Time Course of Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene and Intramuscular and Intranasal Naloxone.

The increase in opioid overdose deaths, particularly involving potent, long-acting synthetic opioids, has led to calls for stronger, longer-acting opioid-overdose-reversal agents. Using an opioid-induced respiratory depression model, we investigated the onset and time course of action of naloxone and a long-acting opioid antagonist, nalmefene, in reversing the effects of an ongoing intravenous fentanyl infusion over a period of up to 100 min. Healthy, moderately experienced opioid users received intramuscular (IM) nalmefene 1 mg, IM naloxone 2 mg, or intranasal (IN) naloxone 4 mg after fentanyl-induced respiratory depression was established based on reduction in respiratory minute volume (MV).

Evaluation of sunobinop for next-day residual effects in healthy participants.

Sunobinop is a novel, potent, selective partial agonist at nociceptin/orphanin FQ peptide (NOP) receptors. The primary objective of this randomized, double-blind, placebo-controlled study was to assess the next-day residual effects of an evening dose of sunobinop in healthy participants. Participants were randomized into 1 of 5 treatment sequences.

Safety, Tolerability, and Pharmacokinetics of Single- and Multiple-Ascending Doses of Sunobinop in Healthy Participants.

Sunobinop is an investigational, potent, selective partial agonist at the nociceptin/orphanin FQ peptide receptor in vitro. Three phase 1 studies were conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of escalating single- and multiple-dose administration of sunobinop in healthy participants. Study 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study.

Evaluation of dermal toxicity and toxicokinetics of povidone‑iodine in Göttingen minipigs.

Background: Povidone‑iodine (PVP-I) is an effective and commonly used broad-spectrum antiseptic; limited information exists around its long-term safety and impact on endocrine disruption. We assessed the dermal toxicity and toxicokinetics following a once-daily application of 7.5% (w/v) and 10% (w/v) PVP-I in Göttingen Minipigs® for up to 39 weeks.

Particulate levodopa nose-to-brain delivery targets dopamine to the brain with no plasma exposure.

Levodopa (L-DOPA) is an oral Parkinson's Disease drug that generates the active metabolite - dopamine (DA) in vivo. However, oral L-DOPA exhibits low oral bioavailability, limited brain uptake, peripheral DA-mediated side effects and its poor brain bioavailability can lead to long-term complications. Here we show that L-DOPA forms stable (for at least 5 months) 300 nm nanoparticles when encapsulated within N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ).

In vitro inactivation of SARS-CoV-2 using a povidone-iodine oral rinse.

Background: Healthcare professionals, especially dentists and dental hygienists, are at increased risk for contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through air-borne particles and splatter. This study assessed the in vitro virucidal activity of 0.5% (w/v) povidone-iodine (PVP-I) oral rinse against SARS-CoV-2 to demonstrate its utility as a professional oral rinse.

In Vitro Evaluation of the Virucidal Activity of Different Povidone-Iodine Formulations Against Murine and Human Coronaviruses.

Introduction: Polyvinylpyrrolidone-iodine (PVP-I) demonstrates broad-spectrum anti-infective activity and is available in different formulations for oral rinse and topical use in medical and personal care settings. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need to supplement available preventive strategies.

Methods: We assessed virucidal activity of PVP-I formulations, including 0.

Effects of paroxetine, a CYP2D6 inhibitor, on the pharmacokinetic properties of hydrocodone after coadministration with a single-entity, once-daily, extended-release hydrocodone tablet.

Purpose: A single-entity, once-daily, extended-release formulation of hydrocodone bitartrate (HYD) has been developed for the management of moderate to severe chronic pain. Hydrocodone undergoes cytochrome P-450 (CYP)-mediated metabolism involving the CYP3A4 and CYP2D6 isozymes. CYP3A4 yields norhydrocodone, a major inactive metabolite, whereas CYP2D6 yields hydromorphone, a minor active metabolite.

Structure-activity relationship studies and discovery of a potent transient receptor potential vanilloid (TRPV1) antagonist 4-[3-chloro-5-[(1S)-1,2-dihydroxyethyl]-2-pyridyl]-N-[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxamide (V116517) as a clinical candidate for pain management.

A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies.

Once-weekly transdermal buprenorphine application results in sustained and consistent steady-state plasma levels.

Context: Transdermal formulations of buprenorphine offer controlled delivery of buprenorphine for sustained analgesic efficacy with reduced adverse events (AEs) compared with the other modes of administration. A buprenorphine transdermal system (BTDS) delivering 5, 10, or 20 mcg/hour for seven days is now marketed in the U.S.

Effect of ketoconazole on the pharmacokinetic profile of buprenorphine following administration of a once-weekly buprenorphine transdermal system.

Background And Objective: Buprenorphine is extensively metabolized by cytochrome P450 (CYP) 3A4. This study evaluated the effect of ketoconazole, a CYP3A4 inhibitor, on the metabolism of buprenorphine following the administration of a buprenorphine transdermal system 10 μg/hour (BTDS 10).

Methods: This single-centre study enrolled 20 healthy subjects who had demonstrated ketoconazole-mediated CYP3A4 inhibition via an erythromycin breath test.

Development and validation of a sensitive LC/MS/MS method for the simultaneous determination of naloxone and its metabolites in mouse plasma.

A rapid, specific, and reliable LC-MS/MS based bioanalytical method was developed and validated for the simultaneous determination of naloxone (NLX) and its two metabolites, 6β-naloxol (NLL) and naloxone-3β-D-glucuronide (NLG) in mouse plasma. The optimal chromatographic behavior of these analytes was achieved on an Aquasil C18 column (50 mm × 2.1 mm, 5 μm) using reversed phase chromatography.

Comparison of the 17 alpha-hydroxylase/C17,20-lyase activities of porcine, guinea pig and bovine P450c17 using purified recombinant fusion proteins containing P450c17 linked to NADPH-P450 reductase.

The cDNAs for cytochrome P450c17 (P450c17) of three species, pig, guinea pig, and cow, representing three families of mammals (suidae, procaviidae, and bovidae, respectively) were each engineered into an expression plasmid (pCWori+). The P450c17 domain of the coding sequence was connected to a truncated form of rat NADPH-P450 reductase by a linker sequence encoding two amino acids (SerThr). These fusion proteins were expressed in E.

Relevance of cytochrome P450s in plants: also one of Ron Estabrook's research interests.

I worked with Dr. Ronald Estabrook for nearly 10 years at The University of Texas Southwestern Medical Center in Dallas, Texas. In Ron's lab, when I joined I was initially involved in the isolation, purification, and characterization of cytochrome P450s and NADPH-P450(c) reductase(s) from plants, which was his new exploratory project at the time.

Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API.

Purpose: The bioavailability of a development candidate active pharmaceutical ingredient (API) was very low after oral dosing in dogs. In order to improve bioavailability, we sought to increase the dissolution rate of the solid form of the API. When traditional methods of forming salts and amorphous material failed to produce a viable solid form for continued development, we turned to the non-traditional approach of cocrystallization.