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PubMed1993

Malaria chemosuppression in pregnancy. I. The effect of chemosuppressive drugs on maternal parasitaemia.

A randomized prophylactic drug trial was conducted in a malaria holoendemic area, in the Muheza District of Tanzania. Of 327 pregnant women, 124 received proguanil (PROG), 113 chloroquine (CQ), 90 the proguanil and chloroquine combination (CQ+PROG). Prophylaxis was supervised. Chemosuppressive efficacy was measured through the incidence of malaria breakthrough parasitaemias and clinical episodes. Groups were comparable by age, parity, residential area, and enrollment gestational age. Compliance and drug bio-availability was good. The median breakthrough time of the first parasitaemia episode for primigravidae (PG) and multigravidae (MG) was significantly shorter for the CQ group (PG = 56, MG = 78 days) than in the PROG (PG = 97, MG = 112 days) and the CQ+PROG (PG = 138, MG = 140 days) groups. 56% of the CQ group experienced 2 or more clinical episodes compared to 19% (PROG) and 10% (CQ+PROG). PROG and CQ+PROG did not differ significantly. Parasite densities and in vitro tests suggested that CQ selected for more and highly resistant strain(s). Proguanil is suitable for prophylaxis. However, proguanil resistance should be monitored as well as controlled drug distribution and usage. Malaria control strategies other than chemoprophylaxis should be investigated.

Adolescent↗
PubMed1993

Malaria chemosuppression in pregnancy. II. Its effect on maternal haemoglobin levels, placental malaria and birth weight.

The malaria prophylactic effects of chloroquine (CQ), proguanil (PROG), and chloroquine-proguanil combination (CQ+PROG) during pregnancy on maternal haemoglobin levels (Hb), placental malaria, and birth weight were assessed in Muheza, Tanzania. Within 2 months of prophylaxis, severe anaemia in primigravidae (PG) was reduced from 21% (22 cases) to 13% (13 cases). There was no positive effect in multigravidae (MG). Sustained increases in the mean Hb occurred in PG of the PROG and CQ+PROG groups. The mean Hb of PG of the CQ group decreased after an initial increase, possibly due to the selection of more and highly chloroquine-resistant strain(s). The mean birth weight of PG was highest in the CQ+PROG (2.89 kg) and least in the CQ group (2.71 kg). The CQ group had the highest low birth weight rate (LBW). The prevalence of placental malaria was highest in the CQ (28%) and lowest in the PROG group (12%). For all the prophylactic effects, PROG and CQ+PROG did not differ significantly. Thence, the deployment of CQ+PROG for prophylaxis would be unnecessary. Proguanil is a suitable alternative to chloroquine prophylaxis. Due to possible emergence of proguanil resistance, deployment of this drug should incorporate constant monitoring for resistance and the eventual prophylaxis efficacy. The search for other effective malaria control measures should continue.

Anemia↗
PubMed2005

[Malaria chemoprophylaxis in traveling children].

In France, 4,000 imported malaria cases are reported each year (7,000 to 8,000 estimated). Chemoprophylaxis is essential for prevention in travelers. When malaria is susceptible to chloroquine, this drug (Nivaquine) has to be used. It is given daily in France (1.5 mg/kg per day), from departure to four weeks after return. When low levels of chloroquino-resistance are reported, French authorities recommend the use of chloroquine + proguanil (Savarine) if the body weight is >50 kg or Nivaquine) + Paludrine), if <50 kg), or atovaquone + proguanil (Malarone). Nivaquine) (1.5 mg/kg per day) and Paludrine) (3 mg/kg per day) have to be pursued for one month after return, although Malarone) (1 pediatric tablet/10 kg per day, in children >10 kg weight) may be disrupted after one single week. Adverse events are rarer with atovaquone + proguanil, than with chloroquine + proguanil. When chloroquino-resistance is high, Malarone) or mefloquine (Lariam) are used. Weekly drug regimen is recommended with mefloquine (5 mg/kg per weight) for the travel duration and four weeks after return and the drug tolerance is good in pediatric prophylaxis. Doxycycline is used under conditions in children >8 years of age. New drugs as for tafenoquine, an amino-8 quinoleine, might enhance patients compliance if given monthly.

Antimalarials↗
PubMed1997

Effects of dual combinations of antifolates with atovaquone or dapsone on nucleotide levels in Plasmodium falciparum.

The triazine antifolates, cycloguanil and 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[(2,4,5-trichlorophenoxy)propy loxy]-1,3,5-triazine hydrobromide (WR99210), and their parent biguanide compounds, proguanil and N-[3-(2,4,5-trichlorophenoxy)propyloxy]-n-(1-methylethyl)-imido dicarbonimidic-diamine hydrochloride (PS-15), were tested in combination with a series of antimalarial drugs for synergism against Plasmodium falciparum growing in erythrocytic culture. Four synergistic combinations were found: cycloguanil dapsone, WR99210-dapsone, proguanil-atovaquone, and PS-15-atovaquone. Cycloguanil-dapsone or WR99210-dapsone had a profound suppressive effect on the concentration of dTTP in parasites while that of dATP increased. Depletion of dTTP is consistent with cycloguanil or WR99210 inhibiting dihydrofolate reductase and dapsone inhibiting dihydropteroate synthase. For the combinations proguanil-atovaquone and PS-15-atovaquone, the levels of nucleoside triphosphates (NTPs) and dNTPs were generally suppressed, suggesting that inhibition is not through nucleotide pathways but probably through another metabolic mechanism(s). Combinations of two synergistic pairs of antimalarial drugs, (proguanil-atovaquone)-(cycloguanil-dapsone) and (PS-15-atovaquone)-(WR99210-dapsone), were tested, and it was found that NTPs and dNTPs decreased much more than for a single synergistic combination. Dual synergistic combinations could play an important role in the therapy of multidrug-resistant malaria, just as combination chemotherapy is used to treat cancer.

Adenosine Triphosphate↗
PubMed2003

Hydroxychloroquine is much less active than chloroquine against chloroquine-resistant Plasmodium falciparum, in agreement with its physicochemical properties.

The 4-aminoquinoline drug hydroxychloroquine (HCQ) is reported to be as active as chloroquine (CQ) against falciparum malaria, and less toxic. Existing prophylactic regimens for areas where there is CQ-resistant malaria recommend CQ with proguanil as an alternative where none of the three preferred regimens (atovaquone-proguanil, doxycycline or mefloquine) is thought suitable. In such cases, toxicity is likely when CQ-proguanil is administered to persons being treated for autoimmune disease with daily HCQ. The question therefore arises whether in such circumstances HCQ could effectively replace the CQ component of the prophylactic combination. We confirmed similar activity of CQ and HCQ against CQ-sensitive Plasmodium falciparum, but found that whereas HCQ in vitro was 1.6 times less active than CQ in a CQ-sensitive isolate, it was 8.8 times less active in a CQ-resistant isolate. The result can also be predicted from an analysis of the physicochemical properties of CQ and HCQ. To give limited protective effect similar to 300 mg CQ base weekly against CQ-resistant P. falciparum would demand daily doses of HCQ above the recommended safe level. These observations contraindicate the use of HCQ in prophylaxis or treatment of CQ-resistant falciparum malaria. Where CQ-proguanil prophylaxis is the only option available in a patient on high-dose HCQ treatment, visiting a CQ-resistant area, replacement of the anti-inflammatory regimen by a daily CQ course at a suitable dose should be considered.

Animals↗
PubMed1981

Malaria prevention in travellers from the United Kingdom. Report of meetings convened by the Ross Institute.

Malaria prophylaxis is relative, not absolute, but can provide much protection. Travellers must take prophylactics regularly while in malarious areas and for one month thereafter; despite doing so, they may still develop malaria. For areas without chloroquine-resistant malaria, chloroquine, 300 mg base weekly, or proguanil, 100-200 mg daily, are preferred. In areas of chloroquine sensitivity there may be places with resistance to proguanil and pyrimethamine, but these places are not delineated. The risk of breakthrough of malaria is, therefore, least with chloroquine, but problems of potential side effects and regular medication are fewer with proguanil than chloroquine. Proguanil is preferred for long-term prophylaxis. Malaria poses a greater hazard for pregnant women and infants than do prophylactics. Pyrimethamine/sulphadoxine (Fansidar) or pyrimethamine/diaminodiphenyl sulphone (maloprim) are the preferred drugs for areas with prevalent chloroquine-resistant plasmodium falciparum. Fansidar is taken once a week and Maloprim also is usually recommended to be taken once a week.

Adolescent↗
PubMed2004

The risk of severe depression, psychosis or panic attacks with prophylactic antimalarials.

INTRODUCTION/OBJECTIVE: Experimental and observational studies have linked mefloquine use to an increased risk of developing neuropsychiatric adverse effects such as depression or psychoses. Most of these reports relied on interview-based information from travellers. We conducted a population-based observational study using a database of medical records to quantify and compare the risk of psychiatric disorders during or after use of mefloquine with the risk during use of proguanil and/or chloroquine, or doxycycline. STUDY DESIGN/METHODS: The study population was drawn from the large UK-based General Practice Research Database (GPRD). Subjects were aged from 17-79 years and were exposed to mefloquine, proguanil, chloroquine or doxycycline (or a combination of these drugs) at some time between 1990 and 1999. We performed a person-time and a nested case-control analysis to assess the risk of developing a first-time diagnosis of depression, psychosis or panic attack during or after use of these antimalarial drugs. RESULTS: Within the study population of 35 370 subjects (45.2% males), we identified 580 subjects with a first-time diagnosis of depression (n = 505), psychosis (n = 16) or panic attack (n = 57) and two subjects committed suicide. The incidence rates of first-time diagnoses of depression during current use of mefloquine, proguanil and/or chloroquine, or doxycycline, adjusted for age, gender and calendar year, were 6.9 (95% CI 4.5-10.6), 7.6 (95% CI 5.5-10.5) and 9.5 (95% CI 3.7-24.1)/1000 person-years, respectively. The incidence rates of psychosis or panic attacks during current mefloquine exposure were 1.0/1000 person-years (95% CI 0.3-2.9) and 3.0/1000 person-years (95% CI 1.6-5.7), respectively, approximately 2-fold higher (statistically nonsignificant) than during current use of proguanil and/or chloroquine, or doxycycline. The nested case-control analysis encompassed 505 cases with depression and 3026 controls, 16 cases with psychosis and 96 controls, and 57 cases with a panic attack and 342 controls. Current use of mefloquine was not associated with an elevated risk of developing depression. In a comparison between patients currently using mefloquine with all past users of antimalarials combined, the risk estimate was elevated for current users of mefloquine for both psychosis (odds ratio [OR] 8.0, 95% CI 1.0-62.7; p < 0.05) and panic attacks (OR 2.7, 95% CI 1.1-6.5; p < 0.05). CONCLUSION: The absolute risk of developing psychosis or panic attack appears low with all the antimalarials tested. No evidence was found in this large observational study that mefloquine use increased the risk of first-time diagnosis of depression when compared with the use of other antimalarials investigated in this study.

Adolescent↗
PubMedDate not supplied

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↗
PubMed1997

Neuro-psychiatric effects of antimalarials.

OBJECTIVE: To study the neuro-psychiatric adverse effects of antimalarial drugs. SETTING: Persons who visited a Travel Clinic in Rotterdam over a period of 3 months. DESIGN: Prospective cohort study on 394 persons taking mefloquine, 493 persons taking proguanil and 340 persons not taking antimalarial drugs who visited Africa, South America, Asia, or the Middle East. METHODS: All persons received a structured questionnaire within 14 days of their return to the Netherlands. The questionnaire consisted of questions regarding use of alcohol, smoking, general health, medical history, tropical diseases during the trip, and other medicines, and contained an extensive list of general complaints regarding all body systems at four levels of severity. A modified and validated version of the Profile of Mood States was included. RESULTS: In the study period, 2541 persons visited the Travel Clinic, of whom 1791 (70%) were both eligible and willing to co-operate. Of these 1791, data were obtained from 1501 (84%). Insomnia was most frequently encountered in users of mefloquine and mouth ulcers in proguanil users. After adjustment for gender, age, destination, and alcohol use, the relative risk for insomnia to mefloquine versus non-users of antimalarials was 1.6, and the excess risk was 6 per 100 users over an average period of 2 months. There were no significant differences between groups in depression, anxiety, agitation, and confusion. Stratification by gender demonstrated that insomnia was more common in women on mefloquine, but not in men. Also, women more frequently mentioned palpitations as an adverse event. After adjustment for age, destination, and alcohol use in women, the relative risks for insomnia and palpitations to mefloquine versus non-use of antimalarials were 2.4, and 22.5, respectively. When travellers were specifically asked for the adverse reactions they had experienced, anxiety, vertigo, agitation, and nightmares were significantly more frequently mentioned by mefloquine users. CONCLUSION: Insomnia was more commonly encountered during use of mefloquine than proguanil or during non-use of antimalarials.

Adult↗
PubMed1993

Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting east Africa.

There is much confusion over which malaria chemoprophylaxis should be used in areas such as East Africa. We did two consecutive studies between 1985 and 1991 to assess the efficacy and side-effects of malaria chemoprophylaxis in short-term travellers to East Africa. All passengers returning from Kenya to Europe received an in-flight questionnaire and a second one three months later. Any report of documented malaria or of admission to hospital for possible side-effects was verified with the physician. 145 003 travellers completed questionnaires. Among the 139 164 who stayed in East Africa for less than one year, 296 cases of confirmed malaria were reported (275 due to P falciparum). In people who used no chemoprophylaxis, the incidence of falciparum malaria was 1.2% per month. Prophylactic effectiveness was 91% (95% Cl 85 to 94) for mefloquine, 82% (71 to 89) for pyrimethamine and sulfadoxine, 72% (56 to 82) for chloroquine plus proguanil, and 10 to 42% for chloroquine at various doses. Rates of side-effects, which were usually mild, were 18.8% for mefloquine users, 17.1% and 18.6% for chloroquine 300 mg and 600 mg base per week, respectively, 30.1% for chloroquine plus proguanil, and 11.7% for sulfadoxine and pyrimethamine. Mefloquine is significantly more effective than chloroquine plus proguanil for malaria prophylaxis in short-term tourists visiting East Africa and has a tolerance similar to that of chloroquine used alone.

Adult↗
PubMed2003

Antidiabetic and antimalarial biguanide drugs are metal-interactive antiproteolytic agents.

Various biguanide derivatives are used as antihyperglycemic and antimalarial drugs (e.g., 1,1-dimethyl biguanide (metformin), phenylethyl biguanide (phenformin), N-(4-chlorophenyl)-N'-(isopropyl)-imidodicarbonimidic diamide (proguanil)); however, no common mechanism has been suggested in these controversial therapeutic actions. Biguanides bind endogenous metals that inhibit cysteine proteases independently, e.g., Zn(2+), Cu(2+), Fe(3+). Here, various biguanide derivatives are reported to be metal-interactive inhibitors of cathepsin B from mammals and falcipain-2 from Plasmodium falciparum. Structural homologies were identified among the Phe-Arg protease substrate motif and the metal complexes of phenformin and proguanil. Molecular modeling revealed that the position of the scissile amide substrate bond corresponds to the biguanide-complexed inhibitory metal when the phenyl groups are homologously aligned. Binding of the phenformin-metal complex within the active site of human cathepsin B was modeled with computational docking. A major binding mode involved binding of the drug phenyl group at the protease S2 subsite, and the complexed inhibitory metal shared between the drug and the protease Cys29-His199 catalytic pair. Cysteine protease inhibition was assayed with carbobenzyloxy-PHE-ARG-7-aminomethylcoumarin substrate. In the absence of metal ions, phenformin was a weakly competitive protease inhibitor (apparent K(i) several microM); however, metformin was noninhibitory. In contrast, the metal complexes of both metformin and phenformin were protease inhibitors with potency at therapeutic concentrations. Biguanide-metal complexes were more potent cysteine protease inhibitors than either the biguanide or metal ions alone, i.e., synergistic. Similar to chloroquine, therapeutic extracellular concentrations of metformin, phenformin, and proguanil caused metal-interactive inhibition of lysosomal protein degradation as bioassayed in primary tissue using perfused myocardium. The biguanide moiety is identified as a past and future structural scaffold for synthesis of many protease inhibitors. Results are discussed in relation to Zn(2+)-interactive inhibition of insulin degradation in hormone target tissues, and Fe(3+)-interactive inhibition of hemoglobin degradation in parasite food vacuoles. Previous studies on insulin hypercatabolism and insulin resistance are speculatively reviewed in light of present findings.

Animals↗
PubMed1999

Cognitive predictors of adherence to malaria prophylaxis regimens on return from a malarious region: a prospective study.

Cases of 'imported malaria' into countries where malaria is not endemic are increasing and evidence suggests that non-use of malaria prophylaxis and lack of adherence are contributing to this increase. Non-adherence may be especially likely because chemoprophylaxis regimens require travellers to continue to take medication for 4 weeks after their return from a malarious region. This study investigated the extent to which cognition measures specified by the theory of planned behaviour and the health belief model could distinguish between those who reported greater or lesser adherence after their return. Cognitions were measured using a brief questionnaire on the day of departure from the malarious region and reports of adherence were collected between 5 and 7 weeks later. Data from two longitudinal samples of UK tourists returning from The Gambia were analysed; 106 mefloquine users and 61 chloroquine and proguanil users. Results suggested that malaria prophylaxis adherence could be improved. 22.5% of mefloquine users and 31% of chloroquine and proguanil users reported adherence for 3 weeks or less. A model based on the theory of planned behaviour explained approximately 50% of the variance in reported adherence amongst mefloquine users and 40% amongst chloroquine and proguanil users, comparing favorably with other published applications of the theory. Findings suggest that targeting key cognitions could enhance adherence on return from malarious regions. Enhancing perceived control over adherence may be important as well as emphasising susceptibility to malaria infection. Reassuring mefloquine users concerning potential side effects of the drug may also encourage adherence on return. Implications for future research are discussed.

Adult↗
PubMed1992

Relation between chloroguanide bioactivation to cycloguanil and the genetically determined metabolism of mephenytoin in humans.

It has been suggested recently that the bioactivation of chloroguanide hydrochloride (proguanil) to its active antimalarial metabolite cycloguanil cosegregates with the genetically determined polymorphism of mephenytoin hydroxylation. We determined the chloroguanide to cycloguanil ratio in urine after oral administration of a single dose of 200 mg proguanil either alone or together with 100 mg racemic mephenytoin or 40 mg dextromethorphan in a randomized crossover study performed in 24 healthy subjects. The mephenytoin hydroxylation index was also determined after administration of 100 mg racemic mephenytoin either alone or together with 200 mg proguanil. Two subjects were poor metabolizers and one subject was an intermediate metabolizer of mephenytoin. These three subjects had chloroguanide to cycloguanil ratios of more than 50. The 21 subjects with the extensive metabolizer phenotype for mephenytoin hydroxylation had chloroguanide to cycloguanil ratios of less than 10. The chloroguanide to cycloguanil ratio was not significantly altered by mephenytoin or dextromethorphan coadministration. The trend toward a correlation between chloroguanide/cycloguanil ratio and log mephenytoin hydroxylation index did not reach statistical significance. Inclusion of the dextromethorphan metabolic ratio into the model did not improve the relationship. These findings confirm that the bioactivation of chloroguanide to cycloguanil cosegregates with the genetically determined activity of the CYP2C family. However, the chloroguanide to cycloguanil ratio and the mephenytoin hydroxylation index do not similarly reflect the variable activity of CYP2C.

Adult↗
PubMed1990

Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria.

Proguanil and pyrimethamine are antifolate drugs with distinct chemical structures that are used commonly in the prophylaxis and treatment of Plasmodium falciparum malaria. Clinical reports and field studies have suggested that some parasites refractory to proguanil can be treated with pyrimethamine, and vice versa. Analysis of the P. falciparum dihydrofolate reductase (DHFR) from different parasites reveals the structural basis for differential susceptibility to these antifolate drugs. Parasites harboring a pair of point mutations from Ala-16 to Val-16 and from Ser-108 to Thr-108 are resistant to cycloguanil (the active metabolite of proguanil) but not to pyrimethamine. A single Asn-108 mutation, on the other hand, confers resistance to pyrimethamine with only a moderate decrease in susceptibility to cycloguanil. Significant cross-resistance to both drugs occurs in parasites having mutations that include Ser-108----Asn-108 and Ile-164----Leu-164. These results reflect the distinct structures of pyrimethamine and cycloguanil and suggest fine differences in binding within the active site cavity of DHFR. Alternative inhibitors, used alone or in combination, may be effective against some strains of cycloguanil- or pyrimethamine-resistant malaria.

Amino Acid Sequence↗
PubMed1957

The inhibitory action of some antimalarial drugs and related compounds on the hexokinase of yeast and of Plasmodium berghei.

Of various antimalarial compounds tested, only proguanil failed to inhibit yeast hexokinase. The metabolite of proguanil, 10,580, was an effective inhibitor. Some compounds tested which were without antimalarial activity were potent inhibitors of yeast hexokinase. The degree of inhibition increased as the time during which the enzyme had been in contact with the drug increased, and the inhibitory action of mepacrine was reduced when the concentration of ATP was raised. The inhibition of yeast hexokinase by 10,732 was independent of the concentration of ATP.The hexokinase of haemolysates of the reticulocytes of mouse or rat blood was not appreciably higher than that of similar haemolysates of normal erythrocytes. Preparations of mouse or rat erythrocytes parasitized with P. berghei possessed a much higher hexokinase activity.The inhibiting action of various compounds on the hexokinase of P. berghei closely resembled those with yeast hexokinase. Again all antimalarial compounds (apart from proguanil) inhibited the enzyme, but some of the most potent inhibitors were devoid of antimalarial action. Amongst the chemotherapeutically active compounds, there appeared to be an approximate parallelism between antimalarial activity and potency as inhibitors of plasmodial hexokinase. The action of mepacrine on plasmodial hexokinase was reduced by raising the concentration of ATP, but, as with yeast hexokinase, the inhibition by 10,732 was independent of the ATP concentration.From a consideration of the results, it seems doubtful whether this type of inhibitory effect plays more than a minor part in the mechanism of antimalarial action in vivo.

Animals↗
PubMed1995

Effect of atovaquone and atovaquone drug combinations on prophylaxis of Pneumocystis carinii pneumonia in SCID mice.

The prophylactic efficacies of atovaquone (ATQ) alone and in combination with azithromycin, clarithromycin, rifabutin, proguanil, PS-15, trimethoprim, co-trimoxazole, or dapsone were investigated in a SCID mouse model of Pneumocystis carinii pneumonia (PCP). ATQ alone was shown to have a significant dose-related effect, and at 200 mg/kg of body weight per day administered orally, the efficacy of ATQ was comparable to that of Septrin (co-trimoxazole). Of the drugs investigated orally in combination with ATQ, only dapsone (25 mg/kg/day) and to a lesser extent PS-15 (5 mg/kg/day) had any noteworthy antipneumocystis activity (at the doses examined) when administered alone. ATQ drug combinations affected the prophylactic efficacy of a subcurative dosage of ATQ (50 mg/kg/day given orally) in the following ways: dapsone (25 mg/kg/day) or co-trimoxazole (25 mg of sulfamethoxazole plus 5 mg of trimethoprim per kg/day) had no significant effect on ATQ, azithromycin (200 mg/kg/day) or clarithromycin (200 mg/kg/day) had a slight additive effect with ATQ, trimethoprim (100 mg/kg/day) or PS-15 (5 mg/kg/day) had an additive effect with ATQ, and proguanil (25 mg/kg/day) or rifabutin (200 mg/kg/day) had a marked synergistic effect on ATQ. The last result was particularly noteworthy as neither proguanil nor rifabutin was effective against PCP when administered alone. None of the drugs examined antagonized the prophylactic activity of ATQ in experimental PCP in SCID mice. The results suggest that clinical trials of ATQ with synergistic drug combinations may now be justified, particularly if such drug combinations improve ATQ's efficacy and broaden its spectrum of activity.

Animals↗
PubMed1999

Alternative oxidase inhibitors potentiate the activity of atovaquone against Plasmodium falciparum.

Recent evidence suggests that the malaria parasite Plasmodium falciparum utilizes a branched respiratory pathway including both a cytochrome chain and an alternative oxidase. This branched respiratory pathway model has been used as a basis for examining the mechanism of action of two antimalarial agents, atovaquone and proguanil. In polarographic assays, atovaquone immediately reduced the parasite oxygen consumption rate in a concentration-dependent manner. This is consistent with its previously described role as an inhibitor of the cytochrome bc1 complex. Atovaquone maximally inhibited the rate of P. falciparum oxygen consumption by 73% +/- 10%. At all atovaquone concentrations tested, the addition of the alternative oxidase inhibitor, salicylhydroxamic acid, resulted in a further decrease in the rate of parasite oxygen consumption. At the highest concentrations of atovaquone tested, the activities of salicylhydroxamic acid and atovaquone appear to overlap, suggesting that at these concentrations, atovaquone partially inhibits the alternative oxidase as well as the cytochrome chain. Drug interaction studies with atovaquone and salicylhydroxamic acid indicate atovaquone's activity against P. falciparum in vitro is potentiated by this alternative oxidase inhibitor, with a sum fractional inhibitory concentration of 0.6. Propyl gallate, another alternative oxidase inhibitor, also potentiated atovaquone's activity, with a sum fractional inhibitory concentration of 0.7. Proguanil, which potentiates atovaquone activity in vitro and in vivo, had a small effect on parasite oxygen consumption in polarographic assays when used alone or in the presence of atovaquone or salicylhydroxamic acid. This suggests that proguanil does not potentiate atovaquone by direct inhibition of either branch of the parasite respiratory chain.

Animals↗
PubMed1999

[In vitro sensitivity of Plasmodium falciparum isolates from Gabon to chloroquine and cycloguanil].

The in vitro susceptibility of 91 Plasmodium falciparum isolates obtained from malaria-infected children living near Libreville (Gabon) was evaluated against chloroquine and cycloguanil (biologically active metabolite of proguanil), using an isotopic micro-drug susceptibility test. In vitro resistance to chloroquine and cycloguanil was observed in 83% (35/42) and in 38% (30/78) of the patients, respectively. Our data showed that 41% (16/39) of Gabonese field isolates were resistant both to chloroquine and cycloguanil. These findings are of great importance because they might indicate imminent chloroquine-proguanil failure, and there are not many affordable antimalarial drugs to replace chloroquine-proguanil combination.

Adolescent↗