Quantitative design of optimal analgesic combination of acetaminophen, caffeine, and butalbital

AIM: 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. CONCLUSION: 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.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11749839&query_hl=5

Persistently elevated acetaminophen concentrations for two days after an initial four-hour non-toxic concentration

The decision to treat patients who overdose with n-acetylcysteine is routinely made with a single APAP concentration drawn 4 or more hours post-ingestion. However, in cases where there are co-ingestants that may delay gastric emptying, there have been recommendations for additional concentrations to determine peak APAP concentrations. This report is of a case of acetaminophen overdose involving narcotic co-ingestants with persistenty elevated acetaminophen concentrations for 2 d, suggesting delayed gastric emptying and/or bezoar formation. A second striking feature of this case was the persistently elevated acetaminophen concentrations without evidence of liver injury despite antidotal therapy not being employed.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11474737&query_hl=5

Isotopic analogues as internal standards for quantitative analyses of drugs and metabolites by GC-MS--nonlinear calibration approaches

In order to achieve accurate quantitation of drugs and metabolites (analytes) in complex matrices, 2H- (and less commonly 13C-) labeled analogues of the analytes are now routinely adapted as the internal standards (IS) using linear calibration models to fit data generated by selected ion monitoring gas chromatography-mass spectrometry (GC-MS) protocols. In this study, the effects of cross-contribution (contribution of the IS to the intensity of the ion designated for the analyte and vice versa) on the linearity of the calibration data are examined. Nonlinear approaches that may address this problem are also studied. Two ion pairs (one with least and one with significant cross-contribution) from each of the following analyte/IS pairs are used as the exemplar systems for this study: butalbital/13C4-butalbital, butalbital/2H5-butalbital, secobarbital/13C4-secobarbital, and secobarbital/2H5-secobarbital. Analyte/IS ion intensity ratios of a series of standard solutions are correlated with the analyte/IS concentration ratios using one-point, multiple-point (unweighted and weighted) linear, and hyperbolic functions. The one-point calibration approach produces excellent calibration results in treating data derived from ion pairs with no significant cross contribution. In cases where significant cross-contribution exists, results derived from the one-point approach show, as expected, significant deviations at both ends of the concentration range. With the cross-contribution phenomenon accounted for, the hyperbolic calibration model is clearly more effective in fitting calibration data at both the lower and higher analyte concentration ends, thus significantly lowering the detection limit and extending the calibration range to a higher level. However, the calibration range cannot be extended indefinitely. At the low concentration end, noise-to-signal ratio and the cross-contribution of the IS to the intensity of the ion designated for the analyte, however insignificant, will incrementally reduce the quality of the observed ion intensity and intensity ratio data. At the high concentration end, detection saturation and the cross-contribution of the analyte to the intensity of the ion designated for the IS, however insignificant, will incrementally decrease the "slope" of the calibration curve. Thus, acceptable sensitivity (increase in analyte/IS ion-pair intensity ratio per unit increase in analyte concentration) of the calibration curve will become the limiting factor

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11327350&query_hl=5

Fioricet is a barbiturate sedative mixed with a non-aspirin pain medication and caffeine. This non-narcotic pain medication and relaxant is often prescribed for tension headaches caused by contractions of the muscles in the neck and shoulder area, and migraine.

Fioricet comes as a capsule and tablet to take by mouth. One or 2 tablets every 4 hours as needed. Total daily dosage should not exceed 6 tablets. Extended and repeated use of this product is not recommended because of the potential for physical dependence.

Side effects cannot be anticipated. If any develop or change in intensity, inform your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking Fioricet. More common side effects may include: Abdominal pain, dizziness, drowsiness, intoxicated feeling, light-headedness, nausea, sedation, shortness of breath, vomiting. Less common or rare side effects may include: Agitation, allergic reactions, constipation, depression, difficulty swallowing, dry mouth, earache, exaggerated feeling of well-being, excessive sweating, excessive urination, excitement, fainting, fatigue, fever, flatulence, headache, heartburn, heavy eyelids, high energy, hot spells, itching, leg pain, mental confusion, muscle fatigue, numbness, rapid heartbeat, ringing in the ears, seizure, shaky feeling, skin redness and/or peeling, sluggishness, stuffy nose, tingling