Encapsulation of pharmaceuticals inside nanoporous materials is of increasing interest due to their possible applications as new generation therapeutics, theranostic platforms, or smart devices. Mesoporous silicas are leading materials to be used as nanohosts for pharmaceuticals. Further development of new generation of nanoscale therapeutics requires complete understanding of the complex host-guest interactions of organic molecules confined in nanosized chambers at different length scales. In this context, we present results showing control over formation and phase transition of nanosize crystals of model flexible pharmaceutical molecule tolbutamide confined inside 3.2 nm pores of the MCM-41 host. Using low loading levels (up to 30 wt %), we were able to stabilize the drug in highly dynamic amorphous/disordered state or direct the crystallization of the drug into highly metastable nanocrystalline form V of tolbutamide (at loading levels of 40 and 50 wt %), providing first experimental evidence for crystallization of pharmaceuticals inside the pores as narrow as 3.2 nm.

Shuanghuanglian Injection (SHLI), one of the most popular herbal prescription in China, has been commonly used to treat pneumonia, tonsillitis, and other respiratory diseases caused by bacterium and virus. This study is to investigate the effects of SHLI on the activities of Cytochrome P450 (CYP) 1A2, 2C11, 2D1 and 3A1/2 in rats. Sixteen rats were randomly divided into two groups (SHLI-treated and blank control). They were administered SHLI or physiological saline for consecutive seven days. On day eight, sixteen animals were administrated cocktail drugs as probe substrates of the four CYP in vivo. In addition, other four probe drugs were added respectively into incubation systems of rat liver microsomes to assess the effects of SHLI on the four CYP isoforms in vitro. SHLI exhibited an inductive effect on CYP2C11 in vivo by decreasing Cmax, t1/2 and AUC0-∞ of tolbutamide, while the main pharmacokinetic parameters of caffeine, metoprolol and dapsone have no significant changes. In vitro study, SHLI showed no significant effects on the activities of CYP1A2, 2D1 and 3A1/2, but increasing the metabolism of tolbutamide in rat liver microsomes (RLM). SHLI induced the activities of CYP2C11, but had no significant effects on the activities of CYP1A2, CYP2D1 and CYP3A1/2 in rats.

Secreted proteins are important metabolic regulators in both healthy and disease states. Here, we sought to investigate the mechanism by which the secreted protein complement-1q-like-3 (C1ql3) regulates insulin secretion from pancreatic β-cells, a key process affecting whole-body glucose metabolism. We found that C1ql3 predominantly inhibits exendin-4 and cAMP-stimulated insulin secretion from mouse and human islets. However, to a lesser extent, C1ql3 also reduced insulin secretion in response to KCl, the potassium channel blocker tolbutamide, and high glucose. Strikingly, C1ql3 did not affect insulin secretion stimulated by fatty acids, amino acids, or mitochondrial metabolites, either at low or submaximal glucose concentrations. Additionally, C1ql3 inhibited glucose-stimulated cAMP levels, and insulin secretion stimulated by exchange protein directly activated by cAMP-2 and protein kinase A. These results suggest that C1ql3 inhibits insulin secretion primarily by regulating cAMP signaling. The cell adhesion G protein-coupled receptor, brain angiogenesis inhibitor-3 (BAI3), is a C1ql3 receptor and is expressed in β-cells and in mouse and human islets, but its function in β-cells remained unknown. We found that siRNA-mediated BAI3 knockdown in INS1(832/13) cells increased glucose-stimulated insulin secretion. Furthermore, incubating the soluble C1ql3-binding fragment of the BAI3 protein completely blocked the inhibitory effects of C1ql3 on insulin secretion in response to cAMP. This suggests that BAI3 mediates the inhibitory effects of C1ql3 on insulin secretion from pancreatic β-cells. These findings demonstrate a novel regulatory mechanism by which C1ql3/BAI3 signaling causes an impairment of insulin secretion from β-cells, possibly contributing to the progression of type 2 diabetes in obesity.

Worldwide, aspirin and ibuprofen are the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs). Some adverse reactions, including gastrointestinal reactions, have been concerned extensively. Nevertheless, the mechanism of liver injury remains unclear. In the present study, we focused on the metabolism of liver cytochrome P450 (CYP450) and ultrastructural morphology of liver cells. A total of thirty rats were divided into three groups of 10. Rats in the aspirin and ibuprofen groups were given enteric-coated aspirin (15 mg/kg) and ibuprofen (15 mg/kg), respectively by gavage for four weeks. The body weights were recorded every two days. Liver function and metabolic capacity of CYP450 were studied on days 14 and 28. We then conducted ultrastructural examinations. Body weights in the Ibuprofen group were lower than those of the Control group, and ALT and AST levels were significantly higher (P < 0.05). There were no significant differences in terms of body weight, ALT or AST between the Aspirin and Control groups. The metabolic capacity of CYP450 was evaluated using five probe drugs, phenacetin, tolbutamide, metoprolol, midazolam, and bupropion. We found that ibuprofen and aspirin induced metabolism of the probe drugs. Moreover, according to the pharmacokinetic data, the Control, Aspirin and Ibuprofen groups could be discriminated accurately. Ultrastructural examination showed that the number of mitochondria was increased in both the Ibuprofen and Aspirin groups. Long-term administration of enteric-coated aspirin and ibuprofen induced the metabolic activity of the CYP450 enzyme. Aspirin had better tolerability than did ibuprofen, as reflected by pharmacokinetic data of probe drug metabolism.

We investigated the metabolic capabilities of C. elegans using compounds whose metabolism has been well characterised in mammalian systems. We find that similar metabolites are produced in C. elegans as in mammals but that C. elegans is deficient in CYP1-like metabolism, as has been seen in other studies. We show that CYP-34A9, CYP-34A10 and CYP-36A1 are the principal enzymes responsible for the metabolism of tolbutamide in C. elegans. These are related to the mammalian enzymes that metabolise this compound but are not the closest homologs suggesting that sequence comparison alone will not predict functional conservation among cytochrome P450s. In mammals, metabolite production from amytryptiline and dextromethorphan is dependent on specific cytochrome P450s. However, in C. elegans we did not find evidence of similar specificity: the same metabolites were produced but in small amounts by numerous cytochrome P450s. We conclude that, while some aspects of cytochrome P450 mediated metabolism in C. elegans are similar to mammals, there are differences in the production of some metabolites and in the underlying genetics of metabolism.

In this study, a novel chitosan (CS)-modified nanoparticles (NPs) were developed to orally deliver tolbutamide (TOL). Methoxy poly(ethylene glycol)- b-poly(ε-caprolactone) carboxylates (mPEG2000-b-PCL4000) was synthesized via an esterification reaction. CS-modified mPEG2000-b-PCL4000-COOH NPs (CS@NPs) were fabricated by injecting mPEG2000-b-PCL4000-COOH NPs suspension (1.0 mg/mL) into CS solution (1.0 mg/mL, pH 5.0). Fourier transform infrared spectroscopy (FTIR) spectra were used to confirm the obtaining of mPEG2000-b-PCL4000-COOH. Transmission electron microscope (TEM) was carried out to observe morphology of all NPs. Nano ZS90 Malvern ParticleSizer were used to monitor the size distribution of obtained NPs. Thermogravimetry analysis (TGA) was performed to investigate the thermostability of CS@NPs. In vitro TOL release profiles were carried out in pH 1.2 and 7.4 buffers. FTIR spectra confirmed the obtaining of mPEG2000-b-PCL4000-COOH. TGA curves indicated that the protection of CS shells improved the thermostability of mPEG2000-b-PCL4000-COOH NPs. Cell tests indicated the CS@NPs had no obvious cytotoxicity, and they were easily taken up by 293T cells. In vitro release profiles showed that 91.0 ± 1.9% of encapsulated TOL were released from TOL-CS@NPs in pH 7.4 buffer. Therefore, the positive potential of CS@NPs could increase their combining capacity with intestinal mucosal cells. Finally, these NPs would improve the bioavailability of hydrophobic drugs.

This class of medications represents a group of anti-hyperglycemic agents mainly used in the treatment of type 2 diabetes mellitus. Sulfonylureas, commonly divided into first and second generations, can be utilized as adjuvant therapy with metformin in patients not at target hemoglobin A1c after 3 months on biguanides. If a patient’s hemoglobin A1c initially is greater than 9.0%, providers can consider combination therapy with metformin and a sulfonylurea or other anti-hyperglycemic agent. Additionally, sulfonylurea monotherapy can be considered in patients intolerant to metformin or in those who have a contraindication to this medication. Sulfonylureas can be used in combination with any other class of oral diabetic medications besides meglitinides. Infants with permanent neonatal diabetes also tend to respond well to sulfonylurea treatment. Examples of first-generation sulfonylureas include chlorpropamide, tolazamide, and tolbutamide, while second-generation sulfonylureas include glipizide, gliclazide, and glyburide. Glimepiride occasionally is referred to as a third-generation medication, though it commonly is classified as second-generation. Furthermore, chlorpropamide, glyburide, and glimepiride have a prolonged duration of action when compared to short-acting medications such as gliclazide and tolbutamide. Due to their low cost, wide availability, and effectiveness, sulfonylureas have remained a frequently prescribed medication despite potential hypoglycemic risks.