Drug class effects: definitions and practical applications.

The concept of drug class effect is profoundly rooted in clinical practice. The use of drugs seen as similar in their clinical effects--and therefore interchangeable--is very frequent: two examples of this are the use of beta-blockers in arterial hypertension and angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure. The definition of drug class effect is based on three concepts: a similar chemical structure (for example, the dihydropyridine ring of some calcium channel blockers), a similar mechanism of action (beta-blockers block adrenoreceptors), or similar pharmacological effects (antihypertensives, antianginals, etc.). In this article, we will describe the type of evidence that a cardiologist can use in order to select a specific drug (from within a class). It constitutes a clinical approach, different from the one that might be used by a third party payer (more interested in cost-effectiveness issues) or the pharmaceutical industry (more interested in promoting sales). As usual, the recommendations are based on the strength of scientific evidence.     

Molecular characterization of methicillin-resistant coagulase-negative staphylococci from a neonatal intensive care unit.

OBJECTIVE: To evaluate clonal dissemination of methicillin-resistant coagulase-negative staphylococci (CNS). SETTING: Neonatal intensive care unit of a 180-bed, university-affiliated general hospital. PATIENTS: Neonates admitted to the neonatal intensive care unit between March 1999 and October 2000, from whom CNS were isolated as a unique pathogen. Patients from other wards from whom epidemiologically unrelated staphylococci strains were obtained served as control-patients. METHODS: Conventional methods were used for phenotypic characterization of CNS. Methicillin resistance was determined by mecA polymerase chain reaction (PCR) amplification. Genotypic characterization was done by random amplification of DNA with degenerated primers (RAPD) and repetitive element sequence-based PCR (rep-PCR). RESULTS: Forty methicillin-resistant CNS isolates obtained from neonates were characterized as Staphylococcus epidermidis (33), S. hominis (5), S. warneri (1), and S. auricularis (1). Both RAPD and rep-PCR indicated the presence of 4 different clones among the 33 S. epidermidis isolates. In turn, the 4 randomly selected, epidemiologically unrelated methicillin-resistant CNS strains obtained from control-patients showed 3 new profiles by RAPD and 2 by rep-PCR, which differed from the corresponding patterns mentioned earlier. Persistence of S. hominis in a neonate could be assessed by both genotypic techniques. CONCLUSIONS: The molecular characterization of the methicillin-resistant CNS studied indicated dissemination of one particular methicillin-resistant CNS clone among the neonates in the ward studied. Although RAPD showed a superior power to discriminate among methicillin-resistant CNS isolates, both RAPD and rep-PCR detected intraspecific and interspecific genomic diversity.     

Indomethacin-loaded nanocapsules treatment reduces in vivo glioblastoma growth in a rat glioma model

Multimodal combinations of target agents with radiation and chemotherapy may enhance cancer treatment efficacy; however, despite these treatments, gliomas recur early due to their highly proliferative, infiltrative and invasive behaviors. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted intensive interest in recent years since they may provide a sustained, controlled and targeted delivery. In the present study, we investigated the effect of indomethacin-loaded nanocapsules in an experimental glioma model. The rats treated with indomethacin-loaded nanocapsules demonstrated a significant reduction in tumor size and half of these animals presented just cells with characteristics of a residual tumor, as shown by immunostaining for nestin. Pathological analyses showed that the treated gliomas presented a significant reduction in the mitotic index and other histological characteristics that indicate a less invasive/proliferative tumor. An important finding of the present study is that indomethacin carried by polymeric nanocapsules achieved higher intracerebral drug concentrations than those of indomethacin in solution. Furthermore, indomethacin achieved a greater concentration in the hemisphere where the glioma was implanted, compared with the contralateral healthy hemisphere. Indomethacin-loaded nanocapsule treatment did not cause characteristics of toxicity and increased the survival of animals. Thus, our results show that polymeric nanocapsules are able to increase the intratumoral bioavailability of indomethacin and reduce the growth of implanted gliomas. Data suggest that indomethacin-loaded nanocapsules could offer new and potentially highly effective strategies for the treatment of malignant gliomas.     

Changes in bioactive composition of fresh-cut strawberries stored under superatmospheric oxygen,low-oxygen or passive atmospheres

The effect of different modified atmosphere packaging conditions (2.5 kPa O₂ + 7 kPa CO₂, 10 kPa O₂ + 5 kPa CO₂, 21 kPa O₂, 60 kPa O₂ and 80 kPa O₂) on the antioxidant properties of fresh-cut strawberries was investigated. Changes in phenolic acids, flavonoids (anthocyanins and flavonols), vitamin C and antioxidant capacity were analyzed for 21 days at 4 °C. O₂, and CO₂ package headspace concentrations were also evaluated. The initial quercetin content was maintained for 11–14 days regardless of the initial in-package atmospheres, but then it was dramatically enhanced in the strawberries stored at ≥21 kPa O₂. High O₂ concentrations inside headspace packages promoted greater losses of phenolic acids (p-coumaric, hydroxybenzoic and ellagic acid) and vitamin C during the storage period compared to low O₂ levels. Anthocyanin content increased significantly beyond day 9 in strawberry wedges stored at ≤21 kPa O₂, whereas it was almost constant throughout the storage in fresh-cut strawberries at superatmospheric O₂ atmospheres. In general, low-O₂ and passive atmospheres best maintained the initial antioxidant capacity of fresh-cut strawberries through the cold storage. Therefore, 2.5 kPa O₂ + 7 kPa CO₂ atmospheres are proposed to prevent oxidation of the main antioxidant compounds in fresh-cut strawberries.     

Additional dose constraints for analytical beam weighting optimization in IMRT.

This work presents an improvement to an algorithm for analytical beam weighting optimization where a flexible objective function, which considers 'importance factors' for each anatomical region and 'allowed deviations' from the prescribed dose, is defined. This upgrading allows forcing the mean value of the dose distribution to be the desired value, by using Lagrange multipliers. A real case is presented to show the effect of this change.     

Cytoreductive surgery and intraoperative intraperitoneal hyperthermic chemotherapy in patients with peritoneal carcinomatosis of colorectal origin

The median survival in patients with peritoneal carcinomatosis from colorectal adenocarcinoma is, with conventional approaches, only about six months. Combined treatment consisting of maximum cytoreductive surgery plus intraoperative intraperitoneal hyperthermic chemotherapy has been shown, albeit in small non-comparative series, to increase disease-free survival and overall survival, compared with previous series. Further, a randomized trial has demonstrated better results (a median survival of 22.4 months) with cytoreduction plus intraperitoneal chemotherapy compared with conventional chemotherapy. Technical considerations, infrastructure requirements and possible complications imply specialized centres and staff. Surgery consists of peritonectomy of affected areas and fulguration of all macroscopic lesions. Intraperitoneal chemotherapy must reach all parts of the peritoneal cavity and the temperature of the hyperthermic procedure must be maintained between 42–44°C. Three prognostic factors associated with this procedure are: pathologic tumour grade, peritoneal carcinomatosis index, and cytoreductive surgery grade.     

Dual inhibition of Raf and VEGFR2 reduces growth and vascularization of hepatocellular carcinoma in an experimental model

Background and aims Activation of the mitogen-activated protein kinase–extracellular-signal-regulated kinase (ERK) pathways plays an important role in the progression of hepatocellular carcinoma (HCC). Importantly, Raf kinases are principal effectors within this oncogenic signaling cascade. We hypothesized that concomitant inhibition of Raf and vascular endothelial growth factor receptor 2 (VEGFR2) will affect tumor growth and angiogenesis of HCC. Materials and methods Human HCC cell lines, endothelial cells (EC), and vascular smooth muscle cells (VSMC) were used. For blocking Raf kinase and VEGFR2, the small molecule inhibitor NVP-AAL881 (Novartis, USA) was used. Activation of signaling intermediates was assessed by Western blotting, and changes in cell motility were evaluated in migration assays. Effects of NVP-AAL881 on HCC growth were determined in a subcutaneous tumor model. Results NVP-AAL881 disrupted activation of ERK and STAT3 in HCC cells and reduced cancer cell motility. In addition, the migration of ECs and VSMC was also significantly impaired. In ECs, HCC-conditioned media-induced activation of STAT3 was diminished by NVP-AAL881 treatment. In vivo, NVP-AAL881 significantly reduced tumor growth, CD31-vessel area, and numbers of BrdU-positive proliferating tumor cells. Conclusions Combined inhibition of Raf and VEGFR2 disrupts oncogenic signaling and efficiently reduces tumor growth and vascularization of HCC. Hence, this strategy could prove valuable for therapy of HCC. German Society of Surgery, Surgical Forum 2008, Best of Abstracts Sven Arke Lang and Isabel Brecht contributed equally to this work. These studies were supported, in part, by the German Cancer Aid (Deutsche Krebshilfe, Max-Eder Programm, Bonn, Germany; O.S.), and a grant from the University of Regensburg, Medical Faculty (ReForM; O.S.; S.A.L.).