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Efficacy of antimalarials in systemic lupus erythematosus.

No recent study has been published on the efficacy of antimalarial drugs in the treatment of systemic lupus erythematosus (SLE). However, antimalarial drug therapy was reported in several early studies to control SLE more effectively than corticosteroids alone and to permit lower doses of steroids to be used. To confirm these findings, we conducted a retrospective study of 43 SLE patients who had been taking antimalarials but in whom such therapy had been discontinued after two to 13 years due to the development of macular changes. Each patient served as his own control by the matching of each year during which antimalarial drugs were taken with one year without antimalarial medication. There was a total of 76 matched years for the 43 patients. Overall, no significant correlation was shown between antimalarial drug therapy and the presence or absence of general symptoms (fever, fatigue, weight loss); skin, cardiac, pulmonary, or central nervous system manifestations, arthritis, or other symptoms or signs that were measured. Although antimalarials reduced the required dosage of corticosteroids significantly (p less than 0.05), the amount of reduction was not considered clinically meaningful. Treatment with antimalarial drugs significantly reduced the number of disease flare-ups (p less than 0.05). There were also significant differences between the years with and without chloroquine therapy 500 mg per day (the only regimen for which adequate data were available for analysis) in terms of general symptoms and skin manifestations (p less than 0.05). A prospective, double-blind study of large numbers of patients would be important to confirm the findings of this retrospective study--and the observations of many rheumatologists that antimalarials are helpful in the treatment of SLE.

Adolescent↗

Cytokine polymorphisms influence treatment outcomes in SLE patients treated with antimalarial drugs.

Antimalarial agents have been widely used as disease-modifying antirheumatic drugs in the treatment of systemic lupus erythematosus (SLE) and other rheumatological diseases, although their mechanism of action has not yet been fully defined. It is known, however, that effective response to treatment is variable among patients. Thus, the identification of genetic predictors of treatment response would provide valuable information for therapeutic intervention. The aim of the present study was to analyze the effect of antimalarial treatment on tumor necrosis factor (TNF)alpha serum levels and evaluate the possible influence of TNFalpha and IL-10 functional genetic polymorphisms on the response to antimalarial drugs. To this end, TNFalpha serum levels were quantified in 171 SLE patients and 215 healthy controls by ELISA techniques and polymorphisms at positions -1,082 and -308 of the IL-10 and TNFalpha gene promoters were determined by PCR amplification followed by hybridization with fluorescent-labeled allele-specific probes in 192 SLE patients and 343 matched controls. Data were related to clinical features and treatment at the time of sampling and during the course of the disease. Results showed a significantly higher amount of serum TNFalpha in the entire SLE population compared with controls. However, TNFalpha serum levels correlated negatively with the use of antimalarial treatment during at least three months before sampling. Patients under single or combined treatment with these drugs had TNFalpha serum levels similar to healthy controls, whereas untreated patients and those under corticosteroid or immunosuppressive therapies had increased amounts of this cytokine. This suggests, however, that antimalarial-mediated inhibition of TNFalpha was only significant in patients who were genetically high TNFalpha or low IL-10 producers. In addition, evaluation of SLE patients administered antimalarial drugs for three or more years who did not require any other specific SLE treatment indicates that patients with the combined genotype low IL-10/high TNFalpha are the best responders to antimalarial therapy, developing mild disease with a good course under this treatment. In conclusion, we proposed that an antimalarial-mediated downregulation of TNFalpha levels in SLE patients is influenced by polymorphisms at IL-10 and TNFalpha promoters. Our results may thus find important clinical application through the identification of patients who are the most likely to benefit from antimalarial therapy.

Adult↗

Characterization of noncovalent complexes of antimalarial agents of the artemisinin-type and FE(III)-heme by electrospray mass spectrometry and collisional activation tandem mass spectrometry.

In this study, we demonstrate, using electrospray ionization mass spectrometry (ESI-MS) and collision-induced dissociation tandem mass spectrometry (ESI-MS/CID/MS), that stable noncovalent complexes can be formed between Fe(III)-heme and antimalarial agents, i.e., quinine, artemisinin, and the artemisinin derivatives, dihydroartemisinin, alpha- and beta-artemether, and beta-arteether. Differences in the binding behavior of the examined drugs with Fe(III)-heme and the stability of the drug-heme complexes are demonstrated. The results show that all tested antimalarial agents form a drug-heme complex with a 1:1 stoichiometry but that quinine also results in a second complex with the heme dimer. ESI-MS performed on mixtures of pairs of various antimalarial agents with heme indicate that quinine binds preferentially to Fe(III)-heme, while ESI-MS/CID/MS shows that the quinine-heme complex is nearly two times more stable than the complexes formed between heme and artemisinin or its derivatives. Moreover, it is found that dihydroartemisinin, the active metabolite of the artemisinin-type drugs in vivo, results in a Na(+)-containing heme-drug complex, which is as stable as the heme-quinine complex. The efficiency of drug-heme binding of artemisinin derivatives is generally lower and the decomposition under CID higher compared with quinine, but these parameters are within the same order of magnitude. These results suggest that the efficiency of antimalarial agents of the artemisinin-type to form noncovalent complexes with Fe(III)-heme is comparable with that of the traditional antimalarial agent, quinine. Our study illustrates that electrospray ionization mass spectrometry and collision-induced dissociation tandem mass spectrometry are suitable tools to probe noncovalent interactions between heme and antimalarial agents. The results obtained provide insights into the underlying molecular modes of action of the traditional antimalarial agent quinine and of the antimalarials of the artemisinin-type which are currently used to treat severe or multidrug-resistant malaria.

Antimalarials↗

A comparison of oral artesunate and artemether antimalarial bioactivities in acute falciparum malaria.

AIMS: Artesunate and artemether are the two most widely used artemisinin derivatives in the treatment of uncomplicated Plasmodium falciparum malaria, but there is little information on their comparative pharmacokinetics. The aim of this study was to examine the relative oral antimalarial bioavailability and pharmacokinetics of the two derivatives. METHODS: The pharmacokinetic properties of oral artesunate and artemether (4 mg kg(-1)) were compared in a randomized cross-over study of 14 adult patients in western Thailand with acute uncomplicated Plasmodium falciparum malaria. Antimalarial activity was compared using a previously validated, sensitive bioassay. RESULTS: Despite a 29% lower molar dose, oral artesunate administration resulted in significantly larger mean area under the plasma antimalarial activity time curve and median maximum plasma antimalarial activity than after oral artemether (P <or= 0.02). The mean (95% CI) oral antimalarial bioavailability of artemether, relative to oral artesunate, corrected for molar dose was 58 (40-76)%. The mean (95% CI) relative antimalarial bioavailability of artemether was lower on the first day of treatment, 31 (17-100)%, compared to the second day, 72 (44-118)% (P = 0.018). In vivo parasite clearance and time above the in vitro IC90 were similar for the two drugs, despite considerable differences in Cmax and AUC. CONCLUSIONS: The oral antimalarial bioavailability following artemether was significantly lower than that after artesunate. Artemether oral antimalarial bioavailability is reduced in acute malaria.

Acute Disease↗

Crystal and molecular structure of the antimalarial agent enpiroline.

To identify common spatial and structural features of amino alcohol antimalarial agents with the eventual goal of designing more effective drugs and a better understanding of the mechanism of action of this class of antimalarial agents, the three-dimensional crystal and molecular structure of enpiroline, a new antimalarial agent active against chloroquine-resistant Plasmodium falciparum, was determined by X-ray crystallography and compared with the crystal structures of the cinchona alkaloids and of the new antimalarial agent WR 194,965. The aromatic rings of the phenyl-pyridine ring system of enpiroline are twisted from each other by approximately 18 degrees. The intramolecular aliphatic N-O distance in enpiroline was 2.80 A (1 A = 0.1 nm), which is close to the N-O distance found in the antimalarial cinchona alkaloids. Enpiroline contains both an intramolecular hydrogen bond between the aliphatic nitrogen and oxygen atoms and an intermolecular hydrogen bond between the aliphatic nitrogen and oxygen atoms of two neighboring molecules. One enantiomer of enpiroline superimposed best with quinine, and the other enantiomer of enpiroline superimposed best with quinidine, suggesting that both enantiomers of enpiroline possess antimalarial activity. Since a common feature of the crystal structures of the amino alcohol antimalarial agents is the formation of intermolecular hydrogen bonds, the common spatial direction of hydrogen bond formation indicates the potential ability of these antimalarial agents to bind to a common receptor site. The crystallographic parameters were as follows: C19H18F6N5O; Mr = 404.3; symmetry of unit cell, monoclinic; space group, P2(1)/a; parameters of unit cell---a = 9.454 +/- 0.004 A, b = 18.908 +/- 0.008 A, c = 10.300 +/- 0.004 A, and beta = 96.55 +/- 0.03 degrees: V (volume of unit cell) = 1829.2 A3; Z (number of molecules per unit cell) = 4; Dchi (calculated density) = 1.46 g cm-3; source of radiation, CuK alpha (lambda = 1.54178 A); mu (absorption coefficient) = 11.49 cm-1; F(000) (sum of atomic scattering factors at zero scattering angle) = 832; room temperature; final R = 8.7% for 1,798 reflections with [F0] > 3 sigma.

Antimalarials↗

Storage of antimalarials at household level and associated factors in Kiromo ward, Bagamoyo Tanzania.

BACKGROUND: Malaria is a highly debilitating and frequently fatal disease of wide distribution. Improper drug storage and rampant self-medication are some of the factors that may contribute to an increase in the development of drug resistance by malaria parasites towards antimalarials. OBJECTIVES: To determine the extent of antimalarial drugs storage, sources and associated factors at household level at Kiromo ward in Bagamoyo, Coast region, Tanzania after the introduction of SP replacing chloroquine as first line. METHODS: A total of 300 households from three villages making up Kiromo ward were included in this study. Swahili version of the questionnaire and a checklist were used in data collection. RESULTS: Of the 300 households visited 25 (8.3%) were found to store antimalarials. The most commonly stored antimalarials were amodiaquine (30.8%) and quinine (34.6%). Most of these were in tablet form (76.9%). The source of these drugs was mostly from dispensaries. Kiromo was the only dispensary in the ward and others were outside the ward. These drugs were stored in special containers for safety. Frequent episodes of illness in the family were given as the most (56%) common reasons for drug storage in the families, followed by distance (20%). There was a statistically significant (p<0.05) association between storage of antimalarial drugs and number of children in the family and presence of a family member with febrile illness. The study further showed that out of 26 different types of antimalarials stored, only 7 (26.9%) had expiry dates on the containers because these were original containers of the drugs. CONCLUSION: The study revealed that few households store antimalarial drugs with amodiaquine and quinine being the most stored. The majority of the households obtained antimalarial drugs from dispensaries. Health education should be given not only to the patients but also the entire general public on the appropriate drug use, safety, expiry dates and appropriate storage. A model dispensary like Kiromo should be implemented in other rural areas.

Adult↗

Overview: clinical pharmacology of antimalarials.

The effectiveness of antimalarials depends on its pharmacodynamics ie inhibitory effect on the parasites and unwanted effects on the host. It also depends on the pharmacokinetics of the drugs. The ideal antimalarials are drugs that show curative activity in the absence of toxicity to the host. Recommendation for antimalarial dosage regimens should be based on pharmacokinetic and pharmacodynamic studies in appropriate populations ie ethnic groups, adults children, and in pregnancy. Chloroquine remains the drug of choice for treating malaria caused by Plasmodium species other than P. falciparum. Even in the presence of chloroquine resistance the drug may still be quite useful, especially in areas with high communal immunity. In general sulfadoxine/pyrimethamine (S/P) should be used as an alternative antimalarial when chloroquine fails. The decision to change to S/P from chloroquine depends on many factors. Quinine still remains the drug of choice for severe chloroquine-resistant falciparum malaria. Resistance to mefloquine has appeared the exact mechanism being unknown. In general, before the use of any combination of antimalarial drugs the superiority (efficacy and side-effects) over each of the individual drugs should be clearly demonstrated. The combination of mefloquine with sulfadoxine/pyrimethamine was made on the grounds that the combination would delay the resistance to mefloquine. Desferrioxamine will hardly be an agent to be used on its own for treating malaria due to the high recrudescent rate. However, a recent report indicated that its association with antimalarial drugs in the management of severe and complicated falciparum malaria shortens fever and parasite clearance time and resolves complications faster than the standard antimalarial drug alone. Clinical trials with halofantrine has been done in several countries in the region from 1988 to the present with diverse results. Further studies on a larger scale should be carried out to ascertain whether these are due to variation in drug absorption or drug resistance. An improved formulation of halofantrine must be developed to ensure adequate absorption and bioavailability. The artermisinin group of antimalarials is known to be highly effective and independent, in its mode of action, from standard malaria drugs but associated with high recrudescent rate. Phase II studies are needed for determining/optimizing therapeutic dose regimens and to ensure safer and more effective use of these compounds.

Antimalarials↗

The efficacy of antimalarials in systemic lupus erythematosus.

The use of antimalarial drugs to treat systemic lupus erythematosus (SLE) is reviewed regarding their value in SLE of mild-to-moderate disease activity, as corticosteroid-sparing agents, and as an adjunctive therapy in severe SLE. A retrospective controlled study of a variety of antimalarials and a randomized discontinuation trial of hydroxychloroquine support the considerable clinical belief that antimalarials are of benefit in mild-to-moderate SLE. Anecdotal reports and the opinion of experienced clinicians suggest that antimalarials permit the use of lower doses of corticosteroids. No controlled study has confirmed a corticosteroid-sparing role for antimalarials, although no controlled study has been conducted specifically to address this hypothesis. The data on antimalarials in severe SLE are scant. Antimalarials are likely effective in at least a subgroup of SLE patients with mild-to-moderate disease activity. Whether these agents are corticosteroid sparing and prevent severe disease exacerbations is unproven. Given the low toxicity of antimalarials, further studies are clearly warranted.

Adrenal Cortex Hormones↗

In vitro antimalarial activity of extracts of Albizia gummifera, Aspilia mossambicensis, Melia azedarach and Azadirachta indica against Plasmodium falciparum.

Since chemotherapy is presently the primary strategy of malaria control in the world, and some malaria parasites are developing resistance to the commonly used antimalarial drugs, new antimalarial compounds are required. Therefore, it is important to test antimalarial activities of medicinal plant extracts which most herbalists claim to cure malaria. We evaluated the antimalarial activities of extracts of Albizia gummiffera, Aspilia mossambicensis, Melia azedar and Azadirahchta indica against laboratory adapted isolates of Plasmodium falciparum using an in vitro radioisotopic uptake technique. Chloroquine was used as a reference antimalarial drug. Al. gummifera had the highest antimalarial activity (mean fifty percent inhibitory concentration {IC(50)S} in ug/ml of test culture =3.5 +1.6SD, n=3) followed by As. mossambicensis (mean IC(50)=29.3+11.8SD, n=4) and Me. Azedarach (mean IC(50) =299.7+202.0SD, n=4). And lastly Az. Indica (mean IC(50)=349.9+213.1 SD, n=4). The antimalarial activities of the reference drug, chloroquine, was far much higher (mean IC(50)=0.065+0.057SD, n=)4). These findings show that Al. gummifera and As. mossambicensis plant extracts have potent antimalarial compounds. Phytochemical analyses should be done on these two plants to isolate the compound(s) containing he active principles(s).

Journal Article↗

Antimalarial drug induced decrease in creatinine clearance.

OBJECTIVE: To confirm the antimalarial drug induced increase of creatinine to determine the factors contributing to this effect. METHODS: Patients with rheumatoid arthritis (RA) (n = 118) who have used or still use antimalarials (chloroquine or hydroxychloroquine). Serum creatinines prior to antimalarials and serum creatinines during antimalarials were recorded and the creatinine clearance was estimated. RESULTS: The mean creatinine clearance decreased from 99 ml/min to 92 ml/min (p < 0.001) after the start of antimalarial drugs. Fifty-five percent of the patients with chloroquine compared to 15% of the patients with hydroxychloroquine (chi 2 = 17.8; p < 0.001) had more than 10% decrease of the creatinine clearance. Age (beta = 0.004; p = 0.0002) and the kind of antimalarial (beta = 0.095; p = 0.0002) were strong independent predictors of the decrease of the creatinine clearance in the multiple regression analysis. For patients using chloroquine the mean age adjusted decrease of creatinine clearance was 11.2%. CONCLUSION: Antimalarials cause a significant reduction of the creatinine clearance. The use of chloroquine and older age were associated with decreased creatinine clearance. Whether antimalarials affect glomerular filtration or tubular excretion of creatinine remains to be investigated.

Adult↗

The antimalarial effect of iron chelators: studies in animal models and in humans with mild falciparum malaria.

In this study we explore the antimalarial effects of 3-hydroxypyridin-4-ones (CP compounds), a family of bidentate orally effective iron chelators in experimental animal systems in vivo and in vitro, and examine whether the iron chelator deferoxamine (DF) is active against human infection with P. falciparum. There was direct relation between lipid solubility of the CP compounds, which would facilitate membrane transit, and their in vivo antimalarial action, suggesting direct intracellular iron chelation as the most likely explantation for the antimalarial effect of iron chelators. Results of the double-blind, placebo controlled trial of DF in humans with asymptomatic parasitemia provided unequivocal evidence that this iron-chelating agent has antimalarial activity. Depriving the parasite of a metabolically important source of iron may represent a novel approach to antimalarial drug development. DF is a relatively ineffective intraerythrocytic chelator, and our data indicate that other orally effective iron chelators may have superior antimalarial activity in vivo. A systematic screening of available iron chelating drugs may result in the identification of potentially useful antimalarial compounds.

Animals↗

Therapeutic responses to antimalarial and antibacterial drugs in vivax malaria.

Plasmodium vivax is the most prevalent malaria infection and is an important cause of morbidity in Central and South America and Asia. P. vivax is generally sensitive to the common antimalarial drugs but high level resistance to chloroquine and/or pyrimethamine has been documented in some geographic locations. In the studies reviewed here, the therapeutic responses to antimalarial and antibacterial drugs in vivax malaria have been assessed in the Bangkok Hospital for Tropical Diseases. The evaluated drugs consisted of the eight most widely used antimalarial drugs and anti-bacterial drugs that possess antimalarial activities (tetracycline, doxycycline, clindamycin or azithromycin). The activities of these drugs in descending order of parasite clearance times were artesunate, artemether, chloroquine, mefloquine, quinine, halofantrine, primaquine, followed by the antibacterial drugs and lastly sulfadoxine-pyrimethamine. Clinical responses to sulfadoxine-pyrimethamine were also poor with evidence of high grade resistance in 42% of the patients. Of the four antibacterial drugs, clindamycin was more effective than azithromycin and can be an alternative to the tetracyclines. Except for chloroquine and mefloquine which have long plasma half lives and may therefore suppress first relapses, the cumulative cure rates for the short acting antimalarial drugs were similar. Double infection with Plasmodium falciparum was common and usually manifested 3-4 weeks following clearance of vivax malaria. The prevalence of cryptic falciparum malaria was 8-15% and was higher in patients treated with less potent antimalarial drugs. Follow-up studies have revealed that the relapse time in Thai patients with vivax malaria is on average only 3 weeks, but can be suppressed by the slowly eliminated antimalarial drugs such as chloroquine and mefloquine. For accurate comparison of relapse/recrudescence rates in vivax malaria, at least 2 month's follow-up is required. It can be concluded that in malarious areas of Thailand, double infection with P. falciparum and P. vivax is common affecting at least 25% of the patients and usually manifests as sequential illnesses. P. vivax in Thailand is sensitive to chloroquine but has acquired high grade resistance to sulfadoxine-pyrimethamine.

Anti-Infective Agents↗

Antimalarial dyes revisited: xanthenes, azines, oxazines, and thiazines.

In 1891 Guttmann and Ehrlich (P. Guttmann and P. Ehrlich, Berlin Klin. Wochenschr. 28:953-956, 1891) were the first to report the antimalarial properties of a synthetic, rather than a natural, material when they described the clinical cure of two patients after oral administration of a thiazine dye, methylene blue. Since that time, sporadic reports of the antimalarial properties of several xanthene and azine dyes related to methylene blue have been noted. We report here the results from a reexamination of the antimalarial properties of methylene blue. Janus green B, and three rhodamine dyes and disclose new antimalarial data for 16 commercially available structural analogs of these dyes. The 50% inhibitory concentrations for the chloroquine-susceptible D6 clone and SN isolate and the chloroquine-resistant W2 clone of Plasmodium falciparum were determined by the recently described parasite lactate dehydrogenase enzyme assay. No cross-resistance to chloroquine was observed for any of the dyes. For the 21 dyes tested, no correlation was observed between antimalarial activity and cytotoxicity against KB cells. No correlation between log P (where P is the octanol/water partition coefficient) or relative catalyst efficiency for glucose oxidation and antimalarial activity or cytotoxicity was observed for the dyes as a whole or for the thiazine dyes. The thiazine dyes were the most uniformly potent structural class tested, and among the dyes in this class, methylene blue was notable for both its high antimalarial potency and selectivity.

Animals↗

Heme binding contributes to antimalarial activity of bis-quaternary ammoniums.

Quaternary ammonium compounds have received recent attention due to their potent in vivo antimalarial activity based on their ability to inhibit de novo phosphatidylcholine synthesis. Here we show that in addition to this, heme binding significantly contributes to the antimalarial activity of these compounds. For the study, we used a recently synthesized bis-quaternary ammonium compound, T16 (1,12-dodecanemethylene bis[4-methyl-5-ethylthiazolium] diodide), which exhibits potent antimalarial activity (50% inhibitory concentration, approximately 25 nM). Accumulation assays reveal that this compound is readily concentrated several hundredfold (cellular accumulation ratio, approximately 500) into parasitized erythrocytes. Approximately 80% of the drug was shown to be distributed within the parasite, approximately 50% of which was located in the parasite food vacuoles. T16 uptake was affected by anion substitution (permeation increasing in the order Cl(-) < Br(-) = NO(3)(-) < I(-) < SCN(-)) and was sensitive to furosemide-properties similar to substrates of the induced new permeability pathway in infected erythrocytes. Scatchard plot analysis of in situ T16 binding revealed high-affinity and low-affinity binding sites. The high-affinity binding site K(d) was similar to that measured in vitro for T16 and ferriprotoporphyrin IX (FPIX) binding. Significantly, the capacity but not the K(d) of the high-affinity binding site was decreased by reducing the concentration of parasite FPIX. Decreasing the parasite FPIX pool also caused a marked antagonism of T16 antimalarial activity. In addition, T16 was also observed to associate with parasite hemozoin. Binding of T16 to FPIX in the digestive food vacuole is shown to be critical for drug accumulation and antimalarial activity. These data provide additional new mechanisms of antimalarial activity for this promising new class of antimalarial compounds.

Animals↗

Cardiomyopathy related to antimalarial therapy with illustrative case report.

The antimalarial agents, chloroquine (CQ) and hydroxychloroquine (HCQ) are used in long-term treatment of connective tissue diseases and dermatological disorders and are generally regarded as safe. We present one case of cardiotoxicity in a 59-year-old woman treated with antimalarials during 13 years for a discoid lupus erythematosus. She progressively developed conduction disturbances and congestive heart failure (CHF). When the diagnosis of antimalarials toxicity was suspected, CQ was withdrawn. However, heart transplantation had to be performed in the following 4 months for severe CHF. Indeed, rare but severe cardiotoxicity may develop following prolonged use of antimalarials with both conduction disturbances (45 patients) and CHF (25 patients). These cardiac toxic effects have been reported with CQ and less frequently with HCQ use alone. Diagnoses are often delayed since the toxicity of the drug might be misattributed to other factors in these patients. The endomyocardial biopsy, or in some cases the muscle biopsy, are essential to confirm the antimalarials toxicity. Antimalarials have been stopped in 12 cases of CHF, leading to improvement in 8 cases (within 3 months to 5 years) and to deaths or to heart transplantation in 4 cases (within 1 week to 3 months). In the latter cases, as in our patient, the lack of improvement may have been explained by the severity of the cardiomyopathy at diagnosis and the short delay since withdrawal. As a consequence, the potential for reversibility and the severity in undiagnosed cases of these toxic cardiomyopathies emphasize the importance of recognizing early signs of toxicity in order to withdraw antimalarials before the occurrence of life-threatening CHF.

Antimalarials↗

[Cytochrome P-450 and the response to antimalarial drugs].

OBJECTIVES: To assess the relationship between the genetic and phenotypic factors linked to the cytochrome P-450 enzyme system and the response to the antimalarial drugs chloroquine, amodiaquine, mefloquine, and proguanil, as well as to determine how certain biological and social factors of the host influence the behavior of this enzymatic complex. METHODS: We performed a systematic review of the medical bibliographic databases PubMed, Excerpta Medica, LILACS, and SciELO by using the following Spanish and English descriptors: "CYP-450" and "citocromo P-450" in combination with "proguanil" (and with "mefloquina," "cloroquina," and "amodiaquina"), "farmacocinética de proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina"), "resistencia a proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina"), "metabolismo," "farmacogenética," "enfermedad," "inflamación," "infección," "enfermedad hepática," "malaria," "nutrición," and "desnutrición." The same terms were used in English. The search included only articles published in Spanish, English, and Portuguese on or before 30 June 2005 that dealt with only four antimalarial drugs: amodiaquine, chloroquine, mefloquine, and proguanil. RESULTS: Some genetic factors linked to human cytochrome P-450 (mainly its polymorphism), as well as other biological and social factors (the presence of disease itself, or of inflammation and infection, the use of antimalarials in their various combinations, and the patient's nutritional status) influence the behavior of this complex enzymatic system. It has only been in the last decade that the genetics of the cytochromes has been explored and that the mechanisms underlying some therapeutic interactions and aspects of drug metabolism have been uncovered, making it possible to characterize the biotransformation pathway of amodiaquine and chloroquine. Hopefully new research will help answer the questions that still remain, some of which pertain to the metabolism of other antimalarial drugs, the distribution in the population of the genetic alleles linked to the enzymes involved in their metabolism, the contribution of these genetic mutations to therapeutic failure, and the possibility of predicting the response to antimalarial therapy. CONCLUSIONS: The therapeutic response to antimalarial drugs is a multifactorial process that is poorly understood, so that it is not possible to ascribe to a specific phenotype or genotype a role in the response to antimalarial therapy. Attention should be given to biological and social factors, such as diet, nutritional status, and inflammatory and infectious processes that are often present in areas where malaria is endemic.

Administration, Oral↗

Optimal use of antimalarials in treating cutaneous lupus erythematosus.

Antimalarials have been used to treat cutaneous and systemic lupus erythematosus (LE) for decades. Although controlled studies comparing the efficacy of antimalarials versus placebo and other treatments are generally lacking, many case reports and series support the therapeutic efficacy of these agents in treating both LE-specific and -nonspecific skin lesions. Currently, the two most frequently used antimalarial agents are chloroquine and hydroxychloroquine. There may be a delay of weeks to months in the onset of therapeutic effects of antimalarials when treating LE. Smoking appears to inhibit the therapeutic efficacy of antimalarials when treating cutaneous LE. Antimalarials have been associated with a number of potentially serious adverse effects, including irreversible loss of vision. The aim of this review is to discuss the many facets of antimalarials that will help clinicians optimally utilize these agents when treating cutaneous LE.

Antimalarials↗

Trends in antimalarial prescriptions in Australia from 1998 to 2002.

BACKGROUND: Previous research in a number of countries has suggested considerable variability in prescribing patterns of antimalarial drugs. The aim of this study was to investigate the trends in prescription of antimalarial drugs recommended for chemoprophylaxis in Australia from 1998 to 2002. METHODS: In 2005 data was extracted from the online Australian Statistics on Medicines reports published by the Pharmaceutical Benefits Advisory Committee, Drug Utilization Sub-committee, on antimalarials used in Australia from 1998 to 2002. RESULTS: Doxycycline probably remains the malaria chemoprophylaxis of choice prescribed for Australians visiting multiple drug-resistant malarious areas. Over the past 10 years, there has been marked drop in the prescription of less useful antifolate drugs such as pyrimethamine combination antimalarial drugs, especially pyrimethamine plus dapsone, which was withdrawn by 1999. There has also been a reduction in the number of prescriptions for chloroquine, mefloquine, and proguanil. The number of prescriptions for atovaquone and proguanil remain small, although they have increased steadily since its introduction in 2000, in the absence of a recommendation in the prevailing Australian guidelines. CONCLUSIONS: The prescription of antimalarials such as proguanil, chloroquine, mefloquine, and the pyrimethamine-containing compounds reduced considerably between 1998 and 2002. This was probably largely influenced by the availability of antimalarials, increasing resistance, the issuing of updated guidelines for malaria chemoprophylaxis, and continuing education. Newer drugs such as atovaquone plus proguanil may displace older antimalarials, particularly in the prevention of Plasmodium falciparum infection.

Antimalarials↗