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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 Univ.rsity School of Pharmacy Philadelphia PA USA NEMA Research Inc. Naples FL USA.

Treatment of health problems that accompany aging often includes pharmacotherapy. It is thus common for older adults—and, increasingly, younger adults—to be on multiple medications, either prescription or ov.r-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 lev.l of drug metabolism. If a drug inhibits (or enhances) the metabolism of another, the blood lev.l (therapeutic effect) can be decreased below the required lev.l, or adv.rse effects can increase. Because most currently used drugs are metabolized v.a cytochrome P450-catalyzed pathways, drug discov.rs seek drugs that are metabolized by alternate pathways. Medicinal chemists hav. come upon a strategy—the incorporation of oxetane rings in the drug structure—that increases the likelihood that a drug will not be metabolized v.a CYP450. The same modification giv.s 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 pav. 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 Discov.ry

Polysubstance Use and Ov.rdose v.sualized v.a 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 Univ.rsity School of Pharmacy (Emeritus) Philadelphia PA USA Univ.rsity of Arizona College of Pharmacy (Adjunct) Tucson AZ USA Neumentum Summit NJ USA Enalare Therapeutics Princeton NJ USA NEMA Research Naples FL USA

Polysubstance (combinations of substances) abuse and ov.rdose deaths now surpass mono-substance abuse and ov.rdose deaths. Sev.ral international and gov.rnmental organizations such as the WHO (World Health Organization), CDC (Centers for Disease Control and Prev.ntion), sev.ral of the Institutes of the NIH (National Institutes of Health), Regulators, and Enforcement Agencies, among others, track and prov.de a v.luable source of statistical information about drug (prescription and illicit) (mis)use and ov.rdose. The information is disseminated free to stakeholders and the general public for use. Although the numeric presentations of the data are helpful and adequate for professionals, the non-expert and the v.sual learner often find v.sual representation more clear and more compelling. With this in mind, the aim of this study was to present polysubstance use and ov.rdose using v.sual maps of the av.ilable data. This article considers the opioids.

关键词： Polysubstance Use Disorder Ov.rdose Maps Opioids

Designing General Anesthetics That Hav. 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 Univ.rsity 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 effectiv.ly and with adequate precaution-safety throughout the world for a multitude of clinical applications, predominantly as adjunctiv. agents for surgical procedures. Nev.rtheless, they hav. potential adv.rse effects (such as a drop in blood pressure and the inhibition of steroid production), particularly in v.lnerable populations such as the v.ry young and the frail elderly. It would be desirable therefore to hav. alternativ. agents that are just as efficacious, but hav. a better safety profile in a broader spectrum of patients. Toward this end, an anesthetic based on a unique chemical core (v.z., an N-arylpyrrole deriv.tiv.) has been reported in preclinical models to produce anesthetic effects without hemodynamic suppression. This lead could pav. the way for new general anesthetics that are safer and easier to use.

关键词： General Anesthetic Intrav.nous Drug Discov.ry GABAA Receptor Molecular Modeling

“Atropisomeric” Drugs: Basic Concept and Example of Application to Drug Dev.lopment

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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 adv.rse effects of racemate drugs: the adv.rse 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 giv. examples.

关键词： Atropisomer Chirality Pharmacotherapy Drug Dev.lopment Nav..7 Inhibitor

Hormone Replacement Therapy for Restoring the HPG Axis in Pain Patients Treated with Long-Term Opioid Analgesics

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Pharmacology & Pharmacy 2018年第11期9卷 473-480页

作者： Sriniv.s Nalamachu joseph v. pergolizzi jr. Robert Taylor jr. Jo Ann Le Quang joseph v. pergolizzi III Robert B. Raffa International Clinical Research Institute and Pain Management Institute Overland Park KS USA NEMA Research Inc. Naples FL USA LeQ Medical Angleton TX USA College of Pharmacy University of Arizona Tucson AZ USA School of Pharmacy Temple University Philadelphia PA USA

Opioids are a treatment option for a v.riety of chronic pain conditions. But long-term opioid use can be associated with side effects, including hypogonadism. Opioid-induced hypogonadism (OIhG) is associated with the alteration of the hypothalamic-pituitary-gonadal axis (HPG). In males, hypogonadism can result in erectile dysfunction, reduced libido, fatigue, worsening mood, and increased risk of osteoporosis;in females, it can result in changes in the menstrual cycle and reduced libido, among other effects. A current treatment option for these patients is hormone replacement therapy. In this report, we discuss the problem of opioid-induced hypogonadism, and the therapeutic approach and the potential complications of treating pain patients using hormone replacement therapy.

关键词： Opioid Therapy Chronic Pain HPG Axis Hormone Replacement Therapy

Polysubstance Use and Ov.rdose v.sualized v.a Maps: Amphetamines and Cocaine

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Pharmacology & Pharmacy 2022年第5期13卷 140-148页

作者： Robert B. Raffa joseph v. pergolizzi jr. Herm Cukier School of Pharmacy (Emeritus) Temple University Philadelphia PA USA Univ.rsity of Arizona College of Pharmacy (Adjunct) Tucson AZ USA Neumentum Summit NJ USA Enalare Therapeutics Princeton NJ USA NEMA Research Naples FL USA

Abuse of drug substances and resultant ov.rdose deaths are no longer v.ry straightforward—v.z., attributable to a single chemical entity of known purity. The reality is that most ov.rdose deaths inv.lv. polysubstance use (i.e., the use of combinations of substances). Further, the combinations are often of unknown purity, and ev.n of unknown composition. Ov.rdose deaths are at all-time highs. The depressing statistics are monitored and reported by sev.ral international and gov.rnmental organizations such as the WHO (World Health Organization), CDC (Centers for Disease Control and Prev.ntion), sev.ral Institutes of the NIH (National Institutes of Health), Regulators, and Enforcement Agencies (e.g., DEA). The information is disseminated for free for rev.ew and use. But it is our observ.tion that although numeric presentation is helpful and adequate for professionals, the non-expert and the v.sual learner often find a v.sual representation clearer and compelling. With this in mind, we present the “gestalt” of polysubstance use and ov.rdose using av.ilable maps of the data. The prev.ous article in the series considered the opioids. This one considers amphetamines and cocaine, and places the rise in opioid-associated ov.rdose deaths in the context of other abused drugs.

关键词： Polysubstance Use/Abuse Use Disorder Ov.rdose Maps Amphetamine Cocaine

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 Univ.rsity School of Medicine Philadelphia PA USA NEMA Research Inc. Naples FL USA Neumentum Inc. Palo Alto CA USA Univ.rsity of Arizona College of Pharmacy Tucson AZ USA Temple Univ.rsity School of Pharmacy Philadelphia PA USA

Two selectiv. phosphodiesterase-4 (PDE4) inhibitors—v.z., crisaborole (Eucrisa®, Pfizer) and apremilast (Otezla®, Celgene)—hav. recently receiv.d approv.l by the United States Food and Drug Administration for the treatment of related but different dermatologic skin conditions (v.z., atopic dermatitis and plaque psoriasis, respectiv.ly). The purpose of this rev.ew is to summarize the underlying biochemistry and pathophysiology associated with these dermatologic conditions, rev.ew the chemistry, pharmacology and safety of each of these products, and present preclinical and clinical ev.dence 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

v.tamin D and Number of Falls in a Long-Term Care Facility

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Pharmacology & Pharmacy 2012年第4期3卷 453-457页

作者： Robert B. Raffa Frank Brev. Robert Taylor jr. joseph v. pergolizzi jr. Mid Atlantic PharmaTech Consultants LLC Ventnor City NJ USA Temple Univ.rsity School of Pharmacy Philadelphia PA USA NEMA Research Inc. Naples FL USA Temple Univ.rsity School of Medicine Temple University Philadelphia PA USA The Johns Hopkins University School of Medicine Baltimore MD and Georgetown University School of Medicine Washington DC USA

Falls represent a significant contribution to the morbidity and mortality of the elderly population. Because v.tamin D is important in bone physiology, the use of v.tamin D to restore deficient bone and ameliorate the effects of bone fractures due to falls has become a common practice in recent years. Following introduction of widespread use, reports began to emerge that v.tamin D not only aided in repair of fall-induced bone fractures, but that it also reduced the occurrence of falls. v.tamin D now has become a routine interv.ntion as a fall-prev.ntion measure. Early analyses found ev.dence of prev.ntion efficacy (reduced falls), but recent analyses are more equiv.cal. We retrospectiv.ly examined the records of 350 patients in a long-term care facility in which v.tamin D administration and the number of falls were recorded as part of a comprehensiv. database of care. We found a dramatic rise in v.tamin D use ov.r the period cov.red (2006 – 2011) and a corresponding dramatic decrease in the number of falls. Howev.r, the number of falls continued to decline after 2008, despite a plateau in number of patients on v.tamin D, particularly females. It appears that other factors contribute to the ov.rall decline.

关键词： Falls Bone Fracture v.tamin D Long-Term Care Facility

The Role of Medical Literature, Clinical Trials and Experimental Research in Drug Product-Injury Litigation: A Primer with Two Examples

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Pharmacology & Pharmacy 2018年第6期9卷 208-227页

作者： Jan M. Kitzen joseph v. pergolizzi jr. Robert Taylor jr. Robert B. Raffa Kitzen Pharmaceutical Consulting Collegeville USA Temple Univ.rsity School of Medicine Philadelphia USA NEMA Research Inc. Naples USA Univ.rsity of Arizona College of Pharmacy Tucson USA Temple Univ.rsity School of Pharmacy PhiladelphiaUSA

When any type of product has been ordered to be remov.d from the marketplace by a gov.rnmental regulatory body, that action is a powerful indicator that the product has been determined to be unsafe for further use, thereby branding the product as defectiv. and opening up the possibility of product liability litigation. When the product is a drug or medical dev.ce, it is especially serious since the possibility of personal injury (acute and/or chronic) or death may occur. Needless to say, in these situations, product injury litigation will almost surely follow. We rev.ew the definition and requisite claims needed to establish drug product liability, and the role that the medical literature, clinical trial data, and ev.n experimental research data can play in product (drug)-injury litigation. We show how each of these resources played a significant role in two well-known cases: Fen-Phen and thimerosal. The ultimate goal of such knowledge is to make better informed decisions about drug safety.

关键词： Drug Safety Product Quality Injury Litigation Fen-Phen Thimerosal