Effect of the prokinetic agent, erythromycin, in the richardson ground squirrel model of cholesterol gallstone disease

Xu, Qi; Scott, Robert B.; Tan, D. T. M.; Shaffer, Eldon A.

doi:10.1002/hep.510280302

Cited by 34 publications

(23 citation statements)

References 49 publications

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“…In a similar type of study with the native IFN alpha-2b the mean values for t 1/2 and MRT were 5.9 h and 10.9 h, respectively [12]. After "pegylation" these parameters were 64.8 h and 123 h, respectively, around 11 fold higher, consistent with previous studies of 40 Kd PEG IFN alpha-2a vs. its conventional IFN counterpart in healthy subjects [13,14]. Median Tmax was lower (48 h) than expected (72 h) for both formulations, although PEG-IFN concentrations remained close to peak levels between 36 and 84 hours (plateau).…”

Section: Discussionsupporting

confidence: 84%

Pharmacokinetic and pharmacodynamic comparison of two "pegylated" interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study

et al. 2010

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BackgroundInterferon (IFN) alpha conjugation to polyethylene glycol (PEG) results in a better pharmacokinetic profile and efficacy. The aim of this study was to compare the pharmacokinetic, pharmacodynamic and safety properties of a new, locally developed, 40-kDa PEG-IFN alpha-2b preparation with a reference, commercially available PEG-IFN alpha-2a in healthy male volunteers.MethodsA randomized, crossover, double-blind study with a 3-weeks washout period, was done. A single 180 micrograms PEG-IFN alpha-2 dose was administered subcutaneously in both groups. Sixteen apparently healthy male subjects were included. Serum PEG-IFN concentration was measured during 336 hours by an enzyme immunoassay (EIA). Other clinical and laboratory variables were used as pharmacodynamic and safety criteria.ResultsThe pharmacokinetic comparison by EIA yielded a high similitude between the formulations. In spite of a high subject variability, the parameters' mean were very close (in all cases p > 0.05): AUC: 53623 vs. 44311 pg.h/mL; Cmax: 333 vs. 271 pg/mL; Tmax: 54 vs. 55 h; half-life (t1/2): 72.4 vs. 64.8 h; terminal elimination rate (lambda): 0.011 vs. 0.014 h-1; mean residence time (MRT): 135 vs. 123 h for reference and study preparations, respectively. There were no significant differences with respect to the pharmacodynamic variables either: serum neopterin and beta-2 microglobulin levels, stimulation of 2'5' oligoadenylate synthetase expression, and serum IFN antiviral activity. A strong Spearman's rank order correlation (p < 0.01) between the pharmacokinetic and pharmacodynamic concentration-time curves was observed. Both products caused similar leukocyte counts diminution and had similar safety profiles. The most frequent adverse reactions were leukopenia, fever, thrombocytopenia, transaminases increase and asthenia, mostly mild.ConclusionsBoth formulations are fully comparable from the pharmacokinetic, pharmacodynamic, and safety profiles. Efficacy trials can be carried out to confirm clinical similarity.Trial registrationRegistro Público Cubano de Ensayos Clínicos RPCEC00000039.

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Section: Discussionsupporting

confidence: 84%

Pharmacokinetic and pharmacodynamic comparison of two "pegylated" interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study

et al. 2010

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“…Thus when Xu and colleagues70 fed a lithogenic diet to ground squirrels, it provoked slow intestinal transit, impaired gall bladder contractility, and induced supersaturated bile. These effects were overcome by the use of erythromycin78 and cisapride27 which also normalised bile acid and bile lipid composition. Similarly, when Marcus and Heaton accelerated intestinal transit with senna, the proportion of DCA in, and the cholesterol saturation of, bile rich duodenal fluid were reduced 50.…”

Section: Discussionmentioning

confidence: 99%

Effects of cisapride on gall bladder emptying, intestinal transit, and serum deoxycholate: a prospective, randomised, double blind, placebo controlled trial

Veysey

Malcolm²,

Mallet³

et al. 2001

Gut

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Background-Octreotide inhibits gall bladder emptying and prolongs intestinal transit. This leads to increases in the proportion of deoxycholic acid in, and cholesterol saturation of, gall bladder bile, factors that contribute to the pathogenesis of octreotide induced gall stones. Aims-To see if an intestinal prokinetic, cisapride, could overcome these adverse eVects of octreotide and if so, be considered as a candidate prophylactic drug for preventing iatrogenic gall bladder stones. Methods-A randomised, double blind, placebo controlled, crossover design was used to examine the eVects of cisapride (10 mg four times daily) on gall bladder emptying, mouth to caecum and large bowel transit times, and the proportions of deoxycholic acid and other bile acids, in fasting serum from: (i) control subjects (n=6), (ii) acromegalic patients not treated with octreotide (n=6), (iii) acromegalics on long term octreotide (n=8), and (iv) patients with constipation (n=8). Results-Cisapride had no prokinetic effect on the gall bladder. In fact, it significantly increased both fasting and postprandial gall bladder volumes. However, it shortened mouth to caecum (from 176 (13) to 113 (11) minutes; p<0.001) and large bowel (from 50 (3.0) to 31 (3.4) h; p<0.001) transit times. It also reduced the proportion of deoxycholic acid in serum from 26 (2.3) to 15 (1.8)% (p<0.001), with a reciprocal increase in the proportion of cholic acid from 40 (3.5) to 51 (3.8)% (p<0.01). There were significant linear relationships between large bowel transit time and the proportions of deoxycholic acid (r=0.81; p<0.001) and cholic acid (r=−0.53; p<0.001) in fasting serum. Interpretation/summary-Cisapride failed to overcome the adverse eVects of octreotide on gall bladder emptying but it countered octreotide induced prolongation of small and large bowel transit. Therefore, if changes in intestinal transit contribute to the development of octreotide induced gall bladder stones, enterokinetics such as cisapride may prevent their formation. (Gut 2001;49:828-834)

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“…Prokinetic agents such as cisapride and the motilide erythromycin restore the impaired contractility of gallbladder strips in animals placed on a lithogenic diet [84,101]. In addition, erythromycin was recently found to reduce the carbachol-induced contraction in isolated strips from human gallbladders [72].…”

Section: Electrical Properties and Ionic Conductancesmentioning

confidence: 99%

“…Alternatively, whole gallbladders of the guinea pig or ground squirrel are studied by tensiometry[83][84][85]. In vitro contractility of gallbladder strips in response to agonists is impaired in cholesterol gallstone disease in humans [38•,55,64,77,86,87••] and in animals receiving a cholesterol-enriched, lithogenic diet [36,62,84,88-91].…”

mentioning

confidence: 99%

Smooth muscle function and dysfunction in gallbladder disease

Portincasa

Ciaula

vanBerge-Henegouwen³

2004

Curr Gastroenterol Rep

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The gallbladder epithelium and smooth muscle layer are exposed to concentrated biliary solutes, including cholesterol and potentially toxic hydrophobic bile salts, which are able to influence muscle contraction. Physiologically, gallbladder tone is regulated by spontaneous muscle activity, hormones, and neurotransmitters released into the muscle from intrinsic neurons and extrinsic sympathetic nerves. Methods to explore gallbladder smooth muscle function in vitro include cholecystokinin (CCK) receptor-binding studies and contractility studies. In human and animal models, studies have focused on cellular and molecular events in health and disease, and in vitro findings mirror in vivo events. The interplay between contraction and relaxation of the gallbladder muscularis leads in vivo to appropriate gallbladder emptying and refilling during fasting and postprandially. Defective smooth muscle contractility and/or relaxation are found in cholesterol stone-containing gallbladders, featuring a type of gallbladder leiomyopathy; defects of CCKA receptors and signal transduction may coexist with abnormal responses to oxidative stress and inflammatory mediators. Abnormal smooth musculature contractility, impaired gallbladder motility, and increased stasis are key factors in the pathogenesis of cholesterol gallstones.

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Effect of the prokinetic agent, erythromycin, in the richardson ground squirrel model of cholesterol gallstone disease

Cited by 34 publications

References 49 publications

Pharmacokinetic and pharmacodynamic comparison of two "pegylated" interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study

Pharmacokinetic and pharmacodynamic comparison of two "pegylated" interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study

Effects of cisapride on gall bladder emptying, intestinal transit, and serum deoxycholate: a prospective, randomised, double blind, placebo controlled trial

Smooth muscle function and dysfunction in gallbladder disease

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