Introduction To The Theme "New Insights, Strategies, and Therapeutics For Common Diseases"

PA62CH32_Insel ARjats.
cls September 24, 2021 11:7
Annual Review of Pharmacology and Toxicology

Introduction to the Theme
“New Insights, Strategies,
and Therapeutics for
Annu. Rev. Pharmacol. Toxicol. 2022.62. Downloaded from www.annualreviews.org
Common Diseases”
Access provided by 180.249.167.153 on 10/12/21. For personal use only.
Paul A. Insel,1 Terrence F. Blaschke,2 Susan G. Amara,3

and Urs A. Meyer4
1
Departments of Pharmacology and Medicine, University of California, San Diego, La Jolla,
California 92093, USA; email: inseloffice@ucsd.edu
2
Stanford University School of Medicine, Stanford, California 94305, USA
3
National Institute of Mental Health, National Institutes of Health, Bethesda,
Maryland 20892, USA
4
Biozentrum, University of Basel, CH-4056 Basel, Switzerland
Annu. Rev. Pharmacol. Toxicol. 2022. 62:32.1–32.6 Abstract

The Annual Review of Pharmacology and Toxicology is The reviews in Volume 62 of the Annual Review of Pharmacology and Toxicology
online at pharmtox.annualreviews.org (ARPT) cover a diverse range of topics. A theme that encompasses many of
https://doi.org/10.1146/annurev-pharmtox-091421- these reviews is their relevance to common diseases and disorders, includ-
094627 ing type 2 diabetes, heart failure, cancer, tuberculosis, Alzheimer’s disease,
Copyright © 2022 by Annual Reviews. neurodegenerative disorders, and Down syndrome. Other reviews highlight
All rights reserved important aspects of therapeutics, including placebos and patient-centric ap-
proaches to drug formulation. The reviews with this thematic focus, as well
as other reviews in this volume, emphasize new mechanistic insights, ex-
perimental and therapeutic strategies, and novel insights regarding topics
in the disciplines of pharmacology and toxicology. As the editors of ARPT,
we believe that these reviews help advance those disciplines and, even more
importantly, have the potential to improve the health care of the world’s
population.
·.•�-
32.1
, Review in Advance first posted on

October 4, 2021. (Changes may
still occur before final publication.)
PA62CH32_Insel ARjats.cls September 24, 2021 11:7
Public health and the health of individuals have been at the forefront of the world’s attention and
that of the scientific community since the onset of the coronavirus disease 2019 (COVID-19) pan-
demic. Mitigation efforts and experimental and clinical studies of potential therapeutics, together
with vaccine development, testing, and delivery, have exposed the general population to aspects of
clinical medicine rarely considered in the past. Such exposure includes aspects of hospital rules and
policies, intensive care unit availability, face masks, the phases of drug testing and approval (e.g.,
Emergency Use Authorization versus full approval by the US Food and Drug Administration), and
the concepts of drug (and vaccine) efficacy versus toxicity/side effects. Terms and concepts of phar-
macology and toxicology that previously were largely the purview of researchers and health-care
providers have become part of the headlines and topics of daily interest among the public at large.
While not explicitly aware of the value of this education of the public during this unique time
frame, the members of the Editorial Committee of the Annual Review of Pharmacology and Toxicol-
ogy chose a number of topics for this volume that provide new ideas, discoveries, and therapeutic
approaches that impact on widely prevalent (common) diseases. In addition to COVID-19, re-
views in this volume address disease settings that include type 2 diabetes, heart failure, cancers,
tuberculosis, Down syndrome, Alzheimer’s disease, and neurodegenerative disorders. Along with
those disease-focused reviews, other reviews in this volume highlight important aspects of thera-
peutics. Below, we briefly summarize articles in this volume that are encompassed by the theme
new insights, strategies, and therapeutics for common diseases.
In their review on experimental models of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infection, Pandamooz et al. (1) emphasize the importance of using experimental
models that recapitulate features of the human disease. The use of such models is critical for inves-
tigators who seek to test and validate potential therapeutics, including antibodies, antiviral agents,
vaccines, and agents that target aspects of the pathobiology in infected humans (2–4). Pandamooz
et al. note the value of integrating data obtained by in vitro, in vivo, and computational/mathematic
models. The authors emphasize findings that provide insights regarding actions of the virus and
response of the host. The combination of findings from these approaches has the potential to pro-
vide novel insights with respect to pathogenesis, immune responses, and ultimately, therapeutics.
The review by Mirzadeh et al. (5) provides a different type of model related to type 2 diabetes:
a new (patho)physiological conceptualization that focuses on the central nervous system (CNS) as
a largely underappreciated contributor to the control of glucose homeostasis. The authors note
the role of the CNS in two aspects of glucose homeostasis: adaptive coupling of insulin secretion
by pancreatic beta cells and the regulation of insulin-independent glucose uptake and disposal.
While a triggering mechanism that drives dysregulation in the CNS has yet to be identified, the
authors suggest that CNS-targeted therapeutics may offer novel approaches for the treatment of
patients with type 2 diabetes.
Induri et al. (6) focus their review on metformin, a drug that is used to treat patients with type
2 diabetes. It has been suggested that metformin may promote healthy aging (7). The authors
propose that gut microbiome–metformin–host interactions may contribute to the efficacy of met-
formin in type 2 diabetes and may promote healthy aging. Such beneficial actions may relate to
metformin-promoted changes in the composition of the gut microbiome, which in turn lead to
less activation of the innate immune response and a decrease in chronic low-grade inflammation.
The authors propose that the impact of metformin on the gut microbiome as a contributor to its
beneficial effects in type 2 diabetes and the aging process merits further study.
Heart failure, commonly associated with aging, requires new therapeutic approaches. As re-
viewed by Patel & Shah (8) in Volume 59 of the Annual Review of Pharmacology and Toxicology, a
lack of therapeutics has been a major challenge in treating patients who have heart failure with
·.•�-
preserved ejection fraction (HFpEF). In this volume, Shah & Fang (9) review the efficacy of
32.2 Insel et al.

inhibitors of the sodium-glucose cotransporter 2 (SGLT2). SGLT2 inhibitors improve control of

blood glucose by inhibiting glucose reabsorption by the kidney while also decreasing body weight
and blood pressure (10). SGLT2 inhibitors also improve cardiac energetics and renal function and
decrease systemic inflammation. The latter effects may help explain the improvement observed in
heart failure with reduced ejection fraction (HFrEF) in both diabetics and nondiabetics in multi-
ple clinical trials. New results reported since this review was prepared indicate efficacy of SGLT2
inhibitors in patients with HFpEF (11, 12). SGLT2 inhibition thus appears to provide a clinically
useful approach for the treatment of HFpEF and HFrEF.
Another new treatment for heart disease is the repurposing of an old drug, colchicine, which
was approved for medical use in the United States in 1961. As reviewed by Bouabdallaoui & Tardif
(13), colchicine, via its inhibition of microtubular assembly, has been used as an anti-inflammatory
agent to treat gout and Familial Mediterranean fever. Studies during the last decade have revealed
that colchicine is also efficacious in treating acute and recurrent pericarditis. Recent clinical trials
have shown that treatment with colchicine can also decrease cardiovascular events in patients with
coronary artery disease, including those receiving statins and antiplatelet therapy (e.g., 14). These
and other data suggest a broader role for colchicine for the treatment of inflammatory disorders in
the cardiovascular system. Intriguingly, the data of these studies also allude to potential benefits of
low-dose colchicine in preventing incident gout and raise the question whether more people with
gout, particularly those with cardiovascular risk factors, would benefit from the use of low-dose
colchicine as a preventive therapy (15).
In recent years, many targeted and immune therapies have been developed and become part
of the standard of care in the treatment of numerous cancers. However, certain old drugs con-
tinue to be used to treat various malignancies. Westaby et al. (16) review the androgen recep-
tor as a target in the treatment of prostate cancer, the most common cancer in men (other
than skin cancer) and the second leading cause of cancer death (after lung cancer) in men
in the United States (https://cancer.org/cancer/prostate-cancer/about/key-statistics.html)
and the United Kingdom (https://www.cancerresearchuk.org/health-professional/cancer-
statistics/statistics-by-cancer-type/prostate-cancer). Because androgens and their receptor
contribute to the development and growth of prostate cancer, patients with such tumors are treated
with drugs that target androgen signaling. The authors provide an update on current agents and
approaches to target the androgen receptor, especially in patients with advanced prostate cancer,
and discuss factors that contribute to resistance to such agents.
The reviews by Gudas (17) and Gencheva & Arnér (18) explore other targets for cancer therapy
and additional potential indications for drugs directed at those targets. Gudas focuses on synthetic
retinoids. Such compounds are approved for the treatment of certain cancers. Gudas notes that
retinoic acid receptor–selective agonists are effective in treating skin disorders and also identi-
fies an emerging role of synthetic retinoids as possible therapeutics in other tissues. Gencheva &
Arnér review the potential of inhibitors of cytosolic selenoprotein thioredoxin reductase, which,
by reducing the enzyme’s ability to reduce cytosolic thioredoxin, increases cellular oxidative stress.
The authors explore issues that need to be resolved if inhibition of this enzyme is to become an
approach to treat cancers.
Tuberculosis (TB; caused by the bacteria Mycobacterium tuberculosis) is the leading cause of death
in the world from a single infectious agent. In 2019, 10 million people became ill, and 1.4 million
people with TB died (https://www.who.int/news-room/fact-sheets/detail/tuberculosis). A
major problem is multidrug-resistant TB, which continues to grow worldwide. Garcia-Cremades
et al. (19) review an important aspect in the treatment of patients with TB: imperfect medication
adherence. This aspect of TB therapy contributes to treatment failure and multidrug resistance.
·.•�-
The authors discuss the use of an emerging technology, digital adherence monitoring, to address
www.annualreviews.org • Introduction to the Theme 32.3

this problem and consider its application in clinical trials and practice. The authors also emphasize
the importance of finding new, safe, and effective drugs to treat patients with multidrug-resistant
TB.
Several reviews in this volume address aspects of pharmacology and toxicology of common
neuropsychiatric disorders, some of which occur across the entire life span. Bartesaghi et al. (20)
review the prenatal and postnatal pharmacotherapy of Down syndrome and its impact on cog-
nitive and behavioral aspects of disease progression, including the development of Alzheimer’s
dementia in older adults. No current therapeutics adequately address these aspects of Down syn-
drome, but experimental approaches are exploring mechanisms that underlie its neurocognitive
features. Since chromosome 21 trisomy is found in many individuals with Down syndrome, the
authors propose that research efforts should use model systems and seek to identify genes whose
overexpression contributes to abnormal cognition and behavior and, based such findings, explore
potential therapeutics that will normalize the expression of such genes.
Abd-Elrahman & Ferguson (21) also focus on Alzheimer’s disease but from the standpoint of
noncanonical metabotropic glutamate receptor 5 (mGluR5) signaling. mGluR5 influences mem-
ory and learning by modulating synaptic transmission and regulating gene and protein expression
of essential synaptic proteins. Of note, β-amyloid proteins, a feature of Alzheimer’s disease, disrupt
mGluR5 signaling and may be a mechanism that contributes to the pathobiology of the disease.
Accordingly, mGluR5 is a potential therapeutic target, perhaps by using allosteric modulators, for
the treatment of Alzheimer’s disease, although, as the authors note, sex-specific differences may
constrain the full utility of such therapeutic approaches.
The review by Cuadrado (22) highlights neurodegenerative disorders and the potential role of
nuclear factor erythroid 2–related factor 2 (NRF2) as a master regulator of functions that include
redox, energy metabolism, neuroinflammation, and proteostasis. The review discusses an age-
related and neurodegenerative disease–associated decrease in NRF2 and thus the potential for
pharmacological activators of NRF2 as possible therapeutics that may modify neurodegenerative
diseases. Another review in this volume by Torrente & DeNicola (23) discusses the potential role
of NRF2 in the context of cancer, focusing on the ability of cancer cells to hijack the ability of
NRF2 to maintain redox balance, aid in their proliferation, and confer resistance to radiotherapy
and chemotherapeutic agents. By contrast to the efforts related to neurodegenerative disorders,
the roles of NRF2 in cancer cells have led to approaches to blunt its signaling in tumors.
E-cigarettes have become popular in recent years, especially among adolescents and young
adults, as an alternative means to deliver nicotine instead of smoking tobacco. Aside from the
nicotine dependence that occurs with this and other forms of delivery of nicotine, e-cigarette va-
ping is associated with toxic effects that are reviewed by Gordon et al. (24). The authors note the
need for additional toxicological studies and highlight the legal and policy issues that have im-
peded such studies, including very important ones that assess the long-term health consequences
resulting from the use of e-cigarettes.
In their review, Benedetti et al. (25) focus on research efforts over the past 30 years that have
studied placebos and nocebos. Unlike placebos, which are presumed to lack effects, nocebos are
harmless substances or treatments that may cause harmful side effects or worsening of symptoms
because the recipient thinks or believes they may occur or expects them to occur. Many clinical
studies have demonstrated effects of placebos and nocebos, as have health-care providers in ob-
serving patients. The authors review biological mechanisms for such effects and emphasize the
similarity of such mechanisms between therapeutic drugs and placebos or nocebos, thus implicat-
ing psychological factors in the actions of drugs. Importantly, the authors note the potential for
placebo effects to be exploited by pseudoscience and practitioners who wittingly or unwittingly
·.•�-
employ those effects in the care of patients.
32.4 Insel et al.

Page et al. (26) highlight a variety of innovative formulation strategies and technologies that
seek to improve therapeutics and, in turn, patient care. The authors discuss the advancements in
mechanistic understanding of diseases and drug action along with the discovery and development
of novel types of therapeutic approaches. As the authors note, the goal is to deliver drugs to the
required site of action and in parallel, to focus on the needs of the patient, that is, patient centricity,
with respect to efficacy, side effects, and adherence. Consistent with these needs are the interac-
tions between patient groups and pharmaceutical companies. In addition to those interactions,
there has been increased recognition of patient centricity as part of the drug approval process and
in the creation of guidelines for drug administration and monitoring.
As the Editors of the Annual Review of Pharmacology and Toxicology, we hope that readers will
find the reviews highlighted above, as well as the other reviews in Volume 62, to be informative
and helpful in stimulating thought regarding the topics that are reviewed in this volume. We are
indebted to the staff of Annual Reviews, in particular the Production Editor Kiri Hagerman. We
also wish to thank the members of the Editorial Committee for their selection of the topics of
these reviews and their assistance in reviewing the initial manuscripts submitted by the authors.
Most importantly, we are grateful to the authors for the insightful and high-quality reviews that
they prepared for Volume 62.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
LITERATURE CITED
1. Pandamooz S, Jurek B, Meinung C-P, Baharvand Z, Sahebi Shahem-abadi A, et al. 2022. Experimental
models of SARS-CoV-2 infection: possible platforms to study COVID-19 pathogenesis and potential
treatments. Annu. Rev. Pharmacol. Toxicol. In press
2. Sriram K, Insel PA. 2020. A hypothesis for pathobiology and treatment of COVID-19: the centrality of
ACE1/ACE2 imbalance. Br. J. Pharmacol. 177:4825–44
3. Bohn MK, Hall A, Sepiashvili L, Jung B, Sheele S, Adeli K. 2020. Physiology 35:288–301
4. Sridhar S, Nicholls J. 2021. Pathophysiology of infection with SARS-CoV-2—what is known and what
remains a mystery. Respirology 26:652–65
5. Mirzadeh Z, Faber CL, Schwartz MW. 2022. Central nervous system control of glucose homeostasis:
a therapeutic target for type 2 diabetes? Annu. Rev. Pharmacol. Toxicol. In press
6. Induri SNR, Kansara P, Thomas SC, Xu F, Saxena D, Li X. 2022. The gut microbiome, metformin, and
aging. Annu. Rev. Pharmacol. Toxicol. In press
7. Glossmann HH, Lutz OMD. 2019. Metformin and aging: a review. Gerontology 65:581–90
8. Patel RB, Shah SJ. 2019. Drug targets for heart failure with preserved ejection fraction: a mechanistic
approach and review of contemporary clinical trials. Annu. Rev. Pharmacol. Toxicol. 59:41–63
9. Shah KS, Fang JC. 2022. Sodium-glucose cotransporter 2 inhibitors in heart failure. Annu. Rev. Pharmacol.
Toxicol. In press
10. Vallon V, Verma S. 2021. Effect of SGLT2 inhibitors on kidney and cardiovascular function. Annu. Rev.
Physiol. 83:503–28
11. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E et al. 2021. Empagliflozin in heart failure with a
preserved ejection fraction. New Engl. J. Med. In press
12. Drazner MH. 2021. SGLT2 inhibition in heart failure with a preserved ejection fraction—a win against
a formidable foe. New Engl. J. Med. In press
13. Bouabdallaoui N, Tardif J-C. 2022. Repurposing colchicine for heart disease. Annu. Rev. Pharmacol. Toxicol.
In press
14. Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, et al. 2020. Colchicine in patients with
·.•�-
chronic coronary disease. New Engl. J. Med. 383:1838–47
www.annualreviews.org • Introduction to the Theme 32.5

15. Russell MD, Bukhari M, Shah AM, Galloway JB. 2021. Colchicine and the heart: old friends, old foes.
Rheumatology 60:2035–36
16. Westaby D, Fenor de La Maza MdlD, Paschalis A, Jimenez-Vacas JM, Welti J, et al. 2022. A new old
target: androgen receptor signaling and advanced prostate cancer. Annu. Rev. Pharmacol. Toxicol. In press
17. Gudas LJ. 2022. Synthetic retinoids beyond cancer therapy. Annu. Rev. Pharmacol. Toxicol. In press
18. Gencheva R, Arnér ESJ. 2022. Thioredoxin reductase inhibition for cancer therapy. Annu. Rev. Pharmacol.
Toxicol. In press
19. Garcia-Cremades M, Solans BP, Strydom N, Vrijens B, Pillai GC, et al. 2022. Emerging therapeutics,
technologies, and drug development strategies to address patient nonadherence and improve tuberculosis
treatment. Annu. Rev. Pharmacol. Toxicol. In press
20. Bartesaghi R, Vicari S, Mobley WC. 2022. Prenatal and postnatal pharmacotherapy in Down syndrome:
the search to prevent or ameliorate neurodevelopmental and neurodegenerative disorders. Annu. Rev.
Pharmacol. Toxicol. In press
21. Abd-Elrahman KS, Ferguson SSG. 2022. Noncanonical metabotropic glutamate receptor 5 signaling in
Alzheimer’s disease. Annu. Rev. Pharmacol. Toxicol. In press

22. Cuadrado A. 2022. Brain-protective mechanisms of transcription factor NRF2: toward a common strategy
for neurodegenerative diseases. Annu. Rev. Pharmacol. Toxicol. In press

23. Torrente L, DeNicola GM. 2022. Targeting NRF2 and its downstream processes: opportunities and chal-
lenges. Annu. Rev. Pharmacol. Toxicol. In press
24. Gordon T, Karey E, Rebuli ME, Escobar YN, Jaspers I, Chen LC. 2022. E-cigarette toxicology. Annu.
Rev. Pharmacol. Toxicol. In press
25. Benedetti F, Frisaldi E, Shaibani A. 2022. Thirty years of neuroscientific investigation of placebo and
nocebo: the interesting, the good, and the bad. Annu. Rev. Pharmacol. Toxicol. In press
26. Page S, Khan T, Kühl P, Schwach G, Storch K, Chokshi H. 2022. Patient centricity driving formulation
innovation: What’s new? Annu. Rev. Pharmacol. Toxicol. In press
·.•�-
32.6 Insel et al.


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PA62CH32_Insel ARjats.

cls September 24, 2021 11:7

Annual Review of Pharmacology and Toxicology

Paul A. Insel,1 Terrence F. Blaschke,2 Susan G. Amara,3

Annu. Rev. Pharmacol. Toxicol. 2022. 62:32.1–32.6 Abstract

, Review in Advance first posted on

32.2 Insel et al.

, Review in Advance first posted on

inhibitors of the sodium-glucose cotransporter 2 (SGLT2). SGLT2 inhibitors improve control of

www.annualreviews.org • Introduction to the Theme 32.3

, Review in Advance first posted on

32.4 Insel et al.

, Review in Advance first posted on

www.annualreviews.org • Introduction to the Theme 32.5

, Review in Advance first posted on

Alzheimer’s disease. Annu. Rev. Pharmacol. Toxicol. In press

for neurodegenerative diseases. Annu. Rev. Pharmacol. Toxicol. In press

, Review in Advance first posted on

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