Requiem for impact factors and high publication charges.

Journal impact factors, publication charges and assessment of quality and accuracy of scientific research are critical for researchers, managers, funders, policy makers, and society. Editors and publishers compete for impact factor rankings, to demonstrate how important their journals are, and researchers strive to publish in perceived top journals, despite high publication and access charges. This raises questions of how top journals are identified, whether assessments of impacts are accurate and whether high publication charges borne by the research community are justified, bearing in mind that they also collectively provide free peer-review to the publishers.

From Gutenberg to Open Science: An Unfulfilled Odyssey.

Preclinical Research With the almost global availability of the Internet comes the expectation of universal accessibility to knowledge, including scientific knowledge-particularly that generated by public funding. Currently this is not the case. In this Commentary we discuss access to this knowledge, the politics that govern peer review and publication, and the role of this knowledge as a public good in medicine.

Nous sommes tous des bacteries: implications for medicine, pharmacology and public health.

As a species we humans are outnumbered by bacteria in both cell and gene count. This somewhat humbling observation is key to the increasing recognition that the long-standing symbiotic and commensal relations between Homo sapiens and bacteria are of great significance to basic human physiology and health. Knowledge of our human bacterial environment is contributing to an understanding of a variety of disorders including obesity and metabolic syndrome, cardiovascular disease, immunity, and neuronal development and behavior.

The chemist as astronaut: searching for biologically useful space in the chemical universe.

Chemical space whether defined by small molecules or large proteins is larger than can be usefully explored. One of the challenges of drug discovery is thus the definition of the overlap between chemical space, biologically useful space and pharmacological space and how this may be employed in the discovery of new small molecule drugs. Despite the decrease in drug discovery productivity in recent years there is no shortage of targets for small molecule intervention, including stroke, pain, neurodegenerative diseases, inflammation and bacterial and viral infections.

What is the future of peer review? Why is there fraud in science? Is plagiarism out of control? Why do scientists do bad things? Is it all a case of: "all that is necessary for the triumph of evil is that good men do nothing"?

Peer review is an essential component of the process that is universally applied prior to the acceptance of a manuscript, grant or other scholarly work. Most of us willingly accept the responsibilities that come with being a reviewer but how comfortable are we with the process? Peer review is open to abuse but how should it be policed and can it be improved? A bad peer review process can inadvertently ruin an individual's career, but are there penalties for policing a reviewer who deliberately sabotages a manuscript or grant? Science has received an increasingly tainted name because of recent high profile cases of alleged scientific misconduct. Once considered the results of work stress or a temporary mental health problem, scientific misconduct is increasingly being reported and proved to be a repeat offence.

Calcium channel antagonists: clinical uses--past, present and future.

The calcium channel antagonists are a mature group of drugs directed at cardiovascular diseases including hypertension, angina, peripheral vascular disorders and some arrhythmic conditions. Their sites and mechanisms of actions have been well explored over the past two decades and their interactions at the alpha(1) subunit of L-type channels (Ca(V)1.1-1.

Drug discovery and delivery in the 21st century.

Drug discovery in the late 20th century has increasingly focused on the definition and characterization of the macromolecular substrates that serve as targets for drug design. The advent of genomics and the molecular biology revolution has permitted both the definition of new targets and the characterization of the genetic basis of disease states. The introduction of powerful new technologies should greatly accelerate the pace of new drug discovery.

L-type calcium channels.

The Ca2+ channel blockers represent a successful group of therapeutic agents directed against cardiovascular targets, including hypertension and angina. These drugs, including the first-generation verapamil, nifedipine and diltiazem are directed against a subclass of voltage-gated Ca2+ channel - the L-type channel. Other subclasses of Ca2+ channel exist and are targets for new indications.

Division of Medicinal Chemistry--small molecule inhibitors of protein-protein interactions.

Protein-protein interactions lie at the heart of the majority of cell recognition and signal transduction processes. Increasingly, medicinal chemistry researchers are interested in small molecule inhibitors of such interactions. This contrasts with approaches based on the design of small molecule receptor ligands mimicking physiological ligands, eg, neurotransmitters and small hormones.

Mechanism of tissue-selective drug action in the cardiovascular system.

Analysis of the human genome project tells us that there may be as few as 3000 genes that are likely to be good drug targets. Although the number of targets is still very large, these data have been interpreted by some to mean that the pharmaceutical industry may someday run out of novel drug targets. Despite the doom and gloom of such analysis, there is considerable reason for optimism.

Drug targets in the voltage-gated calcium channel family: why some are and some are not.

The L-type calcium channel antagonists have been, and continue to be, a very successful group of therapeutic agents targeted at cardiovascular disorders, notably angina and hypertension. The discovery that the voltage-gated calcium channels are a large and widely distributed family with important roles in both the peripheral and central nervous systems has initiated a major search for drugs active at other calcium channel types directed at disorders of the central nervous system, including pain, epilepsy, and stroke. These efforts have not been therapeutically successful thus far, and small molecule equivalents of the L-type blockers nifedipine, diltiazem, and verapamil directed at non-L-type channels have not been found.

1,4-Dihydropyridines as calcium channel ligands and privileged structures.

1. The 1,4-dihydropyridine nucleus serves as the scaffold for important cardiovascular drugs-calcium antagonists-including nifedipine, nitrendipine, amlodipine, and nisoldipine, which exert their antihypertensive and antianginal actions through actions at voltage-gated calcium channels of the CaV1 (L-type) class. 2.

The 1,4-dihydropyridine nucleus: a pharmacophoric template part 1. Actions at ion channels.

The 1,4-dihydropyridine nifedipine is a prototypical example of the group of calcium channel blockers that also includes a number of second and third generation agents. These drugs enjoy substantial therapeutic prominence for their cardiovascular actions, including hypertension and angina. These actions are exerted at a specific member of the voltage-gated calcium channel family -the L-type channel.

Interaction of azimilide with neurohumoral and channel receptors.

Binding of the class III antiarrhythmic agent azimilide to brain, heart, and other organ receptors was assessed by standard radioligand binding techniques. In a survey of 60 receptors, azimilide at 10 microM inhibited binding by more than 50% at serotonin uptake (K(i): 0.6 microM), muscarinic (K(i): 0.

Regulation of L-type calcium channels in pituitary GH(4)C(1) cells by depolarization.

The neurosecretory anterior pituitary GH(4)C(1) cells exhibit the high voltage-activated dihydropyridine-sensitive L-type and the low voltage-activated T-type calcium currents. The activity of L-type calcium channels is tightly coupled to secretion of prolactin and other hormones in these cells. Depolarization induced by elevated extracellular K(+) reduces the dihydropyridine (+)-[(3)H]PN200-110 binding site density and (45)Ca(2+) uptake in these cells ().

Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG.

Administration of certain fluoroquinolone antibacterials has been associated with prolongation of the QT interval on the electrocardiogram and, on rare occasions, ventricular arrhythmia. Blockade of the human cardiac K+ channel HERG often underlies such clinical findings. Therefore, we examined a series of seven fluoroquinolones for their ability to interact with this channel.