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In vitro study of gastrointestinal diffusion system using disopyramide phosphate.

Gastrointestinal Diffusion System (GDS) provides release of a drug by means of a controlled source of diffusion energy. The unit can possibly be used for all soluble agents in which solubility is independent of the pH of the gastrointestinal contents as is the case with disopyramide phosphate. The GDS consists of a soluble tablet-core, surrounded by a cellulose acetate film containing a soluble pore-creating agent. When the pore-creating agent is removed from the coating film, the cellulose acetate membrane which remains is of a porous nature, which controls the diffusion rate of the drug. The release rate of the drug can be varied by changing the composition and mass of the membrane. The resultant system in vitro provides the zero-order drug delivery due to the appropriate selection of manufacturing parameters.

Delayed-Action Preparations↗

[An overview of the regulation of basic functions of the digestive system].

The gastrointestinal system is the gate through which nutritive substances, vitamins, minerals, and fluids enter the body. Proteins, fats and complex carbohydrates are broken down into absorbable units (products of the digestion) in the digestive tract and finally they are absorbed together with vitamins, minerals and water into the blood or the lymph. The digestive and absorptive functions of the gastrointestinal tract depend on the various mechanisms, which adjust the food, put it through the gastrointestinal tract and mix it together with digestive enzymes secreted by the salivary glands, stomach, pancreas, small intestine and with bile. Some of these mechanisms depend on the spontaneous activity of the smooth muscles, others involve the somatic and autonomous reflexes, paracrine effects of the chemical substances, hormones and local gastrointestinal hormones. The aim of this paper is to review the essential factors participating in the regulation of these processes (mainly motility and secretion) from the mouth cavity, stomach, duodenum, gallbladder, pancreas, small intestine and large intestine to the defecation. The basic regulatory factors are summarized in the schemes from the sources of the physiological textbooks, which are accepted in the whole world for the education of physiology in the medical faculties.

Digestive System↗

Aqueous based polymeric dispersion: Plackett--Burman design for screening of formulation variables of atenolol gastrointestinal therapeutic system.

Bilayered osmotically controlled Gastrointestinal Therapeutic System of atenolol has been obtained by using cellulose acetate pseudolatex prepared by polymer emulsification method. Various factors such as orifice size, coating thickness, amount and nature of polymeric excipients, and amount of osmotic agent influence the drug release from GITS. Therefore, in the present study a 7-factor, 12-run Plackett-Burman screening design was employed to evaluate the formulation variables for atenolol GITS coated with CA pseudolatex. The variables studied were orifice size, %coating weight gain, amounts of sodium chloride. Polyox N80 and 303, and Carbopol 934P and 974P on drug release. The screening design has revealed that orifice size, %coating weight gain and amount of Carbopol 934P have prominent influence on in-vitro atenolol release. The response variable was cumulative percent atenolol released (Y) in 24 h with constraints on percent release at 2, 6, 12 and 18 h. The polynomial equation obtained was Y24 = 149.82 - 0.13 X1 - 0.34X2 + 0.06X3 - 0.13X4 - 0.23X5 - 76.25X6 - 2.46X7. The results indicated that the drug release under constrained conditions was influenced by the factors with decreasing order of importance as %coating weight gain > Carbopol 934P > Polyox N80 > Carbopol 974P > Polyox 303 > amount of sodium chloride > orifice size.

Adrenergic beta-Antagonists↗

Assessment of the ruminant digestive system.

Evaluation of the gastrointestinal system of ruminants is a logical progression of investigation and elimination. Important aspects of the animal's history pertinent to the gastrointestinal system are described. A systematic, comprehensive technique for physical examination is presented with emphasis on the digestive and lymphatic systems. Examples of potential signs of disease are provided for each body section.

Animals↗

The enteric nervous system II: gastrointestinal functions.

The enteric nervous system is involved in most of the physiological and pathophysiological processes in the gastrointestinal tract. This Minireview is part two of three and describes the role of the enteric nervous system in gastrointestinal functions (motility, exocrine and endocrine secretions, blood flow, and immune processes) in health and some disease states. In this context, the functional importance of the enteric nervous system for food intake, the gall bladder, and pancreas will be addressed. In specific, dysmotility, diarrhoea, constipation, non-occlusive intestinal ischaemia (intestinal angina), inflammation, cholelithiasis, cholecystitis, postcholecystectomy syndrome, and pancreatitis can be treated with neuroactive pharmacological agents. For example, serotonin receptor type four agonists can be used for the treatment of constipation, while nitric oxide synthesis inhibitors can be employed for the treatment of intestinal angina.

Animals↗

NSAID induced gastrointestinal complications: the ARAMIS perspective--1997. Arthritis, Rheumatism, and Aging Medical Information System.

Gastrointestinal (GI) complications related to nonsteroidal antiinflammatory drug (NSAID) therapy are the most prevalent category of adverse drug reactions. Patients with arthritis are among the most frequent users of NSAID and are therefore particularly at risk for these side effects. To evaluate the nature of NSAID related GI complications and to determine how their frequency can be reduced, a series of studies of such complications in patients with rheumatic disease has been carried out based on data from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS). We review the literature and present findings from the ARAMIS studies. This report addresses whether GI side effects such as dyspepsia can serve as warning symptoms for serious GI complications and describes the risk factors for these life threatening complications. It also describes differences among NSAID with regard to their GI toxicity and describes a study that investigated whether H2-receptor antagonists and antacids affect the development of serious GI complications. In addition, ongoing research and topics to be addressed in future studies are described.

Anti-Inflammatory Agents, Non-Steroidal↗

A personal historical perspective of the development of the gastrointestinal endocrine system.

The growth of gastrointestinal endocrinology has become exponential with the introduction of modern molecular biologic techniques. It had its roots in extirpation, as did all of endocrinology, and was the birthplace of the first hormone secretion. Progress was tardy through the 'physiologic secretion' years but gained pace with the advent of radioimmunoassay. With molecular biologic approaches, a plethora of candidate hormones have outstripped ascribable biologic functions. Nonetheless, a semblance of sanity is presented in recognizable clinical syndromes deriving from gut hormone excesses. This and the potential for application of peptide therapy to deficiencies and excesses of gut humor production are exciting prospects for the future.

Digestive System↗

Gastrointestinal manifestations of systemic sclerosis.

Gastrointestinal (GI) manifestations of systemic sclerosis (SSc) were found in 82% of 262 patients followed up prospectively. Esophageal dysmotility, lower esophageal sphincter laxity, bacterial overgrowth, and wide mouth diverticuli were the most common findings. The disease is usually diffuse with multiple levels of involvement. Gastrointestinal involvement was not significantly correlated with gender, age at SSc diagnosis or disease type (limited or diffuse scleroderma). Upper GI symptoms develop early in the course of SSc and may not correlate with objective findings. Various investigations, treatment regimens, and less frequent disease manifestations are reviewed and discussed.

Adult↗

[Gastrointestinal involvement in systemic sclerosis].

Gastrointestinal involvement is frequent in systemic sclerosis (SSc), occurring in 75 to 90% of patients with diffuse or limited cutaneous SSc. Although all regions of the gut may be affected, the esophagus is the most common gastrointestinal localization of this disease. If not diagnosed at an early stage, resulting complications may include esophagitis (leading to stenosis, strictures, and Barrett's esophagus) and increased risk of interstitial lung disease. Esophageal manometry is the most sensitive test for accurate diagnosis of motor dysfunction. Antisecretory agents (mainly proton-pump inhibitors) are effective for treating esophageal manifestations. Gastrointestinal involvement is reported in 50-88% of patients with SSc. It remains associated with a poor prognosis and leads to death in 6 to 12% of cases. Gastrointestinal impairment may lead to life-threatening complications, including severe dyspepsia, hemorrhage related to watermelon stomach (gastric antral vascular ectasia), malabsorption syndrome (related to bacterial overgrowth), and intestinal pseudo-obstruction. Treatment for the latter two remains difficult, although octreotide has proven to be effective in SSc patients. Small bowel manometry is useful for careful selection of SSc patients who will benefit from this treatment. Anorectal involvement is frequent in SSc patients (50-70%) and causes fecal incontinence and rectal prolapse. Other digestive manifestations, including liver impairment, are less common in SSc.

Barrett Esophagus↗

Trough:peak ratio of nifedipine gastrointestinal therapeutic system and nifedipine retard in essential hypertensive patients: an Italian multicentre study.

OBJECTIVE: To evaluate the antihypertensive effect of nifedipine gastrointestinal therapeutic system and retard in terms of trough:peak ratio efficacy. METHODS: According to a double-blind, randomized, crossover design, 58 patients with mild-to-moderate essential hypertension, after 1 month placebo washout, received 30 mg/day nifedipine gastrointestinal therapeutic system, 20 mg nifedipine retard twice a day and the corresponding placebos for 1 month. At the end of each treatment period, blood pressure was measured by using a mercury sphygmomanometer at trough and 1, 2, 3 and 4 h after the last dosing. The peak effect was identified as the maximum decrement induced by the three randomized treatments with respect to the value at the end of the placebo washout period during the 4 h interval. The trough:peak ratios of systolic and diastolic blood pressure were calculated as group ratios and individual ratios from decrements induced by nifedipine gastrointestinal therapeutic system and retard, corrected for those induced by randomized placebo. Patients were defined as responders to each randomized treatment if their diastolic blood pressure at trough time was reduced by at least 10 mmHg relative to that at the corresponding time at the end of placebo washout. RESULTS: Nifedipine gastrointestinal therapeutic system and retard significantly reduced blood pressure to a similar extent both at trough and at peak. Systolic and diastolic group trough:peak ratios in responders to nifedipine gastrointestinal therapeutic system (n = 41) were 0.80 and 0.88, respectively, and those in responders to nifedipine retard (n = 30) 0.84 and 0.93, respectively. The percentage of patients with trough:peak ratios > 0.50 was > 80% (systolic trough:peak ratios) and above 90% (diastolic trough: peak ratios) for both nifedipine formulations. CONCLUSIONS: Our data show that 30 mg/day nifedipine gastrointestinal therapeutic system and 20 mg nifedipine retard twice a day have a favourable trough:peak ratios efficacy when given as monotherapy to essential hypertensive patients.

Adult↗

Severe gastrointestinal involvement in systemic sclerosis.

Gastrointestinal tract (GIT) is the most common organ system involved in systemic sclerosis (SSc). GIT involvement is mainly attributed to GIT dismobility and wide mouth diverticular. GIT involvement in SSc can be also severely debilitating and even life threatening. To our knowledge, the presence of gastrointestinal bleeding due to the presence of multiple peptic ulcers in scleroderma patients is not well described. In this case report, we describe a scleroderma patient with recurrent gastrointestinal bleeding due to multiple peptic ulcers, in which vagotomy, pyloroplasty, and cholocystectomy were performed and subcutaneous somatostatin was administered to discontinue the recurrent bleeding and stabilize her clinical condition.

Female↗

Once-daily therapy for angina pectoris with nifedipine gastrointestinal therapeutic system. Dosing and clinical efficacy.

The nifedipine gastrointestinal therapeutic system (GITS) is a promising new formulation that provides continuous release of nifedipine over the course of 24 hours with once-daily dosing. Results from a 14-week, open-label, crossover multicenter trial completed by 91 patients with chronic stable angina pectoris demonstrate that patients treated with standard nifedipine capsules may be switched to equivalent total 24-hour doses of nifedipine GITS and achieve comparable or improved efficacy (due to improved compliance) with a more favorable side-effects profile. Furthermore, in a subset of 10 patients who underwent sequential exercise testing, exercise responses obtained throughout 12 weeks of treatment with nifedipine GITS were comparable to measurements obtained during treatment with nifedipine capsules and demonstrated that tolerance did not occur. These patients also experienced significantly fewer vasodilatory side effects during treatment with nifedipine GITS compared with nifedipine capsules. Thus, nifedipine GITS represents a sound pharmacologic approach to the management of ischemic disease; and with once-daily dosing and a favorable side-effect profile this agent affords the potential for better patient compliance and efficacy without concern about the development of tolerance.

Angina Pectoris↗

The efficacy and safety of once-daily nifedipine: the coat-core formulation compared with the gastrointestinal therapeutic system formulation in patients with mild-to-moderate diastolic hypertension. Nifedipine Study Group.

The efficacy and safety of two sustained-release formulations of nifedipine, the coat-core system (NIF CC) and the gastrointestinal therapeutic system (NIF GITS), were examined in 228 patients with mild-to-moderate essential hypertension in this 16-week, multicenter, randomized, double-blind study. The coadministration of food affects the nifedipine pharmacokinetics with differing magnitudes for the two formulations. To evaluate drug safety under the most rigorous circumstances, all medication was given with food. After a 4-week placebo lead-in period, eligible patients were randomized to a parallel-group treatment period of either NIF CC or NIF GITS. 30 mg daily with food for 4 weeks, followed by forced titration to nifedipine 60 mg daily for an additional 4 weeks. For the final 4-week period, half of the patients receiving each formulation were switched to the alternate formulation at a dose of 60 mg daily. Within treatment groups, all four blood pressure variables (systolic and diastolic measurements for both trough and 24-hour periods) demonstrated significant reductions (P < 0.05) from baseline (established after the placebo lead-in period) for both formulations at every subsequent visit and end point. When comparing the two formulations, the mean change from baseline in 24-hour systolic and diastolic blood pressure measurements, determined by using ambulatory monitoring, was not statistically different for both doses (P > 0.05). The mean change in trough blood pressure from baseline during the parallel-group treatment period was statistically significant in favor of NIF GITS for both the 30-mg and 60-mg doses (P < 0.05). The treatment-emergent adverse-event rates for both formulations were similar during the parallel-group period, with the exception of dizziness, which was higher for patients receiving NIF CC. Both formulations were well tolerated and reduced blood pressure over the 24-hour dosing interval even when coadministered with food. When half of the patients receiving NIF GITS 60 mg daily were randomly crossed over to NIF CC 60 mg daily, there were no significant changes in either the trough or 24-hour mean blood pressure measurements (P > 0.05), adverse events, or dropout rates. When patients receiving NIF CC 60 mg were crossed over to NIF GITS 60 mg daily, they exhibited no significant change in diastolic blood pressure (P > 0.05). This study demonstrated that when given with food, both NIF CC and NIF GITS reduce 24-hour mean blood pressure measurements similarly.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Validation of a gastrointestinal explant system for measurement of mucosal antibody production.

A gastrointestinal explant culture system was developed and compared to the mononuclear cell extraction and enzyme-linked immunospot assay method for measurement of immunoglobulin A (IgA) and IgG antibody-secreting cells (ASCs) in gastric antral and duodenal biopsies of non-Helicobacter pylori-infected volunteers. IgA and IgG were detected in explant supernatants during 6 to 7 days of culture in all subjects. IgA containing secretory component was also detected throughout the culture period, although peak production occurred only in the first 3 days. During 7 days of culture, the cumulative geometric mean IgA levels produced were 2.2 and 8.02 microg/ml/10 mg of antral and duodenal biopsy tissues, respectively, while the cumulative geometric mean IgG levels were 1.54 and 2.92 microg/ml/10 mg of antral and duodenal biopsy tissues, respectively. Cycloheximide treatment resulted in a >90% reduction in both immunoglobulin classes after 6 days of treatment compared to levels in untreated controls. The detection of IgA and IgG ASCs extracted from biopsies on days 1 and 6 of culture confirmed that the antibody detected was derived from mucosal lamina propria. The IgA and IgG ASC responses were positively correlated with antibody concentrations detected in culture supernatants (r = 0.87 and 0.85, respectively). These results validate the potential usefulness of our gastrointestinal explant system for the evaluation of mucosal effector B-cell function.

Adolescent↗

Systemic and gastrointestinal candidiasis of infant mice after intragastric challenge.

Systemic and gastrointestinal infection can be established in infant mice after intragastric challenge with Candida albicans. Differences in virulence of the six strains tested were noted. As early as 3 h after infection, some but not all livers, spleens, and kidneys contained C. albicans, but the peak number of colony-forming units in these organs was seen at 6 h. The early colonization of the organs could not be attributed to aspiration of the inoculum since about 90% of lungs and livers tested yielded no colony-forming units at 10 to 15 min postinfection. In animals with systemic infections, lungs, livers, kidneys, and spleens showed similar numbers of colony-forming units within the organs during the first 6 h postinfection- and then the number declined progressively up to 72 h. The gastrointestinal tract was colonized throughout a 20-day period of study. Counts made at intervals beyond day 1 yielded between 10(5) and 10(6) colony-forming units in the stomach, ileum, and cecum. Preparatory techniques for scanning electron microscopy preserved the yeast, intestinal mucus layer, and epithelial surface and made it possible to visualize the association between the pathogen and host tissues within the digestive tract.

Administration, Oral↗

Clinical pharmacokinetics of doxazosin in a controlled-release gastrointestinal therapeutic system (GITS) formulation.

AIMS: A controlled-release gastrointestinal therapeutic system (GITS) formulation of doxazosin mesylate, a long-acting selective alpha1-adrenoceptor antagonist, was developed to enhance the pharmacokinetic profile and simplify the titration schedule by precisely controlling drug delivery rate, permitting an initial dose of 4 mg once daily, compared with standard doxazosin, which is initiated at 1 mg day-1 and titrated to a higher therapeutically effective dose. The aim of the present work was to evaluate the pharmacokinetics and bioavailability of doxazosin GITS with respect to the effect of food, age and gender, and multiple dosing. In addition, in vitro performance was assessed in conditions simulating the gastrointestinal environment. METHODS: A three-way crossover study in 24 subjects assessed the comparative bioavailability of doxazosin GITS under fed and fasting conditions and doxazosin standard under fasting condition. A multiple-dose, two-way crossover study in 35 subjects assessed the comparative pharmacokinetics and bioavailability of doxazosin GITS and doxazosin standard 4 and 8 mg upon multiple dosing. A multiple-dose, four-parallel-group study was conducted to determine the steady-state pharmacokinetics and bioavailability of doxazosin GITS 4 mg in 41 young and elderly male and female subjects. The release-rate profiles of doxazosin GITS were determined in artificial gastric fluid (pH=1.2), intestinal fluid (pH=7.5), and water. The effect of agitation on the dissolution characteristics of doxazosin GITS in artificial gastric fluid was studied at stirring rates of 50, 75, and 100 rev min-1. RESULTS: In vitro studies demonstrated that release rates for the GITS tablet are independent of pH in the range of 1.2 (gastric) to 7. 5 (intestinal), and of stirring rates simulating gastrointestinal motility. Clinical pharmacology studies showed that doxazosin GITS had a lower maximum plasma concentration, prolonged time to reach maximum plasma concentration, and a higher minimum plasma concentration compared with doxazosin standard. Thus, the GITS formulation results in a more gradual absorption of doxazosin, and a reduced plasma doxazosin concentration peak-to-trough fluctuation ratio. The relative bioavailability of doxazosin GITS is approximately 60%. With a high-fat meal, the maximum plasma concentration and area under the concentration-time curve were 31% and 18% higher, respectively (P<0.05). Bioequivalence was established between the dose strengths of two 4 mg doxazosin GITS tablets and one 8 mg doxazosin GITS tablet. For both young adult and elderly subjects, and males and females, the pharmacokinetics of doxazosin GITS once daily for 7 days were comparable. Doxazosin GITS was well tolerated in the subjects studied, including young and elderly males and females. CONCLUSIONS: The GITS formulation of doxazosin enhances the pharmacokinetic profile compared with doxazosin standard, allowing more gradual absorption of doxazosin, and a reduced plasma doxazosin peak-to-trough concentration ratio. Thus, doxazosin GITS therapy can be initiated at a therapeutic dose of 4 mg with reduced haemodynamic side-effects.

Adult↗