Regional inhibition of sympathetic tone during shivering and induced muscle contraction,

Adrenergic vasoconstriction evoked by the stimulation of the decentralized lumbar sympathetic chain can be inhibited during muscle contraction induced by shivering, sciatic nerve stimulation, or activation of the viscero-somatic reflex. Receptors which initiate the inhibition are thought to be present in skeletal muscle and activated by stretch. The specific site at which the inhibition occurs has not been determined but is known to be at a locus in the efferent adrenergic pathway peripheral to the spinal cord.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33435/1/0000837.pd

Cardiovascular actions of the hypotensive agent, N, N-diallylmelamine (U-7720)

Diallylmelamine is an effective hypotensive agent in hypertensive dogs and rats, having a duration of action exceeding twenty-four hours from a single oral dose. It has limited efficacy in normotensive rats. Hypotensive activity of gradual onset is preceded by a latent period of up to two hours and becomes maximal six hours or more after dosing. This agent does not depress cardiac output or sympathetic vasoconstrictor activity. It is suggested that its hypotensive activity results from a direct effect upon vascular smooth muscle.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46303/1/210_2004_Article_BF00245728.pd

Randomized Dose-Ranging Controlled Trial of AQ-13, a Candidate Antimalarial, and Chloroquine in Healthy Volunteers

OBJECTIVES: To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug–resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans. DESIGN: Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose. SETTING: Tulane–Louisiana State University–Charity Hospital General Clinical Research Center in New Orleans. PARTICIPANTS: 126 healthy adults 21–45 years of age. INTERVENTIONS: 10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13. OUTCOME MEASURES: Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation. RESULTS: No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract–related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0–14.7 l/h versus 9.5–11.3 l/h; p ≤ 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ. CONCLUSIONS: These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics

Molecular Properties Determining Unbound Intracellular and Extracellular Brain Exposure of CNS Drug Candidates

In the present work we sought to gain a mechanistic understanding of the physicochemical properties that influence the transport of unbound drug across the blood–brain barrier (BBB) as well as the intra- and extracellular drug exposure in the brain. Interpretable molecular descriptors that significantly contribute to the three key neuropharmacokinetic properties related to BBB drug transport (<i>K</i>_p,uu,brain), intracellular accumulation (<i>K</i>_p,uu,cell), and binding and distribution in the brain (<i>V</i>_u,brain) for a set of 40 compounds were identified using partial least-squares (PLS) analysis. The tailoring of drug properties for improved brain exposure includes decreasing the polarity and/or hydrogen bonding capacity. The design of CNS drug candidates with intracellular targets may benefit from an increase in basicity and/or the number of hydrogen bond donors. Applying this knowledge in drug discovery chemistry programs will allow designing compounds with more desirable CNS pharmacokinetic properties