Ghrnet.org2

Journal of
Gastroenterology and Hepatology Research
Journal of GHR 2013 March 21 2(3): 449-457 ISSN 2224-3992 (print) ISSN 2224-6509 (online) Interaction of Insulin with Prokinetic Drugs in STZ-induced
Diabetic Mice

Mohamed A Fouad, Hekma A Abd El latif, Mostafa E El Sayed Mohamed A Fouad Shalaby, Department of Pharmacology, R&D Erythromycin tended to decrease blood glucose level and increase Senior specialist pharmacist, Kahira Pharmaceutical Company, Cairo, serum insulin level after one week of daily dose administration in diabetic mice. Erythromycin potentiated the effect of insulin given on Hekma A Abd El latif, Professor and head of Pharmacology & blood glucose level and serum insulin level where other prokinetic Toxicology, Faculty of Pharmacy, Cairo University, Giza, Egypt agents failed to do so after repeated dose administration in diabetic Mostafa E El Sayed, Professor of Pharmacology & Toxicology, mice.Metoclopramide or erythromycin in combination with insulin Faculty of Pharmacy, Cairo University, Giza, Egypt significantly (P<0.05) decreased small intestinal transit in diabetic Correspondence to: Mohamed A Fouad Shalaby, Research spe- mice, which was less than that of insulin alone. Administration of cialist pharmacist, Department of Pharmacology, R&D, Kahira Phar- test prokinetic drugs along with insulin antagonized the action of maceutical Company, Cairo, Egypt. Mafrec10@yahoo.com insulin on xylose absorption. These combinations also increased the Telephone: +01220997029 Fax: +00-20-22025477 rate of glucose absorbed from the gut. Received: September 20, 2012 Revised: November 28, 2012 CONCLUSIONS: The present study suggests that prokinetic drugs
Accepted: November 18, 2012 could potentially improve glycemic control in diabetic gastroparesis Published online: March 21, 2013 by allowing a more predictable absorption of nutrients, matched to the action of exogenous insulin. The use of prokinetics i.e. erythromycin may be interesting in the clinic in order to decrease the need for insulin in diabetic patients. The dose of insulin may be AIM: Prokinetic drugs have been used for gastroparesis in diabetic
safely decreased with erythromycin in chronic treatments. patients for a relatively long time already and some data about the interactions with insulin in the clinic should be available. To 2013 ACT. All rights reserved.
study the possible interactions of metoclopramide, domperidone or erythromycin in streptozotocin (STZ)-induced diabetic mice treated Key words: Streptozotocin; Gastrointestinal motility; Insulin; Pro-
with insulin in different parameters. kinetic drugs; Intestinal absorption METHODS: Effects of the individual as well as combined drugs
were studied in diabetic mice via estimation of the blood glucose
Fouad MA, Abd El latif HA, El Sayed ME. Interaction of Insulin and serum insulin levels, small intestinal transit, gastric emptying, with Prokinetic Drugs in STZ-induced Diabetic Mice. Journal of xylose absorption and glucose tolerance tests. The groups included Gastroenterology and Hepatology Research 2013; 2(3): 449-457 were normal control, diabetic control, insulin 2 IU/kg (s.c.), Available from: URL: http://www.ghrnet.org/index./joghr/ metoclopramide 20 mg/kg (p.o.), domperidone 20 mg/kg (p.o.) and erythromycin 6 mg/kg (p.o.) individually and in combination. The first set of experiments was carried out to investigate the subchronic Diabetes mellitus is the most common cause of gastroparesis and effect of one week of daily dose of the tested drugs individually disturbed gastric and small intestine motility. Gastroparesis is a as well as the combination of insulin with each prokinetic drug in syndrome characterized by delayed gastric emptying in absence of diabetic mice on blood glucose and serum insulin levels. The other mechanical obstruction of stomach. The cardinal symptoms include five sets of experiments were carried out to investigate the acute postprandial fullness (early satiety), nausea, vomiting, bloating, or effect of a single dose of each drug individually and in combination epigastric pain. Symptoms attributable to gastroparesis are reported on blood glucose and serum insulin levels, small intestinal transit, by 5 to 12% of patients with diabetes[1,2]. There is an association gastric emptying, oral xylose absorption and glucose tolerance tests.
between self-reported glycemic control and psychological distress and RESULTS: The study included test prokinetic drugs i.e.,
development of gastrointestinal symptoms in diabetics[3]. Impaired metoclopramide (20 mg/kg), domperidone (20 mg/kg) and function of the gastrointestinal tract related to diabetes mellitus results erythromycin (6 mg/kg), as well as insulin (2 IU/kg), which from diabetic autonomic neuropathy, impaired sensory innervation was individually effective in decreasing SIT, enhancing GE and and a direct effect of persistent hyperglycemia[4]. Once established, increasing xylose absorption significantly (P<0.05) in diabetic mice.
diabetic gastroparesis tends to persist, despite amelioration of glycemic 2013 ACT. All rights reserved.
Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice control. Thus, gastric emptying and symptoms are stable during≥12 were used. Insulin injection was diluted with normal saline solution years follow-up, despite improved glycemic control[5]. Gastroparesis for obtaining a suitable strength. Hydroxypropylmethylcellulose affects nutritional state and, in diabetics, it also has deleterious effects (1%) was used as vehicle to administer prokinetic drugs. The other on glycemic control and secondary effects on organs that lead to reagents were the highest grade of commercially available products.
increased mortality[6]. First-line treatment includes restoration of nutrition and medications using prokinetic drugs. Therefore, searching for therapeutic interventions of prokinetic drugs that will improve the Control groups received the equal volumes of vehicle through specific alterations associated with diabetic gastroparesis represents the corresponding routes. The groups included were normal control, most important aim of the present study. Prokinetic drugs have been diabetic control, insulin 2 IU/kg (s.c.), metoclopramide 20 mg/kg used for gastroparesis in diabetic patients for a relatively long time (p.o.), domperidone 20 mg/kg (p.o.) and erythromycin 6 mg/kg (p.o.) already and some data about the interactions with insulin in the clinic individually and in combination. The doses were selected based on should be available. It deemed of interest to investigate the possible the earlier reports and recommended clinical doses and prior pilot drug-drug interactions, which may develop from co-administration of experiments[10,11,12]. Metoclopramide, domperidone or erythromycin insulin and certain prokinetic drugs i.e. metoclopramide, domperidone in the dose mentioned above were given alone 15 minutes before and erythromycin. Also, the study aims to warn about the possibility the administration of insulin/vehicle. Insulin was given 50 minutes that prokinetics might increase the hypoglycemic effect of insulin. before determination of blood glucose and serum insulin levels. Prokinetic drugs, commonly used to treat delayed gastric emptying, Six main sets of experiments were carried out. The first set of have variable effects on small intestinal motility, and little is known experiments carried out to investigate the subchronic effect of one about their effects on glucose absorption. The prokinetic drugs act week of daily dose of insulin, metoclopramide, domperidone and primarily through neurons since peristalsis is based on neural reflexes. erythromycin individually as well as the combination of insulin with Dopamine antagonists such as metoclopramide and domperidone[7] are metoclopramide, domperidone or erythromycin in STZ-induced used in this study. Motilides such as erythromycin enhances peristalsis diabetic male mice on blood glucose and serum insulin level. The by acting on motilin receptors[8].
other five sets of experiments carried out to investigate the acute In the present study, streptozotocin (STZ)-induced diabetic mice were effect of a single dose of insulin, metoclopramide, domperidone and treated with insulin, prokinetic agents i.e. metoclopramide, domperidone erythromycin individually as well as the combination of insulin with or erythromycin individually and in combination. Acute and subchronic metoclopramide, domperidone or erythromycin on blood glucose and study were carried out to determine whether the prokinetic drugs could serum insulin level, small intestinal transit, gastric emptying, oral improve the blood glucose level and neuropathy changes in diabetic xylose absorption and glucose tolerance tests.
conditions treated with insulin. This was achieved by measuring some of the biochemical parameters affected by persistent hyperglycemia Experimental induction of diabetes via estimation of blood glucose and serum insulin levels. Acute Diabetes mellitus was induced in overnight fasted mice by a single study were carried out to determine the effect of the test drugs on the intraperitoneal injection of freshly prepared solution of streptozotocin gastrointestinal tract motility represented in small intestinal transit and 100 mg/kg body weight in 0.1 M cold citrate PH 4.5[13,14]. The gastric emptying, knowing that all of the prokinetic drugs used produce animals were allowed to drink 5% glucose solution to overcome acute actions on the gut. The rate of gastric emptying is an important STZ-induced hypoglycemia[15]. The control mice were injected determinant of carbohydrate absorption and thus of the blood glucose with citrate buffer alone. Two week following STZ injection, blood profile[9]. Oral xylose absorption and glucose tolerance tests were used samples were collected from the tail venopuncture of the mice and as representative indices of carbohydrates absorption changes. used for the estimation of blood glucose levels using advanced Glucometer ACCU-CHEK (Roche, Germany)[16,17]. Overnight fasted MATERIALS AND METHODS
mice with blood glucose level above 200mg/dL were selected and used in the present study.
Animals
Healthy adult male albino mice weighting between 20-30 g were
used in the present study. They were obtained from the animal house
Measurement of blood glucose and serum insulin levels
of the research department of Kahira pharmaceutical company, Cairo, Blood was collected from reto-orbital venous plexus according to Egypt. All animals were fed a standard pellet chow and had free the method of Cocchetto[18]. Blood was collected using heparinized access to water. They were maintained under controlled laboratory microhematocrit capillaries into Wassermann tubes. Blood glucose conditions (temperature, humidity) throughout the study. New level was measured using advanced Glucometer ACCU-CHEK. groups of mice were recommended for each test done. Animals were Serum was separated by centrifugation at 11000 rpm for 2 min. and sacrificed under mild ether anesthesia. Experiments were conducted serum glucose level was determined immediately using glucose in accordance with the guidelines set by the animal's health research kit[19]. There is no significant difference in glucose levels between ethics training initiative, Egypt.
the two methods. The remaining amount of serum was kept frozen at -20ºC for insulin determination. Serum insulin was estimated Drugs and Reagents
by immunoradiometric assay (IRMA) technique[20] using insulin Insulin (Regular insulin, Novonordisk, Denmark), Metoclopramide IRMA Kit. This estimation was done 2 min before drug/vehicle (Memphis Pharmaceutical Co., Cairo, Egypt), Domperidone (El administration and 50 min after insulin/vehicle administration. Kahira Pharmaceutical Co., Cairo, Egypt) and Erythromycin ethylsuccinate (Abbott Laboratories, Cairo, Egypt) were obtained. Small intestinal transit (SIT)
Glucose Reagent Kit (Biomerieux, France), Insulin IRMA Kit The passage of a charcoal meal through the gastrointestinal transit IM3210 (Immunotech Beckman coulter, Czech Republic), in mice was used as parameter for intestinal motility[21,10]. Overnight Streptozotocin (Sigma Aldrich Chemie, Germany), Phloroglucinol fasted mice were treated with test prokinetic drug orally 45 min and/ (Sigma chemical Co., USA) and D-xylose (Acros Organics, USA) or insulin subcutaneously 30 min before administration of charcoal 2013 ACT. All rights reserved. Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice meal (0.3 mL of a 5% suspension of charcoal in 2% hydroxypro glucose solution (2.5 g/kg of body weight) was orally administered, pylmethylcellulose solution). After 20 min, animals were killed and blood was taken from the tail vein at 0, 30, 60 and 120 by cervical dislocation just after mild ether anesthesia. Abdomen min afterward. Blood glucose concentrations were determined opened, the charcoal marker was identified in the small intestine and immediately using an Accu-chek (Roche Diagnostics, Germany).The tied immediately to avoid movement of marker. The entire intestine difference between the value of the diabetic control group and the was removed by cutting at pyloric and ileocaecal ends and then diabetic treated groups represent the amount of glucose absorption washed in water. The distance the meal was traveled through the from the intestine affected by the different drugs used in this study intestine as indicated by the charcoal is measured and expressed as in addition to other factors. The extent of absorption of the glucose percent of the total distance from the pylorus to the caecum. was estimated using the total area under the curve, which represents Small intestinal transit (SIT)=(Distance travelled by charcoal / blood glucose level from t0 to t120. AUCtotal is calculated using the Total length of the small intestine)×100.
trapezoidal rule from t0 to t120.

Gastric emptying
Gastric emptying was determined by the phenol red method[22,12]. All data were expressed as the mean±standard error with 6 to 10 The test prokinetic drug was given alone 45 min before mice per group. Statistical analysis was performed using two ways administration of phenol red meal. Insulin (s.c.) was injected 30 analysis of variance (ANOVA) followed by Tukey-Kramer multiple min before the administration of the meal. A solution of 1.5% Hydr comparisons test. For all the statistical tests, the level of significance oxypropylmethylcellulose containing 0.05% phenol red as a marker was fixed at P< 0.05.
was given intragastrically (0.5 mL/mouse) to overnight fasted mice. 15 min later, Animals were sacrificed by cervical dislocation just after mild ether anesthesia. The abdominal cavity was opened, and Effects of insulin and certain prokinetic drug individually or
the cardiac and pyloric ends of the stomach were clamped, then the combined on blood glucose and serum insulin levels in STZ-
stomach was removed and washed with normal saline. The stomach induced diabetic mice.
was cut into pieces and homogenized with 25 mL of 0.1 N NaOH. Figure 1 and Figure 3 showed antihyperglycemic effect of insulin The suspension was allowed to settle for 1 h, and then 5 mL of the against STZ-induced diabetic mice. Acute administration of insulin supernatant was added to 0.5 mL of 20% trichloroacetic acid (w/v) (2 IU/kg) significantly (p<0.05) decreased blood glucose level and centrifuged at 3000 rpm for 20 min. To one ml of supernatant 4 to 45.37±4.57 mg/dL and increased serum insulin level to 1.96± mL of 0.5 N NaOH was added. The absorbance of this pink colour 0.1 uIU/kg in diabetic mice close to hypoglycemic value. Acute liquid was measured using spectrophotometer at 560nm (Model: effect of single dose of Metoclopramide (20 mg/kg), Domperidone Shimadzu 150-20). Phenol red recovered from animals that were (20 mg/kg) or erythromycin (6 mg/kg) individually did not affect sacrificed immediately after administration of the test meal was blood glucose level and serum insulin level in diabetic mice. Acute used as a standard (0% emptying). Gastric emptying (%) in the 15 effect of metoclopramide, domperidone or erythromycin did not min period was calculated according to the following equation: affect the action of insulin on blood glucose and serum insulin Gastric emptying (GE) %=100 – (X × Y-1 × 100); X=Absorbance level (Figure 1, Figure 2). Erythromycin tended to decrease blood of phenol red recovered from the stomach of animals sacrificed glucose level and increase serum insulin level after one week of 15 min after test meal; Y=mean (n=5) absorbance of phenol red daily dose administration in diabetic mice. Daily dose administration recovered from the stomachs of control animals (killed at 0 min of insulin (2 IU/kg) for one week significantly (p<0.05) decreased following test meal).
blood glucose level to 45.94±2.6 mg/dL and increased serum insulin level to 2.01±0.02 uIU/kg in diabetic mice close to hypoglycemic Oral D-xylose Loading Test
value. There is no interaction between insulin and the test prokinetic This test measures intestinal carbohydrates absorption by calculating namely metoclopramide or domperidone on blood glucose level the plasma concentration of D-xylose after ingestion of a known and serum insulin level after one week of daily dose administration amount of d-xylose[23,24]. The test prokinetic drug was given alone 45 in diabetic mice. On the other hand, Combination of insulin and min before administration of xylose. Insulin (s.c.) was injected 30 erythromycin significantly (p<0.05) decreased blood glucose level min before the administration of xylose. A 30% solution containing to 22.9±1.91 mg/dL and increased serum insulin level to 2.18±0.12 D-xylose (0.8 g/kg body weight) was administrated by oral gavage to uIU/kg in diabetic mice (Figure 3, Figure 4). overnight fasted mice. After 60 min of xylose administration, blood samples were drawn from retro-orbital venous plexus and blood Small intestinal transit
samples were centrifuged at 11 000 rpm for 2 min, plasma xylose The normal control value of the small intestinal transit was 56.61 concentrations were measured using a colorimetric assay. The assay ±2.58 % of the total length of the small intestine. Induction of involved incubation of 20 μL of plasma with 1 mL of colour reagent diabetes in mice significantly (p<0.05) increased SIT to 76.9±6.12%. containing 1 g phloroglucinol in 200 mL glacial acetic acid and 20 Insulin at dose (2 IU/kg) significantly (p<0.05) decreased SIT in mL concentrated HCL and heated for 4 min at 100˚C, followed by diabetic mice to 61.05±3.85% as compared to diabetic control group. reading of the absorbance at 554 nm using spectrophotometer (Model: The test prokinetic drugs namely metoclopramide (20 mg/kg), Shimadzu 150-20).
domperidone (20 mg/kg) and erythromycin (6 mg/kg) significantly (p<0.05) decreased SIT in the diabetic mice to 50.04±2.42%, 48.7 Oral Glucose Tolerance Test
±4.53%, and 43.05±3.5% respectively. Either of metoclopramide The OGTT was used to evaluate intestinal absorption. The test was or erythromycin in combination with insulin significantly (p<0.05) carried out according to the method of Stûmpel et al and Sachin decreased SIT in diabetic mice and this effect was less than that of et al[25,26]. After the mice were fasted for 12 h, the test compound insulin alone. Domperidone did not affect the action of insulin on was administered half an hour before the glucose loading. A 50% SIT in diabetic mice (Table 1). 2013 ACT. All rights reserved.
Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice Blood glucose level (% of diabetic control) Blood glucose level (% of diabetic control) Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) Insulin (2 IU/kg sc) Metoclopramide (20 mg/kg po) Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) Insulin (2 IU/kg sc) Metoclopramide (20 mg/kg po) Domperidone (20 mg/kg po) Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Domperidone (20 mg/kg po) Erythromycin (6 mg/kg po) Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) Erythromycin (6 mg/kg po) Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) Figure 1 Acute effect of a single dose of insulin, metoclopramide,
domperidone and erythromycin individually as well as the combination
Figure 3 Subchronic effect of one week daily dose administration of insulin,
of insulin with metoclopramide, domperidone or erythromycin on blood metoclopramide, domperidone and erythromycin individually as well as the glucose level in STZ-induced diabetic mice. Values represent the mean±s.e.m. combination of insulin with metoclopramide, domperidone or erythromycin of eight mice per group. * Significantly different from the normal control on blood glucose level in STZ-induced diabetic mice. Values represent the value at P<0.05. a Significantly different from the diabetic control value at P mean±s.e.m. of eight mice per group. * Significantly different from the normal <0.05. b Significantly different from insulin value at P<0.05.
control value at P<0.05. a Significantly different from the diabetic control value at P<0.05. b Significantly different from insulin value at P<0.05. Serum insulin level (% of diabetic control) Serum insulin level (% of diabetic control) Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) Insulin (2 IU/kg sc) Metoclopramide (20 mg/kg po) Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) Domperidone (20 mg/kg po) Insulin (2 IU/kg sc) Metoclopramide (20 mg/kg po) Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) Erythromycin (6 mg/kg po) Domperidone (20 mg/kg po) Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Figure 2 Acute effect of a single dose of insulin, metoclopramide,
Erythromycin (6 mg/kg po) domperidone and erythromycin individually as well as the combination Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) of insulin with metoclopramide, domperidone or erythromycin on serum Figure 4 Subchronic effect of one week daily dose administration of insulin,
insulin level in STZ-induced diabetic mice. Values represent the mean±s.e.m. metoclopramide, domperidone and erythromycin individually as well as the of eight mice per group. * Significantly different from the normal control combination of insulin with metoclopramide, domperidone or erythromycin value at P<0.05. a Significantly different from the diabetic control value at on serum insulin level in STZ-induced diabetic mice. Values represent the P<0.05. b Significantly different from insulin value at P<0.05. mean±s.e.m. of eight mice per group. * Significantly different from the normal control value at P<0.05. a Significantly different from the diabetic control value at P<0.05. b Significantly different from insulin value at P<0.05. The normal control value of the gastric emptying was 72.50±1.68 % of the total amount of the phenol red meal given. High blood to 95.87±2.41%, 76.38±7.67%, 90.92±4.92% and 84.77±2.11% glucose level in diabetic control mice delayed GE significantly respectively compared with diabetic control mice. Administration (p<0.05) to 55.23±9.30%. Insulin (2 IU/kg), metoclopramide (20 of prokinetic drugs namely metoclopramide, domperidone or mg/kg), domperidone (20 mg/kg) or erythromycin (6 mg/kg) in the erythromycin along with insulin (2 IU/kg) did not affect the action doses employed increased gastric emptying significantly (p<0.05) of insulin on GE (Table 1).
2013 ACT. All rights reserved.
Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice Table 1 Effects of insulin and prokinetic drugs alone and in combination on
small intestinal transit and gastric emptying in diabetic mice.
Normal control(Citrate buffer) Diabetic control (STZ 100 mg/kg) 76.90±6.12 * 55.23±9.30 * Insulin (2 IU/kg s.c.) 61.05±3.85 a 95.87±2.41 *a Metoclopramide (20 mg/kg p.o.) 50.04±2.42 ab 76.38±7.67 ab Insulin (2 IU/kg s.c.)+Metoclopramide (20 mg/kg p.o) 54.30±3.46 a 94.91±1.01 *a Domperidone (20 mg/kg p.o.) 48.70±4.53 ab 90.92±4.92 *a Insulin (2 IU/kg s.c.)+Domperidone (20 mg/kg p.o) 62.60±3.07 a 92.87±1.14 *a Erythromycin (6 mg/kg p.o.) 43.05±3.50 ab 84.77±2.11 a Insulin (2 IU/kg s.c.)+Erythromycin (6 mg/kg p.o) 49.14±4.57 ab 90.86±3.20 *a Values represent the mean±SE. of eight mice per group; * Significantly different from the normal control value at P<0.05; a Significantly different Blood glucose level (mg/dL) from the diabetic control value at P<0.05. b Significantly different from insulin value at P<0.05.
30-' 0' 30' 60' 120' 240' Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) Insulin (2 IU/kg sc) Δ Metoclopramide (20 mg/kg po) Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) Domperidone (20 mg/kg po) Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Erythromycin (6 mg/kg po) Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) Figure 6 Effect of a single dose of insulin, metoclopramide, domperidone
and erythromycin individually as well as the combination of insulin with
Serum insulin level (% of diabetic control) metoclopramide, domperidone or erythromycin on oral d-glucose tolerance test in STZ-induced diabetic mice. Values represent the mean±s.e.m. of Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) eight mice per group. * Significantly different from the normal control Insulin (2 IU/kg sc) Metoclopramide (20 mg/kg po) value at P<0.05. a Significantly different from the diabetic control value at Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) P<0.05. b Significantly different from insulin value at P<0.05. Domperidone (20 mg/kg po) Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Erythromycin (6 mg/kg po) diabetic mice demonstrated basal hyperglycemia (399±14 mg/dL) Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) which remained above 400 mg/dL during all time points determined. Figure 5 Effect of a single dose of insulin, metoclopramide, domperidone
The peak increase in serum glucose concentrations in diabetic mice and erythromycin individually as well as the combination of insulin was observed after 60 min of glucose treatment, while that of normal with metoclopramide, domperidone or erythromycin on oral d-xylose mice observed after glucose loading, indicating delayed glucose absorption test in STZ-induced diabetic mice. Values represent the mean homeostasis in diabetic mice. STZ significantly (p<0.05) increased ± s.e.m. of eight mice per group. * Significantly different from the normal the area under the curve (Figure 7). Insulin at dose (2 IU/kg) control value at P<0.05. a Significantly different from the diabetic control significantly (p<0.05) decrease blood glucose level to 107.16±8.51 value at P<0.05. b Significantly different from insulin value at P<0.05. mg/dl and 100 mg/dL after 30 min and 60 min of glucose loading resp. and the effects persisted till 120 min (Figure 6). The area under Oral d-xylose absorption test
the curve was significantly reduced to 226.53±12.28 mg/dL. 120 min The normal control value of serum d-xylose concentration was 1.63 (Figure 7). Metoclopramide at dose (20mg/kg) did not affect blood ±0.10 mg/mL after 60 min of d-xylose administration (0.8 g/kg).
glucose level where BGL was 487.5±13.6 mg/dL and 505.5±14.55 The amount of xylose absorbed from the GIT significantly (p<0.05) mg/dL after 30 min and 60 min of glucose loading respectively. decreased in the diabetic mice to 0.606±0.03 mg/mL as compared to While domperidone at dose 20 mg/kg and erythromycin at dose 6 normal control group. Insulin (2 IU/kg), metoclopramide (20 mg/kg), mg/kg produced significant (p<0.05) increase in blood glucose level domperidone (20 mg/kg) and erythromycin (6 mg/kg) in the doses reach to 590±13 mg/dL, 590.8±17.4 mg/dL and 622±23.11 mg/dL, employed individually increased xylose absorption to 1.64±0.16 mg/ 631.5±21.48 mg/dL after 30 min and 60 min of glucose loading ml, 0.989±0.03 mg/mL, 1.162±0.03 mg/mL and 1.469±0.03 mg/mL respectively (Figure 6). In addition, domperidone and erythromycin respectively. Administration of prokinetic drugs i.e. metoclopramide, significantly (p<0.05) increased the area under the curve (Figure 7). domperidone or erythromycin along with insulin antagonized the Administration of metoclopramide, domperidone or erythromycin action of insulin (2 IU/kg) on xylose absorption (Figure 5). There is along with insulin significantly (p<0.05) increases blood glucose antagonism between insulin and the test prokinetic drugs on xylose level as compared to insulin treated value (Figure 6). Combination absorption in diabetic mice.
of insulin with metoclopramide, domperidone or erythromycin significantly (p<0.05) increased the area under the curve as compared Oral d-glucose tolerance test
to insulin treated value (Figure 7). The oral glucose tolerance test (OGTT) can be used to evaluate blood glucose homeostasis and also indirectly evaluate glucose absorption. As shown in figure 6, glucose load (2.5 gm/kg) in normal mice produced rapid increase in blood glucose levels at 30min and Findings of the present investigation revealed that STZ-induced returned to baseline values within 120 min. In contrast, STZ-induced diabetes resulted in a significant increase in small intestinal transit 2013 ACT. All rights reserved.
Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice transporter SGLT1[42]. In the present study, STZ-induced diabetic mice demonstrated basal hyperglycemia which remained above 400 mg/dL during all time points determined. The capacity of the small intestine to absorb glucose increases in experimentally induced diabetic animals as a consequence of the enhanced activity and abundance of SGLT1 as shown by Fedorak et al[43] suggesting SGLT1 as a potential target for glycemic control in diabetic animals. STZ- induced diabetic mice exhibited severe hyperglycemia with increased Na+ dependent glucose uptake activity compared with normal AUC (mg/dL.120 min) 400 mice[44]. Acute effect of insulin induced hypoglycemia increased xylose absorption and glucose absorption from the GIT in the diabetic mice. In the present study, the effects of insulin on the intestinal absorption of sugar did not differentiate between an effect of insulin Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) on the absorption capacity of the mucosa and other factors that may Insulin (2 IU/kg s.c.) Metoclopramide (20 mg/kg po) affect total sugar absorption. Some studies have shown that the effect Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) of insulin leads to increase Na+ dependent glucose carrier activity Domperidone (20 mg/kg po) in the small intestine, which leads to increase glucose absorption[45]. Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Some studies reported that insulin induced hypoglycemia accelerates Erythromycin (6 mg/kg po) gastric empting in type 1 diabetes[37], which decrease time of Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) movement of sugar from stomach to the small intestine, in addition to Figure 7 Effect of a single dose of insulin, metoclopramide, domperidone
its therapeutic effect by decreases the rate of glucose production and and erythromycin individually as well as the combination of insulin with increases the rate of glucose utilization by cells[46].
metoclopramide, domperidone or erythromycin on the area under the curve of blood glucose concentrations during oral glucose absorption test By studying the prokinetic drugs in the current study individually, in STZ-induced diabetic mice. Values represent the mean±s.e.m. of eight domperidone (20 mg/kg po) was found to be the most effective mice per group. * Significantly different from the normal control value at prokinetic agent in the diabetic mice when compared to diabetic P<0.05. a Significantly different from the diabetic control value at P<0.05. control group as well as the other prokinetic drugs. Domperidone, b Significantly different from insulin value at P<0.05.
metoclopramide and erythromycin significantly (p<0.05) decreased small intestine transit and accelerated gastric emptying in STZ- and significant decrease in gastric emptying. Abnormalities in gastric induced diabetic mice. Similar results have been reported by recent emptying and small intestinal motor functions were also reported in studies[47,48,49,50,51]. The inhibitory effect of domperidone on small diabetic mice[27,28]. The mechanism of action of increased intestinal intestinal transit is probably mediated via its action on dopamine transit may be, partially, due to increased cholinergic and decreased since it is dopamine antagonist[52]. Dopamine has an indirect beta-adrenergic receptor activities in diabetic animals[29]. The delay inhibitory effect via inhibition of cholinergic transmission in the in gastric emptying could be partially attributed to the decrease myenteric plexus, which regulates the gastrointestinal tract[53]. It in the number of myenteric neurons in stomach as a result of could be suggested that metoclopramide produced its action through diabetes[30,31,32]. Similarly, the increased in intestinal transit could be inhibition of presynaptic and postsynaptic D2 receptors, stimulation mediated through the same mechanism. All of the stomach's smooth of presynaptic excitatory 5-HT4 receptors and/or antagonism of muscle cells have the ability to produce electric depolarizations presynaptic inhibition of muscarinic receptors. The aforementioned "slow waves" from resting potential. These rhythmic contractions are in accordance with that given by Valenzuela et al[54]. The action of are thought to originate in the non-smooth muscle pacer cells in the erythromycin is probably mediated via its agonistic activity to motilin interstitial cells of Cajal[33]. Gastric emptying is delayed because the receptors, which accelerates gastric emptying[8,33].
number of gastric interstitial cells (ICCs) is markedly diminished Metoclopramide significantly increased xylose absorption but in diabetes[34]. Data of the current study showed that insulin induce did not affect glucose absorption in STZ-induced diabetes. These hypoglycemia significantly attenuated small intestinal transit and finding is in harmony with that given by Paul et al[55]. The action of accelerated gastric emptying in diabetic mice. These results are metoclopramide is mediated via increased plasma concentrations partly in agreement with earlier reports[35,36,37,38]. The mechanism of of glucagon like peptide-1 and glucose dependant insulinotropic action of the obtained results might be due to direct effect of insulin polypeptide, which responsible for delay in glucose absorption, this and not only due to antidiabetic effect of insulin that decreased blood action did not affect rate of xylose absorption. Domperidone (20 glucose level leading to decrease SIT. This effect could be due to mg/kg) and erythromycin (6 mg/kg p.o.) significantly increased counter-regulation of hypoglycemia. The mechanisms of insulin on xylose absorption and glucose absorption in the diabetic mice as stomach could be mediated via insulin stimulant effect on the vagus compared to diabetic control group. The effect of erythromycin could nerve as reported by Quigley et al[39].
be mediated through the action of erythromycin on motilin receptors Data of the present investigation showed that STZ-induced in the GIT. The action of erythromycin is probably mediated via diabetes resulted in a significant decrease in xylose absorption. its agonistic activity to motilin receptors, which accelerates gastric This result is in agreement with Fuessl[40]. The decrease in xylose emptying and increases the rate of sugars absorption.
absorption could be mediated via decreasing the rate of gastric Combination of domperidone (20 mg/kg), metoclopramide (20 emptying which resulted from elevation in BGL as reported by the mg/kg) or erythromycin (6 mg/kg) with insulin (2 IU/kg) decreased present study. This explanation coincides with that given by Rayner the amount of xylose absorbed from the GIT as compared to insulin et al[9] and Marianne et al[41].
given alone in the diabetic mice which indicates antagonistic Recent studies have shown that modifications of systemic interaction between each two drugs on xylose absorption. It is glycemia in OGTT reflect the activity of the intestinal glucose difficult to satisfactory explain this action on the bases of the few 2013 ACT. All rights reserved.
Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice lectures available on the two drugs in this respect. Combination REFERENCES
of insulin with metoclopramide, domperidone or erythromycin increased glucose absorption from the intestine as compared to the 1 Maleki D, Locke GR III, Camilleri M, Zinsmeister AR, Yawn BP, Leibson C, Melton LJ III. Gastrointestinal tract symp- effect of insulin alone in the diabetic mice. These results suggest toms among persons with diabetes mellitus in the commu- that combination of prokinetics with insulin may lead to increase nity. Arch Intern Med 2000; 160: 2808-2816
Na+ dependent glucose carrier activity in the small intestine. In Bytzer P, Talley NJ, Leemon M, Young LJ, Jones MP, addition to treating symptoms, prokinetic drugs could potentially Horowitz M. Prevalence of gastrointestinal symptoms asso- improve glycemic control in diabetic gastroparesis by allowing a ciated with diabetes mellitus: a population-based survey of more predictable absorption of nutrients, matched to the action of 15,000 adults. Arch Intern Med 2001; 161: 1989-1996
exogenous insulin.
Talley NJ, Bytzer P, Hammer J, Young L, Jones M, Horow- The present study warned about the possibility that prokinetics may itz M. Psychological distress is linked to gastrointestinal increase the hypoglycemic effect of insulin. Erythromycin tended to symptoms in diabetes mellitus. Am J Gastroenterol 2001; 96:
decrease blood glucose level and increase serum insulin level after one week of daily dose administration in STZ-induced diabetic mice. Perusicová J .Gastrointestinal complications in diabetes mel- litus. Vnitr Lek 2004; 50: 338-343
Erythromycin in the dose of 6 mg/kg p.o. potentiated the effect of Jones KL, Russo A, Berry MK, Stevens JE, Wishart JM, insulin on blood glucose and serum insulin levels after one week of Horowitz M. A longitudinal study of gastric emptying and daily dose administration in diabetic mice where other prokinetic upper gastrointestinal symptoms in patients with diabetes agents failed to do so after repeated dose administration in diabetic mellitus. Am J Med 2002; 113: 449-455
mice. Similar results have been reported by Ueno et al[56]. The action Camilleri M, Bharucha AE, Farrugia G.Epidemiology, of erythromycin on insulin could be mediated via its action as a mechanisms, and management of diabetic gastroparesis. motilin agonist. It is to be noted that motilin controls cyclic release of Clin Gastroenterol Hepatol 2011;9: 5-12
insulin through vagal cholinergic muscarinic pathways as reported by Tamhane MD, Thorat SP, Rege NN, Dahanukar SA. Effect Suzuki et al[57]. Itoh et al[58] found that there are no motilin receptors of oral administration of Terminalia chebula on gastric emp- in the pancreas. Therefore, the action of erythromycin on insulin tying: an experimental study. J Postgrad Med 1997; 43: 12-3
secretion is probably mediated via vagal-cholinergic muscarinic Janssens J, Peeters TL, Vantrappen G, Tack J, Urbain JL, De Roo M, Muls E, Bouillon R. Improvement of gastric empty- pathways stimulation linking to serotonergic receptors, a common ing in diabetic gastroparesis by erythromycin. Preliminary mechanism in the stimulatory effect of motilin on muscle contraction studies. N Engl J Med 1990; 322: 1028-1031
in the stomach and on pancreatic polypeptide secretion from the Rayner CK, Samsom M, Jones KL, Horowitz M. Relation- ships of upper gastrointestinal motor and sensory function The action of erythromycin on gastrointestinal motility in with glycemic control. Diabetes Care 2001; 24: 371-381
the present study is on discrepancy to some studies which state 10 Peddyreddy M, Steven A, Ramaswamy S. An inherent ac- that motilin receptors do not exist in rodents. They only exist as celeratory effect of insulin on small intestinal transit and its pseudogenes[61,62]. However, the present results are in agreement with pharmacological characterization in normal mice. World J other studies[63,64,65]. It is suggested that the action of erythromycin Gastroenterol 2006; 12: 2593-2600
is mediated by binding to central motilin receptors which might be 11 Harrington RA, Hamilton CW, Brogden RN, Linkewich JA, involved in regulation of gastric motility in diabetic rats. Romankiewicz JA, Heel RC. Metoclopramide. An updated This study dealt with an important issue concerning the use of review of its pharmacological properties and clinical use. Drugs 1983; 25:451-94 prokinetics in insulin-treated diabetic individuals. Not all diabetic 12 Suchitra, Dkhar SA, Shewade DG, Shashindran CH. Rela- patients develop gastrointestinal motility disorders or gastroparesis, tive efficacy of some prokinetic drugs in morphine-induced but the use of prokinetics might be also interesting in these patients. gastrointestinal transit delay in mice. World J Gastroenterol Erythromycin potentiates the effect of insulin given on blood glucose 2003; 9: 779-783
level and serum insulin level after repeated dose administration in 13 Kondo Y, Nakatani A, Naruse A. New model of progressive diabetic mice. It seems to suggest that the use of prokinetics i.e. non-insulin-dependent diabetes mellitus in mice induced by erythromycin might be interesting in the clinic in order to decrease streptozotocin. Biol Pharm Bull 1999; 22: 988-9
the need of insulin. 14 Niu Y, Liang S, Wang X. Abnormal change in body weight In conclusion, combination of insulin with metoclopramide, and non-fasting blood glucose levels of mouse strain domperidone or erythromycin increases glucose absorption. And this C57BL/6J in generating type 2 diabetes model. Zool Res leads to suggestion that this prokinetic may guard against the risk 2007; 28: 507-510
15 Sivaraj, Devi K, Palani S, Vinoth kP, Senthil kB, David E. of sever hypoglycemia associated with diabetic mice treated with Anti-hyperglycemic and anti-hyperlipidemic effect of com- insulin. The present study suggests that the use of prokinetics i.e. bined plant extract of Cassia auriculata and Aegle marmelos erythromycin may be interesting in the clinic in order to decrease in streptozotocin (STZ) induced diabetic albino rats. Int J of the need for insulin in diabetic patients. The dose of insulin may be PharmTech Res 2009; 1: 1010-1016
safely decreased with erythromycin in chronic treatments.
16 Sarac, Arthur WZ, Lindberg I. The lethal Form of cushing' s in 7B2 null mice Is caused by multiple metabolic and hor- monal abnormalities. Endocrinology 2002; 143: 2324-2332
17 Alexander V, Orna G, Sylvia B, Yariv S, Shai E. Application Mohamed A. Fouad Shalaby designed the study and wrote the of muscle biopotential measurement for sustained, noninva- manuscript and performed all of experiments; Hekma A Abd El sive blood glucose survey. J Appl Physi 2009; 107: 253-260
latif and Mostafa E El Sayed involved in editing the manuscript. 18 Cocchetto DM, Bjornsson TD. Methods for vascular access Supported by pharmacology department, kahira pharmaceutical and collection of body fluids from the laboratory rat. J of company and pharmacology and Toxicology department, faculty of Pharm Sci 1983; 72: 465–492
pharmacy, Cairo University, Egypt.
19. Trinder P. Determination of glucose in blood using glucose 2013 ACT. All rights reserved.
Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice oxidase with an alternative oxygen acceptor. Ann Clin Bio- chael H, Karen L. Insulin-Induced hypoglycemia accelerates chem 1969; 6: 24-25
gastric emptying of solids and liquids in long-standing type 20 Mullner, Neubauer H, Konig W. A radioimmunoassay for 1 diabetes. J of Clin Endo & Meta 2005; 90: 4489-4495
the determination of insulin from several animal species, in- 38 Peddyreddy M. The relationship among glycemic, small sulin derivatives and insulin precursors in both their native intestinal transit and insulinemic states in normal mice. Iran and denatured state. J Immunol Methods 1991; 140: 211-218
J of Pharma & Therap 2006; 5: 121-126
21 Leng-Peschlow E. Acceleration of large intestine transit time 39 Quigley JP, Templeton RD. Action of insulin on motility of in rats by sennosides and related compounds. J pharm phar- the gastro-intestinal tract. IV. Action on the stomach follow- macology 1986; 38: 369-373
ing double vagotomy. Am J Physiol 1930; 91: 482-490
22 Brighton SW, Dormehl IC, Pleussis DU, Maree M. The ef- 40 Füessl HS. Delaying carbohydrate absorption in noninsu- fect of an oral gold preparation on the gastrointestinal tract lin-dependent diabetes mellitus: useful therapy? Klin Wo- motility in two species of experimental animals. J pharmaco chenschr 1987; 65: 395-399
Meth 1987; 17: 185-188
41 Marianne JC, Robert JL Fraser, Geoffrey M, Antonietta R, 23 Ijaz MK, Sabara MI, Frenchick PJ, Babiuk LA. Assessment of Max B, Laura K Besanko, Karen L Jones, Ross B, Barry C, intestinal damage in rotavirus infected neonatal mice by a Michael Horowitz. Glucose absorption and gastric empty- D-xylose absorption test. J of Virol Meth 1987; 18: 153-157
ing in critical illness. Crit Care 2009; 13: R140
24 Francesco R, Antonello F, David E, Michel V, Donatella G, 42 Ducroc R., Voisin T., El Firar A., Laburthe M. Orexins Geltrude M, et al. The mechanism of diabetes control after control intestinal glucose transport by distinct neuronal, gastrointestinal bypass surgery reveals a role of the proxi- endocrine, and direct epithelial pathways. Diabetes 2007; 56:
mal small intestine in the pathophysiology of type 2 diabe- tes. Ann Surg 2006; 244: 741-49
43 Fedorak R, Cheeseman C, Thomson A, Porter V.M. Altered 25 Stûmpel F, Burcelin R, Jungermann K, Thorens B. Normal glucose carrier expression: mechanism of intestinal adapta- kinetics of intestinal glucose absorption in the absence of tion during streptozocin-induced diabetes in rats. American GLUT2: Evidence for a transport pathway requiring glucose Journal of Physiology 1991; 261:G585–G591 phosphorylation and transfer into the endoplasmic reticu- 44 Hye Kyung Kim. Ecklonia cava Inhibits Glucose Absorption lum. Proc Natl Acad Sci U S A 2001; 98: 11330-11335
and Stimulates Insulin Secretion in Streptozotocin-Induced 26 Sachin LB, Naimesh MP, Prasad AT, Subhash LB. Interac- Diabetic Mice. Evidence-Based Complementary and Alternative tion of aqueous extract of pleurotus pulmonarius (Fr.) quel- Medicine 2012; 2012: 439294
champ. with glyburide in alloxan induced diabetic mice. 45 Banerjee, Raja K, and Peters TJ. Effect of insulin induced Evid Based Complement Alternat Med 2008; 5: 159-164
hypoglycaemia on in vitro uptake of 3-O-methylglucose by 27 Christopher KR, Michael H. Gastrointestinal motility and rat jejunum. Gut 1989; 30: 1348–1353
glycemic control in diabetes: the chicken and the egg revis- 46 Bergman, E. N., Brockman RP, and Kaufman CF. Glucose ited? J clin Invest 2006; 116: 299-302
metabolism in ruminants: comparison of whole body turn- 28 Wen-Cai Q, Zhi-Gang W, Ran L, Wei-Gang W, Xiao-Dong H, over with production by the gut, liver and kidneys. Fed. Jun Y, et al. Ghrelin improves delayed gastrointestinal tran- Proc 1974; 33: 1849-1854
sit in alloxan-induced diabetic mice. World J Gastroenterol 47 Patterson D, Abell T, Rothstein R, Koch K, Barnett. A 2008; 14: 2572-2577
double-blind multicenter comparison of domperidone 29 Anjaneyulu M, Ramarao P. Studies on gastrointestinal tract- and metoclopramide in the treatment of diabetic patients functional changes in diabetic animals. Methods Find Exp with symptoms of gastroparesis. J Am J Gastroenterol 1999; Clin Pharmacology 2002; 24: 71-75
94:1230-4
30 Fregonesi CE, Miranda-Neto MH, Molinari SL, Zanoni JL. 48 Walter E. Longo, Vernava AM . Prokinetic agents for lower Quantitative study of the myenteric plexus of the stomach gastrointestinal motility disorders. Dis Colon Rectum 1993; of rats with streptozotocin-induced diabetes. Arq Neurop- 36: 696-708
siquiatr 2001; 59: 50-53
49 Kishibayashi N, Karasawa A. Stimulating effects of KW- 31 Cai F, Helke CJ. Abnormal PI3 kinase/Akt signal pathway 5092, a novel gastroprokinetic agent, on the gastric empty- in vagal afferent neurons and vagus nerve of streptozotocin- ing, small intestinal propulsion and colonic propulsion in diabetic rats. Brain Res Mol Brain Res 2003; 110: 234-244
rats. Jpn J Pharmacol 1995; 67:45-50
32 Anitha M, Gondha C, Sutliff R, Parsadanian A, Mwangi S, 50 Peeters TL. The potentials of erythromycin derivatives in Sitaraman SV, Srinivasan S. GDNF rescues hyperglycemia- the treatment of gastrointestinal motility disorders. Z Gesa- induced diabetic enteric neuropathy through activation of mte Inn Med 1991; 46: 349-354
the PI3K/Akt pathway. J Clin Invest 2006; 116: 344-356
51 Allen L, Braden K. Metoclopramide in the treatment of dia- 33 Parkman, Pagano AP, Vozzelli MA, Ryan JP. Gastrokinetic betic gastroparesis. Expert Rev Endocrinol Metab 2010; 5: 653-
effects of erythromycin: myogenic and neurogenic mecha- nisms of action in rabbit stomach. Gastrointestinal & Liver 52 Levant B, Grigoriadis DE, De Souza EB. Relative affinities Physiology 1995; 269: 418-426
of dopaminergic drugs at dopamine D2 and D3 receptors. 34 Ordog T, Takayama I, Cheung WK, Ward SM, Sanders KM. Eur J Pharmacol 1995; 278: 243-247
Remodeling of networks of interstitial cells of Cajal in a 53 Tonini M, Cippollina L, Poluzzi E et al. Clinical implications murine model of diabetic gastroparesis. Diabetes 2000; 49:
of enteric and central D2 receptor blockade by antidopami- nergic gastrointestinal prokinetics. Aliment Pharmacol Ther 35 Schapiro H, Woodward ER. The action of insulin hypogly- 2004; 18: 379-390
cemia on the motility of the human gastrointestinal tract. 54 Valenzuela JE, Dooley CP. Dopamine antagonists in the Am J Dig Dis 1959; 4: 787–791
upper gastrointestinal tract. Scand J Gastroenterol Suppl 1984; 36 Schvarcz E, Palmer M, Aman J, Lindkvist B, Beckman KW. 96: 127-136
Hypoglycaemia increases the gastric emptying rate in 55 Paul K, Max B, Judith W, André JS, Richard HH, Robert JL patients with type 1 diabetes mellitus. Diab Med 1993; 10:
Fraser, et al. Effects of metoclopramide on duodenal motil- ity and flow events, glucose absorption, and incretin hor- 37 Antonietta R, Julie ES, Richard C, Diana G, Richard B, Mi- mone release in response to intraduodenal glucose infusion. 2013 ACT. All rights reserved.
Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice Am J Physiol Gastrointest Liver Physiol 2010; 299:G1326-G33
and its specific receptor genes in rodents. J Mol Endocrinol 56 Ueno N, Inui A, Asakawa A, Takao F, Tani S, Komatsu Y, 2010; 44: 37-44
Itoh Z, Kasuga M. Erythromycin improves glycaemic con- 62 Sanger GJ, Holbrook JD, Andrews PL. The translational trol in patients with Type II diabetes mellitus. Diabetologia value of rodent gastrointestinal functions: a cautionary tale. 2000; 43: 411-415
Trends Pharmacol. Sci 2011; 32: 402-409
57 Suzuki H, Mochiki E, Haga N, Satoh M, Mizumoto A, Itoh Z. 63 Asakawa A, Inui A, Ueno N, Makino S, Uemoto M, Fujino Motilin controls cyclic release of insulin through vagal cho- MA, et al. Ob/ob mice as a model of delayed gastric empty- linergic muscarinic pathways in fasted dogs. Am J Physiol ing. J Diab & its Complications 2003; 17: 27-28
1998; 274: G87-G95
64 Xin F, Theo LP, Ming T. Motilin activates neurons in the rat 58 Itoh Z. Motilin and clinical application. Peptides 1997; 18:
amygdala and increases gastric motility. Peptides 2007; 28:
59 Mochiki E, Inui A, Satoh M, Mizumoto A, Itoh Z. Motilin is 65 Yun-Dan J, Chang-Qin L, Ming T, Zheng-Yao J. Expression a biosignal controlling the cyclic release of pancreatic poly- of motilin in the hypothalamus and the effect of central peptide via the vagus in fasted dogs. Am J Physiol 1997; 272:
erythromycin on gastric motility in diabetic rats. Neurosci- ence Bulletin 2007; 23: 75-82
60 Shiba Y, Mizumoto A, Satoh M, Inui A, Itoh Z, Omura S. Ef- fect of nonpeptide motilin agonist EM523 on release of gut Peer reviewer: Sanda M. Cretoiu, MD, PhD, Division of Cellular
and pancreatic hormones in conscious dogs. Gastroenterology and Molecular Medicine, Department of Morphological Sciences, 1996; 110: 241-50
Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari 61 He J, Irwin DM, Chen R, Zhang YP. Stepwise loss of motilin Blvd., Bucharest 050474, Romania.
2013 ACT. All rights reserved.

Source: http://ghrnet.org/index.php/joghr/article/download/332/191

Guía de práctica clínica no ges para el tratamiento de adolescentes de 10 a 14 años, 2013

Guía de Práctica Clínica No GES para el Tratamiento de Adolescentes de 10 a 14 años, 2013 Ministerio de Salud. Guía Clínica para el Tratamiento de Adolescentes de 10 a 14 años con Depresión. Santiago: MINSAL, 2013. Todos los derechos reservados. Este material puede ser reproducido total o parcialmente para fines de diseminación y capacitación. Prohibida su venta.

Racemic drugs

RACEMIC DRUGS AND ENANTIOMERS Identifying the really useful innovations Many drugs are available as racemic mixtures or 50:50 mixtures of two molecules (enantiomers) that are different merely by one being the non- superimposable mirror image of the other. There are normally two classifications used for en- antiomers: the first one distinguishes the two

Copyright © 2008-2016 No Medical Care