Gastrointestinal tract therapeutic activity

Delivery of peptides and proteins via the gastrointestinal tract has not been successful because of poor penetration through the intestinal epithelium and high levels of proteolytic activity in the gastrointestinal tract. Liposomal encapsulation of proteins and peptides will not improve the efficiency and capacity of this absorption pathway considerably (e.g., Ryman et al., 1982 Machy and Leserman, 1987 Weiner and Chia-Ming Chiang, 1988). These difficulties in delivery via the oral route caused the parenteral route to remain the preferred route for the administration of therapeutic peptides... 

There are a number of side-effects of opiates that are due to their actions on opiate receptors outside the central nervous system. Opiates constrict the pupils by acting on the oculomotor nucleus and cause constipation by activating a maintained contraction of the smooth muscle of the gut which reduces motility. This diminished propulsion coupled with opiates reducing secretion in the gut underlie the anti-diarrhoeal effect. Opiates contract sphincters throughout the gastrointestinal tract. Although these effects are predominantly peripheral in origin there are central contributions as well. Morphine can also release histamine from mast cells and this can produce irritation and broncho-spasm in extreme cases. Opiates have minimal cardiovascular effects at therapeutic doses. 

Cartwright [124] reported that miconazole was slightly absorbed from epithelial and mucosal surface. The drug is well absorbed from the gastrointestinal tract, but caused nausea and vomiting in some patients. The drug may be given intravenously but was associated phlebitis. Up to 90% of the active compound was bound to plasma protein. Distribution into other body compartments was poor. Metabolism was primarily in the liver, and only metabolites were excreted in the urine. At therapeutic levels, they were relatively nontoxic both locally and systematically, but occasionally produced disturbances on the central nervous system. 

In the periphery, 5-HT4 receptor mRNA is found in vascular smooth muscle. Newly developed drugs that activate 5-HT4 receptors are of interest for their potential in treating cardiac arrhythmia. The 5-HT4 receptor is also located on neurons of the alimentary tract, for example the myenteric plexus of the ileum, and on smooth muscle cells and secretory cells of the gastrointestinal tract, where they evoke secretions and the peristaltic reflex. 5-HT4 receptor agonists (e.g. cisapride, prucalopride, tegaserod) are used therapeutically in the treatment of constipation-predominant irritable bowel syndrome and in functional motility disorders of the upper gastrointestinal tract. 

Bupropion is an aminoketone that exerts its therapeutic effect through the inhibition of norepinephrine and dopamine reuptake. Bupropion s receptor occupancy profile shows an absence of anticholinergic and antihista-minic effects (Cusack et ah, 1994). Bupropion is absorbed rapidly from the gastrointestinal tract, and peak blood levels are achieved within 2 hours for regular release and 3 hours for sustained-release preparations = 10 hours). Bupropion undergoes extensive first-pass metabolism in the liver, yielding three active metabolites hydrobupropion, threohydroxybu-propion, and erythrohydrobupropion. The half-lives of the active metabolites are approximately 20 + hours (Preskorn, 1993). 

Table 2.1 presents examples of the main classes of low-molecular-weight bioactive molecules which are currently considered to be helpful for human well-being and which can be therefore used as food supplements as well as active components in skin-care applications (Ratnam et al., 2006 McClements et al., 2009). The required physicochemical properties of effective bioactive compounds, which should be considered in the formulation of the prophylactic and therapeutic dietary supplements at their desired oral dosages, are described in the scientific literature. These properties are (i) solubility in aqueous media (ii) permeability through the gastrointestinal tract and cell membranes (iii) physical stability and (iv) bioavailability. 

Asmussen, B., Cremer, K., Hoffman, H., et al. Expandable gastroretentive therapeutic system with controlled active substance release in the gastrointestinal tract, U.S. Patent 6,290,989, 2001. 

Diphenoxylate is readily absorbed from the gastrointestinal tract. Peak levels occur 3h after a single oral dose. Diphenoxylate is metabolized rapidly in the liver to both active and inactive metabolites. En-terohepatic circulation may occur. The volume of distribution is 4.6lkg. The half-life of diphenoxylate is 2.5 h. The major metabolite difenoxin (dip-henoxylic acid) has a half-life of 4.4 h after therapeutic dosage and is five times more potent than the parent chemical. After overdose, difenoxin s half-life has been reported to extend greater than 12h. Diphenoxylate is excreted in the feces (49%) and urine (13%) primarily as metabolites. 

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