A method for assessing and monitoring consistency of nonclinical ECG analysis.

Cardiovascular safety is a key area of concern for new drugs in development, and the collection and analysis of electrocardiograms (ECGs) is a standard and major component of nonclinical testing. Digital data capture technology allows for high-throughput and long-duration ECG collections, resulting in large volumes of data. Consistent analysis of these ECG data is critical for detecting meaningful changes during nonclinical drug development.

Evaluation of cardiovascular changes in dogs administered three positive controls using jacketed external telemetry-blood pressure (JET-BP).

Introduction: Nonclinical safety studies are increasingly incorporating cardiac safety endpoints to discover potential cardiovascular liabilities. This trend for more thorough cardiovascular nonclinical safety evaluation is prudent given the high attrition rate of potential therapeutics due to unexpected cardiovascular liabilities discovered in late-stage clinical trials or post-market approval. In particular, the causal relationship of blood pressure changes that lead to risk of major adverse cardiac events suggests hemodynamic changes should be critically evaluated in preclinical studies of novel therapeutics.

Intravenous solid tip ECG lead placement in telemetry implanted dogs: Part 2: High quality telemetry signals yield high sensitivity to drug-induced changes.

Introduction: Dogs are commonly used in cardiovascular drug safety assessment, and implanted telemetry models include subcutaneous or epicardial electrocardiogram (ECG) electrode placements. The purpose of this study was to determine the sensitivity of a canine telemetry model with intravenous ECG lead placement: the negative ECG lead (solid tip) inserted into the jugular vein and the positive lead sutured to the diaphragm. Reference drugs were administered to test the sensitivity to drug-induced changes.

Intravenous solid tip lead placement in telemetry implanted dogs. Part 1: Surgical methods, signal quality, and pathological endpoints.

Introduction: Electrocardiogram (ECG) signals in safety pharmacology studies are generally collected via subcutaneous or epicardial leads. Subcutaneous placement is an easier procedure, but signals often contain artifacts. Epicardial leads offer improved quality but require additional surgical expertise.

Differential effects of Vitamin D analogs on calcium transport.

It is well known that the efficiency of intestinal active calcium transport is regulated by the Vitamin D receptor pathway and Vitamin D analogs seem to exhibit differential effects on intestinal active calcium transport. To investigate the molecular basis for the difference among Vitamin D analogs, we tested three Vitamin D analogs: 1,25-dihydroxyvitamin D(3), 19-nor-1,25-dihydroxyvitamin D(2), and 1alpha-hydroxyvitamin D(2) ex vivo and in vitro. In 5/6 nephrectomized rat intestinal active calcium transport, 19-nor-1,25-dihydroxyvitamin D(2) did not show a significant effects on intestinal active calcium transport at all the concentrations tested, while 1alpha-hydroxyvitamin D(2) at 0.

Pharmacological MRI in awake rats reveals neural activity in area postrema and nucleus tractus solitarius: relevance as a potential biomarker for detecting drug-induced emesis.

Drug-induced vomiting (emesis) is a major concern in patient care and a significant hurdle in the development of novel therapeutics. With respect to the latter, rodents, such as the rat and mouse, are typically used in efficacy and safety studies; however, drug-induced emesis cannot be readily observed in these species due to the lack of an emetic reflex. It is known that emesis can be triggered by neural activity in brain regions including area postrema (AP) and nucleus tractus solitarius (NTS).

Predictive, non-GLP models of secondary pharmacodynamics: putting the best compounds forward.

Secondary pharmacodynamic studies of new chemical entities (NCEs) play a critical role in support of efficient drug discovery. In an era in which speed and efficiency are the norm for pharmaceutical discovery, the need to identify NCEs with greater patient tolerability continues to increase. Early use of secondary pharmacodynamic models (in vivo and in vitro) provides the foundation for critical, early decisions regarding lead molecules.

Dopamine D2, but not D4, receptor agonists are emetogenic in ferrets.

Agents that activate the dopamine D2-like family of receptors elicit emesis in humans and other species with a vomiting/emetic reflex; however, the lack of dopamine receptor subtype selective agonists has hampered an understanding of which dopamine D2-like receptor subtype(s) contributes to the emetic response. In this study, stable cell lines expressing the ferret dopamine D2-long (D2L) and D4 receptors were used to characterize known dopamine agonists via radioligand binding and calcium ion flux assays, while emetic activity of these dopamine receptor agonists was determined in male ferrets. Latencies to first emetic event, average number of emetic episodes, and stereotypical behaviors which may be indicative of nausea were also determined.

ABT-089: pharmacological properties of a neuronal nicotinic acetylcholine receptor agonist for the potential treatment of cognitive disorders.

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride salt] is a selective neuronal nicotinic receptor (NNR) modulator with cognitive enhancing properties in animal models of cognitive functioning. Amongst NNR subtypes, ABT-089 shows selectivity for the cytisine binding site on the alpha4beta2 receptor subtype as compared to the alpha-bungarotoxin (alpha-BgT) binding sites on the alpha7 and alpha1beta1deltagamma receptor subtypes. In functional in vitro electrophysiological and cation flux assays, ABT-089 displays differential activity including agonism, partial agonism and antagonism depending upon the NNR subtype and assay.

Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats.

Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) responsible for its erectogenic effect is not known. Here we report that the dopamine D(4) receptor plays a role in the regulation of penile function.

Emetic liability testing in ferrets.

Evidence of a candidate drug's efficacy and safety is mandatory for successful drug registration by regulatory authorities. However, a third property, tolerability, often determines a drug's acceptance by the patient population. Gastrointestinal events often determine the maximum tolerated dose in Phase I clinical trials.