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Efficacy of Ipamorelin, a Novel Ghrelin Mimetic, in a Rodent Model of Postoperative Ileus
Postoperative ileus (POI) is a gastrointestinal (GI) dysfunction that develops as a consequence of abdominal surgery or other major surgical procedures. The mechanisms causing POI are complex, and opioid drugs used for pain management contribute significantly to the delay in GI transit. The main symptoms of POT are abdominal distention, nausea, anorexia, vomiting, and an inability to pass stool. Moreover, POI is the main cause for prolonged hospitalization and often results serious complications in others (Senagore, 2007).
Currently, there are no pharmacological agents available to normalize gut motility, and the pharmacological strategies proposed to accelerate recovery from POI, which is based on the effects of commonly used prokinetic drugs and/or selective periphery-restricted opioid receptor antagonists (Greenwood-Van Meerveld, 2007). Endogenous ghrelin is a multifunctional hormone involved in the regulation of appetite, GI motility and feeding behavior. Also, ghrelin and ghrelin mimetics can stimulate appetite and also enhance gastric motility. Ipamorelin is a selective growth hormone secretagogue and agonist of the ghrelin receptor. Therefore, the present experiment was designed to investigate whether Ipamorelin would accelerate GI transit and also ameliorate the symptoms in a rodent model of POI.
Adult male rats were obtained at an initial body weight of 250 to 270 g. Ipamorelin (0.01?1 mg/kg), growth hormone-releasing peptide GHRP-6 (20 g/kg), or vehicle (saline) were administered via intravenous bolus infusion after a single dosing or a 2-day repetitive dosing regimen (four doses a day at 3-h intervals). At the end of the surgery, a dye marker was injected in the proximal colon to evaluate postsurgical colonic transit time, which was the time to the first bowel movement. Moreover, fecal pellet output, food intake, and body weight were monitored regularly for 48 hours.
The cumulative fecal pellet output was significantly decreased during the first 12 and 24 hours after the surgery. But at the later periods of 12, 24 and 48 hours, food intake was suppressed in the rates with POI. In compliance, the body weight gain in the rats with POI was significantly lower at 24 and 48 hours, compared to the control rats.
Figure 2 indicates that a single postsurgical dose of Ipamorelin (1mg/kg) or GHRP-6 significantly decreased colonic transit time, shortening the time to the first bowel movement.
However, neither Ipamorelin nor GHRP-6 had significant effect on cumulative fecal pellet output, body weight gain, or food intake, measured at 12, 24, and 48 hours after surgery.
There is a separate series of experiments, which are designed to research the dose-response effect of repetitive dosing of Ipamorelin (0.01, 0.1, or 1 mg/kg i.v.) during the first 48 hours after surgery.
Compared to the effect of the vehicle, the colonic transit time to the first bowel movement was significantly decreased by 0.1 or 1 mg/kg Ipamorelin. Moreover, its effect on cumulative fecal pellet output was associated with an increase in the number of fecal pellets.
The number of fecal pellets generated during the 48 hours after surgery was significantly higher with the dose of 0.1 or 1 mg/kg. The regression analysis also demonstrated a linear increase of fecal output during the treatment with Ipamorelin or vehicle.
However, the fecal output increased at a higher rate in the rats with 0.1 or 1mg/kg Ipamorelin injection compared with the rats treated with vehicle. In addition, the repetitive dosing of Ipamorelin also caused a similar increase in food intake.
The rats treated with 1 mg/kg ipamorelin gained significantly more weight during the first 48 hours postoperative, compared with the rats receiving vehicle.
In conclusion, the results of present study demonstrates that postoperative treatment with Ipamorelin administered via multiple intravenous bolus infusions over a period of 48 hours may be useful in the clinic to ameliorate the symptoms and accelerate the recovery in patients with POI.
Postoperative ileus (POI) is a gastrointestinal (GI) dysfunction that develops as a consequence of abdominal surgery or other major surgical procedures. The mechanisms causing POI are complex, and opioid drugs used for pain management contribute significantly to the delay in GI transit. The main symptoms of POT are abdominal distention, nausea, anorexia, vomiting, and an inability to pass stool. Moreover, POI is the main cause for prolonged hospitalization and often results serious complications in others (Senagore, 2007).
Currently, there are no pharmacological agents available to normalize gut motility, and the pharmacological strategies proposed to accelerate recovery from POI, which is based on the effects of commonly used prokinetic drugs and/or selective periphery-restricted opioid receptor antagonists (Greenwood-Van Meerveld, 2007). Endogenous ghrelin is a multifunctional hormone involved in the regulation of appetite, GI motility and feeding behavior. Also, ghrelin and ghrelin mimetics can stimulate appetite and also enhance gastric motility. Ipamorelin is a selective growth hormone secretagogue and agonist of the ghrelin receptor. Therefore, the present experiment was designed to investigate whether Ipamorelin would accelerate GI transit and also ameliorate the symptoms in a rodent model of POI.
Adult male rats were obtained at an initial body weight of 250 to 270 g. Ipamorelin (0.01?1 mg/kg), growth hormone-releasing peptide GHRP-6 (20 g/kg), or vehicle (saline) were administered via intravenous bolus infusion after a single dosing or a 2-day repetitive dosing regimen (four doses a day at 3-h intervals). At the end of the surgery, a dye marker was injected in the proximal colon to evaluate postsurgical colonic transit time, which was the time to the first bowel movement. Moreover, fecal pellet output, food intake, and body weight were monitored regularly for 48 hours.
The cumulative fecal pellet output was significantly decreased during the first 12 and 24 hours after the surgery. But at the later periods of 12, 24 and 48 hours, food intake was suppressed in the rates with POI. In compliance, the body weight gain in the rats with POI was significantly lower at 24 and 48 hours, compared to the control rats.
Figure 2 indicates that a single postsurgical dose of Ipamorelin (1mg/kg) or GHRP-6 significantly decreased colonic transit time, shortening the time to the first bowel movement.
However, neither Ipamorelin nor GHRP-6 had significant effect on cumulative fecal pellet output, body weight gain, or food intake, measured at 12, 24, and 48 hours after surgery.
There is a separate series of experiments, which are designed to research the dose-response effect of repetitive dosing of Ipamorelin (0.01, 0.1, or 1 mg/kg i.v.) during the first 48 hours after surgery.
Compared to the effect of the vehicle, the colonic transit time to the first bowel movement was significantly decreased by 0.1 or 1 mg/kg Ipamorelin. Moreover, its effect on cumulative fecal pellet output was associated with an increase in the number of fecal pellets.
The number of fecal pellets generated during the 48 hours after surgery was significantly higher with the dose of 0.1 or 1 mg/kg. The regression analysis also demonstrated a linear increase of fecal output during the treatment with Ipamorelin or vehicle.
However, the fecal output increased at a higher rate in the rats with 0.1 or 1mg/kg Ipamorelin injection compared with the rats treated with vehicle. In addition, the repetitive dosing of Ipamorelin also caused a similar increase in food intake.
The rats treated with 1 mg/kg ipamorelin gained significantly more weight during the first 48 hours postoperative, compared with the rats receiving vehicle.
In conclusion, the results of present study demonstrates that postoperative treatment with Ipamorelin administered via multiple intravenous bolus infusions over a period of 48 hours may be useful in the clinic to ameliorate the symptoms and accelerate the recovery in patients with POI.
