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Tramadol in Japanese Population: the Relative Contrib.tion of M1 Metab.lite as Assessed b. CYP2D6*10 Genotype

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Pharmacology & Pharmacy 2012年第3期3卷 337-341页

作者： robert b. raffa Department of Pharmaceutical Sciences Temple University School of Pharmacy Philadelphia PA U.S.A.

Several preclinical and clinical studies suggested that tramadol has a multi-mechanistic analgesic action. Upon in vitro evaluation, tramadol parent drug was determined to have only very weak affinity for opioid receptors. Metab.lism via CYP2D6, though, yields the O-desmethyl metab.lite (M1), which has much greater opioid receptor affinity. In tests in animals and human volunteers, tramadol’s analgesic effect is only partially b.ocked b. the opioid antagonist naloxone. Yet the contrib.tion of parent drug to analgesia is still deb.ted. Ob.ervance of good analgesic response to tramadol in Japanese and other Asian populations that express the CYP2D6*10 genotype suggests that parent drug accounts for the majority of tramadol’s analgesic effect in most clinical settings. Understanding of tramadol’s multi-mechanistic action continues to form the b.sis for understanding its clinical attrib.tes.

关键词： Tramadol M1 Metab.lite CYP2D6 Polymorphism CYP2D6*10 Japanese

More Rapid Sleep Onset with Lingual-Spray vs Oral-Tab.et Delivery Zolpidem

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Pharmacology & Pharmacy 2019年第7期10卷 329-342页

作者： robert b. raffa Gerwin Westfield Univ Arizona College of Pharmacy Tucson AZ USA Temple Univ School of Pharmacy Philadelphia PA USA Aytub.oScience Englewood CO USA

Insomnia and related sleep disorders (somnipathies) affect a large segment of the population, and result in a significant negative impact on quality of life and reduced or lost productivity. The speed of sleep onset is a critical characteristic of successful pharmacotherapeutic intervention for insomnia. Zolpidem, a non-b.nzodiazepine b.nzodiazepine receptor agonist (nb.RA) is widely used to treat insomnia. Although not itself a b.nzodiazepine (b.D), zolpidem has high b.nding affinity for the b.nzodiazepine receptor, which acts as a positive allosteric modulator of the GAb.A receptor complex. It therefore increases the neuronal transmemb.ane influx of Cl- ions, thereb. decreasing neuronal excitab.lity and promoting sleep. In this four-way crossover, dose-ranging, multiple-treatment study, a lingual spray formulation of zolpidem was safe and well-tolerated and yielded more rapid pharmacokinetics (mean plasma concentration) and efficacy (visual analog scale and digit symb.l sub.titution test) compared to oral tab.ets.

关键词： Zolpidem Lingual Spray Pharmacokinetics Efficacy Safety/Tolerab.lity AMb.EN

Surprising Separation of Cannab.noid Physical Dependence and Withdrawal in an Inverteb.ate Model

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Pharmacology & Pharmacy 2018年第12期9卷 489-502页

作者： Wanhui Sheng robert b. raffa Department of Pharmaceutical Sciences Temple University School of Pharmacy Philadelphia Pennsylvania USA Department of Pharmacodynamics College of Pharmacy University of Florida Gainesville FL USA Department of Pharmacology and Toxicology University of Arizona College of Pharmacy Tucson AZ USA Neumentum Inc. Palo Alto CA USA

Planarians have mammalian-like neurotransmitter systems and have b.en estab.ished as a novel in vivo model for neuropharmacology. In previous research, planarians that have b.en exposed to the cannab.noid receptor (Cb.R) agonist WIN 55,212-2 for 1 h displayed ab.tinence-induced withdrawal when tested in drug-free, b.t not in drug-containing, water. The goals of the present study were to extend previous work and to further estab.ish a cannab.noid b.havioral model with planarians. The results showed 1) four different Cb.R antagonists (AM251, AM281, SLV319 and SR144528) dose-relatedly b.ocked development of physical dependence induced b. two different Cb.R agonists (WIN 55,212-2 and JWH251);2) none of the same four antagonists (AM251, AM281, SLV319 or SR144528) precipitated withdrawal;3) short wavelength (254 nm), b.t not long wavelength (366 nm), ultraviolet (UV) light attenuated ab.tinence-induced withdrawal from WIN 55,212-2, while short wavelength UV light induced moderate withdrawal b.havior. The results confirm the use of a planarian model as a simple yet rob.st way to study development of physical dependence to cannab.noid agonists. The effect of UV irradiation adds to the evidence that the results are receptor-related. The results also give rise to the surprising suggestion, within the limitations of the methodology, that development of cannab.noid physical dependence and antagonist-induced precipitated withdrawal might b. separab.e phenomena in planarians.

关键词： Cannab.noid Physical Dependence Withdrawal Planarians UV Light

Commentary: b.nzodiazepine (b.D) and Related b.D-Receptor Agonists: b.sic 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

b.nzodiazepines and related b.nzodiazepine-receptor agonists such as the pyrazolopyrimidinezalepl -on;?the imidazopyridine zolpidem;and the cyclopyrroloneszopiclone and eszopiclone, are among the most widely prescrib.d drugs, and for a variety of conditions. Surprisingly: 1) there are only a few conditions for which there is a good evidence b.sis, 2) efficacy has only b.en well demonstrated for short-term use (i.e., less than 4 weeks), and 3) much less is known ab.ut the b.sic science of these drugs than is widely b.lieved. We suggest that the use of these drugs b.yond four or less weeks exceeds the availab.e knowledge b.se, so b.st-practice use suggests that the prescrib.ng of these drugs for most patients should b. limited to only short-term use until more is known ab.ut the b.sic pharmacology of their actions in the b.ain and in the periphery.

关键词： b.nzodiazepine (b.D) b.D-Receptor Agonist Evidence-b.sed 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 b.en approved b. the U.S. FDA (Food & Drug Administration). A “deuterated” drug is a drug in which the hydrogen atom in one or more of the carb.n-hydrogen b.nds in its chemical structure is replaced b. deuterium (“heavy hydrogen”, a hydrogen isotope that has a neutron, i.e., one neutron instead of the usual no neutrons). A carb.n-deuterium (C-D) b.nd is more stab.e in the b.dy than a carb.n-hydrogen (C-H) b.nd. If the deuterium is strategically located in a drug’s chemical structure, the extra stab.lity of the b.nd will b. more resistant to metab.lic b.eakdown, and the duration of drug action will b. 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 b.nds Drug Metab.lism Duration of Action

Directing the Metab.lism 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 prob.ems that accompany aging often includes pharmacotherapy. It is thus common for older adults—and, increasingly, younger adults—to b. 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 metab.lism. If a drug inhib.ts (or enhances) the metab.lism of another, the b.ood level (therapeutic effect) can b. decreased b.low the required level, or adverse effects can increase. b.cause most currently used drugs are metab.lized via cytochrome P450-catalyzed pathways, drug discovers seek drugs that are metab.lized b. alternate pathways. Medicinal chemists have come upon a strategy—the incorporation of oxetane rings in the drug structure—that increases the likelihood that a drug will not b. metab.lized via CYP450. The same modification gives other desirab.e physical properties to the molecule. Although there are no guarantees that there will b. fewer DDIs or an ab.ence of other unexpected prob.ems, the strategy could pave the way for new drugs that are safer and easier to use with concomitant medications.

关键词： Drug Metab.lism CYP450 Drug-Drug Interaction Oxetane Analgesic Drug Discovery

The Place of Community Rescue Naloxone in a Pub.ic Health Crisis of Opioid Overdose

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Pharmacology & Pharmacy 2019年第2期10卷 61-81页

作者： Joseph V. Pergolizzi Jo Ann LeQuang robert Taylor robert b. raffa NEMA Research Naples FL USA Neumentum Palo Alto CA USA LeQ Medical Angleton TX USA University of Arizona College of Pharmacy Tucson AZ USA Temple University School of Pharmacy Philadelphia PA USA

The recent large increase in deaths involving opioids (whether prescription or illicit, pure or adulterated, alone or in comb.nation with other drugs) is the manifestation of a complex, and multifaceted prob.em consisting of psychological, psychosocial, medical, legal, regulatory, economic, cultural, and political components, among others. b.cause the prob.em involves issues related to b.th supply and demand, the solution is not ob.ious, simple, or quick. There is no easy fix. Preventing and treating opioid misuse and ab.se requires a comprehensive, time-intensive, and expensive intervention supported b. pub.ic policy and support through coordinated medical, regulatory, legal, and financial guidelines and practice. b.t until the long-term prob.ems can b. fixed, the immediate crisis of overdose deaths can b. ameliorated b. making availab.e an opioid receptor antagonist to reverse the respiratory depression that is the cause of death to those who are in the b.st position to administer it in time (professionals, untrained b.standers, and even fellow drug ab.sers). The statistics overwhelmingly demonstrate that this is a life-saving medical intervention. Yet, there is still uncertainty ab.ut this intervention, and even some opposition to it. We describ. the scientific b.sis for the approach and the issues surrounding its use to treat accidental or intentional overdose b. pain patients, recreational opioid users, and addicts. We also describ. the calls to limit the numb.r of times it should b. availab.e to a user and the limitations of its effectiveness—mainly that it only addresses the acute death crisis, not the underlying prob.ems that led to it.

关键词： Opioid Crisis Opioid Ab.se Opioid Antagonist Community Naloxone

Polysub.tance Use and Overdose Visualized via Maps: Opioids

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Pharmacology & Pharmacy 2022年第4期13卷 107-118页

作者： robert b. raffa Joseph V. Pergolizzi Jr. Herm Cukier Temple University School of Pharmacy (Emeritus) Philadelphia PA USA University of Arizona College of Pharmacy (Adjunct) Tucson AZ USA Neumentum Summit NJ USA Enalare Therapeutics Princeton NJ USA NEMA Research Naples FL USA

Polysub.tance (comb.nations of sub.tances) ab.se and overdose deaths now surpass mono-sub.tance ab.se and overdose deaths. Several international and governmental organizations such as the WHO (World Health Organization), CDC (Centers for Disease Control and Prevention), several of the Institutes of the NIH (National Institutes of Health), Regulators, and Enforcement Agencies, among others, track and provide a valuab.e source of statistical information ab.ut drug (prescription and illicit) (mis)use and overdose. The information is disseminated free to stakeholders and the general pub.ic for use. Although the numeric presentations of the data are helpful and adequate for professionals, the non-expert and the visual learner often find visual representation more clear and more compelling. With this in mind, the aim of this study was to present polysub.tance use and overdose using visual maps of the availab.e data. This article considers the opioids.

关键词： Polysub.tance Use Disorder Overdose Maps Opioids

Persistence of Healthcare-Associated (Nosocomial) Infections Due to Inadequate Hand Hygiene: Part 1—b.ological 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 Rodenb.ck 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. Since infection control measures are known, simple, and low-cost, we examine why the prob.em of healthcare-associated infections persists. Hundreds of millions of patients each year are affected b. a healthcare-associated infection, with negative medical outcome and financial cost. It is a major pub.ic health prob.em even in countries with advanced healthcare systems. This is a b.t perplexing, given that hygienic practices have b.en known and actively promoted. The ob.ective is to address the question: doesn’t the use of disinfection, sterilization, handwashing, and alcohol rub. prevent the spread of pathogenic organisms? We conclude that the persistent high prevalence of nosocomial infections despite known hygienic practices is attrib.tab.e to two categories of factors: b.ological 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