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Pharmacologic Profiles (pharmacologic + profile)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

Pharmacologic profile of zoledronic acid: A highly potent inhibitor of bone resorption

DRUG DEVELOPMENT RESEARCH, Issue 4 2002
Jonathan R. Green
Abstract Bisphosphonates are effective in treating benign and malignant skeletal diseases characterized by enhanced osteoclastic bone resorption (i.e., osteoporosis, Paget's disease, tumor-induced osteolysis). The nitrogen-containing bisphosphonate pamidronate is currently the standard treatment for hypercalcemia of malignancy (HCM) and skeletal complications of bone metastases. Zoledronic acid, a novel nitrogen-containing bisphosphonate with an imidazole substituent, has demonstrated more potent inhibition of osteoclast-mediated bone resorption than all other bisphosphonates, including pamidronate, in both in vitro and in vivo preclinical models. Zoledronic acid inhibited ovariectomy-induced bone loss in adult monkeys and rats, and long-term treatment prevented skeletal turnover and subsequent bone loss, reduced cortical porosity, and increased mechanical strength. Zoledronic acid also significantly inhibited bone loss associated with arthritis, bone metastases, and prosthesis loosening. The increased potency of zoledronic acid vs. pamidronate has been demonstrated clinically: zoledronic acid (4 or 8 mg iv) was superior to pamidronate (90 mg iv) in normalizing corrected serum calcium in patients with HCM. In patients with bone metastases, low doses of zoledronic acid (, 2 mg) suppressed bone resorption markers , 50% below baseline, whereas pamidronate 90 mg yielded only 20 to 30% suppression. Importantly, the increased potency of zoledronic acid is not associated with an increased incidence of local (bone) or systemic adverse events. Zoledronic acid does not impair bone mineralization and, compared with pamidronate, has a greater renal and intestinal tolerability therapeutic index. Thus, based on preclinical assays and clinical data, zoledronic acid is the most potent bisphosphonate tested to date. Given its potency and excellent safety profile, zoledronic acid is now poised to become the new standard of treatment for HCM and metastatic bone disease. Drug Dev. Res. 55:210,224, 2002. © 2002 Wiley-Liss, Inc. [source]

Cloning and pharmacological characterization of the equine adenosine A2A receptor: a potential therapeutic target for the treatment of equine endotoxemia

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2006
C. I. BRANDON
The aim of the current study was to clone the equine adenosine A2A receptor gene and to establish a heterologous expression system to ascertain its pharmacologic profile via radioligand binding and functional assays. An eA2A -R expression construct was generated by ligation of the eA2A cDNA into the pcDNA3.1 expression vector, and stably transfected into human embryonic kidney cells (HEK). Binding assays identified those clones expressing the eA2A -R, and equilibrium saturation isotherm experiments were utilized to determine dissociation constants (KD), and receptor densities (Bmax) of selected clones. Equilibrium competition binding revealed a rank order of agonist potency of ATL > CV-1808 > NECA > 2-CADO > CGS21680, and a rank order of antagonist potency as ZM241385 > 8-phenyltheophylline > p -sulfophenyltheophylline > caffeine. Furthermore, adenylate cyclase assays using selective A2A -R agonists revealed that the eA2A -R functionally coupled to G,s as indicated by an increase in intracellular [3H]cAMP upon receptor activation. Finally, NF- ,B reporter gene assays revealed a CGS21680 concentration-dependent inhibition of NF- ,B activity. These results indicate that the heterologously expressed eA2A -R has a pharmacological profile similar to that of other mammalian A2A receptors and thus can be utilized for further characterization of the eA2A -R to ascertain whether it can serve as a suitable pharmacological target for equine inflammatory disease. [source]

Coronary Vasoconstrictor Potential of Triptans: A Review of In Vitro Pharmacologic Data

HEADACHE, Issue 2004
Antoinette MaassenVanDenBrink PhD
This article reviews the in vitro pharmacology of the triptans in human isolated coronary arteries. As expected, based on their similar pharmacologic profiles, the triptans cannot be easily differentiated with respect to effects at human isolated coronary arteries. Furthermore, the data show that at therapeutically relevant concentrations, triptans have little potential to cause clinically significant constriction of nondiseased coronary arteries. These data, considered in the context of clinical findings reviewed elsewhere in this supplement, support the conclusion that, while all triptans have the potential to produce small contractions of human isolated coronary arteries, their craniovascular selectivity, when used at therapeutic doses, renders them unlikely to cause serious adverse coronary events in patients with healthy coronary arteries. [source]

Tripstar: A Comprehensive Patient-Based Approach to Compare Triptans

HEADACHE, Issue 2002
Michel D. Ferrari MD
Several second-generation triptans have been introduced that differ in their pharmacologic profiles relative to each other and to sumatriptan. As therapeutic options multiply, clinicians must be able to distinguish among these compounds. Recently, a meta-analysis was conducted on data from 53 double-blind, randomized, placebo- or active-controlled trials involving over 24 000 patients receiving oral triptans. Results indicated that almotriptan 12.5 mg, rizatriptan 10 mg, and eletriptan 80 mg are generally superior to sumatriptan 100 mg based on individual treatment attributes, such as pain relief, sustained pain freedom, consistency of response, and tolerability. Meta-analyses are limited, however, as the analysis can only be performed for individual end points, whereas patients and prescribers balance a variety of treatment attributes when assessing drug acceptability. A flexible overall scoring system ("Tripstar") is proposed that compares triptans to a hypothetical "ideal" using meta-analysis data combined with ratings of the relative importance of clinically relevant treatment criteria. An informal test of the Tripstar model indicated that sumatriptan is most similar to a hypothetical ideal for both mild and severe migraine, primarily due to its high worldwide clinical exposure. However, after exclusion of worldwide exposure as a contributing factor, almotriptan 12.5 mg is most similar to the ideal, principally because of its good tolerability. Further tests of the Tripstar model are planned that will gauge the relative importance of a broader range of attributes. [source]