Malaria; Mefloquine; Piperidines; Plant Extracts; Plants, Medicinal; Quinine; Quinolines; World Health Organization

Topics: Animals; Antimalarials; Chloroquine; Female; Macaca mulatta; Malaria; Male; Mefloquine; Piperidines; Quinolines

Chloroquine-resistant P. falciparum, line FCK from Thailand, was tested for susceptibility to mefloquine in continuous culture. The drug resulted in 50% schizont inhibition at the level of 8.0 nmol/ml of culture when tested for the first time. After three months of discontinuous exposure to mefloquine at increasing levels, the sensitivity of the parasite decreased. A concentration as high as 128 nmol/ml eventually was required for 50% inhibition of growth.

Topics: Animals; Chloroquine; Culture Media; Drug Resistance, Microbial; Humans; In Vitro Techniques; Malaria; Mefloquine; Piperidines; Plasmodium falciparum; Quinolines

Topics: Animals; Antimalarials; Chloroquine; Dimethylpolysiloxanes; Drug Implants; Malaria; Male; Mefloquine; Mice; Mice, Inbred Strains; Naphthoquinones; Piperidines; Plasmodium berghei; Primaquine; Proguanil; Pyrimethamine; Quinolines; Silicone Elastomers; Sulfadiazine; Triazines

Topics: Amino Alcohols; Animals; Antimalarials; Aotus trivirgatus; Drug Resistance; Malaria; Mefloquine; Mice; Piperidines; Plasmodium berghei; Plasmodium falciparum; Quinolines

Topics: Adult; Animals; Antimalarials; Biological Availability; Dogs; Half-Life; Humans; Kinetics; Malaria; Mefloquine; Middle Aged; Piperidines; Quinolines

In 1978, studies on the chloroquine sensitivity of Plasmodium falciparum were carried out in the district of Sennar, Sudan. The results of the in vivo tests showed parasites resistant at the RI level only, but the mean clearance time of trophozoites from the blood was higher than for strains found in many other areas of tropical Africa. The in vitro tests, using the microtechnique, indicated a lower sensitivity to chloroquine in the local P. falciparum isolates than in those of most other African countries. However, similar results have been reported from Ethiopia. The chloroquine sensitivity of P. falciparum from Sennar is close to the critical level of resistance. The in vitro microtechnique was also used to test for the sensitivity to Dabequin, 4-aminobenzo-quinoline, and was generally found to be a suitable and reproducible method, with a greater potential than the standard macro method. At parasite densities of over 100 000 asexual parasites per microlitre of blood the effect of a given concentration of chloroquine was related to the parasite density owing to the selective uptake of the compound by the parasitized cells.

Topics: Adolescent; Adult; Aged; Aminoquinolines; Child; Child, Preschool; Chloroquine; Humans; In Vitro Techniques; Malaria; Mefloquine; Microbiological Techniques; Middle Aged; Piperidines; Plasmodium falciparum; Quinolines; Sudan

Topics: Animals; Antimalarials; Drug Resistance; Haplorhini; Malaria; Mefloquine; Piperidines; Plasmodium berghei; Quinolines

The process of mefloquine accumulation was studied in mouse erythrocytes infected with either Plasmodium berghei CS (chloroquine susceptible) or P. berghei CR (chloroquine resistant). In both cases, mefloquine was accumulated by a saturable process with an apparent dissociation constant of 2.5 x 10(-6) M and an apparent maximal capacity of 700 mumol per kg of erythrocyte pellet; uninfected mouse erythrocytes accumulated more than half as much mefloquine as infected erythrocytes. The process of accumulation was not stimulated by providing glucose as a substrate, and it was not inhibited in infected erythrocytes by azide, iodoacetate, or incubation at 2 degrees C. Although mefloquine was accumulated more effectively than chloroquine by uninfected erythrocytes and by erythrocytes infected with P. berghei CR, competition between chloroquine and mefloquine was observed, raising the possibility that the same process of accumulation serves both drugs. Chloroquine competitively inhibits mefloquine accumulation, with an apparent inhibitor constant of 1.7 x 10(-3) M, and mefloquine competitively inhibits chloroquine accumulation, with an apparent inhibitor constant of 2 x 10(-6) M. The same process of accumulation and the same group of receptors could serve both drugs if mefloquine has greater access than chloroquine to the receptors. Regardless of whether the same process serves both drugs, undiminished accumulation by erythrocytes infected with P. berghei CR provides an explanation for the superiority of mefloquine in treating chloroquine-resistant malaria.

Topics: Animals; Antimalarials; Chloroquine; Drug Resistance, Microbial; Erythrocytes; Malaria; Male; Mice; Piperidines; Plasmodium berghei; Quinolines; Receptors, Drug

Topics: Animals; Antimalarials; Drug Resistance, Microbial; Haplorhini; Humans; Malaria; Piperidines; Plasmodium falciparum; Quinine; Quinolines

Pilot appraisals of the activities of 10 specially selected 2,6-substituted-4-pyridinemethanols against acute Plasmodium falciparum infections in owl monkeys identified three derivatives that were two to three times as active as chloroquine against infections with a 4-aminoquinoline-susceptible strain and, at the same doses, were equally effective against infections with a strain fully resistant to treatment with maximally tolerated doses of chloroquine, quinine, and pyrimethamine. Two of these derivatives, WR-172,435 and WR-180,409, deemed worthy of evaluation in human volunteers, were studied in greater depth in owl monkeys infected with either the multidrug-resistant Smith strain of P. falciparum or the pyrimethamine-resistant Palo Alto strain of P. vivax. These studies showed (i) that at the same total oral dose, 3-day and 7-day treatment schedules were equally effective and slightly superior to a single-dose schedule; (ii) that WR-172,435 was slightly more active than WR-180,409 in each treatment regimen; (iii) that intravenous delivery of WR-180,409 phosphate was feasible and effective; (iv) that both compounds effected control of parasitemia more rapidly than any standard or newly discovered antimalarial drug; and (v) that WR-172,435 and WR-180,409 had therapeutic indexes at least four to eight times those exhibited by chloroquine in infections with 4-aminoquinoline-susceptible strains, indexes retained by these pyridinemethanols against infections with various drug-resistant strains.

Topics: Animals; Aotus trivirgatus; Female; Haplorhini; Malaria; Male; Methanol; Piperidines; Plasmodium berghei; Plasmodium falciparum; Plasmodium vivax; Pyridines

WR-184,806 and WR-226,253, two 4-quinolinemethanols structurally similar to WR-142,490 (mefloquine), have been studied in depth in owl monkeys infected with various drug-resistant and drug-susceptible strains of Plasmodium falciparum and P. vivax in an effort to provide support and guidance for projected evaluations in human volunteers. The results of these studies, confirmatory of preliminary appraisals, showed that WR-184,806 was approximately one-third as active as WR-142,490 against infections with a multidrug-resistant strain of P. falciparum, whereas WR-226,253 was twice as active. Additionally, the current studies showed: (i) that both WR-184,806 and WR-226,253 were significantly more active against infections with blood schizonts of P. vivax than against those of P. falciparum; (ii) that their activities against established infections with either Plasmodium species were functions of the total doses delivered, single doses being as effective as three or seven fractional doses given on successive days; (iii) that WR-184,806 could be administered intravenously as the phosphate salt and was curative via this route in single doses; and (iv) that based on comparative curative doses, WR-184,806 was slightly more active and WR-226,253 was seven times more active against infections with a multidrug-resistant strain of P. falciparum than was chloroquine against infections with a 4-aminoquinoline-susceptible strain.

Topics: Administration, Oral; Animals; Antimalarials; Dose-Response Relationship, Drug; Female; Haplorhini; Injections, Intravenous; Malaria; Male; Piperidines; Plasmodium falciparum; Plasmodium vivax; Propanolamines; Quinolines

Mefloquine (WR 142,490) is a potent blood schizontocide active against drug-sensitive and drug-resistant lines of Plasmodium berghei. The ED50 and ED90 against the P. berghei N strain in albino mice are 1.5 and 3.8 mg/kg respectively. The highly chloroquine-resistant RC line is less sensitive and mefloquine is not fully effective at the maximum tolerated dose in the '4-day test'. Mefloquine has a similar mode of action to quinine both in vitro and (as demonstrated by the morphological changes it induces in P. berghei) in vivo, but is some 100 times more potent. Unlike quinine and WR 122,455 it appears not to interact with DNA. It has no causal prophylactic effect. Mixtures of mefloquine with pyrimethamine, sulphaphenazole or primaquine have an additive effect.

Topics: Animals; Antimalarials; DNA, Bacterial; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Drug Resistance, Microbial; Drug Synergism; Malaria; Mice; Pigmentation; Piperidines; Plasmodium berghei; Quinolines

Topics: Animals; Antimalarials; Drug Combinations; Drug Resistance, Microbial; Malaria; Mice; Piperidines; Plasmodium berghei; Primaquine; Pyrimethamine; Quinolines; Streptomycin; Sulfaphenazole; Time Factors

A strain of Plasmodium falciparum, transmitted in Irian Jaya (Indonesian New Guinea) was isolated in 1974 and sent to the University of Maryland for characterization in nonimmune volunteers. At Maryland the Indonesia (Whit.) strain, as it has been designated, was transmitted to colonized Anopheles stephensi. Prophylactically, it was not suppressed by proguanil hydrochloride 100 mg. daily. Curatively, parasitaemia was not cleared by treatment with 1-5 g. (base) in three days of chloroquine or amodiaquine (RII responses), nor by treatment with 150 mg. of pyrimethamine in three days (RIII), and some resistance was also shown to quinine. A single dose of 1-5 g. of mefloquine (WR 142,490) produced radical cure in the two patients treated with this new 4-quinolinemethanol compound.

Topics: Amodiaquine; Chloroquine; Drug Resistance; Humans; Malaria; Male; Piperidines; Plasmodium falciparum; Proguanil; Pyrimethamine; Quinine; Quinolines

Topics: Animals; Antimalarials; Chloroquine; Cytoplasmic Granules; Erythrocytes; Female; Malaria; Mice; Phenanthrenes; Pigments, Biological; Piperidines; Plasmodium berghei; Quinine; Quinolines; Vacuoles

WR 122,455, 3,6-bis-(trifluoromethyl)-alpha-(2-piperidinyl)-9-phenanthrenemethanol HCl, suppresses infection with drug-sensitive Plasmodium berghei N strain in mice. It acts rapidly and affects all the stages of the asexual intraerythrocytic parasites, the effective dose levels being about three times those of chloroquine and one-twelfth to one-fifteenth those of quinine. Under the influence of WR 122,455 haemozoin seems to disappear from the affected parasites following an initial coarsening of the fine pigment granules. These changes are similar to those exerted by quinine. Large doses of WR 122,455 have a residual affect due in part, at least, to deposition of insoluble material in the tissues. The drug appears to exert an antagonistic action on chloroquine when both drugs are administered simultaneously. It has no causal prophylactic effect. In vitro WR 122,455 is a competitive antagonist of chloroquine in a similar manner to quinine, and appears to have a dissociation constant (Ki) of 2-26 x 10(-8) M, making it about 18 times as active as quinine. WR 122,455 interacts strongly with calf thymus DNA, but the mechanism of interaction has yet to be defined. Mice tolerate single doses of a saline/Tween 80 suspensions up to about 400 mg/kg but sc administration induces necrotic changes at the injection site. Up to 30 mg/kg daily po for seven consecutive days is well tolerated systemically but local tissue reaction may occur if the drug is given by the sc or ip routes. However, systemically up to 60 mg/kg is tolerated sc or ip. The relation of WR 122,455 to drug resistant malaria will be reported later.

Topics: Administration, Oral; Animals; Antimalarials; Chloroquine; Dose-Response Relationship, Drug; Drug Tolerance; Erythrocytes; Injections, Intraperitoneal; Injections, Subcutaneous; Malaria; Male; Mice; Phenanthrenes; Piperidines; Plasmodium berghei

The phenanthrenemethanol compound WR 122,455 is an effective blood schizontocide against lines of Plasmodium berghei that are highly resistant to primaquine, sulphonamides, pyrimethamine and cycloguanil. It is also active against the NS line that is moderately resistant to chloroquine. WR 122,455 is inactive against the RC line which is highly resistant to chloroquine. Resistance to WR 122,455 is fairly readily developed by the drug-sensitive N strain of P. berghei, using a relapse technique. Resistance develops very readily to the NS line of P. berghei. Both resistant lines exhibit cross-resistance to quinine, but a roughly normal response to chloroquine, primaquine, sulphonamides, dapsone, pyrimethamine and cycloguanil. Resistance to WR 122,455 is stable through cyclical transmission and through cryopreservation, as well as in the absence of drug selection pressure. The resistant parasites have an essentially normal morphology and virulence. A warning is given against the widescale use of WR 122,455 or similar new drugs for human malaria other than in a suitable combination, in order to minimize the danger of the development of resistance to them.

Topics: Animals; Antimalarials; Chloroquine; Drug Resistance; Erythrocytes; Malaria; Male; Mice; Phenanthrenes; Piperidines; Plasmodium berghei; Quinine; Virulence

Topics: Administration, Oral; Animals; Antimalarials; Chickens; Chlorobenzenes; Diet; Guanidines; Guinea Pigs; Haplorhini; Injections, Subcutaneous; Malaria; Mice; Piperidines; Plasmodium berghei; Pyrimidines; Rats; Structure-Activity Relationship

Topics: Animals; Antimalarials; Circular Dichroism; Magnetic Resonance Spectroscopy; Malaria; Methanol; Mice; Molecular Conformation; Optical Rotation; Piperidines; Plasmodium berghei; Stereoisomerism

Topics: Animals; Antimalarials; Magnetic Resonance Spectroscopy; Malaria; Methanol; Mice; Molecular Conformation; Piperidines; Plasmodium berghei; Pyridines; Stereoisomerism; Structure-Activity Relationship

Topics: Animals; Antimalarials; Bridged-Ring Compounds; Chickens; Drug Evaluation, Preclinical; Hydrogenation; Malaria; Methods; Mice; Mice, Inbred ICR; Piperidines; Plasmodium; Plasmodium berghei; Quinolines

Topics: Animals; Antimalarials; Chickens; Chlorobenzenes; Dose-Response Relationship, Drug; Furans; Malaria; Mice; Piperidines; Plasmodium berghei; Structure-Activity Relationship

Topics: Animal Feed; Animals; Butylamines; Chlorobenzenes; Chloroquine; Colombia; Darkness; Disease Models, Animal; Drug Resistance, Microbial; Haplorhini; Humans; Injections, Intravenous; Malaria; Methanol; Methods; Piperidines; Plasmodium falciparum; Plasmodium vivax; Pyrimethamine; Quarantine; Quinine; Quinolines; Splenectomy

Topics: Animals; Antimalarials; Birds; Malaria; Methanol; Mice; Piperidines; Plasmodium; Plasmodium berghei; Quinolines

Topics: Animals; Antimalarials; Aza Compounds; Chickens; Malaria; Methanol; Mice; Phenanthrenes; Photosensitivity Disorders; Piperidines; Plasmodium berghei; Pyridines

Topics: Animals; Antimalarials; Chickens; Culicidae; Indoles; Infrared Rays; Lethal Dose 50; Malaria; Methanol; Mice; Piperidines; Spectrum Analysis; Stereoisomerism

Topics: Animals; Antimalarials; Chemical Phenomena; Chemistry; Chickens; Magnetic Resonance Spectroscopy; Malaria; Methanol; Mice; Phenanthrenes; Piperidines; Stereoisomerism

Topics: Animals; Antimalarials; Fluorine; Malaria; Methanol; Mice; Piperidines; Quinolines; Spectrum Analysis; Time Factors; Ultraviolet Rays

Topics: Amino Alcohols; Antimalarials; Furans; Malaria; Models, Structural; Piperidines; Plasmodium; Structure-Activity Relationship

Topics: Alkaloids; Malaria; Piperidines; Plants; Plasmodium vivax; Quinazolines