What Is the Best Method to Achieve Safe and Precise Stent-Graft Deployment in Patients Undergoing TEVAR?

Thoracic endovascular aortic repair (TEVAR) for aortic pathologies requires sufficient landing zone of ideally more than 25 mm for safe anchoring of the stent-graft and prevention of endoleaks. In the aortic arch and at the thoracoabdominal transition, landing zone length is usually limited by the offspring of the major aortic side-branches. Exact deployment of the stent-graft to effectively use the whole length of the landing zone and to prevent occlusion of one of the side-branches is key to successful TEVAR. There are numerous techniques described to lower blood pressure and to reduce or eliminate aortic impulse to facilitate exact deployment of stent-grafts including pharmacologic blood pressure lowering, adenosine-induced asystole, inflow occlusion, and rapid pacing. Aim of this review was to assess the current literature to identify which of the techniques is best suited to prevent displacement and allow for precise placement of the stent-graft and safe balloon-molding.

Interpreting the Benefit and Risk Data in Between-Drug Comparisons: Illustration of the Challenges Using the Example of Mefenamic Acid versus Ibuprofen.

Evidence-based pain therapy should rely on precisely defined and personalized criteria. This includes balancing the benefits and risks not only of single drugs but often requires complex between-drug comparisons. Non-steroidal anti-inflammatory drugs (NSAIDs) have been available for several decades and their use is described in an abundance of guidelines. Most of these guidelines recommend that 'the selection of a particular NSAID should be based on the benefit-risk balance for each patient'. However, head-to-head studies are often lacking or of poor quality, reflecting the lower standards for clinical research and regulatory approval at the time. The inconsistency of approved indications between countries due to national applications adds to the complexity. Finally, a fading research interest once drugs become generic points to a general deficit in the post-marketing evaluation of medicines. Far from claiming completeness, this narrative review aimed to illustrate the challenges that physicians encounter when trying to balance benefits and risks in a situation of incomplete and inconsistent data on longstanding treatment concepts. Ibuprofen and mefenamic acid, the most frequently sold NSAIDs in Austria, serve as examples. The illustrated principles are, however, not specific to these drugs and are generalizable to any comparison of older drugs in daily clinical practice.

Sex-Related Differences in Drugs with Anti-Inflammatory Properties.

There is increasing evidence of sex differences in the action of anti-inflammatory drugs, with women being at significantly higher risk of adverse effects. Nevertheless, clinicians' awareness of the implications of these sex differences on dosing and adverse event monitoring in routine practice is still in need of improvement. We reviewed the literature evaluating sex differences in terms of pharmacokinetics and pharmacodynamics of anti-inflammatory drugs. The anti-thrombotic activity of selective and non-selective COX-inhibitors tends to be stronger in men than women. Side effect profiles differ with regards to gastro-intestinal, renal and hepatic complications. Glucocorticosteroids were found to be more effective in men; women were more sensitive to corticosteroids when their oestradiol levels were high, a finding important for women taking hormonal contraception. TNF-alpha inhibitors have a longer half-life in men, leading to stronger immunosuppression and this a higher incidence of infections as side effects. Although research on sex differences in the effectiveness and safety of drugs is increasing, findings are often anecdotal and controversial. There is no systematic sex-differentiated reporting from clinical trials, and women are often under-represented. As personalized medicine is gaining in importance, sex, and gender aspects need to become integral parts of future research and policy making.

Sex-Related Differences in Pharmacokinetics and Pharmacodynamics of Frequently Prescribed Drugs: A Review of the Literature.

While there is considerable evidence about sex-related differences between men and women in drug metabolism, efficacy and safety of frequently prescribed drugs such as analgesics, tranquillizers, statins and beta-blockers, clinicians' awareness of the implications on dosing and adverse event monitoring in routine practice is inadequate. Some drugs are more effective in men than women (e.g. ibuprofen) or vice versa (e.g. opioids, benzodiazepine), typically owing to pharmacodynamic causes. The 5-hydroxytryptamine (5-HT) receptor 3 antagonist alosetron is approved for women only since it largely lacks efficacy in men. For statins, equal efficacy was demonstrated in secondary prevention of cardiovascular events, but primary prevention is still under debate. For some drugs (e.g. paracetamol, metoprolol), women are at significantly higher risk of adverse effects. Therefore, considering sex-specific features in clinical trials and therapeutic guidelines is warranted to ensure efficacy and safety of medicines.

Mini-review: medication safety of red yeast rice products.

High lipid levels in the blood together with high blood pressure and diabetes are among the highest risks for coronary heart disease. In particular, elevated cholesterol levels promote the progression of atherosclerosis. Red yeast rice, also called red fermented rice or red mold rice, is used as a dietary supplement to lower cholesterol levels. It contains varying amounts of natural monacolin K, which is a structural homolog to lovastatin, and shows hypocholesterolemic properties comparable to synthetic statins. Despite being portrayed as a natural alternative, the potential of red yeast rice for side effects and interactions is comparable to statin drugs. Consumers need to be made aware of the varying monacolin K content in red yeast rice products and the insufficient long-term safety data regarding the potential risks of red yeast rice.

In vivo disposition of irinotecan (CPT-11) and its metabolites in combination with the monoclonal antibody cetuximab.

BACKGROUND: The present study was designed to investigate whether a combination of irinotecan and the monoclonal antibody cetuximab shows potential to modulate the pharmacokinetics of irinotecan and its metabolites. PATIENTS AND METHODS: All patients, suffering from advanced colorectal cancer, received irinotecan (350 mg/m2) every third week and cetuximab as a loading dose (400 mg/m2) on day 2, followed by a weekly maintenance dose (250 mg/m2). Plasma samples were analysed after the first (MONO) and second (CMAB) irinotecan infusions. RESULTS: No significant alterations in the plasma concentrations and pharmacokinetics of irinotecan and its metabolites were observed after combination with cetuximab. Only differentiation of irinotecan into lactone and carboxylate plasma concentrations resulted in a distinctly lower cmax of the active lactone in the CMAB and a significantly higherAUClast in the MONO schedule (p<0.02). CONCLUSION: The results of this study indicated that cetuximab has no clinically relevant impact on the pharmacokinetics of irinotecan, its activation into SN-38, or its detoxification by beta-D-glucuronidation.

Systemic side effects of eye drops: a pharmacokinetic perspective.

When administering eye drops, even when completely correctly applied, several routes of absorption are possible and excess amounts can sometimes cause an unwanted systemic bioavailability of the drops when not completely absorbed into the eye. Furthermore, the concentration of active ingredients in such medicinal preparations is usually very high, so that despite the correct application of the recommended dose, considerable amounts may be absorbed in an unwanted manner through various routes. Children are subject to a much higher risk of systemic side effects because ocular dosing is not weight adjusted and physiological development (eg, liver status) differs from that of adults. There is a lack of information about pediatric dosing in the current literature. This review summarizes the most important clinically relevant systemic side effects that may occur during ophthalmic eye treatments. In this review, we discuss general pharmacokinetic considerations as well as the advantages, disadvantages, and consequences of administering drugs from some important drug groups to the eye.

Clinical pharmacokinetics of capecitabine and its metabolites in combination with the monoclonal antibody bevacizumab.

AIM: Capecitabine, designed as a pro-drug to the cytotoxic agent 5-fluorouracil, is widely used in the management of colorectal cancer. This study was designed to investigate whether co-administration of the monoclonal antibody bevacizumab (BVZ) shows potential to modulate the plasma disposition of capecitabine (CCB) and its metabolites. PATIENTS AND METHODS: Nine patients treated with CCB and BVZ for advanced colorectal cancer entered this pharmacokinetic study. In the first cycle CCB was given alone at doses of 1,250 mg/m2 bi-daily for two weeks with one week rest. In the second cycle BVZ co-administration started simultaneously with oral intake of CCB by short infusion of 7.5 mg/kg. RESULTS: Mean plasma concentration time curves of CCB and its metabolites were insignificantly lower in the BVZ combination regimen compared to CCB monotherapy. After repeated cycles of BVZ no significant pharmacokinetic interaction was observed. CONCLUSION: From the pharmacokinetic point of view and in agreement with numerous clinical study data, co-administration of BVZ with CCB appears to be safe and efficient.

A rapid and simple HPLC assay for quantification of capecitabine for drug monitoring purposes.

AIM: Capecitabine, a 5-fluorouracil prodrug, has been integrated into the management of multiple cancer types. In order to obtain information about plasma levels of capecitabine in patients who had drug intake at home during chemotherapy, a simple HPLC method for capecitabine monitoring has been developed and validated. PATIENTS AND METHODS: Capecitabine levels were quantified by a simple reversed-phase HPLC system with an external standard method. Plasma samples were obtained from 12 colorectal cancer patients who underwent chemotherapy with capecitabine alone (1000 mg/m(2)) or combined with oxaliplatin (130 mg/m(2)). RESULTS: Although there was evidence that capecitabine had not been taken according to the chemotherapeutic schedule in two cases, the study demonstrated that its combination with oxaliplatin showed no significant drug-drug interactions. CONCLUSION: Due to its robustness, specificity and sensitivity, the method is also well-suited for capecitabine analysis in other pharmacokinetic studies.

Pharmacokinetics of irinotecan in combination with biweekly cetuximab in patients with advanced colorectal cancer.

BACKGROUND: The effect of biweekly cetuximab (CTX) on the pharmacokinetics of CPT-11 and its metabolites was evaluated in this prospective, paired, crossover study. PATIENTS AND METHODS: Patients with epidermal growth factor receptor-positive advanced colorectal cancer received infusions of CPT-11 (180 mg/m(2); FOLFIRI schedule) every second week. CTX (500 mg/m(2) for 120 min) was infused on day 2, followed by biweekly infusions (500 mg/m(2) for 120 min). Plasma samples were analysed on day 1 of cycle 1 (CPT-11 monotherapy) and on day 1 of cycle 3 or 4 (CPT-11 plus CTX). The endpoint of this study was to evaluate differences in plasma concentrations of CPT-11 and metabolites between cycle 1 and cycle 3 (or 4). RESULTS: Generally, there was little difference in CPT-11 pharmacokinetics when combined with CTX in the 11 enrolled patients. However, a significantly lower area under the concentration-time curve from 0-48 hours was observed for the SN-38 glucuronide metabolite with combination therapy versus monotherapy (by 27%, p<0.05). CONCLUSION: CTX has no clinically relevant impact on the pharmacokinetics of CPT-11 or its activation into SN-38; however, there may be a delay in detoxification of SN-38 by beta-D-glucuronidation.