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Purpose: This open-label study investigated the pharmacokinetic interaction of phenytoin (PHT) and felbamate (FBM)., Methods: Ten subjects with epilepsy receiving PHT monotherapy were administered increasing doses of FBM (1,200, 1,800, 2,400-3,600 mg/day) at 2-week intervals. PHT doses were reduced by 20% on an individual basis when evidence of clinically significant intolerance was present. With intolerance, the PHT dose was reduced before the next incremental FBM dose. Blood samples were analyzed for FBM, PHT, and PHT metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH)., Results: Total PHT plasma concentrations increased with coadministered FBM. PHT Cmax increased from 15.9 microg/ml at baseline to 20.9 microg/ml after 1,200 mg/day FBM and to 26.8 microg/ml after 1,800 mg/day FBM. Four subjects required a 20% PHT dose reduction after 1,800 mg/day FBM and six after the administration of 2,400 mg/day FBM. All subjects required further 20% PHT reductions before 3,600 mg/day FBM. FBM Cmax and AUCT were reduced, and apparent clearance increased compared with data from FBM monotherapy., Conclusions: With the initiation of FBM therapy in subjects receiving PHT, the PHT dosage should be reduced by 20%. Further PHT dose reductions are likely to be necessary if the FBM dose is increased. The requirements for reductions in dose might be predicted by clinical signs of PHT intolerance.

Purpose: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropion-aldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate to the major human metabolite 3-carbamoyl-2-phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2-phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N-acetyl-cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde-derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine., Methods: We summarize the results of an LC/MS method used to quantify FBM, 3-carbamoyl-2-phenylpropionic acid and two atropaldehyde-derived mercapturic acids in the patient population., Results: Analysis was performed on 31 patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured., Conclusions: This method demonstrated sufficient precision for the identification of patients exhibiting "abnormal" levels of atropaldehyde conjugates and may hold potential for patient monitoring.

Purpose: Felbamate (FBM) pharmacokinetic parameters, safety and tolerability in the dose range of 1,200-6,000 mg/day were assessed in two open-label studies with similar designs., Methods: In study A, newly diagnosed subjects with epilepsy receiving FBM monotherapy at a starting dose of 1,200 mg/day (400 mg/three times daily, t.i.d.) and increased 1,200 mg/day, if tolerated, at 14-day intervals to 3,600 mg/day were investigated. In study B, epilepsy subjects with prior FBM monotherapy exposure received ascending FBM doses in five consecutive 14-day periods with a starting dose of 3,600 mg/day (1,200 mg t.i.d.) FBM. In each successive period, if FBM was well tolerated, the dose was increased by 600 mg/day to a maximum of 6,000 mg/day (2,000 mg t.i.d.)., Results: The pharmacokinetic parameter estimates maximum observed concentration (Cmax), area under the concentration-time curve (AUCtau) Ctrough, and Cav showed a linear dependence to dose above the 1,200-6,000 mg/day FBM dose range (F-tests; p < 0.0001) with apparent clearance (Cl/kg) and Tmax (time to Cmax) independent of dose. When AUCtau, Cmax and Ctrough were adjusted for dose, there were no significant differences between the dosing periods., Conclusions: The data establish that plasma concentrations of FBM are linear with respect to dose to 6,000 mg/day. In addition, FBM was safely administered at these doses for periods as long as 14 days to epileptic subjects with prior exposure to FBM. FBM-naive subjects appeared to report more adverse experiences (generally of mild to moderate severity) than did subjects with prior FBM exposure.

In the aortas and mesenteric arteries from spontaneous hypertensive rats and in the aortas from stress- and desoxycorticosterone-acetate-hypertensive rats, the intracellular cGMP: cAMP ratios were significantly elevated when compared to the ratios in the aortas of the respective controls. Decreases in the intracellular cAMP or cGMP levels were consistently associated with increased activity of the cyclic-nucleotide-specific low K(m) phosphodiesterase (3':5'-cAMP 5' nucleotidohydrolase, EC 3.1.4.17). Increases in intracellular cGMP levels were associated with elevated guanylyl cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] activity. Furthermore, adenylyl cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity was less sensitive to stimulation by the beta-adrenergic stimulant isoproterenol in both the aortas and the hearts of the hypertensive animals. These changes could provide the biochemical basis for the (a) increased vascular smooth muscle tone and peripheral resistance observed in these animals, (b) increased reactivity to norepinephrine, and (c) decreased ability of aortas from hypertensive rats to relax. The presence of these same effects in different etiologic types of hypertension indicates that this aberration in cyclic nucleotide metabolism may represent a common metabolic defect basic to the hypertensive syndrome irrespective of etiology.

Flupirtine, a chemically unique, orally effective, non-narcotic, centrally acting analgesic was evaluated for efficacy and safety in five parallel, double-blind randomized clinical trials which included both placebo and active control comparisons. Flupirtine was given in oral doses of 100 to 300 mg, with a maximum daily dose of 600 mg to patients with pain resulting from episiotomy, surgical or dental procedures. Patients rated pain intensity, pain relief and adverse experiences at regular intervals up to 6 hours following medication. Assessments of efficacy included measures of the sum of pain intensity differences (SPID), total pain relief (TOPAR) and peak analgesia (PPID). More than 1300 patients have been evaluated at 26 study sites in the United States. More than 170 of them received flupirtine 100 mg, 250 received 200 mg and 50 received 300 mg. An additional 415 patients received positive control medications (paracetamol 650 mg, codeine 60 mg, pentazocine 50 mg or oxycodone 10 mg plus paracetamol 650 mg). All doses of flupirtine produced analgesia after a single dose. Pharmacokinetic evaluations have shown linear kinetics for flupirtine and a 100 mg t.i.d. dosage schedule produces average steady-state blood levels equivalent to the peak response for a single 200 mg dose. Adverse experiences occurring in flupirtine clinical studies have been minimal in incidence, nature and degree, with drowsiness being the most frequently reported reaction (approximately 10%).