Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability.

AIM: We aimed to assess the analgesic efficacy, pharmacokinetics, tolerability and safety of a single dose of Δ9-THC in patients with chronic abdominal pain resulting from chronic pancreatitis (CP). METHODS: This was a randomized, single dose, double-blinded, placebo-controlled, two way crossover study in patients suffering from abdominal pain as result of CP (n = 24), post hoc subdivided into opioid and non-opioid users. Δ9-THC (8 mg) or active placebo (5 mg/10 mg diazepam) was administered orally in a double dummy design. RESULTS: No treatment effect was shown for delta VAS pain scores after Δ9-THC compared with diazepam. Δ9-THC was well absorbed with a mean tmax of 123 min. No significant differences were found between Δ9-THC vs. diazepam for alertness, mood, calmness or balance. Feeling anxious and heart rate were significantly increased after Δ9-THC compared with diazepam. The most frequently reported adverse events (AEs) after Δ9-THC administration were somnolence, dry mouth, dizziness and euphoric mood. CONCLUSIONS: A single dose of Δ9-THC was not efficacious in reducing chronic pain resulting from CP, but was well tolerated with only mild or moderate AEs. The PK results in CP patients showed delayed absorption and an increased variability compared with healthy volunteers.

Design, development and in vitro-in vivo study of tramadol-paracetamol inlay tablets.

The objective of this work is to formulate, optimize and evaluate in-lay tablets of tramadol-paracetamol. This study investigated the effect of hydrophobic, plastic and hydrophilic types of polymers and their content level on release profile of a highly water-soluble drug tramadol hydrochloride. A 3(2) full factorial design was employed for the optimization of the sustained release (SR) formula of tramadol hydrochloride using ethyl cellulose, eudragit and carbopol. CP9 (66% carbopol and compression load of 6 ton) with a percentage drug release of 89.03 after 12 hours were found to be most comparable to the marketed product in terms of similarity factor and most appropriately fits to zero-order kinetics. Hence, it was selected for in vivo study. Statistical analysis of in vivo studies showed that the plasma drug level after oral administration from the prepared formulation is almost comparable to the marketed product (p < 0.05). Pharmacokinetic analysis of the optimized tablet formulation CP9 were done to find out relevant pharmacokinetic parameters. The results showed that Cmax, tmax, AUC, AUMC, MRT were comparable to the marketed preparation. The formulation exhibited a good in vitro-in vivo correlation (r(2) = 0.971).

Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults: a randomized controlled trial.

BACKGROUND: Acetaminophen is often used with a non-steriodal anti-inflammatory drug for acute pain. Hitherto, these drugs have had to be given separately, typically at different time intervals. Maxigesic tablets combine acetaminophen and ibuprofen in clinically appropriate doses to simplify administration and dosage regimen. We compared this combination with each of the constituent drugs for the relief of pain after extraction of third molar teeth. METHODS: Adults (more than 16 yr) having one or more wisdom teeth removed under general or local anaesthesia were instructed to take two tablets before operation, then two tablets every 6 h for up to 48 h of: (i) a combination of acetaminophen 500 mg and ibuprofen 150 mg per tablet (Maxigesic); (ii) acetaminophen 500 mg per tablet alone; or (iii) ibuprofen 150 mg per tablet alone. The primary outcome measure was the area under the curve (AUC) of the 100 mm visual analogue scale pain measurements taken for up to 48 h after surgery, divided by time, at rest and on activity. Pharmacokinetic data were collected in a subset of patients. RESULTS: The mean (sem) time-corrected AUC on rest and activity, respectively, were: combination group 22.3 (3.2) and 28.4 (3.4); acetaminophen group 33.0 (3.1) and 40.4 (3.3); and ibuprofen group 34.8 (3.2) and 40.2 (3.4); P<0.01 for each of the four comparisons of combination vs constituent drug. There was no pharmacokinetic interaction between acetaminophen and ibuprofen administered together. CONCLUSIONS: Maxigesic tablets provide superior pain relief after oral surgery to acetaminophen or ibuprofen alone.

A highly sensitive sensor based on a computer-designed magnetic molecularly imprinted membrane for the determination of acetaminophen.

In this paper, a sensor based on a magnetic surface molecularly imprinted membrane (MMIP) was prepared for the highly sensitive and selective determination of acetaminophen (AP). Before the experiment, the appropriate functional monomers and solvents required for the polymer were screened, and the molecular electrostatic potentials (MEPs) were calculated by the DFT/B3LYP/6-31 + G method. MMIP with high recognition of AP was synthesized based on Fe3O4@SiO2nanoparticles (NPs) with excellent core-shell structure. Next, a carbon paste electrode (CPE) was filled with a piece of neodymium-iron-boron magnet to make magnetic electrode (MCPE), and MMIP/MCPE sensor was obtained by attaching a printed polymer to the surface of the electrode under the strong magnetic. Due to the stable molecular structure of the electrode surface, the sensor is highly effective and accurate for detection of AP using DPV. The DPV response of the sensor exhibited a linear dependence on the concentration of AP from 6 × 10-8 to 5 × 10-5 mol L-1 and 5 × 10-5 to 2 × 10-4 mol L-1, with a detection limit based on the lower linear range of 1.73 × 10-8 mol L-1(S/N = 3). When used for determination of AP in actual samples, the recovery of the sensor to the sample was 95.80-103.76%, and the RSD was 0.78%-3.05%.

A novel hydrophilic adhesive matrix with self-enhancement for drug percutaneous permeation through rat skin.

PURPOSE: In transdermal drug delivery system (TDDS), chemical enhancers and crystallization inhibitors added into the adhesive matrixes to improve drug permeation and formulation stability often result in some negative effect on adhesive properties and dressing performance. The aim of this paper is to develop a hydrophilic pressure sensitive adhesive (PSA) for TDDS without using additional chemical enhancers and crystallization inhibitors. METHODS: A quaternary blend (PDGW) composed of polyvinyl pyrrolidone, D,L-lactic acid oligomers, glycerol and water was prepared. The adhesive strength, drug loading capacity, drug state and stability of PDGW were characterized by using ibuprofen (IBU) and salicylic acid (SA) as model drugs. Moreover, In vitro and in vivo drug permeation through rat skin from PDGW patch in comparison to acrylate adhesive (ACA) and nature rubber adhesive (NRA) was investigated. RESULTS: PDGW performs excellent drug loading and crystallization inhibition capacity. Furthermore, the accumulative amount for 24 h in vitro from PDGW patch is far higher than that from ACA and NRA patch. And the plasma concentration of drugs in vivo from PDGW patch is bigger than that from ACA patch. CONCLUSIONS: PDGW possesses excellent PSA properties and self-enhancement for drug percutaneous permeation, which can be used to develop new formulation of TDDS.

Phase 1A safety assessment of intravenous amitriptyline.

UNLABELLED: The antidepressant amitriptyline is used as an adjuvant in the treatment of chronic pain. Among its many actions, amitriptyline blocks Na+ channels and nerves in several animal and human models. As perioperative intravenous lidocaine has been suggested to decrease postoperative pain, amitriptyline, because of its longer half-life time, might be more useful than lidocaine. However, the use of intravenous amitriptyline is not approved by the US Food and Drug Administration. We therefore investigated the adverse effects of preoperative intravenous amitriptyline in a typical phase 1A trial. After obtaining written Food and Drug Administration and institutional review board approval, we obtained written consent for preoperative infusion of amitriptyline in an open-label, dose-escalating design (25, 50, and 100 mg, n=5 per group). Plasma levels of amitriptyline/nortriptyline were determined, and adverse effects were recorded in a predetermined symptom list. Infusion of 25 and 50 mg amitriptyline appears to be well tolerated; however, the study was terminated when 1 subject in the 100-mg group developed severe bradycardia. Intravenous infusion of amitriptyline (25 to 50 mg over 1 hour) did not create side effects beyond dry mouth and drowsiness, or dizziness, in 2 of our 10 otherwise healthy participants receiving the 25- to 50-mg dose. An appropriately powered future trial is necessary to determine a potential role of amitriptyline in decreasing postoperative pain. PERSPECTIVE: Amitriptyline potently blocks the persistently open Na+ channels, which are known to be instrumental in various pain states. As this occurs at very low plasma concentrations, a single preoperative intravenous infusion of amitriptyline could provide long-lasting pain relief and decrease the incidence of chronic pain.

Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin (INN, indometacin) inhibit both the constitutive (COX-1) and inducible (COX-2) isoforms of cyclooxygenase. The induction of COX-2 after inflammatory stimuli has led to the hypothesis that COX-2 inhibition primarily accounts for the therapeutic properties of NSAIDs. METHODS: Chinese hamster ovary (CHO) cell lines that express each COX isoform were used to characterize the in vitro selectivity of rofecoxib. Single oral doses of rofecoxib and indomethacin were then assessed in subjects with use of ex vivo COX-isoform specific assays (serum thromboxane B2 [TXB2] and lipopolysaccharide [LPS]-stimulated whole blood prostaglandin E2 and assays of COX-1 and COX-2 activity, respectively). A double-blind, parallel-group study compared the analgesic efficacy of rofecoxib to placebo and ibuprofen in 102 patients with dental pain. RESULTS: Rofecoxib showed a >800-fold COX-2 selectivity with use of CHO cells that express human COX-1 and COX-2. In subjects, dose- and concentration-dependent inhibition of LPS-stimulated prostaglandin E2 was observed with both rofecoxib (IC50 [the concentration estimated to produce 50% inhibition], 0.77 micromol/L) and indomethacin (IC50, 0.33 micromol/L). Whereas indomethacin inhibited TXB2, (IC50, 0.14 micromol/L), no inhibition was observed with rofecoxib even at doses of up to 1000 mg. In the dental pain study, total pain relief (TOTPAR) over the 6 hours after dosing was similar between 50 mg and 500 mg rofecoxib and 400 mg ibuprofen (P > .20). All active treatments showed greater improvement than placebo (P < .001) CONCLUSIONS: Rofecoxib inhibited COX-2 without evidence of COX-1 inhibition, even at oral doses of up to 1000 mg. Nonetheless, rofecoxib showed analgesic activity indistinguishable from that observed with ibuprofen, a nonisoform-selective COX inhibitor. These results support the hypothesis that the analgesic effects of NSAIDs primarily derive from inhibition of COX-2.

Analgesic efficacy and pharmacokinetics of ketoprofen administered into a surgical site.

A series of three clinical trials in the oral surgery model evaluated the analgesic efficacy and pharmacokinetics of ketoprofen administered locally as a strategy for decreasing systemic exposure to nonsteroidal anti-inflammatory drugs (NSAIDs). A gel formulation was administered directly into extraction sites 1 hour following oral surgery, and pain intensity was evaluated for 6 hours. Significantly less pain was seen following peripheral administration of both 10 and 30 mg ketoprofen in comparison to the placebo. In a second study, peripheral administration of the 1 mg dose resulted in greater analgesia than oral administration of the same dose formulation or the placebo. The third study demonstrated lower plasma drug levels following the peripheral route of administration in comparison to oral administration of the same dose or ingestion of a 25 mg oral capsule. These data indicate that administration of an NSAID to a peripheral site of tissue injury results in greater analgesia than oral administration and suggests the potential for less drug toxicity through lower circulating drug levels.

Influence of water soluble fillers in hydroxypropylmethylcellulose matrices on in vitro and in vivo drug release.

The purpose of this study was to investigate the effect of fillers in gel-forming matrix on in vivo drug release after oral dosing. A further purpose was to predict the in vivo performance from in vitro dissolution test. Three controlled-release acetaminophen tablets containing hydroxypropylmethylcellulose (HPMC) with or without highly water soluble fillers, lactose or polyethylene glycol 6000 (PEG6000), were prepared. Water penetration into the matrix was enhanced by addition of fillers in the matrices, but the three tablets showed similar in vitro dissolution profiles, indicating that fillers in the HPMC matrices little affected the in vitro drug release. In contrast, the fillers in HPMC matrices did affect the in vivo performance in dogs. The absorption profile of HPMC matrix with PEG6000 was the fastest, followed by that with lactose and without water soluble filler, in that order. As the matrix with PEG6000 had a large amount of water and gelated a large portion of the matrix when in contact with water, the gel layer would be disintegrated by the gastrointestinal motility. It was found that dissolution of gel-forming HPMC matrices under mechanical stress by glass beads well correlated with the in vivo performance of the matrix, with little correlation by the conventional paddle method.

Use of salivary acetaminophen concentration to assess gastric emptying rate of liquids.

The gastric emptying rate (GER) of liquids can be quantified by calculating the rate of acetaminophen absorption from serial plasma concentrations. As acetaminophen concentrations in saliva are well correlated with those in plasma, the salivary concentrations may be suitable for use in GER measurement. To evaluate such suitability, salivary and plasma samples were simultaneously obtained from seven healthy volunteers at 0, 0.25, 0.5, 0.75, 1.0, 1.5, and 2.0 h after they had ingested 20 mg/kg of acetaminophen mixed with a 200-ml liquid meal (200 kcal). Commonly used parameters for the rate of acetaminophen absorption were calculated from the salivary and plasma data, including the maximum concentration (Cmax), the time to Cmax (t(max)), the concentration at 0.75 h (C0.75), the area under the curve from 0 to 1.0 h (AUC1.0), and the AUC(0.5)/AUC(2.0) ratio. The mean (SD) salivary/plasma concentration ratio was 2.48 (1.47) at 0.25 h, and the means were almost unity afterwards. Significant correlations between saliva and plasma were found in all parameters studied (r = 0.77-0.90; P < 0.05). However, except for t(max), the salivary parameters overestimated those of plasma. The present results suggest that: (1) the salivary acetaminophen concentration at 0.25 h (C0.25) is a poor reflection of plasma C0.25 (2) thereby the parameters embodying salivary C0.25 such as AUC1.0 and the AUC0.5/AUC2.0 ratio, are unreliable, and (3) liquid GER can be assessed by salivary t(max) with minimal distress to the patient.

Direct injection of large volumes of plasma/serum on a new biocompatible extraction column for the determination of atenolol, propranolol and ibuprofen. Mechanisms for the improvement of chromatographic performance.

Very large volumes of serum/plasma can be directly injected to a new extraction column based on particles with a biocompatible outer surface and C18 groups within the pores. The biocompatibility has been obtained by attaching the human plasma protein alpha 1-acid glycoprotein to the outer surface of the particles. The pores are small enough to exclude the plasma protein molecules. Atenolol and propranolol were extracted on the extraction column as ion-pair with octanesulfonic acid as the counterion. The same counterion was used in the analytical mobile phase. A strong improvement of the recovery can be obtained using octanesulfonic acid as counterion in the extraction mobile phase. The recovery of atenolol increased from about 53.5% to about 93.4% using octanesulfonic acid as counterion. The chromatographic performance was also strongly affected by chromatography of the basic drugs as ion-pair with octanesulfonic acid. The improvement was due to trapping in a smaller section of the extraction column and enrichment of the drug on top of the analytical column. The enrichment was due to the transfer of the analyte to the analytical column in a zone with high concentration of counterion. Furthermore, the sample zone is compressed during the migration on the analytical column. The compression effect was caused by the counterion zone, migrating in front of the sample zone, giving the analyte higher retention on the front side than on the back side of the sample zone. Displacement of protein bound drug (ibuprofen) by addition of octanoic acid, was tested in order to study the influence on the recovery and the effect on the chromatographic performance. The recovery was improved and the chromatographic performance was greatly improved. The improvement obtained on the separation efficiency of ibuprofen was due to enrichment on top of the analytical column and compression during the migration through the analytical column. The enrichment was caused by a reduction of pH in the sample--octanoic acid zone transferred from the extraction column. The octanoic acid zone migrated in front of the sample zone giving a lower pH in front of the ibuprofen zone than behind. Thus, higher retention occurred in front of than behind the sample zone, which gave rise to compression. The methods developed for atenolol, propranolol and ibuprofen could be used for the determination of serum/plasma concentrations after single doses of the drugs with very high accuracy and precision. Linear calibration graphs were obtained and the r values were > or = 0.9999.

Evaluation of acetaminophen P-glycoprotein-mediated salivary secretion by rat submandibular glands.

The constant ratio between saliva and plasma acetaminophen concentrations (S/P) during the elimination phase is assumed to result from the equilibrium established among the free-drug concentrations in the arterial blood, venous blood and saliva. Salivary secretion of acetaminophen is assumed to result from a passive diffusion of the drug to saliva from the blood that supplies the salivary glands. However, the constant S/P ratio during acetaminophen disposition and the finding that P-glycoprotein (P-gp), a protein recognized to pump substrates out of the cell, is expressed in duct cells of the submandibular glands questions the mechanisms involved in acetaminophen salivary secretion. Thus, we intended to evaluate the existence of a P-glycoprotein-mediated transport of acetaminophen in rat submandibular glands. Acetaminophen (30 mg/kg, i.v.) pharmacokinetics was assessed in controls and in rats pre-treated with erythromycin (100 mg/kg) as a P-glycoprotein inhibitor. Acetaminophen pharmacokinetic parameters were calculated from saliva and plasma levels considering a non-compartmental analysis. Mean plasma and salivary profiles of control and pre-treated animals were almost superimposable. No difference could be found in S/P ratios in control and erythromycin pre-treated animals (P > 0.05). Moreover, no statistical difference could be found in the kinetic parameters calculated from saliva or plasma drug level (P > 0.05). These observations indicate that acetaminophen salivary secretion in rat submandibular glands is not related to P-glycoprotein-mediated transport under the experimental conditions of the present work.

Chitosan dispersed system for colon-specific drug delivery.

A chitosan dispersed system (CDS), which was composed of active ingredient reservoir and the outer drug release-regulating layer dispersing chitosan powder in hydrophobic polymer, was newly developed for colon-specific drug delivery. An aminoalkyl methacrylate copolymer RS (Eudragit) RS) was selected as a hydrophobic polymer because it is hardly dissolved in acidic medium in which easily dissolves chitosan. In order to obtain the bi-functional releasing characteristics, i.e. time dependent and site specific, capsules containing the active ingredient (Drug Capsules) were coated by the chitosan dispersed hydrophobic polymer, resulting in CDS Capsules. The release rate could be controlled by changing the thickness of the layer. Furthermore, for colon-specific drug delivery, an additional outer enteric coating was necessary to prevent the drug release from CDS Capsules in the stomach, since chitosan dispersed in the layer dissolves easily under acidic conditions. Resultant enteric-coated CDS Capsules reached the large intestine within 1-3 h after oral administration and they were degraded at the colon in beagle dogs.

Saliva vs. plasma bioequivalence of paracetamol in humans: validation of class I drugs of the salivary excretion classification system.

AIMS: To study saliva and plasma bioequivalence of paracetamol in healthy human volunteers, and to investigate the robustness of using saliva instead of plasma as surrogate for bioequivalence of class I drugs according to the salivary excretion classification system (SECS). METHODS: Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis. Analysis of variance, 90% confidence intervals, intra-subject and inter-subject variability values of pharmacokinetic parameters were calculated after logarithmic transformation. Calculations were done using Kinetica program V5. Descriptive and comparative statistics were also calculated by Excel. RESULTS AND DISCUSSION: Paracetamol falls into class I (High permeability/High fraction unbound to plasma proteins) and was subjected to salivary excretion, with correlation coefficient of 0.99 between saliva and plasma concentrations and saliva/plasma concentrations ratios of 1.45-1.50. The 90% confidence limits of areas under curve (AUC(last) and AUC(∞)) showed similar trend and passed the 80-125% acceptance criteria in both saliva and plasma. On the other hand for maximum concentration (C(max)), the 90% confidence limits passed the acceptance criteria in plasma and failed in saliva. Inter and intra subject variability values in saliva were higher than plasma leading to need for higher number of subjects to be used in saliva. Saliva and plasma parameter ratios were not significantly different (P>0.05). CONCLUSIONS: Saliva instead of plasma can be used as surrogate for bioequivalence of class I drugs according to SECS when adequate sample size is used. Future work is planned to demonstrate SECS robustness in drugs that fall into classes II or III.

Poly(Patton and Reeder's reagent) modified carbon paste electrode for the sensitive detection of acetaminophen in biological fluid and pharmaceutical formulations.

An electrochemical sensor for sensitive detection of acetaminophen (AAP) was developed by electropolymerizing Patton and Reeder's reagent at carbon paste electrode (CPE). Modification improves the redox kinetics of AAP with increased current sensitivity. A similar modification at multiwall carbon nanotube (MWCNT) modified CPE did not result in an impressive charge transfer. Electrochemical impedance spectroscopy (EIS) of the bare and modified electrodes investigated imply a least charge transfer resistance at Patton and Reeder's reagent modified carbon paste electrode (MCPE/PR) as compared to bare CPE and MWCNT modified electrode. Differential pulse voltammetric (DPV) study at MCPE/PR electrode did not suffer any interference from its hydrolytic degradation product 4-aminophenol (4-AP) even in 1000-fold excess of its concentration and enables its detection simultaneously. A linear dynamic range of 0.7-100 µM with detection limit (S/N=3) of 0.53 µM was obtained for AAP. This modified electrode is easy to prepare, cheap, and having good reproducibility and stability. The analytical performance of the modified electrode is assessed by successfully applying it for the estimation of acetaminophen in different pharmaceutical samples and spiked biological fluid.

Modeling the onset and offset of dental pain relief by ibuprofen.

Onset and offset of dental pain relief by ibuprofen following third molar extraction were modeled in a randomized, double-blind, placebo-controlled, parallel-group, 8-hour study of patients receiving either a novel effervescent ibuprofen tablet (400 mg; N = 30), standard ibuprofen tablets (Nurofen(®) 2 × 200 mg; N = 22), or placebo (N = 37). An Emax model was fit to pain relief scores. Linear hazard models were used to analyze the time to first perceptible relief (TFPR), the time to meaningful pain relief (TMPR), and time to remedication (REMD). Nomograms were created to correlate TFPR, TMPR, and REMD with different ibuprofen pharmacokinetic profiles. Effervescent ibuprofen was absorbed rapidly with 95% completion within 15 minutes. Maximum pain relief score by ibuprofen was 1.8 units greater than placebo, with an EC50 (effect-site) for ibuprofen concentration of 10.2 µg·mL(-1). The likelihood to achieve TFPR and TMPR was doubled for every 10 µg·mL(-1) increase in ibuprofen plasma concentration. REMD risk decreased 40-fold as the categorical pain relief score increased from 0 to 3. Rapid absorption of ibuprofen effervescent resulted in an earlier TFPR and TMPR, and a lower REMD rate than standard ibuprofen. The nomograms may be useful in predicting the onset and offset of new faster acting ibuprofen formulations, based on pharmacokinetic profiles.

Effects of poloxamer 407-induced hyperlipidemia on the pharmacokinetics of carbamazepine and its 10,11-epoxide metabolite in rats: Impact of decreased expression of both CYP3A1/2 and microsomal epoxide hydrolase.

The pharmacokinetics of carbamazepine (CBZ) and its active 10,11-epoxide metabolite (CBZ-E) were evaluated after intravenous and oral administration of 5 mg/kg CBZ to rats with hyperlipidemia induced by poloxamer 407 (HL rats) and controls. The total area under the plasma concentration-time curve (AUC) of CBZ in HL rats after intravenous administration was significantly greater than that in controls due to their slower non-renal clearance (CL(NR)). This was due to slower hepatic CL(int) for metabolism of CBZ to CBZ-E in HL rats via CYP3A1/2. This result was consistent with a previous study indicating reduced hepatic CYP3A1/2 expression in HL rats. Interestingly, the AUC of CBZ-E was also increased in HL rats, while AUC(CBZ-E)/AUC(CBZ) ratios remained unchanged. These results suggested that further metabolism of CBZ-E to the inactive metabolite trans-10,11-dihydoxyl-10,11-dihydro-CBZ (CBZ-D) via microsomal epoxide hydrolase (mEH) was also slowed in HL rats. The significantly reduced hepatic mRNA level and expression of mEH protein in HL rats compared to controls confirmed the above hypothesis. Similar pharmacokinetic changes were observed in HL rats after oral administration of CBZ. These findings have potential therapeutic implications assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Caution is required regarding pharmacotherapy in the hyperlipidemic state in cases where drugs that are metabolized principally by CYP3A1/2 or mEH and have a narrow therapeutic range are in use.

Relationship between gelation rate of controlled-release acetaminophen tablets containing polyethylene oxide and colonic drug release in dogs.

PURPOSE: We hypothesized that sufficient gelation of orally administered hydrophilic matrix tablets before they reach the colon could, as a result of continuous erosion of the gelated matrix, prevent the decrease in colonic drug release which normally occurs here. The purpose of this study was to elucidate the effect of gelation of hydrophilic matrices containing polyethylene oxide on colonic drug release in dogs using controlled-release (CR) acetaminophen tablets. METHODS: Two types of CR tablets were prepared, a slow gelling tablet (SG) and a rapid gelling tablet (RG) containing an extra highly water soluble filler. In vitro and in vivo performance were examined. RESULTS: SG and RG showed similar drug release behavior in vitro. In oral administration to dogs, the two formulations showed similar gastrointestinal transit, reaching the colon within 2-4 h after oral dosing. Further, they showed similar maximum plasma levels (Cmax) and time to Cmax (Tmax). In contrast, however, the two tablets produced different plasma levels from 2 h post-dosing, with plasma levels of RG higher than those of SG and with smaller individual variation. Directly observed colonic drug release behavior of RG was similar to in vitro drug release, whereas that from SG was suppressed. CONCLUSIONS: Colonic drug release is closely related to the gelation of hydrophilic matrix, and rapid gelation provides continuous in vivo drug release.

Pharmacokinetics of rectal paracetamol after repeated dosing in children.

Twenty-three children (aged between 9 weeks and 11 yr) were given paracetamol suppositories 25 mg kg-1 every 6 h (maximum 5 days) after major surgery and serum and saliva concentrations were measured. There was a good correlation (r = 0.91, P < 0.05) between saliva and serum concentrations. A one-compartment linear model with first-order elimination and absorption and lag-time was fitted to the data (ADAPT II). At steady state, the mean (SD) concentration was 15.2 (6.8) mg litre-1. Mean (SD) time to reach 90% of the steady state concentration was 11.4 (8.6) h. Body weight, age and body surface area were well correlated (P < 0.05) with clearance and apparent volume of distribution. There was no evidence of accumulation leading to supratherapeutic concentrations during this dosing schedule for a mean of approximately 2-3 days.

Analgesic safety and efficacy of diclofenac sodium softgels on postoperative third molar extraction pain.

PURPOSE: The purpose of this single-blind, placebo-controlled, 3-arm parallel, randomized study was to compare the analgesic efficacy and tolerability of a single dose of 100 mg diclofenac potassium (Cataflam; Novartis, Stein, Switzerland), 100 mg diclofenac sodium softgel, and placebo in patients experiencing moderate to severe postoperative pain after third molar extraction. PATIENTS AND METHODS: Seventy-five patients (67% female with a mean age of 23, age range 18 to 34.5 years) participated in the study following removal of at least 1 impacted mandibular third molar. Patients received a single dose of study medication when their postoperative pain reached a moderate or severe intensity. Analgesic efficacy measures included the time to meaningful pain relief measured using a stopwatch and time to rescue medication. Pain relief (PR) and Pain intensity (PI) ratings were recorded at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours postdosing. Summary analgesic measures, including Summed Pain Relief Score (TOTPAR) and Summed Pain Intensity Differences (SPID), were calculated from the 0.25- to 6-hour responses. The time between pain relief and rescue and a global evaluation for the effectiveness of the study medications were recorded at the end of the study. Seven scheduled blood samples were collected from each patient for determining plasma concentrations of diclofenac anion. RESULTS: Both diclofenac sodium softgel and Cataflam were significantly more effective than placebo (P <.0001) for all summary analgesic measures. The average overall pain relief was substantially better from diclofenac sodium softgel than from Cataflam, but the difference was not statistically significant (P =.14). In patients taking diclofenac sodium softgel, 50% of the patients experienced a time to onset of analgesic activity within 18 minutes and the median analgesic duration was 5 hours (302 minutes). Fifty percent of the patients taking Cataflam had a time to onset of action within 38 minutes, and the median duration of analgesia was 4.5 hours (272 minutes). At the time of rescue drug administration or 6 hours, whichever was earlier, 72% of the patients given diclofenac sodium softgel rated the medication as a very good or excellent pain reliever, whereas only 45% of the patients taking Cataflam gave these ratings. No serious adverse events were observed in this study. The mean concentrations of diclofenac from the diclofenac sodium softgel formulation were significantly different from the Cataflam formulation. The mean C(max) for the softgel was almost twice that of Cataflam and C(max) was reached an hour earlier, on average. CONCLUSIONS: More diclofenac anion was absorbed at a quicker rate using the formulation diclofenac sodium softgel 100 mg than Cataflam. The softgel provided a very rapid onset of analgesic activity, a prolonged analgesic duration, and an acceptable side-effect profile in the postoperative third molar surgery pain model. In an acute pain situation, the rapid absorption of nonsteroidal anti-inflammatory drugs from a formulation like the Softgel may positively affect the time of onset and duration of inflammatory pain compared with other commercially available nonsteroidal anti-inflammatory drug formulations.