Hani Al-Salami

Inflammatory bowel disease: clinical aspects and treatments

Inflammatory bowel disease (IBD) is defined as a chronic intestinal inflammation that results from host-microbial interactions in a genetically susceptible individual. IBDs are a group of autoimmune diseases that are characterized by inflammation of both the small and large intestine, in which elements of the digestive system are attacked by the body’s own immune system. This inflammatory condition encompasses two major forms, known as Crohn’s disease and ulcerative colitis. Patients affected by these diseases experience abdominal symptoms, including diarrhea, abdominal pain, bloody stools, and vomiting. Moreover, defects in intestinal epithelial barrier function have been observed in a number of patients affected by IBD. In this review, we first describe the types and symptoms of IBD and investigate the role that the epithelial barrier plays in the pathophysiology of IBD as well as the major cytokines involved. We then discuss steps used to diagnose this disease and the treatment options available, and finally provide an overview of the recent research that aims to develop new therapies for such chronic disorders.

Probiotic treatment reduces blood glucose levels and increases systemic absorption of gliclazide in diabetic rats.

SummaryThe action of gliclazide, a sulphonylurea with beneficial extrapancreatic effects in diabetes, may be enhanced by administering probiotics. The aim of this study was to investigate the influence of probiotics on gliclazide pharmacokinetics and the effect of both probiotics and gliclazide on blood glucose levels in healthy and diabetic rats. Male Wistar rats (2 to 3 months, weight 350 ± 50 g) were randomly allocated to 4 groups (n =10), two of which were treated with alloxan i.v. 30 mg/kg to induce diabetes. One group of healthy and one group of diabetic rats were then gavaged with probiotics (75 mg/kg) for three days after which a gliclazide suspension (20 mg/kg) was administered by gavage to all groups. Blood samples were collected from the tail vein at various time points for 10 hours post-administration for the determination of blood glucose and gliclazide serum concentrations. It was found that probiotic treatment had no effect on blood glucose levels in healthy rats, but it reduced them (up to 2-fold;p < 0.01) in diabetic rats. Probiotic treatment reduced gliclazide bioavailability in healthy rats (3-fold) whereas it increased gliclazide bioavailability in diabetic rats (2-fold;p < 0.01). Gliclazide had no effect on blood glucose levels in either healthy or diabetic rats despite the changes in its bioavailability. In conclusion, the probiotic treatment of diabetic rats increases gliclazide bioavailability and lowers blood glucose levels by insulin-independent mechanisms, suggesting that the administration of probiotics may be beneficial as adjunct therapy in the treatment of diabetes.

Influence of the semisynthetic bile acid MKC on the ileal permeation of gliclazide in vitro in healthy and diabetic rats treated with probiotics.

The aim of this study was to investigate the influence of sodium 3alpha,7alpha-dihydroxy-12-keto-5beta-cholanate (MKC) on the ileal permeation of gliclazide in healthy and diabetic rats treated with probiotics. Male Wistar rats (2-3 months, 350 +/- 50 g) were randomly allocated into four groups (n = 32); Groups 1 and 2 were healthy controls and Groups 3 and 4 were diabetic rats (alloxan 30 mg/kg was administered i.v.), which were administered probiotics for three days after the rats became diabetics. The rats were sacrificed and tissues were mounted on Ussing chambers. Then, gliclazide (200 microg/ml) was added to all the groups, while MKC (50 microg/ml) was given to Groups 2 and 4, for the measurement of the mucosal to serosal absorption Jss(MtoS) and serosal to mucosal secretion Jss(StoM) of gliclazide. In the tissues of healthy rats treated with probiotics, MKC stimulated the net absorption of gliclazide by stimulating the absorptive and reducing the secretory unidirectional fluxes, while in tissues from diabetic rats treated with probiotics, MKC had no effect. In healthy rats treated with probiotics, the degradation of MKC by bacterial polypeptides produced divalent bile salts that inhibited Mrp2, which resulted in reducing secretion and stimulating the absorption of gliclazide. In contrast, in diabetic rats treated with probiotics, MKC had no effect possibly due to a difference in the metabolic profile and resulting in no net flux.

Probiotic Pre-treatment Reduces Gliclazide Permeation (ex vivo) in Healthy Rats but Increases It in Diabetic Rats to the Level Seen in Untreated Healthy Rats

Aim To investigate the influence of probiotic pre-treatment on the permeation of the antidiabetic drug gliclazide in healthy and diabetic rats. Methods Wistar rats (age 2–3 months, weight 350 ± 50 g) were randomly allocated into one of 4 groups (N = 16 each group): healthy control, healthy probiotic, diabetic control, and diabetic probiotic. Probiotics (75 mg/kg, equal quantities of Lactobacillus acidophilus, Bifidobacterium lactis, and Lactobacillus rhamnosus) were administered twice a day for three days to the appropriate groups after diabetes had been induced with alloxan i.v. 30 mg/kg. Rats were sacrificed, ileal tissues mounted in Ussing chambers and gliclazide (200 µg/mL) was administered for the measurement of the mucosal to serosal absorption Jss(MtoS) and serosal to mucosal secretion Jss(StoM) of gliclazide. Results Treatment of healthy rats with probiotics reduced Jss(MtoS) of gliclazide from 1.2 ± 0.3 to 0.3 ± 0.1 µg/min/cm2 (P < 0.01) and increased Jss(StoM)from 0.6 ± 0.1 to 1.4 ± 0.3 (P < 0.01) resulting in net secretion while, in diabetic tissues, treatment with probiotics increased both Jss(MtoS) and Jss(StoM)fluxes of gliclazide to the comparable levels of healthy tissues resulting in net absorption. Discussion In healthy rats, the reduction in Jss(MtoS) after probiotics administration could be explained by the production of bacterial metabolites that upregulate the mucosal efflux drug transporters Mrp2 that control gliclazide transport. In diabetic rats, the restored fluxes of gliclazide after probiotic treatment, suggests the normalization of the functionality of the drug transporters resulting in a net absorption. Conclusion Probiotics may alter gliclazide transport across rat ileal tissue studied ex vivo.

Gliclazide reduces MKC intestinal transport in healthy but not diabetic rats

SummaryThe aim is to investigate the influence of the antidiabetic drug gliclazide on the ileal permeation of the semisynthetic bile acid, MKC, in tissues from healthy and diabetic rats. Sixteen Wistar rats (350±50 g) were randomly allocated into four groups (4 rats per group, 8 chambers per rat i.e. n=32) two of which were made diabetic (given alloxan i.v.30 mg/kg). Group 1 was used to measure the permeation of MKC (50 μg/ml) alone (control) while group 2 to measure MKC permeation in the presence of gliclazide (200μg/ml). The diabetic groups 3 (gliclazide) and 4 (MKC+gliclazide) were treated in the same way. Rats were sacrificed and tissues were mounted into the Ussing chamber for the measurement of MKC mucosal to serosal (absorptive) and serosal to mucosal (secretory) fluxes. In healthy tissues, gliclazide reduced MKC absorptive flux (p<0.01) and increased its secretory flux (p<0.01). In diabetic tissues, gliclazide had no effect on either the absorptive or the secretory fluxes of MKC. The lack of effect of gliclazide on MKC permeation in diabetic tissues suggests the absence or suppressed drug transporters. Furthermore, gliclazide inhibition of MKC absorptive flux and induction of MKC secretory flux in healthy tissues may result from the selective inhibition of an efflux drug transporter.

The influence of 3α,7α-dihydroxy-12-keto-5β-cholanate on gliclazide pharmacokinetics and glucose levels in a rat model of diabetes

SummaryThe aim of this study was to investigate the pharmacokinetics and glucose-lowering activity of gliclazide alone and in combination with the bile acid salt, sodium 3α,7α-dihydroxy-12-keto-5β-cholanate (MKC), in a rat model of type I diabetes. Eighty male Wistar rats were divided into eight groups (n=10). Four groups were treated with alloxan (30 mg/kg) to induce diabetes. One group of healthy and one group of diabetic rats were administered gliclazide (20 mg/kg), MKC (4 mg/kg) or a combination of gliclazide (20 mg/kg) and MKC (4 mg/kg). One group of healthy and one group of diabetic rats were used as controls. Blood samples were collected from the tail vein 6 hours post-dose and the plasma was analyzed for glucose concentrations. It was found that gliclazide bioavailability was increased in healthy rats when coadministered with MKC, but there was no difference in glucose levels. Gliclazide bioavailability was much lower in diabetic rats and was not altered by MKC. However, the hypoglycemic effect of the combination of gliclazide and MKC was significantly greater in diabetic rats than that of gliclazide alone. It was demonstrated that the combination of MKC and gliclazide produced a significant hypoglycemic effect in a rat model of Type I diabetes. As gliclazide alone does not have a hypoglycemic effect on Type 1 diabetic rats, it can be concluded that gliclazide potentiates hypoglycemic effect of MKC in Type 1 diabetic rats.

Novel artificial cell microencapsulation of a complex gliclazide-deoxycholic bile acid formulation: a characterization study.

Gliclazide (G) is an antidiabetic drug commonly used in type 2 diabetes. It has extrapancreatic hypoglycemic effects, which makes it a good candidate in type 1 diabetes (T1D). In previous studies, we have shown that a gliclazide-bile acid mixture exerted a hypoglycemic effect in a rat model of T1D. We have also shown that a gliclazide-deoxycholic acid (G-DCA) mixture resulted in better G permeation in vivo, but did not produce a hypoglycemic effect. In this study, we aimed to develop a novel microencapsulated formulation of G-DCA with uniform structure, which has the potential to enhance G pharmacokinetic and pharmacodynamic effects in our rat model of T1D. We also aimed to examine the effect that DCA will have when formulated with our new G microcapsules, in terms of morphology, structure, and excipients’ compatibility. Microencapsulation was carried out using the Büchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G-SA (control) at a ratio of 1:30, and G-DCA-SA (test) at a ratio of 1:3:30. Complete characterization of microcapsules was carried out. The new G-DCA-SA formulation was further optimized by the addition of DCA, exhibiting pseudoplastic-thixotropic rheological characteristics. The size of microcapsules remained similar after DCA addition, and these microcapsules showed no chemical interactions between the excipients. This was supported further by the spectral and microscopy studies, suggesting microcapsule stability. The new microencapsulated formulation has good structural properties and may be useful for the oral delivery of G in T1D.

An advanced microencapsulated system: a platform for optimized oral delivery of antidiabetic drug-bile acid formulations

Abstract Introduction: In previous studies, we have shown that a gliclazide–cholic acid derivative (G–CA) mixture resulted in an enhanced ileal permeation of G (ex vivo). When administered orally to diabetic rats, it brought about a significant hypoglycaemic effect. In this study, we aim to create a novel microencapsulated-formulation of G–CA with uniform and coherent structure that can be further tested in our rat model of type 1 diabetes (T1D). We also aim to examine the effect of CA addition to G microcapsules in the morphology, structure and excipients’ compatibility of the newly designed microcapsules. Method: Microencapsulation was carried out using our Buchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G–SA (control) and G–CA–SA (test) at a constant ratio (1:3:30), respectively. Complete characterizations of microcapsules were carried out. Results: The new G–CA–SA formulation is further optimized by the addition of CA exhibiting pseudoplastic-thixotropic rheological characteristics. Bead size remains similar after CA addition, the new microcapsules show no chemical interactions between the excipients and this was supported further by the spectral studies suggesting bead stability. Conclusion: The new microencapsulated-formulation has good and uniform structural properties and may be suitable for oral delivery of antidiabetic-bile acid formulations.

Swelling, mechanical strength, and release properties of probucol microcapsules with and without a bile acid, and their potential oral delivery in diabetes

We have demonstrated a permeation-enhancing effect of deoxycholic acid (DCA), the bile acid, in diabetic rats. In this study, we designed DCA-based microcapsules for the oral delivery of the antilipidemic drug probucol (PB), which has potential antidiabetic effects. We aimed to further characterize these microcapsules and examine their pH-dependent release properties, as well as the effects of DCA on their stability and mechanical strength at various pH and temperature values. Using the polymer sodium alginate (SA), we prepared PB-SA (control) and PB-DCA-SA (test) microcapsules. The microcapsules were examined for drug content, size, surface composition, release, Micro-CT cross-sectional imaging, stability, Zeta potential, mechanical strength, and swelling characteristics at different pH and temperature values. The microencapsulation efficiency and production yield were also examined. The addition of DCA resulted in microcapsules with a greater density and with reduced swelling at a pH of 7.8 and at temperatures of 25°C and 37°C (p < 0.01). The size, surface composition, production yield, and microencapsulation efficiency of the microcapsules remained similar after DCA addition. PB-SA microcapsules produced multiphasic PB release, while PB-DCA-SA microcapsules produced monophasic PB release, suggesting more controlled PB release in the presence of DCA. The PB-DCA-SA microcapsules showed good stability and a pH-sensitive uniphasic release pattern, which may suggest potential applications in the oral delivery of PB in diabetes.

Microencapsulation as a novel delivery method for the potential antidiabetic drug, Probucol

Introduction In previous studies, we successfully designed complex multicompartmental microcapsules as a platform for the oral targeted delivery of lipophilic drugs in type 2 diabetes (T2D). Probucol (PB) is an antihyperlipidemic and antioxidant drug with the potential to show benefits in T2D. We aimed to create a novel microencapsulated formulation of PB and to examine the shape, size, and chemical, thermal, and rheological properties of these microcapsules in vitro. Method Microencapsulation was carried out using the Büchi-based microencapsulating system developed in our laboratory. Using the polymer, sodium alginate (SA), empty (control, SA) and loaded (test, PB-SA) microcapsules were prepared at a constant ratio (1:30). Complete characterizations of microcapsules, in terms of morphology, thermal profiles, dispersity, and spectral studies, were carried out in triplicate. Results PB-SA microcapsules displayed uniform and homogeneous characteristics with an average diameter of 1 mm. The microcapsules exhibited pseudoplastic-thixotropic characteristics and showed no chemical interactions between the ingredients. These data were further supported by differential scanning calorimetric analysis and Fourier transform infrared spectral studies, suggesting microcapsule stability. Conclusion The new PB-SA microcapsules have good structural properties and may be suitable for the oral delivery of PB in T2D. Further studies are required to examine the clinical efficacy and safety of PB in T2D.