Special Issue: Advancements in Pharmacology

SPECIAL ISSUE

Advancements in Pharmacology

RESEARCH ARTICLES

Amanda M. Healana, J. Mcleod Griffissb, Mary Ann O’Riordanc, Wesley A. Grayd, Robert A. Salataa, Jeffrey L. Blumerd

aDivision of Infectious Diseases and HIV Medicine, Case Western Reserve University, Cleveland, OH, USA
bClinicalRM, Hinckley, OH,and Dept. of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA
cDepartment of Pediatrics, Case Western Reserve University,Cleveland, OH, USA
dDepartment of Pediatrics, University of Toledo College of Medicine, Toledo, OH, USA

Abstract

Bedaquiline (BDQ), a diarylquinoline mycobacterial ATP synthase inhibitor approved in the United States for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin (RIF), an essential part of drug-sensitive tuberculosis treatment.  BDQ is used more broadly in some other countries and has been evaluated for treatment of non-tuberculosis mycobacterial infections, often in combination with rifabutin (RBT).  We examined the pharmacokinetic interactions of BDQ plus either RIF or RBT in 33 healthy volunteers.  Subjects were randomly assigned to receive two single 400 mg doses of BDQ, given 29 days apart, and either RBT 300 mg or RIF 600 mg, given daily from day 20 to 41 after the first dose of BDQ.  Blood samples were collected prior to dosing and at multiple subsequent time points to measure plasma drug concentrations, including those of the rifamycin primary metabolites.  BDQ treatment had little effect on the disposition of RIF but resulted in a dramatic shortening of the half-life of RBT and decreased exposure to it.  When the drugs were administered together (Day 29) the peak rifamycin concentrations and peak rifamycin metabolite concentrations were reduced significantly (p <0.001).  This appeared to result from reduced absorption and raises a concern that doses of BDQ and the rifamycins, particularly RBT should be staggered when the two drugs are given on the same day.  The optimum time between dosing should be determined.

Stephen B. Shrewsbury1, Greg Davies1, Lisa McConnachie1, John Hoekman1

1Impel Pharmaceuticals Inc, Seattle, WA, USA

Abstract

Nasal drug delivery presents a potential opportunity for achieving rapid, extensive drug absorption via a nonoral route by 1) avoiding degradation within the gastrointestinal tract and first-pass metabolism in the liver and 2) facilitating faster onset via rapid absorption into the bloodstream. However, the site of drug deposition within the nasal cavity may impact drug pharmacokinetics. Precision Olfactory Delivery (POD®) by Impel Pharmaceuticals Inc. is a new technology that provides handheld, manually actuated, propellant-powered drug delivery to the upper nasal space for rapid and efficient absorption. Rapid onset of effect can be a major advantage in many clinical applications where quick and effective administration is needed (eg, alleviating agitation in emergency settings or reducing debilitating migraine symptoms). Here, we review the pharmacokinetic profile of INP105, which is being developed to deliver olanzapine (OLZ) by POD to treat agitation in patients with autism. Because formulation can play a large role in the pharmacokinetic profile of a nasally administered drug, we provide a comprehensive review of both published and previously unpublished preclinical data outlining how the INP105 formulation was developed and optimized for study in humans. Multiple formulation carriers and excipients were tested to find a stable INP105 formulation with a desirable nasal absorption profile. Because the nasal architecture in nonhuman primates (NHPs) is similar to humans, the pharmacokinetics and tolerability of an INP105 combination product (NHP-INP105) using a clinical formulation combined with a device specifically designed for NHPs has been investigated in preclinical NHP studies, providing translational data for human studies and the pathway for testing novel products and formulations. The pharmacokinetics and tolerability of INP105 were then evaluated in an early clinical study in humans, demonstrating favorable pharmacokinetic and pharmacodynamic profiles. In this review, we aim to illustrate how delivery of therapeutics to the upper nasal space using POD, such as with agents like INP105, has the potential to optimize nasal delivery and unlock the potential of delivery-limited drugs to provide patients with rapid onset of effect, ease of use, and convenience.

Larry L Mweetwa1, DerrickD Tlhoiwe1, TumeloTlhoiwe1, Kabo Osmas Tshiamo1, Sody Mweetwa Munsaka2,Thatoyaone J Kenaope3, Getrude Mothibe3,Ogorogile Mokate1, Emmanuel T. Oluwabusola1

1DDT College of Medicine, Department for Pharmacy and Pharmaceutical Sciences, P.O. Box 70587, Gaborone Botswana, Africa
2University of Zambia, School of Health Sciences, P. O. Box 32379 Lusaka, Africa.
3Department of Pharmacy, Boitekanelo College, Plot 5824 Masetlheng Rd, Gaborone 00000, Botswana.

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or Coronavirus was initially detected in Wuhan China in December 2019 and has subsequently resulted in the COVID-19 pandemic. The disease presents asymptomatically in some of individuals yet also causes symptoms ranging from those associated with influenza and pneumonia, acute respiratory distress syndrome (ARDS) and even death. The world is currently relying on physical (social) distancing, hygiene and repurposed medicines; however, it was predicted that an effective vaccine will be necessary to ensure comprehensive protection against COVID-19. There was a global effort to develop an effective vaccine against SARS-CoV-2 with approximately 300 vaccines in clinical trials, and over 200 more in different stages of development and anticipated that their success will change research clinical trials processes. Although every one of these vaccines comes with its own particular set of characteristics and difficulties, they were all developed as a direct result of research and development efforts that were carried out on a scale that had never been seen before. It is the first time in the history of vaccination that a worldwide immunization campaign has begun during a time of severe pandemic activity that is defined by high virus transmission. This achievement marks an important milestone in the history of vaccination. More than anything else, the most important aspect of the new game change in drug design is that the traditional drug discovery rules have been rewritten. This is especially significant for the development of vaccines, as it is possible for all clinical trials to be accelerated, which would bring a vaccine or drug molecule to market within a year rather than the traditional fifteen years for each phase of drug clinical trials. This review provides insight in respect to first generation COVID-19 vaccines, which were in clinical use as of December 2020 and focused on the Pfizer/ BioNTech/Fosun, Moderna mRNA-1273, Johnson and Johnson and AstraZeneca/Oxford AZD1222 vaccines.

Ronald P. Evens, B.S. Pharm1, Pharm.D., FCCP2

1Adjunct Research Professor, Tufts University
2President, M.A.A.P,S. 4 Biotec, Inc

Abstract

Biotechnology (the science and the business) has revolutionized product development and healthcare worldwide over the past 40 years with novel molecules, new companies, and major advances in disease mitigation. The revolution has continued and even accelerated as can be observed in comparing the last 20 years (2000-2019) versus first 20 years (1980-1999), and the recent years of 2020 and 2021 as well. This biotech review addresses the many product categories, indications, research, companies, business changes, and product sales, especially comparing these two time periods and demonstrating the substantial growth and impact of biotechnology and continuing the revolution through the last two years (2020-2021). Over 500 biotech products are available worldwide in 10 different categories of molecules for over 460 indications with over 160 biotech and pharma companies marketing the products. Biosimilar products (close duplicates of marketed products) have become commonplace in last 15 years. The top companies in biotech research and sales over these 40 years include Roche, Amgen, and Novo Nordisk, along with all the pharma companies becoming engaged.  Twenty plus of the leading biotech companies have been acquired over these times. All of pharma is now dedicated to biotech molecule development independently and mostly in extensive collaboration with biotech companies. Clinical research has expanded with the top 90 biotech companies that spend at least $100 million in one year totaling over $50 billion in 2020, along with tens of billions from pharma companies for biotech research & development. Over 600 molecules are being studied in phase three clinical trials. Worldwide biotech sales grew to $327 million in 2020 from $35 billion in 2001 with biotech over 25% of all drug sales.  The biotech revolution is alive and well and continuing with novel molecules from exiting and more new biotech and pharma companies for further advances in healthcare.

Larry L Mweetwa1, Tiro Mampane1, Thatoyaone J Kenaope1, Bonang Mosala1, Kenneth Pule1, Gerald Juma Obure1, Getrude Mothibe1

1Department of Pharmacy, Boitekanelo College, Plot 5824 Masetlheng Rd, Gaborone 00000, Botswana

Abstract

Nanobiotechnology is a multi-strategic approach that engineers biological components (atoms and molecules) at the nanoscales. The concept was introduced as an effective alternative with drug delivery and targeting properties. Nanobiotechnology has several applications in cancerous disease, autoimmune, inflammation, infectious, and viral diseases, and for the management of COVID-19. Nanoparticles have biomimetic properties, encapsulation, and safety formulation of drugs, and all these properties give them an advantage over conventional drug strategies. Nanobiotechnology research is currently progressive and needs extensive exploration and understanding for its potential use in future innovations. The present review studied the concept of nanobiotechnology, its origin, mechanism of drug delivery and targeting, applications, and future perspective in pharmacology and innovation to decipher its role in future advanced research.

Kamen V. Vlassakov1, Igor Kissin1

1The Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.

Abstract

Purpose: The aim of this study was to determine the time course of growth in general Google-reflected information on drugs used for anesthesia. As a contrast to the changes in general Google-reflected information we used the changes in academic PubMed-reflected information.

Methods: General Google-reflected information on anesthetics was assessed by counting the number of Google Web pages. Academic information was assessed by counting the number of articles in medico-biological journals covered by the PubMed database (The National Library of Medicine). The ratio of Google Web pages to PubMed articles (G/P Ratio) was used to indicate prevalence of Google-related information. Twenty-five agents used for anesthesia were selected from three pharmacological groups – general anesthetics, local anesthetics, and opioids — based on the frequency of their association with anesthesia in academic medical journals. The time course of growth in general Google-reflected information was determined for five 5-year periods, from 1993 to 2017.

Results: With the growing role of the Web, the number of Google Web pages on drugs used for anesthesia increased rapidly. As a result, the relationship between general Google-reflected and academic PubMed-reflected information on anesthetics profoundly changed. Before the 1998-2002 period, the number of Google Web pages on anesthetics was mostly a fraction of the number of PubMed articles. By the 2013-2017 period, the relationship was completely reversed: for any anesthetic, the number of Google Web pages was at least three times greater than the number of PubMed articles. However, the relationship of general Web-related information and academic information with different anesthetics was very variable. In 2013-2017, the G/P Ratio, indicating the magnitude of general information dominance, for the 25 agents varied from 3.0 (remifentanil) to 23.2 (oxycodone). The dominance of Google information was especially profound with drugs that have a wider spectrum of possible use beyond the field of anesthesia, such as oxycodone or diazepam.

Conclusion: General Google-reflected information is rapidly growing and, as a result, its dominance over academic PubMed-reflected information is constantly increasing.

Debora Ferreira Carneiro1

1Oral Health Unit, University Hospital of Brasilia, Brazil

Abstract

Judicial activism can be an important mechanism for citizens to protect their rights against legislative inertia and executive bureaucracy. However, when judges exceed decision-making power, a movement called judicial extremism, they generate legal uncertainty, as they do not have the expected legal basis for a court ruling, but only generic principles and moral values of the judge himself. The extremist judge, disrespects public policies, disrespects the public budget, disrespects the rights of the community, and imposes obligations on the Administration, without evaluating the consequences and without this generating effective social justice. In relation to public policies related to pharmaceutical assistance, judicial activism can help to correct management failures, but judicial extremism imposes on the Public Administration the supply of any medication, even if there is a therapeutic alternative available in public policy. This behavior has become widespread in Brazil and contaminates other countries with public health systems. The pharmaceutical industry gains the most, with marketing strategies or the creation of pseudo-differentiation between new pharmaceuticals and drugs, guarantee, with judicial decisions, an open consumer market, free from questioning and profitable. With the current global health crisis, information and misinformation about the disease and possible forms of treatment have enhanced the discussions and the role of tripartition of powers, collective and individual fundamental rights, economic groups, science, and assistance. A broad dialogue between the main actors in the process is needed so that fundamental rights are efficiently and guaranteed.
 

Gary R. Strichartz1, Douglas E. Raines2, Lawrence P. Cogswell III1

1Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
2Department of Anesthesia and Critical Care Medicine, Massachusetts General Hospital (DER), Harvard Medical School, Boston, MA 02115

Abstract

Binding of local anesthetics to plasma proteins has been presented as an important determinant of their bioavailability. Local anesthetics with a high potential for systemic toxicity, e.g. bupivacaine (BUP), are bound strongly by alpha1-acid glycoprotein (AAG), more weakly by serum albumin, but drug dissociation may be rapid, thus limiting the importance of protein binding. The purpose of this study was to determine the binding kinetics of BUP to AAG. Bupivacaine binding to AAG was monitored by its displacement of the fluorescent probe 1-anilinonaphthalene-8-sulfonic acid (ANS). The increased fluorescence of ANS (λ excit/em = 380/480 nm) upon binding to AAG was used to determine the equilibrium and kinetic characteristics of this reaction. By studying how BUP altered the binding kinetics of ANS to AAG it was possible to calculate the BUPs equilibrium and kinetic rate constants for AAG binding. ANS fluorescence increased ca. 50-fold when bound to AAG.  Increasing [BUP] with a constant [AAG] + [ANS] returned ANS fluorescence to its unbound status, due to complete displacement of ANS from AAG; bupivacaine’s competitive equilibrium constant, Ki , equals 1-2 μM (pH 7.4, 23oC). Pre-equilibrating AAG with BUP before the rapid (0.008s) addition of excess ANS slowed the binding of ANS to a rate limited by BUP’s dissociation: koff = 12.0 ± 0.5 s-1, corresponding to a half-time ~0.06 seconds. Therefore, although much of the total serum BUP at toxic levels (2-4 µg/mL) will be bound by plasma proteins, dissociation from the tightest binding protein shows that drug is rapidly freed during organ perfusion, allowing newly unbound drug to permeate into the perfused tissues. The very rapid dissociation of BUP from AAG means that equilibrium binding is a very poor index of bio-availability and systemic toxicity of that local anesthetic.

Abuelgasim Elrasheed A. Alhassan1, Simon Elliott2,3, Muneeb Venayikot1, Hamad Al Ghafri1

1National Rehabilitation Center (NRC), Abu Dhabi, UAE
2Elliott Forensic Consulting, Birmingham, UK
3Department of Analytical, Environmental and Forensic Sciences, King’s College London, London, UK

Abstract

Within the clinical setting of drug rehabilitation, it is important to be able to monitor for the use of drugs using sensitive and selective techniques whilst accounting for high throughput and numbers of patients to provide rapid results to clinicians. To meet this need, a comprehensive LC-MS-MS method for the confirmation and quantitation of a wide variety of drugs of abuse relevant to drug rehabilitation in the United Arab Emirates has been developed, validated and applied to patient urine samples. Following automated solid phase extraction, detection and quantitation involved multiple reaction monitoring with electrospray ionization. With few exceptions, within and between-batch accuracy and precision performance was shown to be within 20% across all drug types including amphetamines and related stimulants, benzodiazepines, opiates/opioids, cocaine and metabolites, cannabinoids, hallucinogens and ketamine (including metabolites) in urine. Results for 280 drug positive patient specimens showed good agreement with the previous in-house GC–MS approach. The LC-MS-MS replaces the existing GC-MS approach and can be expanded easily with the introduction of additional MRM transitions as and when required (e.g. if new or other drugs of abuse are to be considered) to support the work of the clinical team in this special area of clinical toxicology and medicine.

T Colin Campbell
Jacob Gould Schurman Professor Emeritus of Nutritional Biochemistry Cornell University

Abstract

Addressing the effect of nutrition on heart disease requires a dialogue somewhat different from contemporary practice.

Heart disease is used here as a generic name for at least a dozen or more cardiovascular disease subtypes. Each subtype has its own identity, its own causes, its own pathology, its own biochemistry, and its own treatment protocols. Although disease specification certainly has advantages, it also has a shortcoming that is commonly overlooked. The more detailed this information is, the more difficult it is to comprehend prevention and treatment protocols that may benefit all heart disease subtypes.

Questions arise, for example, whether information specific for one disease subtype applies to other subtypes. This likely requires additional research, regulatory development, and health claims oversight. However effective this information may be, increasing disease fragmentation and specification nonetheless increases opportunities for confusion, both for the public and the practitioner.

Relying on specialized information, however, presents a serious dilemma for understanding nutrition, unless it is characterized by specific nutrients in food, specific mechanisms of action for each nutrient, and specific heart disease subtypes. This is reductionism, which is the popular but incorrect perspective on nutrition.

In contrast, wholist interpretation of nutrition refers to the combined biologic activities of countless nutrients when consumed as food, and countless metabolic activities for each nutrient, working in unison when the proper food is consumed. At the tissue level during metabolism, this dynamic is highly sensitive to change, and it does so very rapidly. Change simultaneously occurs with changing supply of nutrient substrate and changing demand of the tissues. The default position for nutrition, by definition, is that which optimizes health, prevents, and even reverses (treats) disease development. Numerous enzymatic and hormonal mechanisms, acting like transistor switches, are available to manage this extraordinary dynamic.

Oft cited evidence shows that nutrition, when properly understood and used, can control as much as 70-85% of the premature mortality caused by cardiovascular disease. This nutrition is ideally powered by whole foods from the plant kingdom, with nutrients acting wholistically in the body in a way to benefit all disease subtypes, even though effect size and outcome responses for each heart disease subtype may differ.

Cheol Min Lee1, Hyun Jun Kim1, Shreya Timilsina1, Ronny Priefer1

1Massachusetts College of Pharmacy and Health Sciences University, Boston, Ma 02115

Abstract

Even though a myriad of antimicrobial agents have been developed over the decades, resistant mechanisms continually break through, ultimately increasing our mortality and fears. Significant efforts have been made to evade these pathogenic resistances by developing novel antimicrobial agents which work on different targets. One possible, simple solution that has also been investigated has been to modify the counter-anion of cationic-based drugs. Although a multitude of studies have evaluated the efficacy of the active cationic agent, some have also explored the often-neglected influence of the counter-anion. Understanding the role of the counter-anions may provide new antimicrobial agents and an alternative approach to quell antimicrobial resistance. This review focuses on the various studies that have either directly or in-directly evaluated the role of the counter-anion on antimicrobial activities. Indeed, certain cationic-based agents display significant alternation in their activity when paired with the correct anion.

REVIEW ARTICLES

Rucha Mahadik1, Paul Kiptoo2, Thomas Tolbert1, Teruna J. Siahaan1

1Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas 2093 Constant Avenue, Lawrence, KS 66047
2Sanofi Pharmaceuticals, 2 1 The 1 The Mountain Road, Framingham, MA 01701

Abstract

The immune system defends our body by fighting infection from pathogens utilizing both the innate and adaptive immune responses. The innate immune response is generated rapidly as the first line of defense. It is followed by the adaptive immune response that selectively targets infected cells. The adaptive immune response is generated more slowly, but selectively, by targeting a wide range of foreign particles (i.e., viruses or bacteria) or molecules that enter the body, known as antigens. Autoimmune diseases are the results of immune system glitches, where the body’s adaptive system recognizes self-antigens as foreign. Thus, the host immune system attacks the self-tissues or organs with a high level of inflammation and causes debilitation in patients. Many current treatments for autoimmune diseases (i.e., multiple sclerosis (MS), rheumatoid arthritis (RA)) have been effective but lead to adverse side effects due to general immune system suppression, which makes patients vulnerable to opportunistic infections. To counter these negative effects, many different avenues of antigen specific treatments are being developed to selectively target the autoreactive immune cells for a specific self-antigen or set of self-antigens while not compromising the general immune system. These approaches include soluble antigenic peptides, bifunctional peptide inhibitors (BPI) including IDAC and Fc-BPI, polymer conjugates, and peptide-drug conjugates. Here, various antigen-specific methods of potential treatments, their efficacy, and limitations will be discussed along with the potential mechanisms of action.