phenobarbital and Cerebral Malaria studies

Phenobarbital: A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates GAMMA-AMINOBUTYRIC ACID action on GABA-A RECEPTORS, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations.
phenobarbital : A member of the class of barbiturates, the structure of which is that of barbituric acid substituted at C-5 by ethyl and phenyl groups.

Research Excerpts

Excerpt	Relevance	Reference
"Acute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression."	9.30	A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria. ( Abdel Baki, SG; Birbeck, GL; Capparelli, EV; Dzinjalamala, FK; Gardiner, JC; Herman, ST; Mallewa, M; Postels, DG; Seydel, KB; Taylor, TE; Toto, NM, 2019)
"Children with cerebral malaria admitted to one hospital in Kilifi, Kenya, were randomly assigned a single intramuscular dose of phenobarbital (20 mg/kg) or identical placebo."	9.09	Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study. ( Crawley, J; Marsh, K; Mithwani, S; Mwangi, I; Ouma, D; Peto, T; Waruiru, C; Watkins, W; Winstanley, P, 2000)
"Patients with cerebral malaria with polymorphic Cytochrome P450 2C19 (CYP2C19) genotypes who receive concurrent treatment with quinine are at risk of inadequate or toxic therapeutic drug concentrations due to metabolic drug interactions."	8.12	Physiologically based pharmacokinetic modeling for dose optimization of quinine-phenobarbital coadministration in patients with cerebral malaria. ( Karbwang, J; Na-Bangchang, K; Rajoli, RKR; Sae-Heng, T; Siccardi, M, 2022)
"Acute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression."	5.30	A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria. ( Abdel Baki, SG; Birbeck, GL; Capparelli, EV; Dzinjalamala, FK; Gardiner, JC; Herman, ST; Mallewa, M; Postels, DG; Seydel, KB; Taylor, TE; Toto, NM, 2019)
"Phenobarbital is commonly used to treat status epilepticus in resource-poor countries."	5.10	Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions. ( Kokwaro, GO; Muchohi, SN; Newton, CR; Ogutu, BR; Otieno, GO, 2003)
"Children with cerebral malaria admitted to one hospital in Kilifi, Kenya, were randomly assigned a single intramuscular dose of phenobarbital (20 mg/kg) or identical placebo."	5.09	Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study. ( Crawley, J; Marsh, K; Mithwani, S; Mwangi, I; Ouma, D; Peto, T; Waruiru, C; Watkins, W; Winstanley, P, 2000)
"Patients with cerebral malaria with polymorphic Cytochrome P450 2C19 (CYP2C19) genotypes who receive concurrent treatment with quinine are at risk of inadequate or toxic therapeutic drug concentrations due to metabolic drug interactions."	4.12	Physiologically based pharmacokinetic modeling for dose optimization of quinine-phenobarbital coadministration in patients with cerebral malaria. ( Karbwang, J; Na-Bangchang, K; Rajoli, RKR; Sae-Heng, T; Siccardi, M, 2022)
"The prevalence of epilepsy is high in many areas of Africa."	2.43	Epilepsy and mortality in Africa: a review of the literature. ( Diop, AG; Hauser, WA; Hesdorffer, DC; Logroscino, G, 2005)
"Falciparum malaria is the most common cause of convulsions in children admitted to hospital in malaria endemic areas."	2.42	Management of seizures in children with falciparum malaria. ( Newton, CR; Ogutu, BR, 2004)
"People with cerebral malaria become unconscious, and often have protracted convulsions."	2.41	Routine anticonvulsants for treating cerebral malaria. ( Marson, AG; Meremikwu, M, 2002)

Research

Studies (14)

Authors

Clinical Trials (2)

Trial Overview

Trial Outcomes

Mean Time From Admission to BCS >/= 4

Timeframe	Studies, this research(%)	All Research%
pre-1990	0 (0.00)	18.7374
1990's	2 (14.29)	18.2507
2000's	10 (71.43)	29.6817
2010's	1 (7.14)	24.3611
2020's	1 (7.14)	2.80

Authors	Studies
Sae-Heng, T	1
Rajoli, RKR	1
Siccardi, M	1
Karbwang, J	1
Na-Bangchang, K	1
Birbeck, GL	1
Herman, ST	1
Capparelli, EV	1
Dzinjalamala, FK	1
Abdel Baki, SG	1
Mallewa, M	1
Toto, NM	1
Postels, DG	1
Gardiner, JC	1
Taylor, TE	1
Seydel, KB	1
Kokwaro, GO	1
Ogutu, BR	2
Muchohi, SN	1
Otieno, GO	1
Newton, CR	3
Enwere, G	1
Diop, AG	1
Hesdorffer, DC	1
Logroscino, G	1
Hauser, WA	1
Abubakar, A	1
Van De Vijver, FJ	1
Mithwani, S	2
Obiero, E	1
Lewa, N	1
Kenga, S	1
Katana, K	1
Holding, P	1
Kochar, DL	1
Kumawat, BL	1
Kochar, SK	1
Molyneux, ME	1
Crawley, J	1
Waruiru, C	1
Mwangi, I	1
Watkins, W	1
Ouma, D	1
Winstanley, P	1
Peto, T	1
Marsh, K	2
Enwere, GC	1
Verhoef, H	1
West, CE	1
Kok, FJ	1
Meremikwu, M	1
Marson, AG	1
Winstanley, PA	1
Pasvol, G	1
Kirkham, FJ	1
Mberu, E	1
Peshu, N	1
Ward, SA	1
Were, JB	1
Warrell, DA	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
A Safety and Feasibility Study of Enteral Levetiracetam vs. Phenobarbital for Seizure Control in Pediatric Cerebral Malaria[NCT01982812]	Phase 2	44 participants (Actual)	Interventional	2014-01-31	Completed
A Dose-Escalation, Safety And Feasibility Study Of Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria[NCT01660672]	Phase 1/Phase 2	7 participants (Actual)	Interventional	2013-01-31	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

"The mean time in hours from admission until the subject reaches Blantyre Coma Scale of greater than or equal to 4. Participants who died are excluded from this analysis.~The Blantyre Coma Score has ranges from 0-5 based upon the a sum of the following 3 domains- Eye movement~1 - Watches or follows 0 - Fails to watch or follow~Best motor response 2 - Localizes painful stimulus 1 - Withdraws limb from painful stimulus 0 - No response or inappropriate response~Best verbal response 2 - Cries appropriately with pain, or, if verbal, speaks~1 - Moan or abnormal cry with pain 0 - No vocal response to pain" (NCT01982812)
Timeframe: 7 days

Minutes With Seizure on EEG

Intervention	hours of coma from admission (Mean)
Oral Levetiracetam	35.4
Comparison Group	34.6

Comparing LVT to standard AED the number of minutes spent in seizure per cEEG in the 72 hours after treatment allocation. (NCT01982812)
Timeframe: 72 hours

Required Additional AED

Intervention	minutes with seizure (Mean)
Oral Levetiracetam	165.2
Comparison Group	464.8

Additional AEDs required (including for breakthrough seizures in LVT group) during admission for seizure control (yes/no) (NCT01982812)
Timeframe: 7 days

Sequelae

Intervention	Participants requiring additional AEDs (Number)
Oral Levetiracetam	18
Comparison Group	18

"Neurologic outcome in 3 categories--~Neurologically intact at discharge~Neurologic sequelae at discharge--specifically new sensory or motor deficits, ongoing seizures, or behavioral abnormalities based upon a physician examination at discharge~Died during admission, never discharged" (NCT01982812)
Timeframe: 7 days

Freedom From Seizure

Intervention	participants (Number)
	Neurologically intact at discharge	Neurologic sequelae at discharge	Died during admission
Comparison Group	14	2	5
Oral Levetiracetam	19	3	1

Number of subjects free of seizure at 24 hours after initiation of treatment (NCT01660672)
Timeframe: 24 hours

Mean Time to Return to a BCS Score Greater Than or Equal to 4

Intervention	individuals (Number)
LEVETIRACETAM	7

Mean time from admission to a BCS score greater than or equal to 4. The BCS (Blantyre Coma Scale) is a 0-5 scale measuring motor response, verbal response and eye movement assessing the severity of coma in children with cerebral malaria. Lower scores correspond to more profound coma. (NCT01660672)
Timeframe: 7 days

Number of Participants Requiring AED During Admission

Intervention	hours (Mean)
LEVETIRACETAM	35.3

Number of participants who required AEDS during admission(including for breakthrough seizures in the LVT group) during admission. (NCT01660672)
Timeframe: 7 days

Number of Participants With Neurologic Sequelae at Discharge

Intervention	participants (Number)
LEVETIRACETAM	6

Number of participants with neurologic sequelae at discharge (NCT01660672)
Timeframe: day 7

Number of Subjects Exposed to Phenobarbitone Prior to Enrollment

Intervention	participants (Number)
LEVETIRACETAM	2

Pre-enrollment exposure to phenobarbitone may impact LVT efficacy, and analysis base on this characteristic will be evaluated. (NCT01660672)
Timeframe: 0 hour

Number of Subjects With Retinopathy at Enrollment

Intervention	participants (Number)
LEVETIRACETAM	3

Retinopathy status may impact LVT efficacy and subject status will be analyzed based on this characteristic. (NCT01660672)
Timeframe: Upon admission

Range of Plasma Concentration of LVT Across All Individuals

Intervention	participants (Number)
LEVETIRACETAM	4

Range of plasma LVT concentrations will be determined through HPLC method at eight timepoints post administration to evaluate LVT absorption and elimination in pediatric CM. (NCT01660672)
Timeframe: 72 hours

Toxicity Related to LVT

Intervention	mcg/ml (Mean)
LEVETIRACETAM	35

Toxicity including vomiting, aspiration, complications related to the NGT, laboratory parameters at 24 hours and 1 week post LVT administration, and an overall acute case fatality rate significantly above the consistent historical ward average for CM. Pk studies to evaluate LVT absorption and elimination in pediatric CM. (NCT01660672)
Timeframe: 1 week

Article	Year
Management of seizures in children with falciparum malaria. Tropical doctor, 2004, Volume: 34, Issue:2 Topics: Anticonvulsants; Child; Diazepam; Emergency Treatment; Humans; Malaria, Cerebral; Malaria, Falciparu	2004
A review of the quality of randomized clinical trials of adjunctive therapy for the treatment of cerebral malaria. Tropical medicine & international health : TM & IH, 2005, Volume: 10, Issue:11 Topics: Anticonvulsants; Deferoxamine; Dexamethasone; Double-Blind Method; Enzyme Inhibitors; Humans; Malari	2005
Epilepsy and mortality in Africa: a review of the literature. Epilepsia, 2005, Volume: 46 Suppl 11 Topics: Africa; Anticonvulsants; Cause of Death; Child; Developing Countries; Epilepsy; Humans; Malaria; Mal	2005
Routine anticonvulsants for treating cerebral malaria. The Cochrane database of systematic reviews, 2002, Issue:2 Topics: Anticonvulsants; Humans; Malaria, Cerebral; Phenobarbital; Randomized Controlled Trials as Topic; Se	2002

Article	Year
A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria. BMC pediatrics, 2019, 11-01, Volume: 19, Issue:1 Topics: Acute Disease; Anticonvulsants; Benzodiazepines; Child; Child, Preschool; Coma; Cross-Over Studies;	2019
A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria. BMC pediatrics, 2019, 11-01, Volume: 19, Issue:1 Topics: Acute Disease; Anticonvulsants; Benzodiazepines; Child; Child, Preschool; Coma; Cross-Over Studies;	2019
A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria. BMC pediatrics, 2019, 11-01, Volume: 19, Issue:1 Topics: Acute Disease; Anticonvulsants; Benzodiazepines; Child; Child, Preschool; Coma; Cross-Over Studies;	2019
A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria. BMC pediatrics, 2019, 11-01, Volume: 19, Issue:1 Topics: Acute Disease; Anticonvulsants; Benzodiazepines; Child; Child, Preschool; Coma; Cross-Over Studies;	2019
Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions. British journal of clinical pharmacology, 2003, Volume: 56, Issue:4 Topics: Anticonvulsants; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Infusio	2003
Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study. Lancet (London, England), 2000, Feb-26, Volume: 355, Issue:9205 Topics: Adolescent; Animals; Anticonvulsants; Child; Child, Preschool; Female; Humans; Infant; Infusions, In	2000

Article	Year
Physiologically based pharmacokinetic modeling for dose optimization of quinine-phenobarbital coadministration in patients with cerebral malaria. CPT: pharmacometrics & systems pharmacology, 2022, Volume: 11, Issue:1 Topics: Acidosis, Lactic; Acute Kidney Injury; Adolescent; Adult; Anticonvulsants; Antimalarials; Area Under	2022
Assessing developmental outcomes in children from Kilifi, Kenya, following prophylaxis for seizures in cerebral malaria. Journal of health psychology, 2007, Volume: 12, Issue:3 Topics: Anticonvulsants; Child; Child Development; Child, Preschool; Cognition; Female; Humans; Infant; Keny	2007
Seizures in cerebral malaria. QJM : monthly journal of the Association of Physicians, 1997, Volume: 90, Issue:9 Topics: Adolescent; Adult; Aged; Anticonvulsants; Humans; Malaria, Cerebral; Middle Aged; Phenobarbital; Sei	1997
Impact of malaria on the brain and its prevention. Lancet (London, England), 2000, Feb-26, Volume: 355, Issue:9205 Topics: Africa; Animals; Anticonvulsants; Child, Preschool; Cognition Disorders; Humans; Malaria, Cerebral;	2000
Sedation in cerebral malaria. Lancet (London, England), 2000, May-06, Volume: 355, Issue:9215 Topics: Anticonvulsants; Child; Humans; Malaria, Cerebral; Phenobarbital; Seizures	2000
Phenobarbital for children with cerebral malaria. Lancet (London, England), 2000, Jul-15, Volume: 356, Issue:9225 Topics: Anticonvulsants; Chemoprevention; Child; Diazepam; Drug Interactions; Humans; Logistic Models; Malar	2000
Prophylactic phenobarbitone in young children with severe falciparum malaria: pharmacokinetics and clinical effects. British journal of clinical pharmacology, 1992, Volume: 33, Issue:2 Topics: Child; Child, Preschool; Chromatography, High Pressure Liquid; Drug Interactions; Humans; Infant; Ma	1992

phenobarbital and Cerebral Malaria