Pharmacology research & perspectives
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Pharmacol Res Perspect · Apr 2020
Population pharmacokinetic and exposure-response analysis of eptinezumab in the treatment of episodic and chronic migraine.
Eptinezumab is a humanized mAb that targets calcitonin gene-related peptide and is under regulatory review for the prevention of episodic and chronic migraine (EM, CM). It is important to determine whether exposures achieved with intravenous (IV) administration of eptinezumab achieve desired pharmacologic effects. Population pharmacokinetics, including dose- and exposure-response analyses, were performed using patient-level data from the eptinezumab clinical trial program with IV doses ranging from 10 to 1000 mg in pharmacokinetic analyses or 10 to 300 mg in phase 2/3 clinical studies in patients with EM or CM. ⋯ A saturable inhibitory Emax model found the exposure over 12 weeks produced by single-dose eptinezumab 100 and 300 mg exceeded the exposure estimates required to achieve 90% of the maximal efficacy (EC90 ). This pharmacokinetic analysis of eptinezumab supports dosing every 12 weeks with no adjustment for patient characteristics, including exposures associated with 100- or 300-mg doses producing optimal efficacy effects. The similar efficacy profiles support 100 mg as the lowest effective dose of eptinezumab.
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Pharmacol Res Perspect · Apr 2020
Retrospective assessment of acute poisoning incidents by pharmaceutical agents in Jordan: Data from Pharmacy One™ Poison Call Center, 2014 to 2018-Part II.
Poison control centers provide surveillance data that can be used to estimate the magnitude of poisoning cases and the level of public awareness and to evaluate control measures. The aim of this study is to describe the drug-related poisoning queries received by the Pharmacy One™ Poisoning Call Center (P1 PCC) in Jordan. This is a retrospective descriptive study of the acute drug-related poisoning incidents in the Jordanian population recorded by the P1 PCC during the 2014-2018 period. ⋯ Poisoning incidents were mainly classified as mild to moderate (56.1%), while only 16.6% were severe. The P1 PCC has demonstrated an important and vital role in improving patient safety and providing education on rational drug use. Reflections on these data can be used to increase public awareness in promoting the rational use of medications among Jordanian citizens.
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Pharmacol Res Perspect · Feb 2020
T-495, a novel low cooperative M1 receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk.
M1 muscarinic acetylcholine receptor (M1 R) activation can be a new therapeutic approach for the treatment of cognitive deficits associated with cholinergic hypofunction. However, M1 R activation causes gastrointestinal (GI) side effects in animals. We previously found that an M1 R positive allosteric modulator (PAM) with lower cooperativity (α-value) has a limited impact on ileum contraction and can produce a wider margin between cognitive improvement and GI side effects. ⋯ Combination of T-495, but not of MK-7622, and donepezil at each sub-effective dose improved scopolamine-induced memory deficits. Additionally, in mice with reduced acetylcholine levels in the forebrain via overexpression of A53T α-synuclein (ie, a mouse model of dementia with Lewy bodies and Parkinson's disease with dementia), T-495, like donepezil, reversed the memory deficits in the contextual fear conditioning test and Y-maze task. Thus, low cooperative M1 R PAMs are promising agents for the treatment of memory deficits associated with cholinergic dysfunction.
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Pharmacol Res Perspect · Dec 2019
ReviewThe hubris and humility of cancer pharmacology in the post immuno-oncology era.
Cancer is a dreaded word, which has stimulated monumental efforts to discover and deliver effective cancer treatments for more than half a century. During the past two decades, our understanding of the molecular pathogenesis of cancer has increased remarkably. ⋯ Moreover the common combination of cancer drugs prescribes the need for a better understanding of the fundamental pharmacology of each agent. Here I briefly outline some of the fundamental changes that have and have not occurred in cancer pharmacology during the past two decades and prognosticate on possible future directions.
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Pharmacol Res Perspect · Feb 2019
Treatment with new organic nitrites in pulmonary hypertension of acute experimental pulmonary embolism.
Acute pulmonary embolism may cause right heart failure due to increased pulmonary vascular resistance and arterial hypoxemia. Effective vasodilator therapy of the pulmonary hypertension is highly needed. Therefore, we investigated the effects of a newly developed effective pulmonary vasodilator, the organic mononitrites of 1,2-propanediol (PDNO), in a rabbit model of acute pulmonary embolism. ⋯ PDNO significantly decreased and normalized pulmonary vascular resistance and the right ventricle rate-pressure product, without causing tolerance, with no significant side effects on the systemic circulation, nor on blood-gas values or on methemoglobin formation. In conclusion, PDNO is a NO donor and an efficient vasodilator in the pulmonary circulation. Treatment with this or similar organic nitrites intravenously may be a future option to avoid right heart failure in life-threatening acute pulmonary embolism.