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PubMed1994

[Synthesis of 4-methyl-5-substituted phenoxy-primaquine analogues and preliminary evaluation on their antimalarial activity].

On basis of our previous work, seven 4-methyl-5-substituted phenoxy-6-methoxy-8-(1-methyl-4-amino-butylamino)-quinolines (II2-8) were synthesized and their antimalarial activities were preliminarily evaluated. The target compounds were prepared from 2-nitro-4-methoxy-5-bromo-acetanilide as previously described. The structures of II2-8 and all of the unknown intermediates were confirmed by elementary and spectral analyses. Preliminary biological evaluation revealed that all of II2-8 exhibited significant blood schizonticidal activity and were 4-8 times as effective as primaquine in causal prophylactic test in mice.

Animals↗
PubMedDate not supplied

[Malaria morbidity and therapeutic efficacy of antimalarials. Study conducted in the Dakar region].

During November and December 1992, the authors surveyed the malaria morbidity and the drugs efficiency in an urban area of Dakar region. Malaria represented 13.68% of the fevers in Dakar district and 12.4% in Pikine. The mean parasitic density was evaluated at 5000/mm3. Good efficiency of antimalarial drugs were noted but chloroquine-resistance is present with 24% of prevalence.

Adolescent↗
PubMed1994

Antimalarial action of hydrophilic drugs: involvement of aqueous access routes to intracellular parasites.

The antimalarial action and intracellular distribution of the hydrophilic agents phloridzin (PHL) (a bioflavonoid glycoside) and desferrioxamine (DFO) (an iron chelator) were studied in cultures of Plasmodium falciparum-infected human erythrocytes. When added to cultures, these agents arrested parasite growth with IC50 values of 12 microM (PHL) and 22 microM (DFO). At 37 degrees, PHL (40 microM) was virtually impermeant to uninfected cells but permeated with a mean t1/2 of 1.5 hr in trophozoites (30% accessible cell volume) and 8 hr in rings (10% of accessible cell volume). PHL, in analogy with DFO, was demonstrably permeant to infected cells harboring mature forms of the parasites. Permeation was restricted to only a fraction of the infected cell volume. PHL elicited inhibition of nucleic acid synthesis within 1 hr of exposure of trophozoites to PHL (40 microM) and in > 8 hr of exposure of rings. Red cell containers into which millimolar concentrations of PHL or DFO were encapsulated demonstrably supported parasite invasion and subsequent parasite growth and maturation (48-hr incubation). Under culture conditions, uninfected or parasite-infected red cell containers that were loaded with either agent retained the drugs for at least 42 hr at hundred-micromolar concentrations. The agent present in the cells was fully active after release from cells and administration to test cultures of parasites. PHL added to parasite cultures was active at micromolar concentrations, but when present intracellularly it was virtually inactive even at millimolar concentrations. The data presented are consistent with direct access of hydrophilic agents from medium to parasite, a process referred to as fenestration. Permeation into parasites might constitute the rate-limiting step in drug uptake and drug-mediated arrest of parasite growth by PHL and DFO. The putative role of the parasitophorous duct in providing aqueous access routes from medium to parasites is discussed.

Animals↗
PubMed1993

Antimalarial drug utilization by women in Ethiopia: a knowledge-attitudes-practice study.

A survey was undertaken between December 1991 and February 1992 to assess the knowledge, attitudes, and practices with respect to malaria of 300 women from six randomly selected rural communities in central Ethiopia. A total of 85% were able to recognize one or more of the common symptoms of the disease; however, the modes of transmission were generally misunderstood and only 23% believed that transmission could be prevented. More women preferred to obtain antimalarials from government clinics rather than from private drug shops, mission clinics, unofficial suppliers of injections, open markets, or from leftover sources. Under-5-year-olds were identified as the most malaria-vulnerable group and given priority for treatment; severity of illness was the principal determinant in seeking treatment. Decisions about treatment were generally made jointly by both parents. Knowledge about the transmissibility of malaria decreased with increasing distance from a health unit (odds ratio: 0.48; 95% confidence interval: 0.27, 0.86). A logistic regression analysis indicated that literacy and village were the most important variables associated with knowledge about preventing malaria.

Adolescent↗
PubMed1993

Mode of action of iron (III) chelators as antimalarials: I. Membrane permeation properties and cytotoxic activity.

We have designed two subfamilies of lipophilic iron (III) chelators previously termed reversed siderophores (RSFs). The agents display physicochemical properties that favor extraction of iron beyond membrane barriers of Plasmodium falciparum-infected red blood cells. We studied the in vitro antimalarial potency of RSFs and their relationship to the membrane permeation properties of these agents. The mode of RSF action involves: (1) fast access to intracellular compartments of parasitized cells; (2) selective and high-affinity chelation of iron (III) from parasitized cells; (3) fast exit from cells after iron (III) complexation; and (4) exertion of cell damage on parasites exposed for 3 to 5 hours to drugs, irrespective of the stage of parasite development. These results suggest that on reaching a critical intraerythrocyte target, RSFs induce an iron deficit that parasites in general, and rings in particular, have limited capacity to restore.

Animals↗
PubMed1993

Ophthalmologic safety profile of antimalarial drugs.

The ophthalmologic safety of antimalarial drugs is well established, but absolute safety cannot be assured. Three types of side effects may develop. Corneal deposits and neuromuscular-associated blurred vision are always reversible and therefore benign. Visual loss has occurred in patients with retinopathy. Retinopathy may be divided into true retinopathy and premaculopathy. It is true retinopathy that may be associated with visual loss, while premaculopathy consists of subtle visual field and funduscopic abnormalities. These premaculopathic changes are generally completely reversible with drug discontinuation and have not been shown to progress. Hydroxychloroquine appears safer than chloroquine when currently accepted equivalent doses are used. Fewer than 20 patients with true retinopathy caused by hydroxychloroquine have been reported; more patients have developed true retinopathy when taking chloroquine. The safety profile is most dependent on low daily dose and regular ophthalmologic monitoring. The optimal strategy of ophthalmologic testing has not yet been determined, but visual acuity, funduscopic examination and visual field examination should be monitored. Self-administered ophthalmologic testing with Amsler grids may contribute additional safety but is not a replacement for physician testing.

Antimalarials↗
PubMed1995

The antimalarial drug, Ro 42-1611 (arteflene), does not affect cytoadherence and cytokine-inducing properties of Plasmodium falciparum malaria parasites.

The purpose of this study was to investigate the ability of the antimalarial drug, Ro 42-1611 to block parasite mediated cytokine induction in vitro as well as cytoadherence of infected erythrocytes to melanoma cells in vitro. The biological activity of Ro 42-1611 was confirmed as it blocked Plasmodium falciparum growth in cultures. Ro 42-1611, had no major effect on TNF, IL-alpha or IL-6 cytokine release from mononuclear cells stimulated with malaria antigens or lipopolysaccharide and it did not affect cell viability. Ro 42-1611 only slightly suppressed cytoadherence of infected erythrocytes to melanoma cells. The therapeutic effect of To 42-1611 appears to be confined to its parasite killing activity.

Adult↗
PubMed1995

Antimalarial activity of oxidized starch and cellulose imine derivatives.

With the purpose of screening potential antimalarial agents, oxidized starch imine derivatives of sulfonamides or pyrimidine - derivatives of sulfisoxazole (ML8), sulfameter (ML11) and trimethoprim (ML13) - and oxidized cellulose imine derivatives of dapsone (ML14), sulfadiazine (ML17), sulfamethoxazole (ML18), sulfisoxazole (ML19), sulfamethoxypyridazine (ML20) and sulfameter (ML22) were submitted to in vivo biological assays with mice infected with Plasmodium berghei. Only ML11 was 100% curative in test conditions; ML 17 showed the same effect as its prototype. The drug content in both prodrugs is lower in the applied dose than that used in the original drugs. It can be suggested that the latentiation enhanced the effectiveness of the prototypes.

Animals↗
PubMed1995

[Decision making policies on the utilization of antimalarials in response to a modification of chloroquine efficacity. Applications to Africa].

The strategy for malaria control in Africa is based on the association of malaria case management, selective and lasting vector control and prevention and control of outbreaks. Emergence and wide-spread of Plasmodium falciparum chloroquine resistance enjoins a change of the malaria case management. This change is difficult. It is function of the quality of health services, the epidemiological surveillance of malaria, the monitoring of drug efficacy and acceptability, the drug utilization policy, the time for reaction and adaptation to changes in new drug policy, the different epidemiological patterns. In Africa, alternatives to the loss of chloroquine efficacy are the implementation of public health performances, the control of the circulation of antimalarials, the training of health operators, the education of the beneficiary target populations and to draw up and implement strategies that are relevant, i.e. useful and usable.

Africa↗
PubMed1994

[The effect of an antimalarial agent (chloroquine) on acute phase reactants in patients with rheumatoid arthritis].

The effect of chloroquine on acute phase reactants and clinical features in rheumatoid arthritis patients was evaluated. The patients had also one of nonsteroid antiinflammatory drugs therapy. Following acute phase reactans were evaluated: erythrocyte sedimentation rate and haptoglobin. The number of swollen and painful joints were also evaluated. All parameters were evaluated before the beginning of the therapy and each 3 months of medication during 9 months. The patients were analyzed by therapy effect and they were divided in 3 groups: all patients, only the patients who responded and the patients who did not respond on antimalarials. Assessed clinical and laboratory parameters were most improved in patients who responded on therapy. Acute phase reactants are markers of activity of illness, better CRP and less other haptoglobin and other parameters erythrocyte sedimentation rate and haemoglobin.

Acute-Phase Proteins↗
PubMed1996

The use of antimalarials in combination with other disease modifying agents in rheumatoid arthritis--the French experience.

A significant proportion of patients with rheumatoid arthritis have an aggressive, severe disease that may contribute to excess mortality. It has been suggested that early, aggressive therapy might improve the prognosis of these patients with active, severe rheumatoid arthritis. Combinations of disease modifying anti-rheumatic drugs including antimalarials are increasingly used in patients with active disease. While several open trials showed encouraging results, some controlled studies gave less support for the use of combination therapy. Ongoing controlled trials of double or triple combination therapy, such as hydroxychloroquine, methotrexate and sulphasalazine, should help define its place in treating patients with rheumatoid arthritis.

Antimalarials↗
PubMed1996

Retinopathy and antimalarial drugs--the British experience.

A study at St. Thomas' Hospital and review of the literature show that retinopathy associated with antimalarial treatment is now much less common. This is probably due to the prescription of lower dosages and shorter durations of treatment and possibly due to the tendency to prescribe hydroxychloroquine rather than chloroquine. The dosage parameters associated with retinopathy are still uncertain as well as the best way to screen for it but the dosage/kg body weight appears to be important. We suggest that if hydroxychloroquine is prescribed in doses of less than 6.5 mg/kg the incidence of retinopathy is minimal. Ophthalmic screening can then be restricted to a baseline examination at the onset of treatment with a yearly examination of visual acuity and fundoscopy if treatment carries on after three years. Patients who have had over ten years of treatment need more careful and detailed follow up.

Antimalarials↗
PubMed1995

Status of antimalarial drugs under development.

Despite the urgent need of a new antimalarial drugs, particularly those against multiresistant falciparum malaria, only a limited number of drugs are now at an advanced stage of preclinical or clinical development. They include artemisinin derivatives, pyronaridine and benflumetol (all originally developed in China), as well as new antifolate combinations, the hydroxynaphoquinone atovaquone which has a novel mode of action, and a new 8-aminoquinoline which appears more active and less toxic than primaquine. Some of these drugs may become available in the next few years. It is therefore essential to find mechanisms to ensure that they are made available at an affordable price to the populations that really need them.

Antimalarials↗
PubMed1996

[Mechanisms and epidemiology of resistances to antimalarials].

Drug resistant malaria is mostly due to Plasmodium falciparum, a species highly prevalent in tropical Africa, Amazonia and South-East Asia and responsible for severe involvement of fever or anemia prompting more than a million death per year. Resistance originate from chromosomic mutations. Antimetabolite-resistant mutants (pyrimethamine and proguanil) are highly prevalent in Asia, America and East Africa. One to 3 point mutations on the dihydrofolate-reductase gene, the target enzyme, give moderate to high level of resistance. Molecular biology furnishes sensitive tools for population-based studies of resistance to these compounds. Four-aminoquinolines resistant mutants (chloroquine and amodiaquine) were encountered more than 10 years after a huge amount of these drugs has been sold. The level of resistance varies among parasites isolates populations. Impaired uptake of the drug by the parasite vacuole is a common characteristic of resistant strains. This phenotype is poorly correlated with PfMDR1 gene mutations on chromosome 5 but is strongly associated with a particular RFLP profile on chromosome 7. Amino-alcohol resistant falciparum malaria is scarce (quinine, mefloquine, halofantrine) and supposed to be associated with impaired uptake of the drug by the parasite, the mechanism of which is still unclear. In each of these three antimalarial drugs groups, the highly resistant level to a peticular compound, the highly prevalence of cross resistance of the malaria isolate. An established and strong drug pressure probably explains the multi-chemoresistance encoutered in South-East Asia and forests of South America. In Africa, frequent genetic recombinations in Plasmodium originates from a high level of malaria transmission, and falciparum chloroquine-resistance prevalence seems to stabilize at an equal level as chloroquine-sensitive malaria.

Animals↗
PubMed1997

[Adverse effects associated with antimalarial chemoprophylaxis].

BACKGROUND: To evaluate the frequency and type of adverse drug reactions associated to the antimalarial chemoprophylaxis advised to travellers visiting endemic areas. SUBJECTS AND METHODS: We included the travellers who from july 1992 to june 1994 came to the Travellers Advise Department and made short-term travels to areas with malarial infection risk. The adverse drug reactions were reported by the travellers through a questionnaire handed at the consulting room. The pharmacological regimens advised were: a) chloroquine base 5 mg/kg/week. b) chloroquine base 5 mg/kg/week + proguanil 100 mg/day if weight less than 55 kg and 200 mg/day if weight more than 55 kg. c) mefloquine 250 mg/week. RESULTS: We evaluated 1,054 questionnaires for the study. The 18.4% of the travellers reported adverse drug reactions. The 12.4% of the travellers who were on chloroquine, the 17.2% of those who were on chloroquine + proguanil and the 20.3% from mefloquine group presented adverse drug reactions (differences without significance). Comparing the regimens studied, we observed that neuropsychiatric reactions were more frequent in the mefloquine group (p < 0.01), the gastrointestinal reactions were less common in the chloroquine group (p = 0.04) and the transitory eye disorders were more frequent in the chloroquine + proguanil group (p = 0.01). In the mefloquine group the travellers with adverse drug reactions had a significantly lower weight than those who did not present them (p < 0.01). CONCLUSIONS: The adverse drug reactions reported agree with the toxicologic profile described in the literature about these drugs. Mefloquine presents an outstanding neuropsychiatric toxicity and is worse tolerated in low weight patients.

Adolescent↗
PubMed1997

The rat biliary metabolites of dihydroartemisinin, an antimalarial endoperoxide.

[13-14C]Dihydroartemisinin was administered to male rats (35 micromol kg-1, iv). Within 0-1 hr and 0-5 hr of dosing, 34.8 +/- 5. 2% (mean +/- SD, N = 6) and 48.4 +/- 5.9% of the radiolabel, respectively, was recovered in bile. Only 1.1 +/- 1.2% was recovered in bladder urine after 5 hr. The biliary metabolites were identified by LC/MS. The principal metabolite (21.1 +/- 9.3% of dose) was the biologically inactive dihydroartemisinin (DHA) glucuronide. The other metabolites were products of reductive cleavage and rearrangement of the endoperoxide bridge, a process known to generate reactive radical intermediates and abolish antimalarial activity. They were desoxy-DHA (3.3 +/- 2.0%) and its glucuronide (1.1 +/- 1.0%), 3-hydroxydesoxy-DHA glucuronide (2.9 +/- 1.8%), and the glucuronide of a ring-contracted tetrahydrofuran acetate isomer of DHA (6.9 +/- 5.6%).

Animals↗
PubMed1997

[Impact of antimalarial drug accessibility on malarial morbidity and chloroquine resistance. A study carried out in Touba (Senegal)].

In Touba, more important accessibility to antimalarial drugs and their uncontrolled use let to assure that the rate of malarial morbidity would be lower there than in other place in Senegal whereas the rate of chloroquine resistance would be higher. A checking survey of these assumptions has been carried out from october 15 to november 10, 1995 in Touba's health center. Among 227 feverish subjects investigated, 111 were Plasmodium falciparum carriers. Malarial bouts accounted for 48.9% of the feverish fits observed and for the major cause of consultation during the rainy season. These figures are higher than those usually observed in urban environment. Conversely, the rate of chloroquine resistance is lower than those observed in urban zones, since the therapeutic efficacy of chloroquine on Plasmodium falciparum was 100% in that survey.

Adolescent↗
PubMed1997

In vitro sensitivity of Plasmodium falciparum to eight antimalarials in China-Myanmar and China-Lao PDR border areas.

In 1991-1995 by using the Rieckmann in vitro micro-method, susceptibilities of Plasmodium falciparum to eight antimalarials in the China-Lao PDR and China-Myanmar border areas were tested. The resistant rates of P. falciparum to chloroquinine were 95.0%-100%; IC50 114-240nmol/l. P. falciparum resistant rates to amodiaquine resistance accounted for 83.5%-100%, IC50 52-72nmol/l. All cases were sensitive to quinine, IC50 470-608nmol/l. P. falciparum isolates from the Lao PDR frontier were highly sensitive to artesunate, dihydroartemisinin, and arteether. Resistant rates from other areas were 0-11%. P. falciparum from China-Myanmar and Lao PDR border areas were also sensitive to mefloquine, IC50 68-88nmol/l. A longitudinal survey of the sensitivity of P. falciparum in vivo on the China-Lao PDR border showed that the average defervescent time of falciparum malaria was treated by pyronaridine increased from 32.7 +/- 16.0 hours during 1984-85 to 56.2 +/- 27.4 hours in 1995; the recrudescence rate rose up from 15.2% to 37.5%. The results monitored in vitro showed that all cases assessed in 1988 for response to pyronaridine were sensitive, but 36.4% of cases had emerging resistance, IC50 increased from 13nmol/l to 40 nmol/l. The above results suggested that P. falciparum in these areas has expressed resistance to chloroquine and amodiaquine. However, the parasites are still sensitive to artemisinin, pyronaridine, mefloquine, quinine, but with a declining sensitivities.

Amodiaquine↗