Gastrokinetic activity of Morinda citrifolia aqueous fruit extract and its possible mechanism of action in human and rat models.

AIMS OF THE STUDY: This study was to investigate the gastrokinetic activity of Morinda citrifolia aqueous fruit extract (AFE) in human subjects by examining the GI absorption of ranitidine, a putative indicator of GI motility and to elucidate its possible gastrokinetic mechanism of action in rats. MATERIALS AND METHODS: The single-dose, randomized, open-label and 2-period crossover study was performed on 20 Thai healthy volunteers with a washout period of 14 day between the doses. AFE or drinking water was administered orally 30 min prior to a single oral administration of ranitidine (300 mg). Blood samples were collected over a 12 h period after drug administration and the pharmacokinetic parameters of ranitidine were calculated. The gastrokinetic mechanism of action of AFE was elucidated by measurement of its contractile response on the isolated rat gastric fundus strip. RESULTS: The area under the plasma ranitidine concentration-time curve and the maximal plasma ranitidine concentration were significantly increased after pretreatment with AFE (p=0.001). The plasma ranitidine concentrations were significantly greater at 30-120 min after its administration. AFE produced a definite contractile response of a rat gastric fundus strip with a dose dependency. Scopoletin at the same equivalent dose present in AFE elicited a concentration-dependent contraction that amounted to 45% of the maximal response to AFE. The contractile response of both AFE and scopoletin was mediated through the 5-HT(4) receptor. CONCLUSION: AFE has a unique gastrokinetic activity in enhancement of the rate and the extent of ranitidine absorption. The underlying mechanism can be attributed, at least in part, to the ability of its active component: scopoletin to stimulate the 5-HT(4) receptor.

Effects of Morinda citrifolia aqueous fruit extract and its biomarker scopoletin on reflux esophagitis and gastric ulcer in rats.

AIMS OF THE STUDY: The present study was carried out to evaluate the effect of dried mature unripe Morinda citrifolia L. (Rubiaceae) fruit, commonly known as "Noni", in an aqueous extract preparation (AFE) as used in Thai traditional medicine and its biomarker scopoletin on gastro-esophageal inflammatory models that are related to the claimed pharmacological properties of AFE and/or resembled the human esophagitis or gastric ulcer. MATERIALS AND METHODS: The powder of dried mature unripe Noni fruit was boiled in water until it became a sticky paste and was then dried into a powder by lyophilization. The pharmacological activity of AFE and pure scopoletin at the same equivalent dose present in AFE was investigated in rat on gastro-esophageal inflammatory models (acid reflux esophagitis, acute gastritis induced by ethanol and serotonin, and chronic gastric ulcer induced by acetic acid); gastric biochemical parameters and gastrointestinal motility. RESULTS: AFE (0.63-2.50 g/kg) significantly prevented the formation of acid reflux esophagitis, reduced the formation of ethanol-induced acute gastric lesions, suppressed the development of gastric lesions in response to serotonin, and accelerated the healing of acetic acid-induced chronic gastric ulcer in rats with equal potency to those obtained by standard antisecretory agents (ranitidine and lansoprazole). AFE also significantly inhibited gastric acid secretion and pepsin activity in pylorus ligated rats. Additionally, AFE strongly increased the gastrointestinal transit of charcoal meal with a higher potency than cisapride. Pure scopoletin, when compared at the same equivalent dose containing in AFE, possessed similar antiulcer and antisecretory properties to that of AFE although it exerted a less prokinetic activity than AFE. CONCLUSION: The findings indicated that AFE as well as its biomarker: scopoletin may be beneficial as a potential preventive and therapeutic agent for gastro-esophageal inflammatory diseases, mainly through its antisecretory and prokinetic activities including an inhibitory activity on serotonin, free radicals, and cytokine-mediated inflammation. Additionally, scopoletin might be one of the biomarker constituents to use for the quality assessment of Noni fruit products used for treating gastro-esophageal inflammatory diseases.

Clearance of vancomycin during high-efficiency hemodialysis.

BACKGROUND: Vancomycin is commonly used for the treatment of MRSA infections in critically ill patients with renal diseases. Vancomycin is mainly eliminated through the kidney. Its excretion is therefore substantially reduced in severe renal impaired patients. Although several studies have demonstrated that significant amounts of vancomycin are removed during High-Flux/High-Efficiency Hemo Dialysis (HF/HEHD), more data are required to optimize clinical applications. OBJECTIVE: Predict the appropriate vancomycin intradialytic dosage and dosing interval among patients receiving HEHD. MATERIAL AND METHOD: Twenty patients who were receiving HEHD with cellulose triacetate dialyzer were included to determine the vancomycin intradialytic clearance. Two patients were included twice and one patient was included three times due to reinfections. This gave rise to 24 patient-times. The study was carried out at Songklanagarind Hospital between January 2003 and March 2004. RESULTS: In a prospective opened label design, each patient received 1g vancomycin, 1 hour infusion, immediately after completion of HEHD. Six scheduled blood samples were drawn as follows: (1) 60 minutes following completion of vancomycin infusion (Cmax); (2) immediately before starting the second HEHD; (3) 2 hours after starting the second HEHD; (4) immediately after completion of the second HEHD; (5) immediately before starting the third HEHD; and (6) immediately after the third HEHD ended (Cmin). The authors measured vancomycin serum levels using HPLC technique. The serum concentrations were used to calculate all relevant pharmacokinetic parameters. The pharmacokinetic parameters (mean +/- SD) were: intradialytic clearance (CLHD) 93.4 +/- 37.1 mL/min; intradialytic elimination rate constant (k) 1.1 +/- 0.5 hr(-1); overall elimination half-life (t(1/2)) 77.1 +/- 37.8 hr; volume of distribution (Vd) 82.1 +/- 40.3 L; Cmax 25.8 +/- 8.12 mg/L (range 12.04-48.80); Cmin 6.2 +/- 3.1 mg/L; and % removal during the second HEHD 37.9 +/- 12.9. Subtherapeutic levels were found in 66.7% (16/24) and 91.6% (22/24) of patients after the second and the third HEHD, respectively. CONCLUSION: HEHD with cellulose triacetate dialyzer removes significant amount of vancomycin. Based on the authors' findings, a loading dose of 1 g, and 500 mg after every subsequent HEHD is recommended.

Ambroxol Lozenge Bioavailability : Part II - Analysis of Additional Systemic AvailabilityPart I of this article was published in Clin Drug Invest 2003; 23 (4): 273-80.

OBJECTIVE: To examine whether or not the early dissolution/absorption in the oral cavity of lozenge administration contributes to superior bioavailability of ambroxol compared with the commercially available tablet. METHODS: 24-hour plasma level pharmacokinetic profiles of 20 healthy volunteers receiving oral administration of identical single doses (30mg) of lozenges and a commercially available tablet with a 1-week washout period were collected. The data were analysed by a non-compartmental model with a statistical moment and mean transit time concept. The mean transit times obtained after lozenge and tablet administration were compared. RESULTS: The variance in absorption phase was significantly higher than that in the distribution/elimination phase in the pharmacokinetic profiles of the lozenge, suggesting additional absorption processes. The mean transit time of the tablet was significantly greater than that of the lozenge, by 7.69 hours with a 90% confidence interval (CI) of 3.11, 12.27. Early drug dissolution/absorption in the oral cavity and gastrointestinal absorption was successfully modelled to the pharmacokinetic profiles after lozenge administration. The additional availability of the drug to systemic circulation was mainly due to complete dissolution in the oral cavity prior to absorption as well as to oral mucosal transport. Between the two processes, dissolution was proposed to be a limiting step, since oral mucosal absorption was at a very high rate. The estimated average dissolution rate constant (90% CI) in first-order fashion was 0.13h(-1) (0.08, 0.32). CONCLUSION: Absorption rates between lozenge and tablet could be differentiated with the aid of the mean transit time concept. However, estimation of oral mucosal absorption was not possible because the blood sampling intervals were not sufficiently frequent.

Ambroxol lozenge bioavailability : an open-label, two-way crossover study of the comparative bioavailability of ambroxol lozenges and commercial tablets in healthy thai volunteers.

OBJECTIVE: To compare the bioavailability of two 15mg ambroxol lozenges with a commercial 30mg ambroxol tablet. DESIGN: Open-label, two-way crossover study. METHOD: Each formulation was randomly administered to 20 healthy Thai volunteers (ten male and ten female) with a 1-week washout period between formulations. After administration, serial blood samples were collected over a 24-hour period and the plasma concentration of ambroxol was subsequently measured using high performance liquid chromatography with ultraviolet detection after liquid-liquid extraction. Pharmacokinetic parameters were analysed by a noncompartmental pharmacokinetic model and compared between formulations using analysis of variance with a significance level of 0.05. RESULTS: The point estimates (90% CI) of the area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) ratios between lozenge and commercial tablet were 1.07 (0.89 to 1.28) and 1.20 (1.04 to 1.40), respectively. The point estimate (90% CI) of the difference between formulations for time to C(max) was 0.40 (-0.20 to 1.00). CONCLUSION: The two formulations under test were not bioequivalent based on the stipulated bioequivalence criteria. The bioavailability from the ambroxol lozenge might be better, since the 90% CI of the AUC(0-infinity) fell outside the bioequivalence range, and its range was narrower. The difference in rate of absorption was not conclusive because ambroxol was delivered from the lozenge by two parallel processes, namely absorption via oral and gastrointestinal mucosa. The additional oral mucosal absorption might not only contribute more absorption but also introduce variability compared with that of tablet administration. The relative importance of oral versus gastrointestinal mucosal absorption of ambroxol from the lozenge formulation, and the clinical significance of this, requires further study.

Characterization of mefenamic acid-guaiacol ester: stability and transport across Caco-2 cell monolayers.

PURPOSE: Prodrug of non-steroidal anti-inflammatory drugs (NSAIDs) or NSAIDs linked with guaiacol have been reported to suppress gastrointestinal (GI) toxicity or induce GI protective effect. In this study. mefenamic-guaiacol ester was synthesized and its physicochemical properties. stability, and transport across Caco-2 monolayers were investigated. METHODS: Synthesis of the ester was carried out using mefenamic acid, guaiacol. N. N'-dimethylaminopyridine, and N,N'dicyclohexylcarbodiimide. The hydrolysis of the ester was investigated in aqueous buffer solutions pH 1-12 as well as in Caco-2 homogenate, human plasma, and porcine liver esterase. Caco-2 cell monolayers were utilized for transport studies. Due to the high lipophilicity of the ester with a calculated logP of 6.15, bovine serum albumin (BSA, 4%) was included in the receiver compartment to obtain a good in vitro-in vivo correlation. Permeation of the ester was assessed with or without the exposure of cells to PMSF, an inhibitor of esterase. RESULTS: The ester was stable at a wide pH range from 1-10. However, it was hydrolyzed by enzymes from porcine liver esterase and Caco-2 homogenate. With the PMSF exposure on the apical (AP) side and in the presence of 4% BSA on the basolateral (BL) side, the transported amount of the ester from AP-to-BL direction was 14.63% after 3 hr with a lag time of 23 min. The Papp for the ester was 4.72 x 10(-6) cm s(-1). CONCLUSION: The results from hydrolysis studies indicate that this ester is a prodrug. The Papp value suggests the moderate absorption characteristic of the compound. The accumulation of this highly lipophilic ester in Caco-2 cells is reduced in the presence of BSA.