Trends of adverse drug reactions related-hospitalizations in Spain (2001-2006)

<p>Abstract</p> <p>Background</p> <p>Adverse drug reactions (ADR) are a substantial cause of hospital admissions. We conducted a nationwide study to estimate the burden of hospital admissions for ADRs in Spain during a six-year period (2001-2006) along with the associated total health cost.</p> <p>Methods</p> <p>Data were obtained from the national surveillance system for hospital data (Minimum Basic Data Set) maintained by the Ministry of Health and Consumer Affairs, and covering more than 95% of Spanish hospitals. From these admissions we selected all hospitalization that were code as drug-related (ICD-9-CM codes E), but intended forms of overdoses, errors in administration and therapeutics failure were excluded. The average number of hospitalizations per year, annual incidence of hospital admissions, average length of stay in the hospital, and case-fatality rate, were calculated.</p> <p>Results</p> <p>During the 2001-2006 periods, the total number of hospitalized patients with ADR diagnosis was 350,835 subjects, 1.69% of all acute hospital admissions in Spain. The estimated incidence of admissions due to ADR decreased during the period 2001-2006 (p < 0.05). More than five percent of patients (n = 19,734) died during an ADR-related hospitalization. The drugs most commonly associated with ADR-related hospitalization were antineoplastic and immunosuppressive drugs (n = 75,760), adrenal cortical steroids (n = 47,539), anticoagulants (n = 26,546) and antibiotics (n = 22,144). The costs generated by patients in our study increased by 19.05% between 2001 and 2006.</p> <p>Conclusions</p> <p>Approximately 1.69% of all acute hospital admissions were associated with ADRs. The rates were much higher for elderly patients. The total cost of ADR-related hospitalization to the Spanish health system is high and has increased between 2001 and 2006. ADRs are an important cause of admission, resulting in considerable use of national health system beds and a significant number of deaths.</p

In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization

Treating pain by inhibiting ATP activation of P2X3-containing receptors heralds an exciting new approach to pain management, and Afferent's program marks the vanguard in a new class of drugs poised to explore this approach to meet the significant unmet needs in pain management. P2X3 receptor subunits are expressed predominately and selectively in so-called C- and Aδ-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing system in the human body. P2X3 antagonists block the activation of these fibers by ATP and stand to offer an alternative approach to the management of pain and discomfort. In addition, P2X3 is expressed pre-synaptically at central terminals of C-fiber afferent neurons, where ATP further sensitizes transmission of painful signals. As a result of the selectivity of the expression of P2X3, there is a lower likelihood of adverse effects in the brain, gastrointestinal, or cardiovascular tissues, effects which remain limiting factors for many existing pain therapeutics. In the periphery, ATP (the factor that triggers P2X3 receptor activation) can be released from various cells as a result of tissue inflammation, injury or stress, as well as visceral organ distension, and stimulate these local nociceptors. The P2X3 receptor rationale has aroused a formidable level of investigation producing many reports that clarify the potential role of ATP as a pain mediator, in chronic sensitized states in particular, and has piqued the interest of pharmaceutical companies. P2X receptor-mediated afferent activation has been implicated in inflammatory, visceral, and neuropathic pain states, as well as in airways hyperreactivity, migraine, itch, and cancer pain. It is well appreciated that oftentimes new mechanisms translate poorly from models into clinical efficacy and effectiveness; however, the breadth of activity seen from P2X3 inhibition in models offers a realistic chance that this novel mechanism to inhibit afferent nerve sensitization may find its place in the sun and bring some merciful relief to the torment of persistent discomfort and pain. The development philosophy at Afferent is to conduct proof of concept patient studies and best identify target patient groups that may benefit from this new intervention

Influence of visco-elasticity of low-k dielectrics on thermo-mechanical behavior of dual damascene process

\u3cp\u3eFor backend processes, thermo-mechanical failure is one of the major failure modes. A representative metal structure in a Cu/low-k dual damascene process is examined, considering the major thermal loads and process steps through combined finite element simulation with experiments. Firstly, the low-k material, in our case the polymeric material SiLK (trade name of the Dow Chemical Company) is characterized and modeled to provide a reliable material model and data for the simulations. Characterization measurements (nano-indentation-creep test) are carried out on a polymer film deposited on a substrate. Here a quasi-elastic approach is used to account for the substrate influence and the time dependency acting at the same time. Elastic indentation curves are simulated with a varying modulus of the film within an expected interval. The coefficients for a Maxwell relaxation model are calculated, and verified through FEM simulations. Furthermore results of temperature dependency and influence on the modulus are examined and the WLF coefficients are calculated providing time and temperature dependent material parameters for the process simulations. The main dual damascene process steps are simulated using the obtained material model. Stresses are examined at different critical locations. Furthermore an initial defect is placed at a low-k-oxide interface, where energy release rates are determined. Our results show that Cu/low-k structures exhibit significantly different reliability characteristics than their aluminum predecessors, which are more critical from several design aspects. This not only makes the stress management in the stacks more difficult, but also strongly impacts packaging.\u3c/p\u3

The effect of material properties and initial defects on the thermo-mechanical behavior of a dual damascene module

\u3cp\u3eFor backend processes, thermo-mechanical failure is one of the major failure modes. A representative metal structure in a Cu/low-k dual damascene process is examined considering the major thermal loads and process steps through combined finite element simulation with experiments. Firstly the low-k material, in our case the polymeric material SiLK (trade name of the DOW Chemical Company), is characterized and modeled to provide a reliable material model and data for the simulations. The coefficients for a Maxwell relaxation model are calculated, temperature dependency and its influence on the modulus are examined and the WLF coefficients are calculated providing time and temperature dependent material parameters for the process simulations. The main dual damascene process steps are simulated using the obtained material model. Stresses are examined at different critical locations. Furthermore an initial defect is placed at a low-k-oxide interface, where energy release rates are determined. Our results show that Cu/low-k structures exhibit significantly different reliability characteristics than their aluminum predecessors, are more critical from several design aspects. This not only makes the stress management in the stacks more difficult, but also strongly impact packaging.\u3c/p\u3

Mechanical characterization and modeling of low-dielectric-constant SiLK films using nano-indentation:Time- and temperature-effects

\u3cp\u3eSiLK [1] semiconductor dielectric is a polymeric material developed for use as a thin film dielectric in the interconnect structure of high density integrated circuits. Among others, its thermo-mechanical properties play a dominant role for the integrity and reliability of the interconnect, during processing, testing and use. Being a polymer, SiLK films may show viscoelastic (time-dependent) behavior. In this paper, we use nano-indentation experiments to determine the viscoelastic properties of a thin SiLK film on a silicon substrate as a function of temperature within the range 25-100°C. Also, the effect of the degree of curing of the films on the viscoelastic properties is studied. The experiments indeed show that the SiLK film responds in a viscoelastic way. The viscoelastic behavior can be described by a linear viscoelastic generalized Maxwell model with a power law relaxation spectrum. The effect of temperature can be modeled by an Arrhenius time-temperature superposition in the temperature range 25-100°C. Thus, we obtain a full description of the viscoelastic properties of the SiLK film that can be directly implemented in a (commercially available) Finite Element Modeling package like Marc or Ansys. Furthermore, the degree of curing of the SiLK film clearly affects the viscoelastic properties. Within the range of cure index from 0.65 to 0.98, a significant change in the relaxation modulus is observed.\u3c/p\u3