Use of Evidence-Based Herbal Medicines for Patients with Functional Gastrointestinal Disorders: A Conceptional Framework for Risk-Benefit Assessment and Regulatory Approaches.

BACKGROUND: Herbal or complementary medicines are frequently used for the treatment of patients with functional gastrointestinal disorders (FGID). Regulatory requirements for herbal therapies are inconsistent and, in many jurisdictions, herbal therapies are either self-, minimally- or unregulated. AIM: To provide guidance for the appropriate and safe use of herbal medicines in patients with FGID patients with special consideration of the regulatory frameworks. METHODS: A PubMed search of the literature was performed; relevant articles were included. RESULTS: Similar to chemically defined therapies herbal medicines can cause adverse events. Thus, a risk-benefit appraisal should be undertaken for these therapies. While there is no disease specific mortality in FGID patients, patients with FGID who fail to respond to "empiric" chemically defined therapies undergo diagnostic and therapeutic measures that can be associated with appreciable morbidity and mortality. Thus, effective herbal treatments that subsequently reduce health-care utilization, reduce risks related to diagnostic or therapeutic measures that are initiated if no improvement of symptoms occurs. This "protective" effect of effective treatments for FGID needs to be taken in consideration when the risks and benefits of treatments are determined. In addition, standards that mirror regulations for chemically defined treatments should apply and the components of the respective preparations should undergo ongoing toxicological testing and rigorous quality assurance measures (including pharmacovigilance) applied. CONCLUSIONS: Some herbal therapies offer significant benefits for patients with FGID. To ensure the safety of these treatments, the regulatory requirements should mirror requirements for chemically defined treatments.

Truncated IRAG variants modulate cGMP-mediated inhibition of human colonic smooth muscle cell contraction.

Nitric oxide (NO) induces relaxation of colonic smooth muscle cells predominantly by cGMP/cGMP-dependent protein kinase I (cGKI)-induced phosphorylation of the inositol 1,4,5-trisphosphate receptor (IP(3)R)-associated cGMP kinase substrate (IRAG), to block store-dependent calcium signaling. In the present study we analyzed the structure and function of the human IRAG/MRVI1 gene. We describe four unique first exon variants transcribed from individual promoters in diverse human tissues. Tissue-specific alternative splicing with exon skipping and alternative splice donor and acceptor site usage further increases diversity of IRAG mRNA variants that encode for NH(2)- and COOH-terminally truncated proteins. At the functional level, COOH-terminally truncated IRAG variants lacking both the cGKI phosphorylation and the IP(3)RI interaction site counteract cGMP-mediated inhibition of calcium transients and relaxation of human colonic smooth muscle cells. Since COOH-terminally truncated IRAG mRNA isoforms are widely expressed in human tissues, our results point to an important role of IRAG variants as negative modulators of nitric oxide/cGKI-dependent signaling. The complexity of alternative splicing of the IRAG gene impressively demonstrates how posttranscriptional processing generates functionally distinct proteins from a single gene.

Cannabinoid-1 (CB1) receptors regulate colonic propulsion by acting at motor neurons within the ascending motor pathways in mouse colon.

Cannabinoid-1 (CB(1)) receptors on myenteric neurons are involved in the regulation of intestinal motility. Our aim was to investigate CB(1) receptor involvement in ascending neurotransmission in mouse colon and to characterize the involved structures by functional and morphological means. Presence of the CB(1) receptor was investigated by RT-PCR, and immunohistochemistry was used for colabeling studies. Myenteric reflex responses were initiated by electrical stimulation (ES) at different distances, and junction potentials (JP) were recorded from circular smooth muscle cells by intracellular recording in an unpartitioned and a partitioned recording chamber. In vivo colonic propulsion was tested in wild-type and CB(1)(-/-) mice. Immunostaining with the cytoskeletal marker peripherin showed CB(1) immunoreactivity both on Dogiel type I and type II neurons. Further neurochemical characterization revealed CB(1) on choline acetyltransferase-, calretinin-, and 5-HT-immunopositive myenteric neurons, but nitrergic neurons appeared immunonegative for CB(1) immunostaining. Solitary spindle-shaped CB(1)-immunoreactive cells in between smooth muscle cells lacked specific markers for interstitial cells of Cajal or glial cells. ES elicited neuronally mediated excitatory JP (EJP) and inhibitory JP. Gradual increases in distance resulted in a wave-like EJP with EJP amplitudes being maximal at the location of stimulating electrode 6 and a maximal EJP projection distance of approximately 18 mm. The CB(1) receptor agonist WIN 55,212-2 reduced the amplitude of EJP and was responsible for shortening the oral spreading of the excitatory impulse. In a partitioned chamber, WIN 55,212-2 reduced EJP at the separated oral sites, proving that CB(1) activation inhibits interneuron-mediated neurotransmission. These effects were absent in the presence of the CB(1) antagonist SR141716A, which, when given alone, had no effect. WIN 55,212-2 inhibited colonic propulsion in wild-type mice but not in SR141716A-pretreated wild-type or CB(1)(-/-) mice. Activation of the CB(1) receptor modulates excitatory cholinergic neurotransmission in mouse colon by reducing amplitude and spatial spreading of the ascending electrophysiological impulses. This effect on electrophysiological spreading involves CB(1)-mediated effects on motor neurons and ascending interneurons and is likely to underlie the here reported in vivo reduction in colonic propulsion.

Are gap junctions truly involved in inhibitory neuromuscular interaction in mouse proximal colon?

1. Gap junctions exist between circular muscle cells of the colon and between interstitial cells of Cajal (ICC) in the myenteric plexus of the gastrointestinal tract. They also probably couple intramuscular ICC with smooth muscle cells. Recent functional evidence for this was found in dye-coupling and myoelectrical experiments. 2. In the present study, we tested the hypothesis of gap junctions putatively being involved in neuromuscular interaction in mouse colon by using different classes of gap junction blockers. 3. Electrical field stimulation of the myenteric plexus elicited tetrodotoxin-sensitive and hexamethonium-independent fast and slow inhibitory junction potentials (fIJP and sIJP, respectively) in circular smooth muscle cells, as evaluated by intracellular recording techniques in impaled smooth muscle cells. Heptanol produced a time-dependent hyperpolarization of the membrane potential (MP) and abolished fIJP and sIJP. Octanol had no effect on the MP and abolished fIJP and sIJP. Carbenoxolone produced a time-dependent depolarization of the MP without any effect on fIJP or sIJP. The connexin 43 mimetic gap junction blocker GAP-27 had no effect on MP, fIJP or sIJP. 4. Based on the presently available gap junction blockers we found no evidence that gap junctions are involved in neuromuscular transmission in mouse colon, as suggested by morphological studies.

Effects of endomorphin-1 and -2 on mu-opioid receptors in myenteric neurons and in the peristaltic reflex in rat small intestine.

1. The aim of the present investigations was to characterize the effect of endomorphins on the function of rat small intestine smooth muscle and on the electrically induced ascending and descending reflex pathway of rat small intestine in vitro. 2. Endomorphin-1 and -2 left the basal tonus and the pharmacologically stimulated smooth muscle unchanged. In contrast, electrically induced twitch contractions were significantly reduced by endomorphin-1 and -2 and this reduction was reversed by the mu-opioid receptor antagonist Cys-Tyr-Orn-Pen-amide (CTOP), suggesting a specific mu-opioid receptor-mediated effect on neural tissue. 3. In the reflex model, endomorphin-1 caused a significant inhibition (IC50 2.3 x 10(-8) mol/L) of the ascending contraction (10(-8) mol/L: -28.3 +/- 5.8%; 10(-7) mol/L: -94.7 +/- 0.2.8%; both P < 0.05; n = 7). Descending relaxation increased at a concentration of 10(-8) mol/L endomorphin-1 (+61.6 +/- 24.5%; 10(-7) mol/L: +237.0 +/- 65.4%; both P < 0.05; n = 6). 4. Endomorphin-1 caused a further significant increase in the latency of the ascending contraction (10(-8) mol/L: +44.7 +/- 20.5%; 10(-7) mol/L: +93.5 +/- 16.1%; both P < 0.05; n = 7), whereas the latency of the descending relaxation was unaltered (n = 7). Similar results were observed for endomorphin-2. 5. All effects could be reversed by a wash-out afterwards and were blocked by pre-incubation with CTOP (10-6 mol/L). 6. Reverse transcription-polymerase chain reaction demonstrated mRNA expression of mu-opioid receptors in the rat ileum longitudinal muscle/myenteric plexus preparation, as well as in the oesophagus and stomach. 7. Endomorphin-1 and -2 reduce the cholinergic-induced contractile response of the rat ileal smooth muscle preparation via a presynaptic mechanism. 8. By a specific and reversible interaction with mu-opioid receptors, the ascending excitatory and descending inhibitory reflex responses were attenuated or facilitated, respectively. 9. In conclusion, the endomorphins may be the physiological endogenous mu-opioid receptor agonists in the rat small intestine.