Treatment of reflux oesophagitis of moderate and severe grade with ranitidine or pantoprazole--comparison of 24-hour intragastric and oesophageal pH

BACKGROUND: Proton pump inhibiting drugs strongly decrease gastric acid secretion and have proven more effective in the treatment of reflux oesophagitis than H2-receptor antagonists. METHODS: In a double-blind randomized trial, 24 patients with oesophagitis grade II (n = 15) and III (n = 9) were treated for 4 weeks with either ranitidine 150 mg b.d. (n = 13) or pantoprazole 40 mg o.m. (n = 11). Before the trial and on the last day of medication, 24-h intragastric pH and oesophageal pH profiles were performed. Healing was assessed by endoscopy. RESULTS: Pantoprazole increased median gastric pH from 1.7 to 3.9. Virtually no change in gastric pH was seen in the ranitidine group. Pantoprazole reduced the fraction time of pH < 4 in the oesophagus from 21% to 3% (P = 0.0005), and the median number of refluxes from 206 to 56 (P = 0.022). Oesophageal acid exposure was not decreased by ranitidine. Healing of the oesophagitis was seen in 6/11 cases after pantoprazole and in 3/13 cases after ranitidine (N.S.) CONCLUSION: In patients with oesophagitis of moderate and severe grade, pantoprazole 40 mg o.m. decreases intragastric acidity and gastro-oesophageal acid reflux more effectively than ranitidine 150 mg b.d.     

Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects

BACKGROUND & AIMS: Proton pump inhibitors administered twice daily do not provide complete nocturnal acid suppression. Acid breakthrough, or decrease in intragastric pH to <4 for an hour or longer, occurs in three quarters of normal subjects and patients at night. We compared the effect of a third dose of omeprazole at bedtime with that of a dose of ranitidine at bedtime on residual nocturnal acid secretion in patients receiving omeprazole twice daily. METHODS: Twelve volunteers underwent overnight intragastric pH monitoring after 7 days of treatment with omeprazole, 20 mg twice daily, followed by different treatment supplements at bedtime: placebo; additional omeprazole, 20 mg; ranitidine, 150 mg; and ranitidine, 300 mg. RESULTS: Additional omeprazole at bedtime reduced the percentage of time with intragastric pH of <4 from 48% to 31% (P < 0.005) compared with omeprazole twice daily with placebo at bedtime. Ranitidine at bedtime reduced this parameter more, 5% with 150 mg and 6% with 300 mg (P <0.01 vs. omeprazole twice daily plus bedtime). Results for percentage of time with intragastric pH <3 were similar. Eleven subjects had acid breakthrough with placebo at bedtime; 7 with omeprazole at bedtime (P = NS); 4 with ranitidine, 150 mg at bedtime; and 3 with ranitidine, 300 mg at bedtime (P < 0. 05, ranitidine vs. placebo). CONCLUSIONS: Bedtime ranitidine is more effective than bedtime omeprazole on residual nocturnal acid secretion in patients receiving omeprazole twice daily. This finding suggests that fasting breakthrough nocturnal acid secretion in patients receiving omeprazole twice daily is most likely histamine related.     

Diurnal secretory patterns and tolerance during individually titrated infusions of ranitidine

BACKGROUND: Gastric acid secretion in humans shows chronobiological patterns that modify the efficacy of antisecretory agents. The ability of individually titrated ranitidine infusions to overcome circadian patterns of gastric acidity and tolerance during prolonged dosing was assessed. METHODS: Eleven healthy subjects were randomized to receive ranitidine infusions of up to 600 mg/24 hours by a pH feedback-regulated pump before and after 9 days of oral dosing with ranitidine, 300 mg four times daily, beginning either in the evening or in the morning in a cross-over, third party-blinded and placebo-controlled study design. RESULTS: Mean 24-hour intravenous ranitidine doses given to attain the target pH of 4 were greater after 9 days of treatment with oral ranitidine than before in the morning and evening studies (P < 0.01). The median 24-hour pH decreased from 5.1 before to 3.6 after oral dosing in the morning study (P < 0.001) and from 4.4 to 2.8 in the evening study (P < 0.001). Before oral dosing of ranitidine, the time of pH > 4 in the evening and morning fasting periods was 71% and 84%, respectively (P < 0.05). After 9 days oral ranitidine, the respective results were 20% and 53% (P < 0.05). CONCLUSIONS: The reduced responsiveness to ranitidine in the evening and the tolerance to ranitidine with repeated dosing were not overcome by individually titrated, high intravenous doses of ranitidine.     

Regional gastrointestinal absorption of ranitidine in the rat

PURPOSE: Ranitidine absorption from isolated segments of rat small intestine (duodenum, midgut, and terminal ileum) was investigated to examine the influence of pH and 50% bile, and to determine if ranitidine is absorbed preferentially from a specific region. METHODS: Ranitidine (50 mg/kg) was administered into each segment in pH 5 or pH 7 buffer, or in 50% bile. Venous blood was collected at various times for 40 min from the right jugular vein. RESULTS: When ranitidine was administered in pH 7 buffer or in 50% bile, Cmax and AUC0-40 were significantly greater after administration into the terminal ileum compared to the duodenum and midgut. AUC0-40 was significantly greater when ranitidine was administered in pH 5 buffer or in 50% bile into the duodenum compared to the midgut. Cmax was significantly different between administration into the duodenum and midgut only when ranitidine was administered in 50% bile. Ranitidine administration in pH 5 buffer significantly decreased AUC0-40 and Cmax after administration into the midgut, and AUC0-40 after administration into the terminal ileum compared to administration with pH 7 buffer or in 50% bile. Bile had no significant effect on AUC0-40 after ranitidine administration into the duodenum and midgut compared to administration in pH 7 buffer. However, bile significantly increased AUC0-40 and Cmax after ranitidine administration into the terminal ileum compared to administration with pH 7 and pH 5 buffer. CONCLUSIONS: Results suggest that ranitidine is absorbed from the entire small intestine. However, the terminal ileum is the optimal site of gastrointestinal absorption. Furthermore, bile enhances ranitidine absorption from the terminal ileum.     

Randomized controlled trial of effects of Escherichia coli antiserum on serum immunoglobulin G concentrations and morbidity and mortality rates in foals

OBJECTIVE: To determine whether administration of commercially available Escherichia coli antiserum to neonatal foals would affect serum IgG concentration or morbidity and mortality rates during the first 60 days of life. DESIGN: Randomized controlled trial. ANIMALS: 271 neonatal foals on 4 well-managed farms. PROCEDURE: Foals were randomly assigned to a treatment or control group. All foals were allowed to suckle colostrum normally. In addition, treatment-group foals were given E coli antiserum (10 micromilligrams) orally between 0 and 8 hours after birth. Serum samples were obtained between 18 and 36 hours after birth, and serum IgG concentration was determined. Foals were monitored for the first 60 days after birth, and causes of disease or death were recorded. RESULTS: Groups did not differ significantly in regard to breed, sex, month of birth, season of birth, age of dams, parity of dams, duration of gestation, or specific gravity of colostrum before suckling. In addition, groups did not differ significantly in regard to mean serum IgG concentration, prevalence of complete or partial failure of passive transfer of immunity, frequency or causes of disease, or frequency of death from infectious causes. CLINICAL IMPLICATIONS: In this group of foals on well-managed farms, administration of E coli antiserum did not alter serum IgG concentrations or morbidity and mortality rates during the first 60 days of life.     

Implant and prosthetic principles according to the desired prosthesis

BACKGROUND/AIMS: Prolonged infusions of H2-antagonists are commonly used in intensive care units, although little is known about their antisecretory efficacy beyond the initial 24 hours of dosing. The aim of this study was to assess the antisecretory effects of infusions of ranitidine and omeprazole for a period of 72 hours. METHODS: Twelve healthy volunteers received individually titrated 72-hour intravenous infusions of omeprazole, ranitidine, or placebo in a double-blind, crossover study. Gastric pH and dosing requirements were compared. RESULTS: The median percentage of time with pH > 4 (interquartile range) was 93% (88%-95%) on day 1 and 96% (94%-99%) on day 3 with omeprazole and 67% (56%-78%) and 43% (31%-51%), respectively, with ranitidine (both P < 0.001 vs. omeprazole). The mean doses (+/- SD) required on days 1 and 3 for omeprazole were 235.8 +/- 44 mg and 134.0 +/- 37 mg (P < 0.0001), and ranitidine doses were 502.5 +/- 76 mg and 541.8 +/- 25 mg, respectively (P = 0.05). CONCLUSIONS: Omeprazole infusions consistently maintained gastric pH above 4 over a period of 72 hours with progressively lower doses. Significant tolerance to the antisecretory effect of ranitidine infusion developed in 72 hours, which was not overcome despite individually titrated doses of more than 500 mg/24 hours. Consequently, application of pharmacodynamic results of single-day H2-blocker and proton-pump inhibitor studies to prolonged infusion trials for stress ulcer-related bleeding is inappropriate.     

Pharmacokinetics of cefepime and comparison with those of ceftiofur in horses

OBJECTIVE: To determine pharmacokinetics of i.v., i.m., and oral administration of cefepime in horses and to compare pharmacokinetics of i.m. administration of cefepime with those of ceftiofur sodium. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Horses received 3 doses of cefepime (11 mg/kg of body weight, PO; 2.2 mg/kg, i.v.; and 2.2 mg/kg, i.m.) and 1 dose of ceftiofur (2.2 mg/kg, i.m.). Two horses also received L-arginine, p.o. and i.v., at doses identical to those contained in the cefepime dihydrochloride-L-arginine preparations previously administered. Blood samples were collected for 24 hours after administration of cefepime or ceftiofur and were assayed for cefepime and ceftiofur concentrations. RESULTS: Pharmacokinetic analysis of disposition data indicated that i.v. administration data were best described by a 2-compartment open model, whereas i.m. administration data were best described by a 1-compartment absorption model. Median elimination half-life and volume of distribution after i.v. administration of cefepime were 125.7 minutes and 225 ml/kg, respectively. After i.m. administration of cefepime, mean maximal plasma concentration of (8.13 microg/ml) was reached at a mean time of 80 minutes. Absorption of cefepime after i.m. administration was complete, with a median bioavailability of 1.11. Intramuscular administration of ceftiofur resulted in similar mean maximal plasma concentration (7.98 microg/ml) and mean time to this concentration (82 minutes). Cefepime was not detected in samples collected after oral administration. Adverse effects consisting principally of gastrointestinal disturbances were observed after oral and i.m. administration of cefepime and after 1 i.m. administration of ceftiofur. CONCLUSIONS AND CLINICAL RELEVANCE: Cefepime, administered i.v. or i.m. at a dosage of 2.2 mg/kg, every 8 hours is likely to provide effective antibacterial therapy for cefepime-sensitive organisms in horses. Further studies are needed to evaluate adverse effects on the gastrointestinal tract.     

Incidence of fatal pulmonary embolism after 1,390 knee arthroplasties without routine prophylactic anticoagulation, except in high-risk cases

OBJECTIVE: To determine whether the time of administration (morning vs. evening) of pantoprazole influences the effect of a 40 mg dose upon intragastric pH in healthy subjects. DESIGN: Randomized, double-blind, two-period crossover study to compare intragastric pH following treatment with pantoprazole, 40 mg once daily for 7 days, the drug being given as either a morning or an evening dose before meals. METHODS: Intragastric pH was measured for 24 h on three occasions. The baseline recording was made 2 days prior to the first treatment period and subsequent measurements were made on days 6 to 7 of each period. Adverse events were recorded and fasting laboratory variables measured. RESULTS: Twelve subjects were evaluable for efficacy. Increases in median pH over 24 h were observed in all subjects with both dosage regimens. There was a greater increase from baseline in 24-h median pH values following morning than evening administration of pantoprazole (P < 0.05). This difference was due to a greater effect on median daytime pH (07.00-19.00 h, P < 0.01) compared with that after evening administration. No adverse events were reported and there were no clinically significant changes in laboratory variables. CONCLUSION: The study supports the recommendation of a once-daily morning dosage regimen of pantoprazole 40 mg in the treatment of acid-related diseases.     

Cardiopulmonary and anesthetic effects of propofol in wild turkeys

OBJECTIVE: To determine safety, anesthetic variables, and cardiopulmonary effects of i.v. infusion of propofol for induction and maintenance of anesthesia in wild turkeys. ANIMALS: 10 healthy, adult wild turkeys. PROCEDURE: Anesthesia was induced by i.v. administration of propofol (5 mg/kg of body weight) over 20 seconds and was maintained for 30 minutes by constant i.v. infusion of propofol at a rate of 0.5 mg/kg/min. Heart and respiratory rates, arterial blood pressures, and arterial blood gas tensions were obtained prior to propofol administration (baseline values) and again at 1, 2, 3, 4, 5, 10, 15, 20, 25, and 30 minutes after induction of anesthesia. All birds were intubated immediately after induction of anesthesia, and end-tidal CO2 concentration was determined at the same time intervals. Supplemental oxygen was not provided. RESULTS: Apnea was observed for 10 to 30 seconds after propofol administration, which induced a decrease in heart rate; however, the changes were not significant. Compared with baseline values, respiratory rate was significantly decreased at 4 minutes after administration of propofol and thereafter. Systolic, mean, and diastolic pressures decreased over the infusion period, but the changes were not significant. Mean arterial blood pressure decreased by 30% after 15 minutes of anesthesia; end-tidal CO2 concentration increased from baseline values after 30 minutes; PO2 was significantly decreased at 5 minutes after induction and thereafter; PCO2 was significantly (P < 0.05) increased after 15 minutes of anesthesia; and arterial oxygen saturation was significantly (P < 0.05) decreased at the end of anesthesia. Two male turkeys developed severe transient hypoxemia, 1 at 5 and the other at 15 minutes after induction. Time to standing after discontinuation of propofol infusion was 11 +/- 6 minutes. Recovery was smooth and unremarkable. CONCLUSION: Propofol is an effective agent for i.v. induction and maintenance of anesthesia in wild turkeys, and is useful for short procedures or where the use of inhalational agents is contraindicated.     

A conceptual framework for thinking about risk assessment and case management in child protective service

BACKGROUND: High-dose once daily oral omeprazole dosing can inhibit acid secretion almost completely but several days elapse before maximum efficacy is established. The acid inhibitory effect obtained with high doses of a histamine H2-receptor antagonist is built up rapidly but has the tendency to fade--the term 'tolerance' has been applied to characterize this phenomenon. METHODS: To obtain more information on the dynamics of acid inhibition during prolonged dosing, we compared the acid suppressory effects of oral high-dose omeprazole with high-dose ranitidine. Twenty-eight healthy volunteers were randomly assigned to a 2-week dosing with omeprazole or ranitidine in a double-blind, double-dummy, parallel-group study design. Omeprazole was given as 1 capsule of 40 mg mane and ranitidine as 2 tabs of 150 mg q.d.s. The median 24-h pH, daytime pH and night-time pH were measured by ambulatory continuous 24-h pH metry on days -8, -6, 1, 2, 7 and 14. RESULTS: High reproducibility was observed for the two baseline acidity measurements. Ranitidine exerted its peak acid suppressant effect on day 1 of dosing; the degree of acid inhibition faded from day 2 to 7, with no significant change thereafter. The decline in antisecretory activity was more pronounced during the day than the night. In contrast, acid inhibition by omeprazole increased throughout the first week, and antisecretory activity was stable thereafter. Despite the considerable differences in median intragastric pH values at the end of the 14-day study, plasma gastrin levels were elevated to a similar degree with both medications. CONCLUSIONS: This study confirms the 'tolerance' phenomenon previously observed with high-dose histamine H2-receptor antagonist dosing. The dynamics with which it occurs exclude a typical exaggerated first-dose response. Prolonged high-dose histamine H2-receptor dosing compromises the feedback mechanism regulating gastrin release, whilst this is maintained during dosing with omeprazole.     

Multicystic cavernous hemangioma of the liver: report of a case including diagnostic imaging and pathologic correlation

For systemic use, the anti-cytomegalovirus (CMV) agent foscarnet must be given intravenously because oral administration results in unmeasurable or barely measurable plasma levels. At low pH, foscarnet decomposes via an acid-catalyzed decarboxylation; therefore, poor oral bioavailability might be due to decomposition of foscarnet in gastric acid. We evaluated whether increasing gastric pH with ranitidine would enhance the absorption of oral foscarnet in six asymptomatic HIV-infected individuals. Each volunteer received two oral 4000-mg (60 mg/kg) doses of foscarnet, preceded intravenously by a 20-min infusion of either ranitidine 50 mg in D5W or D5W alone in a randomized, double-blind, cross-over study. Intragastric pH monitoring revealed that subjects had evidence of gastric acid production (pH < 2.0) prior to administration of ranitidine and increased gastric pH (pH > 6.0) following ranitidine administration. Most foscarnet plasma levels were below the assay limit of detection (33 microM) with only 4/30 levels detectable after D5W and 8/30 after ranitidine. Urinary recovery of foscarnet increased after ranitidine pretreatment. A mean recovery of 9.9% of the drug was realized in the urine in 24 h following ranitidine pretreatment compared to 6.2% of the dose after D5W pretreatment (P < 0.03). We estimate that 9.9% recovery in the urine in 24 h is equivalent to absorption of 17.1% of the oral dose. In spite of the enhanced bioavailability associated with ranitidine pretreatment, the degree of absorption is still insufficient to achieve effective plasma concentrations for the treatment of CMV or acyclovir-resistant herpes viruses. We conclude that gastric acidity is a determinant of foscarnet absorption, albeit not a major one. Oral foscarnet is unlikely to be clinically useful even if administered in the setting of increased gastric pH.     

Role of nitric oxide in regulation of gastric acid secretion in rats: effects of NO donors and NO synthase inhibitor

1. The role of nitric oxide (NO) in the regulation of acid secretion was examined in the anaesthetized rat. 2. A rat stomach was mounted in an ex vivo chamber, instilled with 2 ml of saline every 15 min, and the recovered sample was titrated at pH 7.0 against 0.1 N NaOH by use of an automatic titrator for acid secretion. Gastric mucosal blood flow (GMBF) was measured simultaneously by laser Doppler flowmeter. 3. Intragastric application of NO donors such as FK409 (3 and 6 mg ml[-1]) and sodium nitroprusside (SNP; 6 and 12 mg ml[-1]) as well as i.p. administration of cimetidine (60 mg kg[-1]), a histamine H2-receptor antagonist, significantly inhibited the increase in acid secretion in response to pentagastrin (60 microg kg(-1) h(-1), i.v.), in doses that increased gastric mucosal blood flow (GMBF). 4. Intragastric application of FK409 (6 mg ml[-1]) increased both basal and stimulated acid secretion induced by YM-14673 (0.3 mg kg(-1), i.v.), an analogue of thyrotropin-releasing hormone (TRH), but had no effect on the acid secretory response induced by histamine (4 mg kg(-1) h(-1), i.v.). 5. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME; 10 mg kg(-1), i.v.) did not affect basal acid secretion, but significantly potentiated the increase in acid secretion induced by YM-14673 and slightly augmented the acid secretory response to pentagastrin. 6. Both pentagastrin and YM-14673 increased the release of nitrite plus nitrate (NOx), stable NO metabolites, into the gastric lumen, and these changes were completely inhibited by prior administration of L-NAME (10 mg kg(-1), i.v.). 7. Pentagastrin caused an increase in luminal release of histamine and this response was significantly suppressed by intragastric application of FK409 (6 mg ml[-1]). 8. These results suggest that either exogenous or endogenous NO has an inhibitory action on gastric acid secretion through suppression of histamine release from enterochromaffin-like (ECL) cells.     

Three methods of oxytocin-induced parturition and their effects of foals

OBJECTIVE: To compare effects of 3 oxytocin-based induction techniques on fetal and neonatal foals. DESIGN: Prospective randomized controlled trial. ANIMALS: 16 pregnant mares. PROCEDURE: Parturition was induced in mares by use of 3 treatments: group 1, 75 U of oxytocin, IM; group 2, 15 U of oxytocin, IM, q 15 minutes, for a maximum of 75 U; group 3, 75 U of oxytocin in 1 L of 0.9% NaCl solution IV (1 U/min), for a maximum of 75 U. Blood gas values and indices of vitality were measured in foals, and variables describing parturition were measured in mares. RESULTS: Group-3 mares had a shorter interval from administration of oxytocin to rupture of the chorioallantois (OTCA) than group-2 mares. More foals were abnormal when the interval from oxytocin administration to delivery of the foal (OTDE) was > or = 60 minutes. Arterial blood gas values, measurements of vitality, and plasma cortisol concentrations did not differ among foals in various treatment groups. Increased interval for OTCA and OTDE resulted in higher neonatal PaCO2, and a longer interval for OTCA resulted in lower arterial pH. Time required for birth was shorter in mares with a dilated cervix. More abnormal foals than normal foals were delivered after premature placental separation or dystocia. Abnormal foals took longer to stand and suckle than normal foals. Interval from delivery to suckling was positively correlated with OTCA, OTDE, and PaCO2. CLINICAL IMPLICATIONS: Method of oxytocin-induced parturition did not impact neonatal outcome. Interval from induction until parturition, degree of cervical dilatation, and intrapartum complications influenced induction success.     

Interposed bone grafts to accommodate endosteal implants for retaining mandibular overdentures. A 1-7 year follow-up study

STUDY OBJECTIVES: To examine the effect of timing of an intravenous (i.v.) dose (intraoperative vs. postoperative) of ketorolac tromethamine on pain scores and overall outcome after total abdominal hysterectomy (TAH) and myomectomy. DESIGN: Prospective, randomized, placebo-controlled study. PATIENTS: 248 ASA physical status I and II adult female patients scheduled for elective hysterectomy or myomectomy. INTERVENTIONS: General anesthesia was administered that consisted of thiopental sodium for induction, enflurane or isoflurane in nitrous oxide-oxygen for maintenance, and small doses of fentanyl and midazolam. Patients were randomized into three groups to receive toradol/placebo on a dosing schedule of dose 1 given one-half hour prior to expected end of surgery, dose 2 given on awakening in the postanesthesia care unit, and doses 3, 4, and 5 given at 6, 12, and 18 hours, respectively, after dose 2; Group 1 patients received placebo (saline) for dose 1, ketorolac 60 mg i.v. for dose 2, and ketorolac 30 mg i.v. for doses 3, 4, and 5. Group 2 patients received ketorolac 60 mg i.v. for dose 1, placebo for dose 2, and ketorolac 30 mg i.v. for doses 3, 4, and 5. Group 3 patients received placebo for all doses. All patients were given i.v. morphine PCA postoperatively, and morphine usages, visual analog pain intensity (VAS) scores, as well as adverse events and median times to recovery milestones were recorded. MEASUREMENTS AND MAIN RESULTS: VAS scores (mean) before dose 2 were significantly lower in Group 2 than Group 1, as were at-rest evaluations at 15 minutes and one hour. Group 2 patients also had decreased morphine requirements as compared to placebo. Both ketorolac groups (Groups 1 and 2) had significantly higher values for patient and observer overall ratings, case of nursing care, and tolerability as compared to placebo (Group 3). There were no significant differences among groups in adverse events or median times to recovery milestones. CONCLUSIONS: Although it is possible to demonstrate an improvement in early postoperative pain scores with intraoperative ketorolac and better overall ratings of ketorolac both intraoperatively and postoperatively as compared with placebo, the lack of clinically significant differences in analgesic efficacy in the two active study groups indicates the need for a careful consideration by the clinician of the risks versus benefits involved in the administration of antiplatelet medication in the perioperative period.     

The subepithelial formation of immune complexes in membranous glomerulonephritis may be harmless and secondary to toxic or allergic factors

BACKGROUND: Amongst the low-dose H2-receptor antagonists available for the self-medication of dyspepsia, both famotidine 10 mg and cimetidine 200 mg have been shown to raise intragastric pH, but there is a delay after ingestion before significant effects can be demonstrated. A new effervescent preparation of cimetidine 200 mg releases an acid buffer which has a more rapid effect on intragastric pH. AIM: To investigate the relative abilities of low-dose famotidine and effervescent cimetidine to raise intragastric pH after a single postprandial evening dose. METHODS: Twenty-four healthy subjects (12 men, 12 women, median age 32 years) completed a three-period crossover trial of famotidine 10 mg, effervescent cimetidine 200 mg and placebo. After a standard meal was given at 18.30 h to subjects fasted for 5.5 h, drug or placebo was given at 19.30 h. Intragastric pH was recorded with combined glass electrodes from 18.00 to 07.30 h by digital recorders. RESULTS: Over the 12 h post-dose period the mean area under the pH/time curve (AUC) after famotidine 10 mg was 3.73, after cimetidine 200 mg effervescent 2.79, and after placebo 2.07. Over the same period the median pH and percentage of time that recordings were above pH 3 were 3.45 and 52.5 after famotidine 10 mg, 2.40 and 33.8 after cimetidine 200 mg effervescent, and 1.68 and 15.9 after placebo. Both active treatments were significantly different from placebo by each measure (P < 0.001), and famotidine 10 mg was significantly more effective than cimetidine 200 mg effervescent by each measure over the 0-12 h period (P < 0.001). Comparisons of mean AUCs for each 15 min period after dosing showed that decrease in acidity was significantly greater after cimetidine 200 mg effervescent than after famotidine 10 mg for the first 60 min. In the later post-dose period only famotidine 10 mg raised pH for all time points to 12 h, whilst the effect of effervescent cimetidine 200 mg was detectable to = 8 h. CONCLUSIONS: Inhibition of gastric acidity over the 12 h post-dose period was significantly greater and endured longer after famotidine 10 mg than after effervescent cimetidine 200 mg, but for the 60 min period immediately after dosing the effect on intragastric pH was significant following effervescent cimetidine 200 mg but not famotidine 10 mg. This suggests effervescent formulations of H2-receptor antagonists with an acid buffer have a more rapid effect on intragastric pH than film-coated tablets.     

Influence of gastrointestinal site of drug delivery on the absorption characteristics of ranitidine

The absorption characteristics of ranitidine after delivery to three locations in the gastrointestinal tract were compared in an open-label study of eight healthy males. Subjects received ranitidine HCl (150 mg) for injection via a nasoenteric tube directly into their stomach, jejunum, or cecum sequentially in three separate periods (24 hr apart). Plasma samples were collected at periodic time intervals for 12 hr following each dosing and analyzed for ranitidine concentration by high-pressure liquid chromatography. Mean concentrations following cecal dosing were lower (P less than 0.05) than concentrations following gastric or jejunal dosing at each sampling time except baseline. Mean concentrations following gastric and jejunal dosing were similar except at 2 hr (gastric greater than jejunal). Mean pharmacokinetic parameters for cecal administration were different (P less than 0.05) from either the gastric or the jejunal periods with the exception of Tmax. There was no difference in any pharmacokinetic parameter after gastric or jejunal dosing. The relative bioavailability after cecal administration was less than 15% of that observed after administration into the stomach or jejunum. Additionally, Wagner-Nelson analysis indicated that the rate of ranitidine absorption was much slower following cecal administration than after gastric or jejunal dosing. Two plasma concentration peaks were observed in three of eight subjects after gastric dosing, in eight of eight subjects after jejunal dosing, and in zero of eight subjects after cecal dosing. These data demonstrate that the absorption profile of ranitidine is equivalent, in extent and duration, after delivery to the stomach or jejunum, while absorption from the cecum is significantly less.(ABSTRACT TRUNCATED AT 250 WORDS)     

Age-related differences in norfloxacin pharmacokinetic behaviour following intravenous and oral administration in sheep

The pharmacokinetics of norfloxacin after intravenous (i.v.) and oral (PO) administration in lambs (n = 5) and adult sheep (n = 5) were studied. After i.v. administration (10 mg.kg-1) plasma concentrations were best fitted by a three-compartment open model in both age groups. Distribution volumes were significantly larger in lambs (approximate 4.0 fold difference between 4 week old and adult sheep). There was no significant difference (p < 0.05) between the groups in terms of elimination halflife but plasma clearance was significantly higher in lambs. Norfloxacin was poorly absorbed after oral administration (60 mg.kg-1) in sheep (F = 4.04%). Mean oral bioavailability was 73.51% in lambs (30 mg.kg-1). Norfloxacin elimination was faster in lambs after oral administration. MRTt was significantly prolonged in both age groups when compared with the respective data for i.v. administration.     

Prediction of spinal cord ischemia with a retrievable stent graft on endovascular treatment for a case of thoracic aortic aneurysm

OBJECTIVE: To determine the pharmacokinetics and absolute bioavailability of ciprofloxacin in 12 critically ill patients receiving continuous enteral feeding. Design: a prospective, cross-over study. SETTING: 12-bed surgical intensive care unit in a University Hospital. PATIENTS: 12 stable critically ill patients on mechanical ventilation and receiving continuous enteral feeding (Normoreal fibres) without diarrhea or excessive residual gastric contents ( < 200 ml/4 h). None had gastro-intestinal disease, renal insufficiency (estimated creatinine clearance > or = 50 ml/min) or was receiving medications that could interfere with ciprofloxacin absorption or metabolism. MEASUREMENTS AND MAIN RESULTS: The study was carried out after the fourth (steady state) b. i. d. intravenous (i. v.) 1-h infusion of 400 mg and the second b. i. d. nasogastric (NG) dose of 750 mg (crushed tablet in suspension). Plasma concentrations were measured by high-performance liquid chromatography. The median (range) peak concentration after i. v. infusion was 4.1 (1.5-7.4) mg/l, and that after NG administration was 2.3 (0.7-5.8) mg/l, occurring 1.25 (0.75-3.33) h after dosing. The median [range] areas under plasma concentration-time curves were similar for the two administration routes (10.3 [3.3-34.6] and 8.4 [3.6-53.4] for i.v. infusion and NG administration, respectively). Ciprofloxacin bioavailability ranges from 31 to 82 % (median, 44%). CONCLUSIONS: In tube-fed critically ill patients, a switch to the NG ciprofloxacin after initial i. v. therapy to simplify the treatment of severe infections is restricted to those for whom serial assessments of ciprofloxacin levels are routinely available.     

The venous antithrombotic profile of naroparcil in the rabbit

The venous antithrombotic profile of naroparcil or (4-[4-cyanobenzoyl]-phenyl)-1.5-dithio-beta-D-xylopyranoside was investigated in the rabbit following single i.v. and oral administration. Naroparcil attenuated thrombus development in a Wessler stasis model of venous thrombosis (jugular vein) employing bovine factor Xa as a thrombogenic stimulus giving ED50 values of 21.9 mg/kg and 36.0 mg/kg after respectively i.v. and oral administration. Venous antithrombotic activity was maximal 2-3 h after i.v. administration and 4-8 h after oral administration. Four hours after the oral administration of maximal antithrombotic (Wessler model, factor Xa) doses (100 and 400 mg/kg), naroparcil had no significant effect on bleeding time. In platelet poor plasma obtained from animals treated 4 h previously with various doses (25 to 400 mg/kg) of naroparcil, there was no detectable anti-factor Xa nor antithrombin activity. Similarly, naroparcil had no effect on APTT nor on thrombin time. A sensitized thrombin time (to about 35 s) was modestly but significantly increased following oral administration of the compound at 400 mg/kg. However, thrombin generation by the intrinsic pathway was reduced in a dose-related manner, maximal reduction being 65% at 400 mg/kg. The same dose of naroparcil enhanced the formation of thrombin/heparin cofactor II complexes at the expense of thrombin/antithrombin III complexes in plasma incubated with (125I)-human alpha-thrombin and induced the appearance of dermatan sulfate-like material in the plasma of treated rabbits, as measured by a heparin cofactor II-mediated thrombin inhibition assay.(ABSTRACT TRUNCATED AT 250 WORDS)