The administration of phenytoin suspension in conjunction with enteral nutrition supplements through nasogastric (NG) feeding tubes to humans has been associated with suboptimal phenytoin absorption, ...subtherapeutic concentrations, and breakthrough seizures. Postulated mechanisms include chelation to proteins and electrolytes in the enteral feeding, binding to NG tubing, and alterations in gastrointestinal pH resulting in precipitation of phenytoin. The purpose of this pilot study was to evaluate the oral absorption of commercially available fosphenytoin injectable solution compared to phenytoin suspension in the rat to determine whether equivalent oral fosphenytoin and phenytoin suspension doses should be used for future human studies of fosphenytoin oral absorption in the presence of concomitant enteral nutrition. A single oral 30 mg/kg phenytoin equivalents dose of either commercially available fosphenytoin or phenytoin suspension was administered to male Wistar rats following an overnight fast. Blood samples (0.3 ml) for phenytoin plasma concentration were obtained from a jugular vein catheter at baseline and 0.5, 1, 1.5, 2, 3, 4, 5, 8, 12 and 24 h post-study drug administration and analyzed by high performance liquid chromatography (HPLC) (CV%<6). Mean phenytoin
C
max was 46% (
P=0.010) higher in fosphenytoin vs phenytoin treated rats.
T
max was 2.4 h (62%,
P=0.021) shorter in fosphenytoin vs phenytoin treated rats. No significant differences in AUC
last were found. The presence of a phosphate ester moiety does not appear to inhibit the appearance of phenytoin following oral administration of fosphenytoin. Phenytoin plasma concentration profiles following oral administration of fosphenytoin are characterized by higher
C
max and shorter
T
max values relative to oral administration of phenytoin suspension.
beta(3)-Adrenoceptors(beta(3)-AR) are expressed by cholinergic myenteric neurons and beta(3)-AR agonists are effective in experimental models of diarrhea. Our aim was to explore the effects of a ...beta(3)-AR agonist, solabegron, on gastrointestinal transit, safety, bowel function, plasma somatostatin, and solabegron pharmacokinetics (PK) following single and multiple doses. In a single-center, double-blind, parallel-group trial, 36 healthy volunteers were randomized to oral solabegron (50 or 200 mg twice daily) or placebo. Transit was measured by a validated method ((99m)Tc-labeled egg meal and (111)In charcoal delivered to the colon via delayed-release capsule). Stool frequency, form, and ease of passage were measured on a validated daily diary; plasma somatostatin by radioimmunoassay and plasma solabegron and its active metabolite by validated liquid chromatography-tandem mass spectroscopy analysis followed by PK analysis using noncompartmental methods. There were no overall or dose-related effects of solabegron on gastric, small bowel, or colonic transit, plasma somatostatin levels, stool frequency, form, or ease of passage in healthy volunteers. Solabegron and active metabolite exposures (area under the curve and maximum serum concentration) at both dose levels were consistent with PK at similar doses in previous phase I studies. We concluded that 7 days of the beta(3)-AR agonist, solabegron, 50 or 200 mg twice daily, did not significantly alter gastrointestinal or colonic transit or bowel function. In this study, medication was generally well tolerated with few adverse events reported and no clinically significant changes in vital signs observed. Further studies on clinical efficacy, visceral sensitivity, and gastrointestinal transit are required in irritable bowel syndrome patients.
Enaminone derivatives of the 4-carbomethoxy-5-methylcyclohexane-1,3-dione series represent a new and potentially active series of compounds for the treatment of Epilepsy. Enaminone esters have been ...previously evaluated as compounds with potent oral anticonvulsant activity similar to class 1 anticonvulsants phenytoin, carbamazepine, and lamotrigine. DM5, a member of this class with –Cl in the para-substituted position, has been assessed to have the most potent pharmacological activity (ED
50) in both the mouse and rat. A selective and specific high-performance liquid chromatography method was developed to quantitate DM5 in plasma and brain tissue in mice. Reverse phase chromatography with ultraviolet (
λ=307 nm) detection was utilized to quantitate eluate. A C
18 analytical column was used and the mobile phase consisted of acetonitrile and 0.05
M NaH
2PO
4 buffer (60:40; v/v). Liquid–liquid extraction with ether was used to extract the DM5 from plasma or brain homogenates. DM5 and carbamazepine (internal standard) eluted at ∼6.0 and 9.0 min without any interfering peaks. The calibration curves were found to be linear (
r≥0.9999) in the range of 0.1–5.0 μg/ml or μg/g. Intra-run precision’s were in all in the range of 90%. The absolute recovery of the analyte in brain and plasma samples was ≤90%. The valid method accurately quantified DM5 in plasma and brain tissue samples collected from a pharmacokinetic study consisting of an intravenous bolus in the tail vein of wild type and genetically altered mice.
Background.In this paper, results are reported from a pilot study designed to test the feasibility of a proactive educational intervention delivered to callers of the Cancer Information Service ...(CIS).
Methods.The study used a randomized two-group design (intervention vs control). Callers assigned to the intervention condition received a brief educational intervention at the end of usual service to increase fruit and vegetable consumption. As part of the intervention, key educational messages and materials drawn from the 5 A Day for Better Health program of the National Cancer Institute were provided to CIS callers over the telephone and then reinforced with two follow-up mailings.
Results.Results from this pilot study indicated high levels of adherence to protocol by CIS Information Specialists who delivered the intervention to eligible CIS callers. Results obtained from the 4-week telephone follow-up interviews indicated that intervention subjects (n= 142) reported higher consumption of fruits and vegetables, averaging approximately 0.75 servings more per day (P< 0.01) than control subjects (n= 134).
Conclusion.Nearly 80% of CIS callers endorsed the strategy of providing 5 A Day information at the end of usual service, even if such information was not specifically requested by the caller (i.e., the information was provided to CIS callers proactively).
Early Central Nervous System (CNS) discovery generated new pharmaceuticals based on two properties of the compound, lipophilicity and molecular size. Almost all CNS pharmaceuticals presently in ...clinical trials possess both of these criteria and are capable of crossing the blood-brain barrier (BBB). Currently, modern methods of drug discovery utilize high throughput screening methods that may select molecules that lack both properties and will not undergo transport across the BBB. With the advent of in vitro cell culture models that mimic the BBB in vivo, researchers are now able to evaluate drug interactions at the BBB and to elucidate mechanisms at both the cellular and molecular levels pertinent for drug delivery. The utilization of both in vitro models for relatively rapid screening of permeability and related transport mechanisms, and in vivo models to assess drug pharmacokinetic distribution to the CNS provides a powerful assessment of drug delivery across the BBB to the CNS. Enaminone esters in the carbomethoxy series have previously been evaluated and shown to possess potent oral anticonvulsant activity in the mouse and rat. However, preliminary studies assessing enaminone analogs did not show expected correlations between relevant physiochemical parameters such as lipophilicity and BBB permeability. Therefore, in vitro models were utilized to assess factors associated with drug transport. An in vitro model of the BBB, Bovine Brain Microvessel Endothelial cells (BBMECs) were isolated and used to evaluated permeability and cellular mechanisms influencing enaminone transport. Results demonstrated that a multidrug resistant protein (MDR) influences enaminone permeability at the BBB. Further elucidation of possible mechanisms influencing enaminone distribution and pharmacokinetics were performed in a genetically altered mouse model mdr1a/ b (–/–) deficient in the expression of P-glycoprotein. Results comparing the brain distribution and partition coefficients in knockout mdr1a/b (–/–) versus wild type (+/+) counterparts demonstrated a higher accumulation of enaminones in brain tissue of knockout mice. Pharmacokinetic analysis of the tissue disposition of enaminones additionally demonstrated that the lack of P-glycoprotein in the lung and liver influence drug disposition in knockout animals. Lastly, a physiological based pharmacokinetic model was developed and found to be predictive of DM5 methyl 4-(4-chlorophenyl) amino-6-methyl-2-oxocyclohex-3-en-1-oate tissue distribution in mdr1a/b (–/–) knockout and wild type mice.
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