The pharmacokinetics (PK) of ethanol are important in pharmacology and therapeutics because of potential drug‐alcohol interactions as well as in forensic science when alcohol‐related crimes are investigated. The PK of ethanol have been extensively studied since the 1930s, although some issues remain unresolved, such as the significance of first‐pass metabolism, whether zero‐order kinetics apply, and the effects of food on bioavailability. We took advantage of nonlinear mixed‐effects modeling to describe blood‐alcohol concentration (BAC) profiles derived from 3 published clinical studies involving oral, intraduodenal, and intravenous administration of ethanol with and without food. The overall data set included 1510 BACs derived from 72 healthy subjects (60 men, 12 women) aged between 20 and 60 years. Two‐compartment models with first‐order absorption and Michaelis‐Menten elimination kinetics adequately described the BAC profiles. Food intake had 2 separate effects: It reduced the absorption rate constant and accelerated the maximum elimination rate. Estimates of the maximum elimination rate (fasted) and the food effect (as a factor) were 6.31 g/h (95%CI, 6.04‐6.59 g/h) and 1.39‐fold (95%CI, 1.33‐1.46‐fold), respectively. Simulations showed that the area under the BAC‐time curve (AUC) was smaller with lower input rate of ethanol, irrespective of any first‐pass metabolism. The AUC from time 0 to 10 hours for a 75‐kg subject was 2.34 g • h/L (fed) and 3.83 g • h/L (fasted) after an oral dose of 45 g ethanol. This difference was mainly attributable to the food effect on ethanol elimination and depended less on the absorption rate. Our new approach to explain the complex human PK of ethanol may help when BAC predictions are made in clinical pharmacology and forensic medicine.

Hintergrund/Einleitung: Protonenpumpeninhibitoren (PPI) wie z.B. Lansoprazol sind Medikamente erster Wahl in Regimen zur Eradikation von Helicobacter pylori (HP). Diese werden überwiegend durch das polymorphe CYP2C19 System metabolisiert. Bei asiatischen Patienten wurde eine geringere Eradikationsrate bei schnellen Metabolisierern (EM) von CYP2C19 bei dualen Regimen festgestellt.

This review describes the pharmacokinetics of the major drugs used for the treatment of inflammatory bowel disease. This information can be helpful for the selection of a particular agent and offers guidance for effective and well tolerated regimens. The corticosteroids have a short elimination half-life (t1/2beta) of 1.5 to 4 hours, but their biological half-lives are much longer (12 to 36 hours). Most are moderate or high clearance drugs that are hepatically eliminated, primarily by cytochrome P450 (CYP) 3A4-mediated metabolism. Prednisone and budesonide undergo presystemic elimination. Any disease state or comedication affecting CYP3A4 activity should be taken into account when prescribing corticosteroids. Depending on the preparation used, 10 to 50% of an oral or rectal dose of mesalazine is absorbed. Rapid acetylation in the intestinal wall and liver (t1/2beta 0.5 to 2 hours) and transport probably by P-glycoprotein affect mucosal concentrations of mesalazine, which apparently determine clinical response. Any clinical condition influencing the release and topical availability of mesalazine might modify its therapeutic potential. Metronidazole has high (approximately 90%) oral bioavailability, with hepatic elimination characterised by a t1/2beta of 6 to 10 hours and a total clearance of about 4 L/h/kg. Ciprofloxacin is largely excreted unchanged both renally (about 45% of dose) and extrarenally (25%), with a relatively short t1/2beta (3.5 to 7 hours). Thus, renal function affects the systemic availability of ciprofloxacin. Both mercaptopurine and its prodrug azathioprine are metabolised to active compounds (6-thioguanine nucleotides; 6-TGN) by hypoxanthine-guanine phosphoribosyltransferase and to inactive metabolites by the polymorphically expressed thiopurine S-methyltransferase (TPMT) and xanthine oxidase. Patients with low TPMT activity have a higher risk of developing haemopoietic toxicity. Both mercaptopurine and azathioprine have a short t1/2beta (1 to 2 hours), but the t1/2beta of 6-TGN ranges from 3 to 13 days. Therapeutic response seems to be related to 6-TGN concentration. Almost complete bioavailability has been observed after intramuscular and subcutaneous administration of methotrexate, which is predominantly (85%) excreted as unchanged drug with a t1/2beta of up to 50 hours. Thus, renal function is the major determinant for disposition of methotrexate. Cyclosporin is slowly and incompletely absorbed. It is extensively metabolised by CYP3A4/5 in the liver and intestine (median t1/2beta and clearance 7.9 hours and 0.46 L/h/kg, respectively), and inhibitors and inducers of CYP3A4 can modify response and toxicity. Infliximab is predominantly distributed to the vascular compartment and eliminated with a t1/2beta between 10 and 14 days. No accumulation was observed when it was administered at intervals of 4 or 8 weeks. Methotrexate may reduce the clearance of infliximab from serum.

In recent years, the issue of herbal medicine-drug interactions has generated significant concern. Such interactions can increase the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index (e.g. warfarin, ciclosporin and digoxin). The present article summarizes herbal medicine-drug interactions involving mainly inhibition or induction of cytochrome P450 enzymes and/or drug transporters. An increasing number of in vitro and animal studies, case reports and clinical trials evaluating such interactions have been reported, and the majority of the interactions may be difficult to predict. Potential pharmacodynamic and/or pharmacokinetic interactions of commonly used herbal medicines (black cohosh, garlic, Ginkgo, goldenseal, kava, milk thistle, Panax ginseng, Panax quinquefolius, saw palmetto and St John's wort) with conventional drugs are presented, and sometimes the results are contradictory. Clinical implications of herbal medicine-drug interactions depend on a variety of factors, such as the co-administered drugs, the patient characteristics, the origin of the herbal medicines, the composition of their constituents and the applied dosage regimens. To optimize the use of herbal medicines, further controlled studies are urgently needed to explore their potential for interactions with conventional drugs and to delineate the underlying mechanisms.

For several decades paracetamol has proven its clinical efficacy and safety in the treatment of various acute and chronic pain states. Whereas its pharmacokinetic properties (high oral bioavailability, good penetration into the brain, relative rapid hepatic elimination) are well known, its exact central mode of action remains to be elucidated. According to many international guidelines/recommendations paracetamol is a drug of first choice for relieving mild to moderate pain. It has been successfully combined with opioids for severe pain. Due to its cardiovascular, renal and gastrointestinal safety paracetamol offers several advantages vs. NSAIDs. It should be realized that the maximum daily dose is restricted to 4 g to avoid unnecessary hepatic complications. Keeping this limitation in mind paracetamol still represents a valuable first-line agent in the pharmacological management of pain.

For more than 30 years mesalazine (5-aminosalicylic acid; 5-ASA) has been used for the treatment of chronic inflammatory bowel disease (IBD) especially in ulcerative colitis (UC). During this time various rectal and oral formulations have been developed. The modified drug delivery systems were designed to release sufficient 5-ASA at the sites of inflammation. Such a drug targeting strategy is needed for its topical action and especially because local concentrations in the mucosa will determine the clinical outcome. The absorbed part (20-40% of the dose) of 5-ASA is rapidly and presystemically acetylated (t(1/2): 1-2.5h; CL: 300-690 mL/min). Consequently, the systemic exposure of 5-ASA is low and adverse effects are in the range of placebo treatment. The polypotent 5-ASA has a wide spectrum of pharmacological properties and its exact mode of action is not yet clear. Recent meta-analyses of randomized placebo-controlled clinical trials provide convincing data that 5-ASA is the preferred first-line therapy for the acute treatment of mild-to-moderate UC (NNT:6) and for remission management (NNT:4). There is also some clinical benefit for patients with active Crohn's disease (NNT:7) and in the prevention of post-surgical relapse (NNT:10). There is increasing evidence that 5-ASA also has some therapeutic potential for chemoprevention of colorectal cancer, diverticular disease and irritable bowel syndrome. In all clinical studies, the side effects of 5-ASA were very low (5-10%), mild and comparable to placebo. Thus, its use is very safe and 5-ASA will remain an interesting and valuable agent. It is anticipated that more selective drug targeting, including galenic innovations and an optimized dosaging schedule, could result in some improvement of the wide use of 5-ASA.

Nanoparticles delivery of oligonucleotides represents a potential approach for cancer treatment. However, most of the experiments were based on established cancer cell lines and may not reflect the original solid tumor in vivo. Both, tumor microenvironment and tumor cell biological properties in the tumor can influence the delivery efficiency of oligonucleotides. Therefore, it is important to understand the effect of nanoparticles delivery of oligonucleotides on tumor response in intact tissue architecture of individual tumors. We used freshly isolated human tumor tissue slices and primary lung cancer cells from non-small cell lung cancer patients to evaluate this nanocarrier system. Chitosan-coated poly(lactide-co-glycolide) (PLGA) nanoparticles were used to form oligonucleotide–nanoparticle-complexes (nanoplexes) with antisense 2′-O-methyl-RNA (OMR) that can inhibit telomerase activity by binding to the RNA component of telomerase. OMR cellular uptake was strongly enhanced by nanoplexes mediated delivery in both, primary cells and tissue slices. More than 80% of primary cancer cells and 50% of cells in tissue slices showed OMR uptake. Telomerase activity was inhibited by approximately 45% in primary cancer cells and about 40% in tissue slices. Nanoplexes could penetrate into tumor tissue without influencing tissue architecture and the delivered OMR was able to inhibit telomerase activity with relatively low cytotoxicity.

Troglitazone (CAS 97322-87-7), rosiglitazone (CAS 155141-29-0) and pioglitazone (CAS 111025-46-8) represent novel agents for the treatment of diabetes mellitus. Very often such patients receive several drugs at the same time and consequently their interaction potential needs to be known, especially as troglitazone was recently withdrawn from the market partly because it inhibited and induced drug metabolism.

The therapeutic effects and metabolism of mesalazine (5-aminosalicylic acid) in patients with inflammatory bowel disease require intracellular accumulation of the drug in intestinal epithelial cells and hepatocytes. The molecular mechanisms of mesalazine uptake into cells have not been characterized so far. Using human embryonic kidney cells stably expressing uptake transporters of the organic anion-transporting polypeptide (OATP) family, which are expressed in human intestine and/or liver, we found that mesalazine uptake is mediated by OATP1B1, OATP1B3, and OATP2B1 but not by OATP1A2 and OATP4A1. Moreover, genetic variations (*1b, *5, *15) in the SLCO1B1 gene encoding OATP1B1 reduced the Km value for mesalazine uptake from 55.1 to 16.3, 24.3, and 32.4 μM, respectively, and the respective Vmax values. Finally, budesonide, cyclosporine, and rifampin were identified as inhibitors of OATP1B1-, OATP1B3-, and OATP2B1-meditated mesalazine uptake. These in vitro data indicate that OATP-mediated uptake and its modification by genetic factors and comedications may play a role for mesalazine effects.

Ageing is characterized by a progressive decline in the functional reserve of multiple organs and systems, which can influence drug disposition. In addition, comorbidity and polypharmacy are highly prevalent in the elderly. As ageing is associated with some reduction in first-pass metabolism, bioavailability of a few drugs can be increased. With ageing body fat increases and total body water as well as lean body mass decrease. Consequently, hydrophilic drugs have a smaller apparent volume of distribution (V) and lipophilic drugs have an increased V with a prolonged half-life. Drugs with a high hepatic extraction ratio display some age-related decrease in systemic clearance (CL), but for most drugs with a low hepatic extraction ratio, CL is not reduced with advancing age. In general, activities of cytochrome P450 enzymes are preserved in normal ageing and the genetic influence is much more striking than age effects. Drug transporters play an important role in pharmacokinetic processes, but their function and pharmacology have not yet been fully examined for agerelated effects. One third of elderly persons show no decrease in renal function (GFR > 70 mL/min/1.73 m2). In about two thirds of elderly subjects, the age-related decline of renal function was associated with coexisting cardiovascular diseases and other risk factors. In the elderly a large interindividual variability in drug disposition is particularly prominent. In conclusion, the complexity of interactions between comorbidity, polypharmacy, and age-related changes in pharmacokinetics (and pharmacodynamics) justify the old and well-known dosing aphorism " start low, go slow" for aged individuals.

A promising approach for treatment of non-small cell lung cancer (NSCLC) is based on the inhibition of telomerase in cancer cells. The antisense oligonucleotide 2′-O-methyl-RNA binding to the RNA component of telomerase acts as a selective telomerase inhibitor. We developed chitosan-coated polylactide-coglycolide (PLGA) nanoparticles to mediate efficient delivery of 2′-O-methyl-RNA into human lung cancer cells. Cellular uptake of the inhibitor mediated by chitosan-coated PLGA nanoparticles was greatly enhanced compared to the uptake of antisense oligonucleotide alone as shown by flow cytometry analysis. Confocal laser scanning microscopy clearly demonstrated internalization of 2′-O-methyl-RNA. 2′-O-methyl-RNA-nanoparticle complexes exhibited nearly no acute cytotoxicity in human lung cancer cells and did not influence the viability of primary tumor lung fibroblasts. Human NSCLC A549 cells treated with 2′-O-methyl-RNA-nanoparticle complexes showed 87% viability compared to untreated control cells. 2′-O-methyl-RNA delivered by nanoparticle complexes inhibited telomerase activity in a sequence-specific manner. During long-term treatment (15 weeks) telomerase activity was continuously reduced by approximately 80%. Furthermore, nanoparticle mediated delivery of 2′-O-methyl-RNA resulted in significant telomere shortening from 5.9kb to 4kb (p=0.008) in A549 cells. In summary, our data demonstrate that nanoparticle mediated delivery of 2′-O-methyl-RNA induces effective telomerase inhibition and telomere shortening in human lung cancer cells and therefore represents a novel and promising strategy for the treatment of lung cancer.

Viele Patienten erhalten gleichzeitig mehrere Medikamente, die sich in ihrer Wirkung gegenseitig beeinflussen können. Hat dies Auswirkungen für die therapeutische Anwendung, spricht man von Arzneimittelinteraktionen (bzw. Wechselwirkungen).

Tailorable cationic chitosan/PLGA nanoparticles (CPNP) were used for the delivery of an antisense 2'-O-methyl-RNA (2OMR) directed against RNA template of human telomerase. Here, we describe the influence of the chitosan content on binding efficiency, complex stability, uptake in different human lung cell types and finally demonstrate the efficacy of this nanoplex system.CPNPs were prepared by the emulsion-solvent evaporation method using different amounts of chitosan and purified by preparative size exclusion chromatography. The characterization by photon correlation spectroscopy and zeta potential measurements showed a small increase in size and an increase of zeta potential with increasing amounts of chitosan. Binding efficiency and complex stability with 2OMR was high in water and correlated well with the chitosan content of particles but was weak in physiologically relevant media (PBS and RPMI cell culture medium). However, flow cytometry analysis showed that the uptake of 2OMR into A549 lung cancer cells was considerably higher in combination with nanoparticles and dependent on the amount of chitosan when compared to 2OMR alone. Confocal laser scanning microscopy revealed that the uptake into A549 cells is mediated via complexes of 2OMR and chitosan/PLGA nanoparticles despite the weak binding in cell culture medium. The nanoparticles were well tolerated and efficient in inhibiting telomerase activity. (C) 2009 Published by Elsevier B.V,

Drug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLA-B*1502, are at a higher risk for Stevens-Johnson syndrome when using carbamazepine, are helpful to increase our knowledge how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individuals with epilepsy.

The antisense oligonucleotide 2'-O-methyl-RNA is a selective telomerase inhibitor targeting the telomerase RNA component and represents a potential candidate for anticancer therapy. The poor cellular uptake of 2'-O-methyl-RNA is a limiting factor that may contribute to the lack of functional efficacy. To improve delivery of 2'-O-methyl-RNA and consequently antitumoral efficiency in human lung cancer cells, we have investigated several transfection reagents. The transfection reagents DOTAP, MegaFectin 60, SuperFect, FuGENE 6 and MATra-A were tested for intracellular delivery. A FAM-labeled 2'-O-methyl-RNA was used to assess the intracellular distribution by confocal laser scanning microscopy in A549 human non-small cell lung cancer cells. Telomerase activity was measured using the telomeric repeat amplification protocol. Cell viability after transfection was quantified by the MTT assay. All transfection reagents enhanced 2'-O-methyl-RNA uptake in A549 cells but the cationic lipid reagents DOTAP and MegaFectin 60 were most efficient in the delivery of 2'-O-methyl-RNA resulting in telomerase inhibition. Among both DOTAP exhibited the lowest cytotoxicity. Our experiments show that DOTAP is the most suitable transfection reagent for the delivery of 2'-O-methyl-RNA in human lung cancer cells according to its relatively low cytotoxicity and its ability to promote efficient uptake leading to the inhibition of telomerase.