Randomized controlled trial of levamisole hydrochloride as adjunctive therapy in severe falciparum malaria with high parasitemia.

BACKGROUND: Cytoadherence and sequestration of erythrocytes containing mature stages of Plasmodium falciparum are central to the pathogenesis of severe malaria. The oral anthelminthic drug levamisole inhibits cytoadherence in vitro and reduces sequestration of late-stage parasites in uncomplicated falciparum malaria treated with quinine. METHODS: Fifty-six adult patients with severe malaria and high parasitemia admitted to a referral hospital in Bangladesh were randomized to receive a single dose of levamisole hydrochloride (150 mg) or no adjuvant to antimalarial treatment with intravenous artesunate. RESULTS: Circulating late-stage parasites measured as the median area under the parasite clearance curves were 2150 (interquartile range [IQR], 0-28 025) parasites/µL × hour in patients treated with levamisole and 5489 (IQR, 192-25 848) parasites/µL × hour in controls (P = .25). The "sequestration ratios" at 6 and 12 hours for all parasite stages and changes in microvascular blood flow did not differ between treatment groups (all P > .40). The median time to normalization of plasma lactate (<2 mmol/L) was 24 (IQR, 12-30) hours with levamisole vs 28 (IQR, 12-36) hours without levamisole (P = .15). CONCLUSIONS: There was no benefit of a single-dose of levamisole hydrochloride as adjuvant to intravenous artesunate in the treatment of adults with severe falciparum malaria. Rapid parasite killing by intravenous artesunate might obscure the effects of levamisole.

Magnetic resonance imaging of the brain in adults with severe falciparum malaria.

BACKGROUND: Magnetic resonance imaging (MRI) allows detailed study of structural and functional changes in the brain in patients with cerebral malaria. METHODS: In a prospective observational study in adult Bangladeshi patients with severe falciparum malaria, MRI findings in the brain were correlated with clinical and laboratory parameters, retinal photography and optic nerve sheath diameter (ONSD) ultrasound (a marker of intracranial pressure). RESULTS: Of 43 enrolled patients, 31 (72%) had coma and 12 (28%) died. MRI abnormalities were present in 79% overall with mostly mild changes in a wide range of anatomical sites. There were no differences in MRI findings between patients with cerebral and non-cerebral or fatal and non-fatal disease. Subtle diffuse cerebral swelling was common (n = 22/43), but mostly without vasogenic oedema or raised intracranial pressure (ONSD). Also seen were focal extracellular oedema (n = 11/43), cytotoxic oedema (n = 8/23) and mildly raised brain lactate on magnetic resonance spectroscopy (n = 5/14). Abnormalities were much less prominent than previously described in Malawian children. Retinal whitening was present in 36/43 (84%) patients and was more common and severe in patients with coma. CONCLUSION: Cerebral swelling is mild and not specific to coma or death in adult severe falciparum malaria. This differs markedly from African children. Retinal whitening, reflecting heterogeneous obstruction of the central nervous system microcirculation by sequestered parasites resulting in small patches of ischemia, is associated with coma and this process is likely important in the pathogenesis.

N-acetylcysteine as adjunctive treatment in severe malaria: a randomized, double-blinded placebo-controlled clinical trial.

OBJECTIVE: Markers of oxidative stress are reported to be increased in severe malaria. It has been suggested that the antioxidant N-acetylcysteine (NAC) may be beneficial in treatment. We studied the efficacy and safety of parenteral NAC as an adjunct to artesunate treatment of severe falciparum malaria. DESIGN: A randomized, double-blind, placebo-controlled trial on the use of high-dose intravenous NAC as adjunctive treatment to artesunate. SETTING: A provincial hospital in Western Thailand and a tertiary referral hospital in Chittagong, Bangladesh. PATIENTS: One hundred eight adult patients with severe falciparum malaria. INTERVENTIONS: Patients were randomized to receive NAC or placebo as an adjunctive treatment to intravenous artesunate. MEASUREMENTS AND MAIN RESULTS: A total of 56 patients were treated with NAC and 52 received placebo. NAC had no significant effect on mortality, lactate clearance times (p = 0.74), or coma recovery times (p = 0.46). Parasite clearance time was increased from 30 hours (range, 6-144 hours) to 36 hours (range, 6-120 hours) (p = 0.03), but this could be explained by differences in admission parasitemia. Urinary F2-isoprostane metabolites, measured as a marker of oxidative stress, were increased in severe malaria compared with patients with uncomplicated malaria and healthy volunteers. Admission red cell rigidity correlated with mortality, but did not improve with NAC. CONCLUSION: Systemic oxidative stress is increased in severe malaria. Treatment with NAC had no effect on outcome in patients with severe falciparum malaria in this setting.

Comparison of structural protein and proteolytic enzyme levels in degenerating and regenerating rat muscle induced by Notechis scutatus venom.

To develop a clear understanding of the biochemical mechanism of muscle degeneration and regeneration induced by a single dose of Notechis scutatus scutatus venom, we have correlated changes in the levels of a series of muscle structural proteins and proteolytic enzymes. The degradation of structural proteins post-injection fell into two broad groups; those completely degraded within 3-6 hr (e.g. C- and M-proteins, skelemin), and within 1-2 days (e.g. myosin, actin, troponin), respectively. Similarly, activation of proteases followed two general patterns; those enzymes showing substantially increased activity after 12-24 hr (lysosomal cathepsins, leucyl aminopeptidase) and those enzymes showing decreased activity after 12-24 hr, with substantially increased activity after 3-4 days (mainly cytoplasmic proteases). The data suggest that activation of cathepsins B, L and D and in particular leucyl aminopeptidase, may be responsible for the early stages of structural protein catabolism, and are thus potential therapeutic targets to prevent myonecrosis following envenomation.