title: Slow and continuous delivery of a low dose of nimodipine improves survival and electrocardiogram parameters in rescue therapy of mice with experimental cerebral malaria.
abstract: BACKGROUND
  Human cerebral malaria (HCM) is a life-threatening complication caused by Plasmodium falciparum infection that continues to be a major global health problem despite optimal anti-malarial treatment. In the experimental model of cerebral malaria (ECM) by Plasmodium berghei ANKA, bolus administration of nimodipine at high doses together with artemether, increases survival of mice with ECM. However, the dose and administration route used is associated with cardiovascular side effects such as hypotension and bradycardia in humans and mice, which could preclude its potential use as adjunctive treatment in HCM.
  
  
  METHODS
  In the present study, alternative delivery systems for nimodipine during late-stage ECM in association with artesunate were searched to define optimal protocols to achieve maximum efficacy in increasing survival in rescue therapy while causing the least cardiac side effects. The baseline electrocardiogram (ECG) and arterial pressure characteristics of uninfected control animals and of mice with ECM and its response upon rescue treatment with artesunate associated or not with nimodipine is also analysed.
  
  
  RESULTS
  Nimodipine, given at 0.5 mg/kg/day via a slow and continuous delivery system by osmotic pumps, increases survival of mice with ECM when used as adjunctive treatment to artesunate. Mice with ECM showed hypotension and ECG changes, including bradycardia and increases in PR, QRS, QTc and ST interval duration. ECM mice also show increased QTc dispersion, heart rate variability (HRV), RMSSD, low frequency (LF) and high frequency (HF) bands of the power spectrum. Both sympathetic and parasympathetic inputs to the heart were increased, but there was a predominance of sympathetic tone as demonstrated by an increased LF/HF ratio. Nimodipine potentiated bradycardia when given by bolus injection, but not when via osmotic pumps. In addition, nimodipine shortened PR duration and improved HRV, RMSSD, LF and HF powers in mice with ECM. In addition, nimodipine did not increased hypotension or decreased the speed of arterial pressure recovery when used in rescue therapy with artesunate.
  
  
  CONCLUSIONS
  These data show that slow and continuous delivery of lower doses of nimodipine improves survival of mice with ECM in rescue therapy with artesunate while showing a safer profile in terms of cardiovascular effects.
authors.affiliation: Center for Malaria Research, La Jolla Bioengineering Institute, 3535 General Atomics Court Suite 210, 92121, San Diego, CA, USA. ymartins@ljbi.org
authors.forename: Yuri C
authors.initials: YC
authors.lastname: Martins
authors.forename: Leah
authors.initials: L
authors.lastname: Clemmer
authors.forename: Pamela
authors.initials: P
authors.lastname: Orjuela-Sánchez
authors.forename: Graziela M
authors.initials: GM
authors.lastname: Zanini
authors.forename: Peng Kai
authors.initials: PK
authors.lastname: Ong
authors.forename: John A
authors.initials: JA
authors.lastname: Frangos
authors.forename: Leonardo J M
authors.initials: LJ
authors.lastname: Carvalho
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D000962:Antimalarials / Q000008:administration & dosage; D037621:Artemisinins / Q000008:administration & dosage; D000077332:Artesunate; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D009553:Nimodipine / Q000008:administration & dosage*; D010962:Plasmodium berghei / Q000187:drug effects*; D016879:Salvage Therapy / Q000379:methods*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D000962:Antimalarials; D037621:Artemisinins; D009553:Nimodipine; D000077332:Artesunate