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Pharmacology & Pharmacy 2023年第3期14卷 72-83页

作者： Cheyenne Moffett Katherine J. Kost Austen Thompson Joseph V. Pergolizzi Jr. Tally M. Largent-Milnes Robert B. Raffa Todd Vanderah Department of Pharmacology and Comprehensive Pain and Addiction Center University of Arizona Tucson AZ USA nema inc. Naples FL USA Neumentum inc. Summit NJ USA Enalare Therapeutics Naples FL USA School of Pharmacy Temple University Philadelphia PA USA College of Pharmacy (Adjunct) University of Arizona Tucson AZ USA

Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite their popularity, benzodiazepine prescribing often exceeds recommendations and the consequences can be severe. On September 23, 2020, the United States FDA announced a new requirement for a Boxed Warning for benzodiazepines prescribing. Along with this announcement, the FDA stated that relevant information regarding the initiation, continuation, and discontinuation of benzodiazepines is lacking. Here, we describe initial pilot studies intended to investigate the questions 1) can animal models be developed that demonstrate benzodiazepine physical dependence and/or withdrawal symptoms, and 2) determine whether translocator protein (TSPO) plays a role in benzodiazepine dependence and/or withdrawal processes. The former was demonstrated, methodological limitations prevented the latter.

关键词： Benzodiazepine TSPO Rats In Vivo Tests Western-Blot Analysis

“Atropisomeric” Drugs: Basic Concept and Example of Application to Drug Development

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Pharmacology & Pharmacy 2020年第1期11卷 1-8页

作者： Robert B. Raffa Joseph V. Pergolizzi Jr. Robert Taylor Jr. Neumentum inc. Palo Alto CA USA College of Pharmacy University of Arizona Tucson AZ USA School of Pharmacy Temple University Philadelphia PA USA nema Research inc. Naples FL USA

Many therapeutic drugs are racemates;i.e. they are chiral molecules consisting of “left”- and “right-handed” enantiomers (stereoisomers that are mirror images of each other, and are non-superimposable). In some cases, both enantiomers of the drug contribute to some extent (or equally) to the therapeutic effect;in other cases they contribute not at all. The same is true for the adverse effects of racemate drugs: the adverse effects of a racemate drug can be greater-than, less-than, or equal to one or the other enantiomer. An unusual situation arises when a drug consists of “atropisomers”, stereoisomers arising because of hindered rotation about a single chemical bond. We summarize the concept of atropisomerism, and give examples.

关键词： Atropisomer Chirality Pharmacotherapy Drug Development NaV1.7 Inhibitor

Designing General Anesthetics That Have a Better Safety Profile

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Pharmacology & Pharmacy 2019年第10期10卷 407-415页

作者： Robert B. Raffa Joseph V. Pergolizzi Jr. Robert Taylor Jr. Neumentum inc. Palo Alto CAUSA College of Pharmacy University of Arizona Tucson AZ USA Temple University School of Pharmacy Philadelphia PA USA nema Research inc. Naples FL USA.

General anesthetics constitute some of the most important and widely-used therapeutic drugs in the pharmacotherapeutic armamentarium. They are routinely used effectively and with adequate precaution-safety throughout the world for a multitude of clinical applications, predominantly as adjunctive agents for surgical procedures. Nevertheless, they have potential adverse effects (such as a drop in blood pressure and the inhibition of steroid production), particularly in vulnerable populations such as the very young and the frail elderly. It would be desirable therefore to have alternative agents that are just as efficacious, but have a better safety profile in a broader spectrum of patients. Toward this end, an anesthetic based on a unique chemical core (viz., an N-arylpyrrole derivative) has been reported in preclinical models to produce anesthetic effects without hemodynamic suppression. This lead could pave the way for new general anesthetics that are safer and easier to use.

关键词： General Anesthetic Intravenous Drug Discovery GABAA Receptor Molecular Modeling

<i>Commentary</i>: Benzodiazepine (BZD) and Related BZD-Receptor Agonists: Basic Science Reasons to Limit to Four Weeks or Less

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Pharmacology & Pharmacy 2019年第8期10卷 357-364页

作者： Robert B. Raffa Joseph V. Pergolizzi Neumentum Inc. Palo Alto CA USA Univ Arizona College of Pharmacy Tucson AZ USA Temple Univ. School of Pharmacy Philadelphia PA USA nema Research Inc. Naples FL USA

Benzodiazepines and related benzodiazepine-receptor agonists such as the pyrazolopyrimidinezalepl -on;?the imidazopyridine zolpidem;and the cyclopyrroloneszopiclone and eszopiclone, are among the most widely prescribed drugs, and for a variety of conditions. Surprisingly: 1) there are only a few conditions for which there is a good evidence basis, 2) efficacy has only been well demonstrated for short-term use (i.e., less than 4 weeks), and 3) much less is known about the basic science of these drugs than is widely believed. We suggest that the use of these drugs beyond four or less weeks exceeds the available knowledge base, so best-practice use suggests that the prescribing of these drugs for most patients should be limited to only short-term use until more is known about the basic pharmacology of their actions in the brain and in the periphery.

关键词： Benzodiazepine (BZD) BZD-Receptor Agonist Evidence-Based Short-Term Use

The First Approved “Deuterated” Drug: A Short Review of the Concept

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Pharmacology & Pharmacy 2018年第10期9卷 440-446页

作者： Robert B. Raffa Joseph V. Pergolizzi Robert Taylor Neumentum Inc. Palo Alto CA USA Colleges of Pharmacy University of Arizona Tucson AZ USA Temple University School of Pharmacy Philadelphia PA USA nema Research Inc. Naples FL USA

The first “deuterated” drug has recently been approved by the U.S. FDA (Food & Drug Administration). A “deuterated” drug is a drug in which the hydrogen atom in one or more of the carbon-hydrogen bonds in its chemical structure is replaced by deuterium (“heavy hydrogen”, a hydrogen isotope that has a neutron, i.e., one neutron instead of the usual no neutrons). A carbon-deuterium (C-D) bond is more stable in the body than a carbon-hydrogen (C-H) bond. If the deuterium is strategically located in a drug’s chemical structure, the extra stability of the bond will be more resistant to metabolic breakdown, and the duration of drug action will be prolonged. We review the general concept of deuterated drugs, historical examples of the classes of application, and the new approval.

关键词： Deuterium Drug Structure Chemical Bonds Drug Metabolism Duration of Action

Directing the Metabolism of Drugs Away from CYP450: The Use of Oxetane Rings

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Pharmacology & Pharmacy 2019年第11期10卷 465-473页

作者： Robert B. Raffa Joseph V. Pergolizzi Jr. Neumentum inc. Palo Alto CA USA Enalare LLC Naples FL USA College of Pharmacy University of Arizona Tucson AZ USA Temple University School of Pharmacy Philadelphia PA USA nema Research inc. Naples FL USA

Treatment of health problems that accompany aging often inc.udes pharmacotherapy. It is thus common for older adults—and, inc.easingly, younger adults—to be on multiple medications, either prescription or over-the-counter (OTC). With the consumption of multiple medications, drug-drug interactions (DDIs) are a concern. The site of drug-drug interactions is often at the level of drug metabolism. If a drug inhibits (or enhances) the metabolism of another, the blood level (therapeutic effect) can be decreased below the required level, or adverse effects can inc.ease. Because most currently used drugs are metabolized via cytochrome P450-catalyzed pathways, drug discovers seek drugs that are metabolized by alternate pathways. Medicinal chemists have come upon a strategy—the inc.rporation of oxetane rings in the drug structure—that inc.eases the likelihood that a drug will not be metabolized via CYP450. The same modification gives other desirable physical properties to the molecule. Although there are no guarantees that there will be fewer DDIs or an absence of other unexpected problems, the strategy could pave the way for new drugs that are safer and easier to use with concomitant medications.

关键词： Drug Metabolism CYP450 Drug-Drug Interaction Oxetane Analgesic Drug Discovery

Differences in the Receptor Binding Profile of Lofexidine Compared to Clonidine

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Pharmacology & Pharmacy 2019年第1期10卷 1-10页

作者： Robert B. Raffa Joseph V. Pergolizzi Robert Taylor Robert P. James Mark Pirner Neumentum Inc. Palo Alto CA USA University of Arizona College of Pharmacy Tucson AZ USA Temple University School of Pharmacy Philadelphia PA USA nema Research Inc. Naples FL USA US WorldMeds LLC Louisville KY USAs

Lucemyra? (lofexidine hydrochloride) has recently been approved by the US FDA for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults. Lofexidine is an alpha-2 adrenoceptor agonist. However, the clinical attributes of lofexidine differ in advantageous ways from the classical alpha-2 adrenoceptor agonist clonidine. In the present study, we measured the receptor binding profile of lofexidine and clonidine in an effort to gain an insight into the clinical difference(s).

关键词： Lofexidine Clonidine Opioid Withdrawal Receptor Affinity Alpha-2 Agonist

Persistence of Healthcare-Associated (Nosocomial) Infections Due to Inadequate Hand Hygiene: Part 1—Biological and Treatment Factors

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Pharmacology & Pharmacy 2018年第8期9卷 293-309页

作者： Robert B. Raffa Joseph V. Pergolizzi Robert Taylor Sanjib Choudhuri Robert Rodenbeck University of Arizona College of Pharmacy Tucson AZ USA Professor Emeritus Temple University School of Pharmacy Philadelphia PA USA Neumentum Inc. Palo Alto CA USA nema Research Inc. Naples FL USA Delta Faucet Co. Indianapolis IN USA

The most frequent adverse event in the healthcare delivery system is acquisition of an infection within a healthcare facility. Sinc. infection control measures are known, simple, and low-cost, we examine why the problem of healthcare-associated infections persists. Hundreds of millions of patients each year are affected by a healthcare-associated infection, with negative medical outcome and financial cost. It is a major public health problem even in countries with advanced healthcare systems. This is a bit perplexing, given that hygienic practices have been known and actively promoted. The objective is to address the question: doesn’t the use of disinfection, sterilization, handwashing, and alcohol rubs prevent the spread of pathogenic organisms? We conclude that the persistent high prevalence of nosocomial infections despite known hygienic practices is attributable to two categories of factors: biological and inherent shortcomings of some practices (considered in Part 1), and human factors (considered in Part 2). A new approach is presented in Part 3.

关键词： Infection Nosocomial Hospital Healthcare-Associated Hygiene Handwashing

Short Review of Ischemia- and Hypoxia-Protective Roles of “Big Potassium” (BK) Channels

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Journal of Biosciences and Medicines 2021年第6期9卷 150-160页

作者： John F. Peppin Joseph V. Pergolizzi Alexander Kraus Robert B. Raffa Marian University College of Osteopathic Medicine Indianapolis USA Pikeville University College of Osteopathic Medicine Pikeville Kentucky USA Enalare Therapeutics inc. Princeton USA nema Research inc. Naples USA Neumentum inc. Morristown USA University of Arizona College of Pharmacy Tucson USA Temple University School of Pharmacy Philadelphia USA

There is accumulating evidence that the subfamily of large-conductance potassium (“big”, “BK”) channels are involved in diverse, and perhaps coordinated, protective or counteractive responses to local or generalized ischemia and hypoxia. Although widely distributed, the physiological differences among BK channels which results from posttranslational modification (alternative splicing) and co-assembly with auxiliary modulatory subunits (β1-4 and γ1-4), bestows localized differences in subunit composition, distribution, 2nd-messenger coupling, and pharmacologic properties. Due to the ubiquitous nature of BK channels and the multiplicity of subtypes, they have many potential therapeutic applications in the maintenance of oxygen homeostasis, cerebro- and cardio-protection, and stimulation of respiration in response to drug-induced respiratory depression. BK channels may also offer other potentially broad and underrecognized promising targets for novel pharmaceutical development.

关键词： Big potassium Channels BKCa Ischemia Hypoxia Respiratory Stimulation ENA-001

Crisaborole and Apremilast: PDE4 Inhibitors with Similar Mechanism of Action, Different Indications for Management of Inflammatory Skin Conditions

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Pharmacology & Pharmacy 2018年第9期9卷 357-381页

作者： Jan M. Kitzen Joseph V. Pergolizzi Jr. Robert Taylor Jr. Robert B. Raffa Kitzen Pharmaceutical Consulting Collegeville PA USA Temple University School of Medicine Philadelphia PA USA nema Research Inc. Naples FL USA Neumentum Inc. Palo Alto CA USA University of Arizona College of Pharmacy Tucson AZ USA Temple University School of Pharmacy Philadelphia PA USA

Two selective phosphodiesterase-4 (PDE4) inhibitors—viz., crisaborole (Eucrisa®, Pfizer) and apremilast (Otezla®, Celgene)—have recently received approval by the United States Food and Drug Administration for the treatment of related but different dermatologic skin conditions (viz., atopic dermatitis and plaque psoriasis, respectively). The purpose of this review is to summarize the underlying biochemistry and pathophysiology associated with these dermatologic conditions, review the chemistry, pharmacology and safety of each of these products, and present preclinical and clinical evidence that may help explain why these two PDE4 inhibitors offer new treatment options for these skin conditions.

关键词： Crisaborole Apremilast Phosphodiesterase PDE4 Inflammation Cytokines Interleukins cAMP