title: Quantitative design of optimal analgesic combination of acetaminophen, caffeine, and butalbital.
abstract: OBJECTIVE
  To quantitatively seek an optimal analgesic combination of acetaminophen (Ace), butalbital (Bul), and caffeine (Caf), and to characterize the pharmacodynamics of interaction among the three drugs.
  
  
  METHODS
  The models of acute inflammatory pain in carrageenin-injected rats were applied to measure the vocalization threshold to paw pressure. Six groups with different ratios and doses were set to seek an optimal combination of Ace, Caf, and Bul, analyzed by the weighted modification method. Based on the ratio and doses in the optimal combination, four continuous doses were set to analyze the interactions of therapeutic effects by the reflection method. The interaction of the acute toxicity was evaluated by the parameter method.
  
  
  RESULTS
  According to the degree of importance to the combined analgesic effect, Ace > Caf > Bul; Ace showed a significant dose-response relationship, whereas in Caf and Bul, this relationship was not apparent. A new combination was obtained by the theoretical analysis and confirmed further by experimentation. Namely, at a ratio of 8.6:1:1.5 Ace + Caf + Bul (240 + 28 + 42 mg/kg, ig) was an optimal combination. Both Caf and Bul had a synergism to Ace, but Caf was a stronger synergist in contrast to Bul. Such synergism increased the therapeutic effects in the range of Ace 153.6 - 300 mg/kg combined with Caf 17.9 - 35 mg/kg and Bul 26.8 -5 2.5 mg/kg (8.6:1:1.5). However, the dose of Ace + Caf + Bul at 300 + 35 + 52.5 mg/kg resulted in sedation in rats. The peak latency was approximately 1 h for all four continuous doses, but the peak amplitude was dose-related, and the duration of the therapeutic effect was less than 2 h. The acute toxicity of the three drugs in combination remained the same.
  
  
  CONCLUSIONS
  Ace + Caf + Bul at a dose of (240 + 28 + 42) mg/kg (ig) results in an optimal combination. The therapeutic window of the combination is located in the range of Ace (153.6 - 240 mg/kg)+Caf (17.9 - 28 mg/kg)+Bul (26.8 - 42 mg/kg) (8.6:1:1.5). Caf has a stronger synergism with Ace than Bul.
authors.affiliation: Laboratory of Structure Biology, School of Life Science, University of Science and Technology of China, Hefei 230021, China. zhengqs@mail.ahwhptt.net.cn
authors.forename: Q S
authors.initials: QS
authors.lastname: Zheng
authors.forename: X W
authors.initials: XW
authors.lastname: Wang
authors.forename: C Q
authors.initials: CQ
authors.lastname: Gui
authors.forename: R Y
authors.initials: RY
authors.lastname: Sun
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001463:Barbiturates / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology*; D002351:Carrageenan; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D004357:Drug Synergism; D005260:Female; D008297:Male; D051379:Mice; D010146:Pain / Q000139:chemically induced; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018712:Analgesics, Non-Narcotic; D001463:Barbiturates; D000082:Acetaminophen; D002110:Caffeine; D002351:Carrageenan; C004470:butalbital