While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Numerous analyses conducted to date have clearly identified measures that need to be taken to improve research rigor. Supported through the European Union's Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions. EQIPD defines research quality as the extent to which research data are fit for their intended use. Fitness, in this context, is defined by the stakeholders, who are the scientists directly involved in the research, but also their funders, sponsors, publishers, research tool manufacturers and collaboration partners such as peers in a multi-site research project. The essence of the EQIPD Quality System is the set of 18 core requirements that can be addressed flexibly, according to user-specific needs and following a user-defined trajectory. The EQIPD Quality System proposes guidance on expectations for quality-related measures, defines criteria for adequate processes (i.e., performance standards) and provides examples of how such measures can be developed and implemented. However, it does not prescribe any pre-determined solutions. EQIPD has also developed tools (for optional use) to support users in implementing the system and assessment services for those research units that successfully implement the quality system and seek formal accreditation. Building upon the feedback from users and continuous improvement, a sustainable EQIPD Quality System will ultimately serve the entire community of scientists conducting non-regulated preclinical research, by helping them generate reliable data that are fit for their intended use.

SUMMARY1. The whole-cell voltage-clamp technique was applied to isolated rat ventricular myocytes to investigate the effects of D600 (10-9-10-3 M) on the intracellular calcium-independent component of transient outward current, I,, recorded in a sodium-free medium containing 0-5 x 10' M-cadmium and 10-6 M-ryanodine.2. Externally applied D600 reduced I' in a dose-dependent, reversible manner, and accelerated the decay of the current.3. Current-voltage relationships and corresponding activation curves (determined assuming Ilo to be a pure potassium current) were shifted towards positive potentials in the presence of 10' M but not 10-5 M-D600. Steady-state inactivation curves were not affected by either low or high concentrations of D600.4. Under control conditions, the inactivation of 11o is composed of a fast and a slow component. The amplitude of the slow component was more strongly reduced by D600 than that of the fast one. In the presence of 10' M-D600, the slow component was entirely suppressed. 5. Both the time to peak Ilo and the time constant of the fast component of inactivation were markedly reduced at all potentials by D600. The time constant of the slow component was less sensitive to the drug. 6. When the relative quantity of charge carried by each kinetic component of II1 was plotted versus the concentration of D600, the data could be fitted by two distinctly separate dose-response curves with an almost 100-fold difference between the two apparent dissociation constants, of which the values were 2-88 x 10-6 M for the slow phase of inactivation and 2-07 x 10-4 M for the fast one, with Hill coefficients of 0-68 and 0 73 respectively. EFFECT OF D600 ON OUTWARD CURRENT several points, this observation raises the possibility that, besides clear differences, certain similarities may exist between the channels responsible for I,. and ICa.

Ca2+- and Ba2+-permeable channel activity from adult rat ventricular myocytes, spontaneously appeared in the three single-channel recording configurations: cell-attached, and excised inside-out or outside-out membrane patches. Single-channel activity was recorded at steady-state applied membrane potentials including the entire range of physiologic values, and displayed no "rundown" in excised patches. This activity occurred in irregular bursts separated by quiescent periods of 5 to 20 min in cell-attached membrane patches, whereas in excised patch experiments, this period was reduced to 2 to 10 min. During activity, a variety of kinetic behaviors could be observed with more or less complex gating patterns. Three conductance levels: 22, 45 and 78 pS were routinely observed in the same excised membrane patch, sometimes combining to give a larger level. These channels were significantly permeable to divalent cations and showed little or no permeability to potassium or sodium ions. The inorganic blockers of voltage-gated Ca channels, cobalt (2 mM), cadmium (0.5 mM) or nickel (3 mM), had no apparent effect on these spontaneous unitary currents carried by barium ions. Under 10(5) M Bay K 8644 or nitrendipine, the activity was clearly increased in about half of the tested excised inside-out membrane patches. Both dihydropyridines enhanced openings of the larger conductance level, which was only very occasionally seen under control conditions. When the single-channel activity became sustained under 5 x 10(-6) M Bay K 8644, it was possible to calculate the mean unitary current at different membrane potentials and show that the mean current value increased with membrane potential.

While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Numerous analyses conducted to date have clearly identified measures that need to be taken to improve research rigor. Supported through the European Union’s Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions. EQIPD defines research quality as the extent to which research data are fit for their intended use. Fitness, in this context, is defined by the stakeholders, who are the scientists directly involved in the research, but also their funders, sponsors, publishers, research tool manufacturers and collaboration partners such as peers in a multi-site research project. The essence of the EQIPD Quality System is the set of 18 core requirements that can be addressed flexibly, according to user-specific needs and following a user-defined trajectory. The EQIPD Quality System proposes guidance on expectations for quality-related measures, defines criteria for adequate processes (i.e., performance standards) and provides examples of how such measures can be developed and implemented. However, it does not prescribe any pre-determined solutions. EQIPD has also developed tools (for optional use) to support users in implementing the system. Further, EQIPD is preparing training support and assessment services for those research units that successfully implement the quality system and would like to seek formal accreditation. Building upon the feedback from users and continuous improvement, a sustainable EQIPD Quality System will ultimately serve the entire community of scientists conducting non-regulated preclinical research, by helping them generate reliable data that are fit for their intended use.