Paracetamol Absorption Research Articles

Impact of the Reconstruction Method on Delayed Gastric Emptying After Pylorus‐Preserving Pancreaticoduodenectomy: A Prospective Randomized Study

Delayed gastric emptying (DGE) is of considerable concern in patients undergoing pylorus-preserving pancreaticoduodenectomy (PPPD). Prolonged hospital stay, increased cost, and decreased quality of life add on to interventions needed to treat DGE. This study was conducted to determine if performing duodenojejunostomy via the antecolic rather than the retrocolic route improved incidence of DGE. Patients undergoing PPPD between April 2007 and November 2009 were randomized for either antecolic or retrocolic reconstruction of the duodenojejunostomy. DGE was then assessed by clinical criteria on postoperative day (POD) 10. A paracetamol absorption test was also administered with a liquid meal, and serial plasma levels of intestinal peptides were measured. Overall, 64 patients were amenable for analysis: 36 in the antecolic group and 28 in the retrocolic group. The incidences of DGE on POD 10 were 17.6 and 23.1 % (antecolic vs. retrocolic, respectively) (p = 0.628). The two groups did not differ in regard to their median (interquartile range) postoperative hospital length of stay [13.0 (10.0–17.5) vs. 12.5 (11.0–17.0) days; p = 0.446], time to regular diet [5 (5–7) vs. 5 (4–6) days; p = 0.353], or morbidity (52.9 vs. 50.0 %; p = 0.777). The median length of nasogastric tube decompression was similar in the two groups [4 (3–7) vs. 3 (3–5) days; p = 0.600]. Levels of paracetamol and glucagon-like peptide-1 were markedly decreased in patients with DGE. Antecolic reconstruction after PPPD does not improve the occurrence/the incidence of DGE and is similar to retrocolic reconstruction with regard to secondary outcome parameters.

Distal Gastrectomy in Pancreaticoduodenectomy is Associated with Accelerated Gastric Emptying, Enhanced Postprandial Release of GLP-1, and Improved Insulin Sensitivity

ObjectiveThis study aims to investigate the relationship between gastric emptying, postprandial GLP-1 and insulin sensitivity after pancreaticoduodenectomy (PD). BackgroundAbnormal glucose regulation is highly prevalent in patients with pancreatic neoplasm and resolves in some after PD, the cause of which is unclear. The procedure is carried out with pylorus preservation (PPPD) or with distal gastrectomy (Whipple procedure). Accelerated gastric emptying and ensuing enhanced release of glucagon-like peptide-1 (GLP-1) conceivably play a role in glucose metabolism after PD. It was the purpose of this study to shed light on the relationship between gastric emptying, GLP-1 and glycemic control after PPPD and the Whipple procedure. MethodsA 75-g oral glucose tolerance test was carried out in 13 patients having undergone PPPD and in 13 after the Whipple procedure, median age 61 (range, 32–70) years, following an interval of 23 (range, 5–199) months. Gastric emptying was measured by the paracetamol absorption method. Plasma concentrations of glucose, insulin, GLP-1 and paracetamol were measured at baseline, 10, 20, 30 60, 90, 120, 150 and 180 min. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) and oral glucose insulin sensitivity were calculated from glucose and insulin concentrations. ResultsPatients with Whipple procedure as compared to PPPD had accelerated gastric emptying (p = 0.01) which correlated with early (0–30 min) integrated GLP-1 (AUC30; r2 = 0.61; p = 0.02) and insulin sensitivity (r2 = 0.41; p = 0.026) and inversely with HOMA-IR (r2 = 0.17; p = 0.033). Two of 13 Whipple patients (15 %) as compared to seven of 13 after PPPD (54 %) had postload glucose concentrations (i.e. 120 min postmeal) ≥200 mg/dl (p < 0.05). None of 13 (0 %) after Whipple procedure but four of 13 patients (31 %) after PPPD had fasting glucose concentrations ≥126 mg/dl (p < 0.05) ConclusionsGastric emptying was accelerated after Whipple procedure as compared to patients who have undergone PPPD, resulting in higher postprandial GLP-1 concentrations and insulin sensitivity and improved glycemic control.

Liraglutide suppresses postprandial triglyceride and apolipoprotein B48 elevations after a fat‐rich meal in patients with type 2 diabetes: a randomized, double‐blind, placebo‐controlled, cross‐over trial

Postprandial triglyceridaemia is a risk factor for cardiovascular disease (CVD). This study investigated the effects of steady-state liraglutide 1.8 mg versus placebo on postprandial plasma lipid concentrations after 3 weeks of treatment in patients with type 2 diabetes mellitus (T2DM). In a cross-over trial, patients with T2DM (n = 20, 18-75 years, BMI 18.5-40 kg/m²) were randomized to once-daily subcutaneous liraglutide (weekly dose escalation from 0.6 to 1.8 mg) and placebo. After each 3-week period, a standardized fat-rich meal was provided, and the effects of liraglutide on triglyceride (primary endpoint AUC(0-8h)), apolipoprotein B48, non-esterified fatty acids, glycaemic responses and gastric emptying were assessed. ClinicalTrials.gov ID: NCT00993304. Novo Nordisk A/S. After 3 weeks, mean postprandial triglyceride (AUC(0-8h) liraglutide/placebo treatment-ratio 0.72, 95% CI [0.62-0.83], p = 0.0004) and apolipoprotein B48 (AUC(0-8h) ratio 0.65 [0.58-0.73], p < 0.0001) significantly decreased with liraglutide 1.8 mg versus placebo, as did iAUC(0-8h) and C(max) (p < 0.001). No significant treatment differences were observed for non-esterified fatty acids. Mean postprandial glucose and glucagon AUC(0-8h) and C(max) were significantly reduced with liraglutide versus placebo. Postprandial gastric emptying rate [assessed by paracetamol absorption (liquid phase) and the ¹³C-octanoate breath test (solid phase)] displayed no treatment differences. Mean low-density lipoprotein and total cholesterol decreased significantly with liraglutide versus placebo. Liraglutide treatment in patients with T2DM significantly reduced postprandial excursions of triglyceride and apolipoprotein B48 after a fat-rich meal, independently of gastric emptying. Results indicate liraglutide's potential to reduce CVD risk via improvement of postprandial lipaemia.

Gastrointestinal peptides, gastrointestinal motility, and anorexia of aging in frail elderly persons

The mechanisms involved in anorexia in frail elderly people remain unclear. The objective of this study was to establish whether fasting and postprandial levels of gastrointestinal peptides, gastrointestinal motility, and hunger are modified by age and frailty. Three groups of subjects were studied: (a) frail elderly (>70 years) persons, (b) non-frail elderly (>70 years) persons, and (c) healthy adults (aged 25-65 years). After an overnight fast, participants ingested a 400 Kcal liquid meal and appetite, hormonal, and gastrointestinal responses were monitored during early (0-60 min) and late (60-240 min) postprandial periods. Frail persons showed poor nutritional status, sarcopenia, and almost absence of hunger during fasting and postprandial periods. Older persons presented higher levels of glucose and insulin during fasting, enhanced postprandial CCK release in early postprandial period and postprandial hyperglycemia and hyperinsulinemia, but similar ghrelin levels than younger adults. Ultrasound scan showed that the fasting antral area was higher and antral compliance lower in old persons. The paracetamol absorption test showed enhanced postprandial gastric emptying in the frail. Non-gallbladder contractors showed no CCK peak in younger and non-frail groups, but the same high CCK peak as contractors in the frail. Frailty was associated with anorexia, risk of malnutrition, and sarcopenia. Frail persons showed impaired gastric motility (larger antral area at rest, impaired antral compliance, and enhanced postprandial emptying), impaired gallbladder motility, and fasting and/or postprandial alterations in CCK, glucose, and insulin release. Further studies are needed to determine if these factors may contribute to anorexia of aging in frail persons.

A new rapidly absorbed paediatric paracetamol suspension. A six-way crossover pharmacokinetic study comparingthe rate and extent of paracetamol absorption from a new paracetamol suspension with two marketed paediatric formulations

The objective of this study was to compare the rate and extent of paracetamol absorption from the new Paracetamol pediatric suspension (PPS) with two marketed paracetamol suspensions: Children’s panadol (CP) and Panodil baby & infant (PBI). The study also assessed the effect on paracetamol absorption of light-calorie, low-fat food consumed 2 h before dosing. Twenty eight male adult volunteers received a single oral dose of 1000 mg of paracetamol from each of three treatments, in both fasted and fed states according to a randomized, single-center, open-label, six-way crossover study design. PPS was bioequivalent to both CP and PBI for AUC0–10 h, AUC0–inf and Cmax in both fasted and fed state. However, PPS had greater rate of paracetamol absorption and a faster speed of onset. Tmax for PPS was significantly shorter than for PBI in both fasted (p = 0.0005) and fed state (p = 0.0001). Median Tmax for PPS was also 10 min shorter than CP in fasted state. Time to reach minimum effective concentration (MEC) for PPS was significantly shorter than CP and PBI. Early paracetamol exposure of PPS was significantly higher than that of the two existing paracetamol products. Food had a significant effect in the early exposure and onset of therapeutic level of paracetamol from PPS. AUC0–30 min was significantly higher and time to reach plasma paracetamol at MEC level was significantly shorter than in the fasted state.

Inclusion of Paracetamol into β-cyclodextrin nanocavities in solution and in the solid state

We report on steady-state UV–visible absorption and emission characteristics of Paracetamol, drug used as antipyretic agent, in water and within cyclodextrins (CDs): β-CD, 2-hydroxypropyl- β-CD (HP- β-CD) and 2,6-dimethyl- β-CD (Me- β-CD). The results reveal that Paracetamol forms a 1:1 inclusion complex with CD. Upon encapsulation, the emission intensity enhances, indicating a confinement effect of the nanocages on the photophysical behavior of the drug. Due to its methyl groups, the Me- β-CD shows the largest effect for the drug. The observed binding constant showing the following trend: Me- β-CD > HP- β-CD > β-CD. The less complexing effectiveness of HP- β-CD is due to the steric effect of the hydroxypropyl-substituents, which can hamper the inclusion of the guest molecules. The solid state inclusion complex was prepared by co-precipitation method and its characterization was investigated by Fourier transform infrared spectroscopy, 1H NMR and X-ray diffractometry. These approaches indicated that Paracetamol was able to form an inclusion complex with CDs, and the inclusion compounds exhibited different spectroscopic features and properties from Paracetamol.

The absorption of aspirin and paracetamol in patients with achlorhydria.

The absorption of aspirin and paracetamol in patients with achlorhydria.

A physiologically-based pharmacokinetic model for absorption of oral paracetamol in man [proceedings

A physiologically-based pharmacokinetic model for absorption of oral paracetamol in man [proceedings

The gastrointestinal absorption of paracetamol in the rat.

The absorption of [3H]paracetamol by rat small intestine, colon and stomach was studied in vivo and in vitro. Small intestinal in vivo studies, using a wide range of drug concentrations, showed that absorption was efficient and uniform throughout the small bowel, no site showing preferential absorption. Double reciprocal and direct plots indicated first order kinetics. The pattern was not observed when uptake was occurring from high concentrations of paracetamol in suspension. Gastric and colonic in vivo studies showed that there was appreciable absorption of [3H]paracetamol from these sites. In vitro studies using everted intestinal sacs showed no effect on paracetamol transfer when the incubation temperature was lowered to 10 degrees C or when iodoacetate (5 X 10(-2)M) and 2.4 dinitrophenol (5 X 10(-4)M) was added to the incubation medium. There was, however, a significant reduction in transfer of paracetamol against a concentration gradient of 10:1 applied across the mucosa. These data suggest that the uptake of paracetamol is by a passive transport process and confirm the efficiency of paracetamol absorption observed indirectly by others.

Some factors affecting the absorption of paracetamol

Abstract Blood concentration and urinary excretion data demonstrated that subjects who had ingested 1 g of paracetamol after fasting overnight absorbed the drug up to 5 times more rapidly but to the same extent as when they ingested the drug after a substantial high carbohydrate breakfast. Subjects who had ingested 1 g of paracetamol immediately before sleep at night excreted up to 36% less than when they took the drug at 8.30 a.m.

Dexmedetomidine inhibits gastric emptying and oro-caecal transit in healthy volunteers

Dexmedetomidine is a potent and selective α2-adrenoceptor agonist used for perioperative and intensive care sedation with certain beneficial qualities. However, based on preclinical observations, it might inhibit gastric emptying and gastrointestinal transit, which could result in unwanted effects in intensive care patients. This study evaluated the effects of dexmedetomidine on gastric emptying and oro-caecal transit time in healthy volunteers. Twelve healthy male subjects were given 1 µg kg(-1) of dexmedetomidine i.v. over 20 min followed by a continuous i.v. infusion of 0.7 µg kg(-1) h(-1) for 190 min. For comparison, subjects were also given 0.10 mg kg(-1) of morphine hydrochloride i.v. over 20 min and a placebo infusion in a randomized order. Gastric emptying was assessed with the paracetamol absorption test and oro-caecal transit time with the hydrogen breath test. The time to maximum paracetamol concentration in plasma was significantly longer, maximum paracetamol concentration was significantly lower, the area under the plasma paracetamol concentration-time curve was significantly smaller, and oro-caecal transit time was significantly longer during dexmedetomidine infusion compared with morphine or placebo infusion. Dexmedetomidine markedly inhibits gastric emptying and gastrointestinal transit in healthy volunteers.

Randomised Controlled Trial Comparing Oral and Intravenous Paracetamol (Acetaminophen) Plasma Levels when given as Preoperative Analgesia

Gastric absorption of oral paracetamol (acetaminophen) may be unreliable perioperatively in the starved and stressed patient. We compared plasma concentrations of parenteral paracetamol given preoperatively and oral paracetamol when given as premedication. Patients scheduled for elective ear; nose and throat surgery or orthopaedic surgery were randomised to receive either oral or intravenous paracetamol as preoperative medication. The oral dose was given 30 minutes before induction of anaesthesia and the intravenous dose given pre-induction. All patients were given a standardised anaesthetic by the same specialist anaesthetist who took blood for paracetamol concentrations 30 minutes after the first dose and then at 30 minute intervals for 240 minutes. Therapeutic concentrations of paracetamol were reached in 96% of patients who had received the drug parenterally, and 67% of patients who had received it orally. Maximum median plasma concentrations were 19 mg.l(-1) (interquartile range 15 to 23 mg.l(-1)) and 13 mg.l(-1) (interquartile range 0 to 18 mg.l(-1)) for the intravenous and oral group respectively. The difference between intravenous and oral groups was less marked after 150 minutes but the intravenous preparation gave higher plasma concentrations throughout the study period. It can be concluded that paracetamol gives more reliable therapeutic plasma concentrations when given intravenously.

Pharmacokinetic and Bioequivalence Study Evaluating a New Paracetamol/Caffeine Formulation in Healthy Human Volunteers

Purpose: Aim of this study was to evaluate the bioequivalence and clinical pharmacokinetics of newly developed paracetamol 500 mg and caffeine 65 mg combination (PANADOL® EXTRA ADVANCE product), compared with currently marketed conventional paracetamol/caffeine caplet (PANADOL EXTRA® product) in fasted and semi-fed states. Methods: Thirty subjects were enrolled and all completed this 4-way crossover study. Serial blood samples were collected pre-dose until 10-hours post-dose for each period. Plasma samples were assayed for paracetamol and caffeine concentration using HPLC/MS methods. PK parameters were computed using non-compartmental model. Linear mixed-effect model was used to analyze logarithmically transformed AUC0-∞, AUC0-t and Cmax as well as AUC0-30min and AUC0-60min values. Tmax was analyzed by signed rank test on within-subject differences. Time to reach minimum therapeutic concentration in plasma of 4 μg/ml (T4) for paracetamol was evaluated. The AEs were also assessed. Ratios of AUC0-∞, AUC0-t, and Cmax were compared for new formulation vs. PANADOL EXTRA® in fasted and semi-fed states, and analyzed for bioequivalence as determined by 90% confidence intervals (CI90%). Results: Bioequivalence was established between these two formulations in both fasted and semi-fed states, as the ratios were within 0.8-1.25, except the Cmax of paracetamol in fasted state. In addition, the new formulation showed significantly greater early absorption (AUC0‑30min and AUC0-60min), as well as significantly shorter Tmax, for both paracetamol and caffeine compared to PANADOL EXTRA® in fasted and semi-fed states. Based on T4, paracetamol absorption was twice as fast for the new formulation as compared to the corresponding conventional caplet in the fasted and fed states. The new formulation was safe and well tolerated. Conclusions: The new Panadol® Extra Advance formulation is bioequivalent to the currently marketed conventional formulation. Both paracetamol and caffeine are absorbed significantly faster with the new formulation compared to Panadol® Extra product.

Systems biology approach to study permeability of paracetamol and its solid dispersion

Physiological changes that take place at cellular level are usually reflective of their level of gene expression. Different formulation excipients have an impact on physiological behavior of the exposed cells and in turn affect transporter genes, enterocyte-mediated metabolism and toxicity biomarkers. The aim of this study was to prepare solid dispersion of paracetamol and evaluate genetic changes that occur in Caco-2 cell lines during the permeability of paracetamol alone and paracetamol solid dispersion formulations. Paracetamol–PEG 8000 solid dispersion was prepared by melt fusion method and the formulation was characterised using differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Formulation of solid dispersion resulted in the conversion of crystalline drug into an amorphous form. Permeability studies showed that paracetamol absorption was higher from the solid dispersion formulation. DNA microarrays analysis was carried out in order to investigate the involvement of any efflux/uptake transporters in paracetamol or its solid dispersion permeability. Neither transporter carriers nor efflux proteins were found to be involved in the absorption of paracetamol or its PEG solid dispersion. Gene expression analysis established that paracetamol toxicity was potentially reduced upon formulation into solid dispersion when ATP binding cassette (ABC) and solute carrier transporter (SLC) genes were analyzed.

The comparative pharmacokinetics of modified‐release and immediate‐release paracetamol in a simulated overdose model

Panadol Extend (PEx) is an over-the-counter, modified-release formulation of paracetamol. Each 665 mg tablet contains 69% slow-release and 31% immediate-release paracetamol. In simulated human overdose, PEx exhibits lower and later peak serum concentrations and a lower area-under-the-curve (AUC) than comparable doses of immediate-release paracetamol (APAP-IR). The lower AUC might result from incomplete absorption of paracetamol or simultaneous metabolism with absorption. Do differences in pharmacokinetics (PK) between PEx and APAP-IR result from incomplete absorption or simultaneous absorption and metabolism of paracetamol? Cross-over study of 80 mg/kg of PEx or APAP-IR in nine volunteers. Serial plasma paracetamol, glucuronide, sulphate and cysteine metabolite estimates performed over 24 h. Peak plasma concentration (Cmax), AUC((0-∞),) time to peak concentration (Tmax) and elimination half-life (t(1/2) ) were compared. PEx exhibited significantly lower paracetamol Cmax (252.33 µmol/L vs 565.56 µmol/L, P= 0.0421), AUC((0-∞)) (2133 µmol/h/L vs 2637 µmol/h/L, P= 0.0004) and delayed Tmax (2.889 h vs 1.389 h, P= 0.0189) than APAP-IR. Sulphate metabolite PK parameters for both preparations, PEx vs APAP-IR, showed similar AUC((0-∞)) (1369 µmol/h/L vs 1089 µmol/h/L), Tmax (3.889 h vs 4.444 h), Cmax (95.889 µmol/L vs 95.889 µmol/L) and t(1/2) (3.895 h vs 3.810 h). Glucuronide metabolite concentrations revealed that PEx produced a lower Cmax (257.44 µmol/L vs 335.22 µmol/L, P= 0.0239) than APAP-IR. All other pharmacokinetic parameters were similar. Cysteine metabolite was not detected. There were minor differences between the PK parameters of the two major paracetamol metabolites of these two preparations in simulated overdose. The variability in paracetamol AUC seen between the two preparations in moderate overdose might be explained by concurrent metabolism of paracetamol during slower absorption with PEx.

The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol

BackgroundIbuprofen and paracetamol differ in their mode of action and related therapeutic effects, suggesting that combined administration may offer improved analgesia. Reported here are the results of two studies on the pharmacokinetic properties of a novel ibuprofen (200 mg) and paracetamol (500 mg) fixed-dose combination tablet.MethodsBoth studies were open-label, randomised studies in healthy volunteers: Study 1 was a four-way crossover, single-dose study; Study 2 was a two-way cross-over, repeat-dose study.ResultsPharmacokinetic parameters for ibuprofen and paracetamol were similar for the combination and monotherapy tablets (values falling within the 80% to 125% acceptable bioequivalence range) except for the rate of absorption of paracetamol from the combination (tmax), which was significantly faster compared with monotherapy (median difference 10 minutes; p < 0.05). Mean plasma concentrations of both drugs were higher, earlier, following administration of the combination tablet compared with monotherapy. Mean plasma levels at 10 and 20 minutes were 6.64 μg.mL-1 and 16.81 μg.mL-1, respectively, for ibuprofen from the combination, compared with 0.58 μg.mL-1 and 9.00 μg.mL-1, respectively, for monotherapy. For paracetamol, mean plasma levels at 10 and 20 minutes were 5.43 μg.mL-1 and 14.54 μg.mL-1, respectively, for the combination compared with 0.33 μg.mL-1 and 9.19 μg.mL-1, respectively, for monotherapy. The rate of absorption of both ibuprofen and paracetamol was significantly delayed when the combination tablet was administered in the fed versus fasted state; median delay was 25 minutes for ibuprofen (p > 0.05) and 55 minutes for paracetamol (p < 0.001). The pharmacokinetic parameters were comparable irrespective of whether the combination tablet was given twice or three times daily; systemic exposure was, however, approximately 1.4 times greater for both drugs when given three times daily.ConclusionsAdministration of ibuprofen and paracetamol in a fixed-dose combination tablet does not significantly alter the pharmacokinetic profiles of either drug, except for enhancing the rate of paracetamol absorption, offering potential therapeutic benefits in relation to the onset of analgesia. Concentrations of both drugs reached previously reported therapeutic levels when the combination tablet was administrated in the fed or fasted state. Three times daily dosing may offer enhanced therapeutic effect for longer than twice daily dosing.

Comparison of paracetamol pharmacokinetics in Panadol&lt;sup&gt;®&lt;/sup&gt; and Panadol extra&lt;sup&gt;®&lt;/sup&gt;

The influence of caffeine (60mg) was studied on the pharmacokinetic characteristics of paracetamol (1000mg single dose) in six healthy male human volunteers. A double beam spectrophotometer was used to analyse salivary paracetamol concentrations. Caffeine caused a significant (p< 0.05) decrease in the saliva concentration of paracetamol (C ) and area under salivary paracetamol concentration curve (AUC). There was no statistically significant increase in max elimination half-life (t ) and clearance (Cl) of paracetamol in man. There was statistically significant increase in half 1/2el life of absorption of paracetamol (t ) from Panadol Extra®. The results indicated impaired absorption of paracetamol 1/2abfrom Panadol Extra®.

Effects of Fat Supplementation on Postprandial GIP, GLP-1, Ghrelin and IGFBP-1 Levels: A Pilot Study on Adolescents with Type 1 Diabetes

Aims: To compare the responses of GIP, GLP-1, ghrelin and IGFBP-1 between meals with different fat and energy content in adolescents with type 1 diabetes (T1DM) and to relate them to gastric emptying and glycaemia. Methods: On different days and in a random order, 7 adolescents with T1DM ingested a high- and low-fat meal (fat content: 38 and 2 g, energy content: 640 and 320 kcal, respectively). At normoglycaemia, the same prandial insulin dose was given at both meals and to all subjects. Postprandial blood samples were taken repeatedly over 4 hours. Gastric emptying was estimated by the paracetamol absorption method. Results: The area under the curve (AUC) for GIP_{0–240 min} and for GLP-1_{0–120 min} was larger, but smaller for relative ghrelin_{0–240 min}, after the high-fat meal (p = 0.002, 0.030 and 0.043, respectively). IGFBP-1 decreased significantly, but not differently, after the meals. Larger GLP-1 secretion correlated with slower gastric emptying (p = 0.029) and higher fasting ghrelin levels correlated with lower postprandial glycaemia (p = 0.007). Conclusion: In adolescents with T1DM, the postprandial responses of GIP, GLP-1 and ghrelin, but not that of IGFBP-1, depend more on meal size than on insulin.

The influence of morphine on the absorption of paracetamol from various formulations in subjects in the supine position, as assessed by TDx measurement of salivary paracetamol concentrations

The aim of this study was to determine the influence of the type of paracetamol formulation on the rate of absorption when subjects are in the supine position, with or without taking concomitant morphine. Two groups of healthy volunteers were used, who were in the fasting state and remained in the supine position during the study. One group took 1,500 mg of paracetamol on three occasions as conventional tablets, dispersible tablets or a suspension in a randomized crossover design. Seventeen saliva samples per subject were obtained (time zero to 360 min post-dose), which were then centrifuged and kept at -20 degrees C prior to analysis. The second group repeated the study following four doses of morphine syrup (10 mg 4 hourly) in the 12 h preceding paracetamol ingestion. In this phase of the study, paracetamol absorption from suspension was not investigated. A TDx assay was used to determine salivary paracetamol concentrations. The tmax for conventional tablets when taken concomitantly with morphine was 160 (+/- 81) min compared to 51 (+/- 58) min for subjects not taking morphine. For dispersible tablets the tmax in the morphine group was 14 (+/- 9) min compared to 15 (+/- 12) min without morphine. The results suggest that patients who are confined to bed and taking morphine will have an unacceptably long delay between taking conventional paracetamol tablets and the paracetamol reaching therapeutic plasma concentrations. Conversely, there is little effect on the absorption of dispersible paracetamol under the same conditions.

The Effect of Celiac Plexus Block in Critically Ill Patients Intolerant of Enteral Nutrition

In this study, we evaluated the efficacy of celiac plexus block for the treatment of feeding intolerance in critically ill patients. Nineteen mechanically ventilated medical patients intolerant of enteral nutrition and receiving metoclopramide underwent bilateral celiac plexus block. The anterior procedure was accomplished under sonographic guidance with the injection of either 25 mL bupivacaine 0.25% (celiac group, n = 10) or saline (control group, n = 9) bilaterally. Gastric emptying was assessed by the acetaminophen absorption method. After the block, nasogastric feeding was commenced, and nasogastric aspirates were collected once every 24 hours. Successful feeding was defined as 24-hourly gastric residual volume <250 mL with a feeding rate > or = 40 mL/h. Demographic data were similar for the 2 groups. The area under the plasma paracetamol absorption curve (383.8 +/- 248.1 mg . min . L(-1)) and the peak plasma paracetamol concentration (C(max); 3.28 +/- 2.15 mg/L) in the celiac group were significantly lower than the area under the curve value (1233.5 +/- 771.2) and C(max) value (10.14 +/- 6.04) in controls (P < 0.001 for all). After treatment, celiac plexus block reduced the mean gastric residual volume (celiac group: 430 +/- 32 mL to 205 +/- 30 mL, P < 0.001; control group: 450 +/- 33 mL to 461 +/- 19 mL, P > 0.05) and improved the proportion of patients with successful feeding (celiac block 80% vs controls 0%, P < 0.001). In critical illness, celiac plexus block is effective for treating feeding intolerance when IV drug therapy has failed to improve gastrointestinal dysfunction.