Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation

The basic motor function of the colon is to mix and knead its contents, propel them slowly in the caudad direction, hold them in the distal colon until defecation, and provide a strong propulsive force during defecation. Infrequently, it also produces mass movements in the proximal colon. These motor functions are achieved in most species by three different types of contractions: the individual phasic contractions that include the short- and long-duration contractions, organized groups of contractions that include the migrating and nonmigrating motor complexes, and special propulsive contractions (giant migrating contractions). The spatial and temporal patterns of all of these contractions are controlled by myogenic, neural, and chemical control mechanisms. The individual phasic contractions are highly disorganized in time and space in the colon. For this reason, they are effective in mixing and kneading and slow distal propulsion. The underlying cause of the disorganization of short duration contractions is the irregularity in the frequency and waveshape of colonic electrical control activity and its phase unlocking throughout the colon. The individual contractions in many species occur in cyclic bursts called contractile states. At least in some species, these contractile states exhibit mostly caudad and sometimes orad migration. However, there are also nonmigrating or randomly migrating contractile states in the colon. These two patterns of contractile states are called colonic migrating motor complexes and colonic nonmigrating motor complexes, respectively. The giant migrating contractions provide the strong propulsive force for defecation and mass movements. The neural control of colonic contractions is organized at three levels--enteric, autonomic, and central. The enteric nervous system contains cholinergic and peptidergic neurons and plays a major role in the control of colonic contractions. The autonomic nerves, the vagi, pelvic, lumbar colonic, hypogastric, and splanchnic nerves, seem to continuously monitor the state of the colon and provide a modulatory input when necessary. These nerves play a major role in the reflexive control of colonic motor function. The voluntary input from the central nervous system coordinates the motor activity of the colon, rectum, anal canal and sphincters for orderly evacuation of feces during defecation. The role of acetylcholine, nonadrenaline, and the yet to be completely identified nonadrenergic, noncholinergic neurotransmitter, possibly VIP, in the control of contractions is fairly well established. Besides these, there are several other peptides and chemicals that are localized in the colonic wall; their physiological roles remain unknown. Colonic motor activity has been studied in several disease states. The findings have not always been consistent.(ABSTRACT TRUNCATED AT 400 WORDS)

Physiology and pathophysiology of colonic motor activity (2).

Dyssynergic Defecation and Biofeedback Therapy

We aimed to determine whether rectal distension and/or infusion of bile acids stimulates propagating or nonpropagating activity in the unprepared proximal colon in 10 healthy volunteers using a nasocolonic manometric catheter (16 recording sites at 7.5-cm spacing). Sensory thresholds and proximal colonic motor responses were assessed following rectal distension by balloon inflation and rectal instillation of chenodeoxycholic acid. Maximum tolerated balloon volume and the volume that stimulated a desire to defecate were both significantly (P < 0.01) reduced after rectal chenodeoxycholic acid. The frequency of colonic propagating pressure wave sequences decreased significantly in response to initial balloon inflations (P < 0.05), but the frequency doubled after subsequent chenodeoxycholic acid infusion (P < 0.002). Nonpropagating activity decreased after balloon inflation, was not influenced by acid infusion, and demonstrated a further decrease in response to repeat balloon inflation. We concluded that rectal chenodeoxycholic acid in physiological concentrations is a potent stimulus for propagating pressure waves arising in the proximal colon and reduces rectal sensory thresholds. Rectal distension inhibits all colonic motor activity.

The Proximal Colonic Motor Response to Rectal Mechanical and Chemical Stimulation

Background
Until recently, investigations of the normal patterns of motility of the healthy human colon have been limited by the resolution of in vivo recording techniques.

Methods
We have used a new, high-resolution fiber-optic manometry system (72 sensors at 1-cm intervals) to record motor activity from colon in 10 healthy human subjects.

Key Results
In the fasted colon, on the basis of rate and extent of propagation, four types of propagating motor pattern could be identified: (i) cyclic motor patterns (at 2–6/min); (ii) short single motor patterns; (iii) long single motor patterns; and (iv) occasional retrograde, slow motor patterns. For the most part, the cyclic and short single motor patterns propagated in a retrograde direction. Following a 700 kCal meal, a fifth motor pattern appeared; high-amplitude propagating sequences (HAPS) and there was large increase in retrograde cyclic motor patterns (5.6 ± 5.4/2 h vs 34.7 + 19.8/2 h; p < 0.001). The duration and amplitude of individual pressure events were significantly correlated. Discriminant and multivariate analysis of duration, gradient, and amplitude of the pressure events that made up propagating motor patterns distinguished clearly two types of pressure events: those belonging to HAPS and those belonging to all other propagating motor patterns.

Conclusions & Inferences
This work provides the first comprehensive description of colonic motor patterns recorded by high-resolution manometry and demonstrates an abundance of retrograde propagating motor patterns. The propagating motor patterns appear to be generated by two independent sources, potentially indicating their neurogenic or myogenic origin.

/pdf/quantification-of-in-vivo-colonic-motor-patterns-in-healthy-36c1uoljgv.pdf

Quantification of in vivo colonic motor patterns in healthy humans before and after a meal revealed by high‐resolution fiber‐optic manometry

The motor activity of colonic segments proximal to the rectosigmoid junction are poorly understood. We investigated colonic peristalsis (high-amplitude propagated contractions; HAPCs) in 20 healthy volunteers by means of a colonoscopically positioned manometric probe and low-compliance infusion system. In all, 110 HAPCs were recorded from the ascending, transverse, descending, and sigmoid colon, and their features and daily distribution were analyzed and characterized. Mean frequency was 6.1 +/- 0.9 (SE) per subject per 24 h, mean amplitude was 110.37 +/- 6.3 mmHg, mean duration was 14.15 +/- 0.8 s, and mean propagation velocity was 1.11 +/- 0.1 cm/s. There were no significant differences among colonic segments. Diurnal changes of HAPCs were also noted, with a maximum frequency after meals and after awakening in the morning, and a minimum recorded in the late afternoon and during the night. These HAPCs may represent the manometric equivalent of mass movements.

Manometric investigation of high-amplitude propagated contractile activity of the human colon

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Manometric investigation of high-amplitude propagated contractile activity of the human colon