Enhancing Pharmacovigilance from the US Experience: Current Practices and Future Opportunities.

This review is intended to present perspectives from the US experience in enhancing pharmacovigilance on current practices and future opportunities. Best practices concepts could be applied worldwide through the presentation of how three pillars of pharmacovigilance: (1) medical and scientific excellence, (2) operational and compliance excellence, and (3) knowledge sharing and experts development in the field could serve as a framework for the establishment of an efficient and successful global pharmacovigilance system.

Hormesis pervasiveness and its potential implications for pharmaceutical research and development.

This mini-review illustrates that hormesis is not only confined to the areas of biochemistry, radiation biology and toxicology, where it is traditionally known, but illustrates, by citing published scientific literature, that it is found across a wide range of biomedical science and clinical medicine such as neuroscience, cardiology and oncology. The use of techniques and technology, including high through-put screening, micro-dosing or phase 0 studies, pharmacometrics and adaptive trial design in the clinic, are proposed to illustrate how acknowledging the potential impact of hormesis throughout different stages of drug discovery and development, including hurdles related to efficacy and safety, could help the pharmaceutical industry address some of its major and frequently mentioned challenges.

Acute studies of a new primate model of reversible middle cerebral artery occlusion.

The recent failure of many clinical trials of neuroprotective compounds may be due in part to poor animal models of human stroke. We have developed an endovascular stroke model in nonhuman primates that is compatible with serial magnetic resonance imaging (MRI) monitoring. Using cynomologous macaques (n = 4), a microcatheter was navigated transarterially (under fluoroscopic guidance) from the femoral artery to the middle cerebral artery (MCA).

Delayed treatment with nicotinamide inhibits brain energy depletion, improves cerebral microperfusion, reduces brain infarct volume, but does not alter neurobehavioral outcome following permanent focal cerebral ischemia in Sprague Dawley rats.

Delayed treatment with nicotinamide (NAm) reduces infarction induced by middle cerebral artery occlusion (MCAO) in rats. This study explored some potential mechanisms by which delayed NAm treatment may confer protection in the brain of Sprague-Dawley rats following permanent MCAO (pMCAO). NAm (500 mg/kg) or vehicle was given 2 h after the onset of pMCAO.

Nicotinamide modulates energy utilization and improves functional recovery from ischemia in the in vitro rabbit retina.

The central nervous system depends critically on a regular supply of oxygen and glucose for the formation of adenosine triphosphate (ATP) and the sustenance of its energy metabolism. Consequently, a significant reduction in the supply of oxygen and glucose to neuronal tissue causes an imbalance between the energy supply and demand, inducing the onset of neuronal ischemia and triggering many metabolic cascades leading to irreversible injury and cell death. Nicotinamide (NAm), an essential precursor to nicotinamide adenine dinucleotide (NAD+), which raises brain ATP levels, may improve cerebral blood flow and is neuroprotective against ischemia-induced injury.

The acoustic startle reflex in Sprague-Dawley rats is altered by permanent middle cerebral artery occlusion.

The startle reflex is an unconditioned, quantifiable behavior used to study sensory modalities. We examined whether the acoustic startle reflex (ASR) was sensitive to lesions induced by focal cerebral ischemia. Sprague-Dawley rats were pre-screened for startle reflex responses 3-6 days prior to surgery and there were no differences in mean startle amplitude across groups.

ACEA 1021: flip or flop?

Inasmuch as glutamate is the main excitatory neurotransmitter in the central nervous system, strategies aimed at counteracting glutamate excitotoxicity, which is at least partially involved in many acute neurologic, chronic neurodegenerative and psychiatric diseases, are challenging. Blockade of the NMDA receptor was identified as one way of achieving selective antagonism and overcoming glutamate neurotoxicity, yet not without liabilities. Glycine site antagonism of the NMDA receptor in 1987 offered a significant advance in blocking this receptor because such drugs were shown to lack most of the side effects, such as memory impairment, ataxia, lack of motor coordination and psychotomimetic effects, which accompanied competitive and non-competitive NMDA receptor antagonists.

Delayed treatment with 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione, a glycine site N-methyl-D-aspartate antagonist, protects against permanent middle cerebral artery occlusion in male rats.

The glycine site, N-methyl-D-aspartate antagonist 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA1021) was previously tested only in models of transient stroke with pre-treatment paradigms. We therefore tested whether it would protect in two models of permanent stroke in two rat strains with delayed treatment. Intravenous ACEA1021 reduced cerebral infarction by 62% (15 min treatment delay) and 42% (2 h treatment delay), relative to vehicle-injected rats, when subjected to a modified Tamura and permanent intraluminal filament model of stroke, respectively.

Metabolic effects of hypothermia and its neuroprotective effects on the recovery of metabolic and electrophysiological function in the ischemic retina in vitro.

Objective: Reduction in energy usage has been investigated as the mechanism by which hypothermia provides protection during ischemia. We describe experiments using hypothermia in the rabbit retina in vitro that show a correlation between hypothermia-induced reductions in energy usage and neuroprotection.

Methods: We examined energy metabolism and electrophysiological function under control/nonischemic conditions during 1 or 2 hours of "ischemia" (induced by decreasing glucose from 6 to 1 mmol/L and oxygen from 95 to 15%) and during 3 to 4 hours of "return-to-control" conditions.

Acute administration of Ginkgo biloba extract (EGb 761) affords neuroprotection against permanent and transient focal cerebral ischemia in Sprague-Dawley rats.

We examined the neuroprotective action of a standardized extract of Ginkgo biloba leaves (EGb 761) in permanent and transient middle cerebral artery (MCA) occlusion models in Sprague-Dawley rats. Forty-four animals were given either EGb 761 (50-200 mg/kg) or vehicle intraperitoneally, 1 hr before permanent MCA occlusion, to evaluate the dose-response effects. An additional 58 animals received EGb 761 (200 mg/kg) or vehicle, 0.

Functional CT perfusion imaging in predicting the extent of cerebral infarction from a 3-hour middle cerebral arterial occlusion in a primate stroke model.

Background And Purpose: Our purpose was to determine whether cerebral perfusion functional CT (fCT), performed after endovascular middle cerebral artery (MCA) occlusion, can be used to predict final cerebral infarction extent in a primate model.

Methods: fCT with bolus tracking was performed before and 30 and 150 minutes after 3-hour digital subtraction angiography (DSA)-guided endovascular MCA occlusion in five baboons. Parametric cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) maps were constructed by voxel-by-voxel gamma variate fitting and used to determine lesion sizes.

Delayed treatment with nicotinamide (vitamin B3) reduces the infarct volume following focal cerebral ischemia in spontaneously hypertensive rats, diabetic and non-diabetic Fischer 344 rats.

Since hypertension and/or hyperglycemia are risk factors for stroke, we examined whether the putative neuroprotectant, nicotinamide (NAm), could protect spontaneously hypertensive rats (SHR) or diabetic Fischer 344 rats against focal cerebral ischemia using a model of permanent middle cerebral artery occlusion (MCAo). Intravenous NAm given 2 h after MCAo significantly reduced the infarct volume of SHR (750 mg/kg, 31%, P<0.01) and diabetic (500 mg/kg, 56%, P<0.

Therapeutic window for nicotinamide following transient focal cerebral ischemia.

The therapeutic window with the neuroprotectant nicotinamide (NAm) was tested in a model of stroke. Either 2, 4 or 6 h after the onset of transient (2 h) focal cerebral ischemia, Wistar rats received either saline or NAm (500 mg/kg). Sensory and motor behavioral scores and weight of the animals were obtained before surgery, and 2 h, 3 and 7 days after stroke onset.