There is increasing evidence that tyrosine kinase inhibitors (TKIs) have significant blood glucose lowering effects. A 70-year old Caucasian male with liver cirrhosis Child-Pugh A, advanced hepatocellular carcinoma and diabetes had a stable glycemic control being treated with glibenclamide (3.5 mg twice daily). After the first daily dose of the TKI sorafenib (800 mg) the patient experienced acute nocturnal disorientation and somnolence with a corresponding blood glucose of 37 mg/dl. After administration of glucose intravenously the neurological disturbances were completely reversible. As there was no intercurrent deterioration neither of hepatic nor of renal function, the severe hypoglycemia can likely be attributed to a drug-drug interaction of sorafenib with the sulfonylurea. The complete inhibition of the CYP2C9 and CYP3A4 mediated metabolic pathway of glibenclamide through sorafenib might have resulted in a rapid accumulation of glibenclamide. Profound blood glucose lowering effects of sorafenib might have additionally contributed to the hypoglycemic episode.

Introduction: The cytochrome P4502C enzymes account for the metabolism of approximately 20% of therapeutic drugs including certain oral antidiabetic drugs (OADs). Areas covered: This review focuses on the effect of CYP2C enzymes on metabolism of sulphonylureas (SUs), meglitinides, and thiazolidinediones (TZDs) discussing their impact on pharmacokinetics, drug interactions and toxicological profiles. Pharmacogenetic aspects reflecting individual gene variants and variable drug effects are also considered. Expert opinion: Genetic polymorphisms of CYP2C9 enzymes ((star)2/(star)2, (star)2/(star)3, (star)3/(star)3) influence the glycaemic response to SUs and impair their substrate metabolism. Restricted data from small-sized studies with heterogenous definitions of hypoglycaemia revealed no clear association between CYP2C9 genotypes and the risk of hypoglycaemia. Functional polymorphisms of CYP2C8- and CYP2C9 drug metabolizing genes affect markedly pharmacokinetics of meglitinides. Compared to wild-type carriers, patients treated with TZDs and carrying the common CYP2C8(star)3 and (star)4 variants showed a reduced glycaemic control. The strong CYP2C8 and OATP1B1 inhibitor gemfibrozil increases substantially the plasma concentrations of repaglinide and TZDs. Numerous metabolic drug interactions exist between SUs and commonly prescribed drugs, especially anti-infectives. The complex pharmacokinetic and pharmacogenetic properties and the unfavourable short and long term risk profile of glibenclamide and glimepiride raise the question whether their use can be justified any longer.

Introduction: The cytochrome P4502C enzymes account for the metabolism of approximately 20% of therapeutic drugs including certain oral antidiabetic drugs (OADs). Areas covered: This review focuses on the effect of CYP2C enzymes on metabolism of sulphonylureas (SUs), meglitinides, and thiazolidinediones (TZDs) discussing their impact on pharmacokinetics, drug interactions and toxicological profiles. Pharmacogenetic aspects reflecting individual gene variants and variable drug effects are also considered. Expert opinion: Genetic polymorphisms of CYP2C9 enzymes (*2/*2, *2/*3, *3/*3) influence the glycaemic response to SUs and impair their substrate metabolism. Restricted data from small-sized studies with heterogenous definitions of hypoglycaemia revealed no clear association between CYP2C9 genotypes and the risk of hypoglycaemia. Functional polymorphisms of CYP2C8- and CYP2C9 drug metabolizing genes affect markedly pharmacokinetics of meglitinides. Compared to wild-type carriers, patients treated with TZDs and carrying the common CYP2C8*3 and *4 variants showed a reduced glycaemic control. The strong CYP2C8 and OATP1B1 inhibitor gemfibrozil increases substantially the plasma concentrations of repaglinide and TZDs. Numerous metabolic drug interactions exist between SUs and commonly prescribed drugs, especially anti-infectives. The complex pharmacokinetic and pharmacogenetic properties and the unfavourable short and long term risk profile of glibenclamide and glimepiride raise the question whether their use can be justified any longer.

DPP-4 inhibitors glucose-dependently stimulate insulin secretion and inhibit glucagon release; in theory, DDP-4 inhibitors can be combined with any other therapy approach available. Administering metformin together with DPP-4 inhibitors combines a variety of synergetic principles, with metformin increasing GLP-1 formation and DDP-4 inhibitors inhibiting GLP-1 breakdown. DPP-4 inhibitors reduce HbA(1c) values by an additional 0.7 to 1.1 percentage points in combination with metformin, and do not pose any inherent risk of inducing hypoglycaemia. DPP-4 inhibitors vary in certain pharmacodynamic and pharmacokinetic properties. According to the data available, vildagliptin is the fastest acting DDP-4 inhibitor, raising GLP-1 levels to a significantly higher degree in direct comparison with sitagliptin. Sitagliptin is primarily excreted unchanged via the kidneys by P-glycoprotein transport. Vildagliptin is hydrolysed outside the liver, and eliminated as an inactive metabolite via the kidneys. Saxagliptin is mainly metabolised by cytochrome P450 3A4. Of the three DDP-4 inhibitors, vildagliptin has the lowest potential for interaction with other drugs.

Interleukin-8 (IL-8) plays a central role in the pathogenesis of Helicobacter pylori infection. We used four different H. pylori strains isolated from patients with gastritis or duodenal ulcer disease to examine their differential effects on signaling pathways and IL-8 gene response in gastric epithelial cells. IL-8 mRNA level is elevated in response to high (100) multiplicity of infection (MOI) independent of cagA, vacA, and dupA gene characteristics. By lower MOIs (1 or 10), only cagA + strains significantly induce IL-8 gene expression. This is based on differential regulation of IL-8 promoter activity. Analysis of intracellular signaling pathways indicates that H. pylori clinical isolates induce IL-8 gene transcription through NF-κB p65, but by a MOI-dependent differential activation of MAPK pathways. Thus, the major virulence factors of H. pylori CagA, VacA, and DupA might play a minor role in the level of IL-8 gene response to a high bacterial load.

BACKGROUND/AIMS:The role of H. pylori in the pathogenesis of ulcer disease in cirrhotic patients is poorly defined. Therefore, we sought to investigate the prevalence of H. pylori infection and the occurrence of gastroduode-nal lesions in patients with liver cirrhosis.METHODS AND PATIENTS:Seroprevalence of H. pylori was tested in 110 patients with liver cirrhosis and 44 asymptomatic patients with chronic hepatitis without cirrhosis using an anti-H. pylori-IgG-ELISA. Cirrhotic patients underwent upper intestinal endoscopy for macroscopic and histological evaluation of gastric mucosa, and for the detection of mucosal colonisation of H. pylori using Giemsa staining and urease test.RESULTS:There was no significant difference between the H. pylori seroprevalence in patients with liver cirrhosis (76/110; 69%) and patients with chronic viral hepatitis (27/44, 63%, p=0.465). Gastric mucosal colonization with H. pylori in cirrhotic patients was significantly lower than the serologically determined H. pylori prevalence (45% vs. 69%, p=0.001). Etiology of liver cirrhosis did not influence the prevalence of H. pylori infection. 8 of 110 cirrhotic patients had gastric ulcers and 10 had duodenal ulcers. 61% of cirrhotic patients with peptic ulcers were asymptomatic. H. pylori was histologically identified in 61% of gastroduodenal ulcers, and 47% of gastroduodenal erosions.CONCLUSIONS:Patients with liver cirrhosis have a high prevalence of gastroduodenal ulcers. The lack of a firm association between H. pylori prevalence and ulcer frequency in cirrhotic patients argues against a pivotal role of H. pylori in the etiology of ulcers in cirrhotic patients.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

AbstractThe new anthracycline‐type antibiotic aranciamycin anhydride (I) shows weak antibacterial activity only against Bacillus subtilis.

Background: Type 2 diabetes is progressive in nature and so to control cardiovascular risk, most patients need combinations of oral antidiabetic drugs (OADs) plus or minus insulin. Thus, drug-drug interactions may substantially contribute to harmful effects of intensive glucose lowering therapy. Methods: A PubMed literature search was performed to select the most recent and relevant publications examining OAD metabolism and the effects of concomitant use of OADs. Results/conclusion: Considering the individual sensitivity to OADs, pharmacogenetic factors could be of critical importance. The therapeutic range and efficacy as well as adverse effects of OADs may be significantly affected by genetic polymorphisms of cytochrome P450 drug metabolising enzymes, organic cation transporters or organic anion transporting polypeptides. Although current data suggest that modest pharmacokinetics interferences among some OAD combinations exist, they do not seem to have substantial clinical consequences. As long-term adherence to multi-drug treatment is poor in diabetic patients, the future will show a strong move towards earlier treatment with combination therapies. As metformin is cardiovascular protective and is not metabolised through the hepatic cytochrome P450 system, it is a key compound for any OAD combination. There is an overwhelming amount of small-sized in vitro studies and investigations mostly including healthy volunteers dealing with short-term effects and surrogate parameters of concomitant OAD use. Further evidence from large-scale studies including typical subjects with type 2 diabetes, in particular multimorbid and geriatric patients with polypharmacy, is needed. Postmarketing surveillance using large patients' registries could be helpful to improve the early detection of clinically relevant drug-drug interactions.

Piceamycin, a new macrolactam polyketide antibiotic, was detected by HPLC-diode array screening in extracts of Streptomyces sp. GB 4-2, which was isolated from the mycorrhizosphere of Norway spruce. The structure of piceamycin was determined by mass spectrometry and NMR experiments. It showed inhibitory activity against Gram-positive bacteria, selected human tumor cell lines and protein tyrosine phosphatase 1B.

The proximicins A–C (1–3) are novel naturally occurring γ-peptides with a hitherto unknown 2,4-disubstituted furan amino acid as a core structure. They show a moderate cytotoxic activity and induce upregulation of cell cycle regulating proteins (p53 and p21) and lead to cell cycle arrest in G0/G1-phase. Hybrid molecules combining structural motifs of the proximicins and of netropsin (4), a structurally related natural product, seem to have similar effects. Herein we describe the synthesis of a netropsin–proximicin-hybrid library and its evaluation regarding cytotoxicity and minor groove binding activity.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Caboxamycin, a new benzoxazole antibiotic, was detected by HPLC-diode array screening in extracts of the marine strain Streptomyces sp. NTK 937, which was isolated from deep-sea sediment collected in the Canary Basin. The structure of caboxamycin was determined by mass spectrometry, NMR experiments and X-ray analysis. It showed inhibitory activity against Gram-positive bacteria, selected human tumor cell lines and the enzyme phosphodiesterase.

The emergence of antibiotic resistant H. pylori strains has necessitated the identification of alternative additive therapies for the treatment of this infection. The study tested whether a specific pine bark extract (Pycnogenol is effective in inhibiting the growth and adherence of H. pylori in vitro. Inhibition of H. pylori growth by Pycnogenol was tested in liquid medium as well as in an in vitro model by using sessile bacteria attached to AGS cells. Adherence was determined by co-incubation of gastric cells with Pycnogenol and H. pylori in vitro. Pycnogenol inhibited H. pylori growth in suspension with an MIC(50) of 12.5 microg/mL. Growth of H. pylori in infected cells was reduced to 10% of the control value by 125 microg/mL Pycnogenol. Adherence of H. pylori to gastric cells was reduced by 70% after 3 h incubation with 125 microg/mL Pycnogenol. The results show a significant, yet limited inhibition of growth and adherence of H. pylori to gastric cells by Pycnogenol. In vivo studies have to demonstrate the clinical relevance of these findings.

Induction of apoptosis by the PP1/PP2A inhibitor calyculin A was inhibited if the CaMKII inhibitor KN-93 was added no later than 10 min after addition of calyculin A. The physiological relevance and mechanism of CaMKII during apoptosis, however, remains largely unclear. Here we show in MDCK and gastric parietal cells that normal transregulation of CaMKII terminates the initial burst of autophosphorylation after only 10 min. The kinetics of CaMKII involved transregulation by PP1, PP2A, PP2B and PKCalpha. Transregulation of CaMKII resulted in two kinetic phases for phosphorylation of the autoactivation site at T286/287. During the initial phase, there was a clear peak of phosphorylation that lasted 10 min. This phase was subsequently followed by a half but constant level of T286/287 phosphorylation. Calyculin A perturbed this transregulation, resulting in a hyperphosphorylated CaMKII. This effect of CA on the kinetics of CaMKII was observed in vivo as well as in vitro using isolated tubulovesicles. Calyculin A-induced hyperphosphorylation of CaMKII appears to be at least one mechanism used by cells to trigger apoptosis. Therefore, stringent limitation of CaMKII autophosphorylation at T286/287 by transregulation and prevention of hyperphosphorylation seems to restrict apoptosis.

Wirkstoffe aus dem Meer: Drei neue Netropsin-artige Antibiotika (1–3) mit einer bisher unbekannten Furangrundstruktur wurden aus marinen Actinomyceten isoliert und ihre Struktur mithilfe von Massenspektrometrie und 2D-NMR-Spektroskopie aufgeklärt. Sie haben Antitumoraktivität und induzieren im Unterschied zu Netropsin eine Hochregulation von p53 und des Cyclinkinase-Inhibitors p21.