Mefloquine to prevent malaria: a systematic review of trials.

OBJECTIVE: To evaluate the research evidence on the efficacy and tolerability of mefloquine chemoprophylaxis. SEARCH STRATEGY: Any potentially relevant trial from the Cochrane Infectious Disease Group''s register of controlled trials; systematic searches of Medline, Embase, Lilacs and Science Citation Index; scanning citations; and consulting drug companies and key investigators. We considered studies in all languages. INCLUSION CRITERIA: Trials carried out in non-immune adult travellers, and in non-travelling volunteers, where an attempt had been made to conduct a randomised comparison of mefloquine against placebo or against alternative standard prophylaxis. RESULTS: 37 potentially eligible trials of mefloquine prophylaxis were identified, and 10 met the inclusion criteria. These 10 trials comprised a total of 2750 non-immune adult participants randomised to mefloquine or to a control. One placebo controlled trial examined malaria incidence directly and showed mefloquine to be highly effective in preventing malaria in an area of drug resistance. However, four placebo controlled trials showed that mefloquine was not well tolerated, and withdrawals were consistently higher in mefloquine treatment arms than in placebo arms (odds ratio 3.49 (95% confidence interval 1.42 to 8.56)). Five field trials compared mefloquine with other chemoprophylaxis. Mefloquine was no worse tolerated than other chemoprophylaxis, although there was possibly a trend towards higher withdrawals in mefloquine arms (odds ratio 1.33 (0.75 to 2.36)). CONCLUSION: One trial showed mefloquine to be effective in preventing malaria, but withdrawal rates, presumably from side effects, were high across most studies. This is likely to impair mefloquine''s effectiveness in general travellers, and it may therefore not be useful for routine prophylaxis. Mefloquine may be useful in specific situations such as for groups travelling to regions with a high risk of chloroquine resistant malaria and only limited access to effective medical care.     

Size‐Assortative Shoaling in the Guppy (Poecilia reticulata): The Role of Active Choice

Many fish species exhibit size‐assortative shoaling, which is often thought to be driven by predation risk. Recent fieldwork has revealed that guppies (Poecilia reticulata) are more size assorted in high‐predation populations than in low‐predation ones. However, size assortment does nonetheless occur in some low‐predation populations, suggesting that predation is unlikely the sole driving force behind size‐assortment. Here, we investigated in the laboratory the potential role of active choice in size‐assortative shoaling in wild‐caught female guppies originating from two populations of the same river system in Trinidad. Small or large focal females from each population were offered a binary choice of shoaling with either four small female conspecifics or four large ones. Observed shoaling preferences depended on the body size of the focal fish, suggesting phenotype‐mediated conflict over group composition. Large focal fish preferred to shoal with the size‐matched stimulus shoal of large fish. In contrast, small focal fish did not shoal assortatively but also preferred to shoal with larger females. Our results suggest that size‐assortative shoaling in female guppies is likely to be due to factors other than active choice, such as habitat segregation and sexual harassment.     

Metallocene-based antimalarials: an exploration into the influence of the ferrocenyl moiety on in vitro antimalarial activity in chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum

To establish the role of the ferrocenyl moiety in the antiplasmodial activity of ferroquine, compounds in which this moiety is replaced by the corresponding ruthenium-based moieties were synthesized and evaluated. In both the sensitive (D10) and resistant (K1) strains of Plasmodium falciparum, ruthenoquine analogues showed comparable potency to ferroquine. This suggests that a probable role of the ferrocenyl fragment is to serve simply as a hydrophobic spacer group. In addition, ferroquine analogues with different aromatic substituents were synthesized and evaluated. Unexpectedly high activity for quinoline compounds lacking the 7-chloro substituent suggests the ferrocenyl moiety may have an additive and/or synergistic effect.     

Antiprotozoal and cytotoxicity evaluation of sulfonamide and urea analogues of quinacrine

Sulfonamide and urea derivatives of quinacrine with varying methylene spacer lengths were synthesised and tested for inhibition of trypanothione reductase (TryR) and for activity in vitro against strains of the parasitic protozoa Trypanosoma, Leishmania, and Plasmodium. These derivatives are superior inhibitors of TryR relative to quinacrine with the best compound being 40 times more potent. Urea derivatives generally displayed good in vitro activity against all parasites.     

The effect of mobile phone electromagnetic fields on the alpha rhythm of human electroencephalogram

Mobile phones (MP) emit low-level electromagnetic fields that have been reported to affect neural function in humans; however, demonstrations of such effects have not been conclusive. The purpose of the present study was to test one of the strongest findings in the literature; that of increased "alpha" power in response to MP-type radiation. Healthy participants (N = 120) were tested using a double-blind counterbalanced crossover design, with each receiving a 30-min Active and a 30-min Sham Exposure 1 week apart, while electroencephalogram (EEG) data were recorded. Resting alpha power (8-12 Hz) was then derived as a function of time, for periods both during and following exposure. Non-parametric analyses were employed as data could not be normalized. Previous reports of an overall alpha power enhancement during the MP exposure were confirmed (relative to Sham), with this effect larger at ipsilateral than contralateral sites over posterior regions. No overall change to alpha power was observed following exposure cessation; however, there was less alpha power contralateral to the exposure source during this period (relative to ipsilateral). Employing a strong methodology, the current findings support previous research that has reported an effect of MP exposure on EEG alpha power.     

Kinetoplastida: new therapeutic strategies

New formulations and therapeutic switching of the established drugs, amphotericin B and paromomycin, together with the discovery of miltefosine, have significantly improved the opportunities for treatment of visceral leishmaniasis (VL) chemotherapy. However, for human African trypanosomiasis (HAT), Chagas disease and cutaneous leishmaniases there has been limited progress. For HAT, a novel diamidine, parfuramidine, is in phase III clinical trial for early-stage disease, but for the treatment of late-stage disease there are no new drugs and combinations of eflornithine with melarsoprol or nifurtimox have been the focus of clinical studies. For Chagas disease, different classes of compounds that have validated biochemical targets, sterol biosynthesis methylases and cysteine proteases, are in various stages of development. The genome sequences that are now available for the pathogens that cause the leishmaniases and trypanosomiases, and new methods for rapid validation of targets, are part of the solution to discover new drugs. The integration of medicinal chemistry, pharmacokinetics, project planning and interaction with the pharma/biotech sector are essential if progress is to be made. Although there are financial constraints, the appearance of new funding sources and not-for-profit product development partnerships offers hope for drug development.