Download and Read online, DOWNLOAD EBOOK, [PDF EBOOK EPUB ], Ebooks

download, Read Ebook EPUB/KINDE, Download Book Format PDF

Drug repositioning : approaches and applications

for neurotherapeutics 1st Edition Berliocchi

OR CLICK LINK
https://textbookfull.com/product/drug-
repositioning-approaches-and-applications-for-
neurotherapeutics-1st-edition-berliocchi/

Read with Our Free App Audiobook Free Format PFD EBook, Ebooks dowload PDF
with Andible trial, Real book, online, KINDLE , Download[PDF] and Read and Read
Read book Format PDF Ebook, Dowload online, Read book Format PDF Ebook,
[PDF] and Real ONLINE Dowload [PDF] and Real ONLINE
More products digital (pdf, epub, mobi) instant
download maybe you interests ...

Drug Delivery Approaches and Nanosystems Volume 1 Novel

Drug Carriers 1st Edition Raj K. Keservani

https://textbookfull.com/product/drug-delivery-approaches-and-
nanosystems-volume-1-novel-drug-carriers-1st-edition-raj-k-
keservani/

Drug Delivery Challenges and Novel Therapeutic

Approaches for Retinal Diseases Christopher L. Cioffi

https://textbookfull.com/product/drug-delivery-challenges-and-
novel-therapeutic-approaches-for-retinal-diseases-christopher-l-
cioffi/

Green Approaches in Medicinal Chemistry for Sustainable

Drug Design 1st Edition Bimal K. Banik (Editor)

https://textbookfull.com/product/green-approaches-in-medicinal-
chemistry-for-sustainable-drug-design-1st-edition-bimal-k-banik-
editor/

Drug Delivery Approaches and Nanosystems Two Volume Set

1st Edition Raj K. Keservani

https://textbookfull.com/product/drug-delivery-approaches-and-
nanosystems-two-volume-set-1st-edition-raj-k-keservani/
Repositioning Pedagogical Content Knowledge in Teachers
Knowledge for Teaching Science Anne Hume

https://textbookfull.com/product/repositioning-pedagogical-
content-knowledge-in-teachers-knowledge-for-teaching-science-
anne-hume/

Drug utilization research: methods and applications 1st

Edition Monique Elseviers

https://textbookfull.com/product/drug-utilization-research-
methods-and-applications-1st-edition-monique-elseviers/

Innovative Approaches in Drug Discovery

Ethnopharmacology Systems Biology and Holistic
Targeting 1st Edition Bhushan Patwardhan

https://textbookfull.com/product/innovative-approaches-in-drug-
discovery-ethnopharmacology-systems-biology-and-holistic-
targeting-1st-edition-bhushan-patwardhan/

Integration of Omics Approaches and Systems Biology for

Clinical Applications 1st Edition Antonia Vlahou

https://textbookfull.com/product/integration-of-omics-approaches-
and-systems-biology-for-clinical-applications-1st-edition-
antonia-vlahou/

Multi-Target Drug Design Using Chem-Bioinformatic

Approaches Kunal Roy

https://textbookfull.com/product/multi-target-drug-design-using-
chem-bioinformatic-approaches-kunal-roy/
 Drug Repositioning
Approaches and Applications for
Neurotherapeutics
FRONTIERS IN NEUROTHERAPEUTICS SERIES
Series Editors
Diana Amantea, Laura Berliocchi, and Rossella Russo

Drug Repositioning: Approaches and Applications for Neurotherapeutics

Joel Dudley, Mount Sinai School of Medicine, New York, New York, USA
Laura Berliocchi, Magna Græcia University, Catanzaro, Italy

Mapping of Nervous System Diseases via MicroRNAs

Christian Barbato, Institute of Cell Biology and Neurobiology (IBCN), Rome, Italy
Francesca Ruberti, Institute of Cell Biology and Neurobiology (IBCN), Rome, Italy

Rational Basis for Clinical Translation in Stroke Therapy

Giuseppe Micieli, IRCCS, Pavia, Italy
Diana Amantea, University of Calabria, Rende, Italy
 Drug Repositioning
Approaches and Applications for
Neurotherapeutics

Edited by
Joel Dudley and Laura Berliocchi
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742

©2017 by Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group, an Informa business

No claim to original U.S. Government works

Printed on acid-free paper

International Standard Book Number-13: 978-1-4822-2083-4 (Hardback)

This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have
been made to publish reliable data and information, but the author and publisher cannot assume responsibility
for the validity of all materials or the consequences of their use. The authors and publishers have attempted to
trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if
permission to publish in this form has not been obtained. If any copyright material has not been acknowledged
please write and let us know so we may rectify in any future reprint.

Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or
utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including
photocopying, microfilming, and recording, or in any information storage or retrieval system, without written
permission from the publishers.

For permission to photocopy or use material electronically from this work, please access www.copyright.com
(http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive,
Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration
for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system
of payment has been arranged.

Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only
for identification and explanation without intent to infringe.

Library of Congress Cataloging-in-Publication Data

Names: Dudley, Joel T. | Berliocchi, Laura.

Title: Drug Repositioning: Approaches and Applications for Neurotherapeutics
/ [edited by] Joel Dudley and Laura Berliocchi.
Description: Boca Raton: CRC Press, [2017] | Series: Frontiers in
Neurotherapeutics series | Includes bibliographical references and index.
Identifiers: LCCN 2016059349| ISBN 9781482220834 (hardback: alk. paper) |
ISBN 9781315373669 (ebook)
Subjects: LCSH: Drug development. | Neuropharmacology.
Classification: LCC RM301.25 .D786148 2017 | DDC 615.1/9--dc23
LC record available at https://lccn.loc.gov/2016059349

Visit the Taylor & Francis Web site at

http://www.taylorandfrancis.com

and the CRC Press Web site at

http://www.crcpress.com
Contents
Preface........................................................................................................................ix
Editors........................................................................................................................xi
Contributors.............................................................................................................xiii

Section I  The Rationale and Economics

of Drug Repositioning

Chapter 1 Scientific and Commercial Value of Drug Repurposing.......................3

David Cavalla

Chapter 2 Repurposing for Alzheimer’s and Parkinson’s Diseases: The

Ideas, the Pipeline, the Successes, and the Disappointments..............23
Hermann Mucke

Chapter 3 Contribution of Not-for-Profit Organizations to Drug Repurposing..... 41

Bruce Bloom

Section II  Repositioning Approaches and

Technologies: From Serendipity to
Systematic and Rational Strategies
Chapter 4 Systematic Drug Repositioning...........................................................61
Spyros N. Deftereos, Aris Persidis, Andreas Persidis,
Eftychia Lekka, Christos Andronis, and Vassilis Virvillis

Chapter 5 Technical Tools for Computational Drug Repositioning.....................83

Francesco Napolitano

Chapter 6 RNAi Screening toward Therapeutic Drug Repurposing..................105

Nichole Orr-Burks, Byoung-Shik Shim, Olivia Perwitasari,
and Ralph A. Tripp

v
vi Contents

Chapter 7 Phenotypic Screening........................................................................121

Christine M. Macolino-Kane, John R. Ciallella,
Christopher A. Lipinski, and Andrew G. Reaume

Section III  D
 rug Repositioning for
Nervous System Diseases

Chapter 8 A Case Study: Chlorpromazine.........................................................147

Francisco López-Muñoz, Cecilio Álamo,
and Silvia E. García-Ramos

Chapter 9 Drug Repurposing for Central Nervous System Disorders: A

Pillar of New Drug Discovery...........................................................169
Mondher Toumi, Aleksandra Caban, Anna Kapuśniak,
Szymon Jarosławski, and Cecile Rémuzat

Chapter 10 Repurposing Opportunities for Parkinson’s Disease Therapies........177

Giulia Ambrosi, Silvia Cerri, and Fabio Blandini

Chapter 11 Drug Candidates for Repositioning in Alzheimer’s Disease.............201

Maria P. del Castillo-Frias and Andrew J. Doig

Chapter 12 Promising Candidates for Drug Repurposing in Huntington’s

Disease..............................................................................................221
Francesca Romana Fusco and Emanuela Paldino

Chapter 13 Drug Repositioning Opportunities in Psychiatry..............................241

Alexander W. Charney, Joseph R. Scarpa, Douglas M. Ruderfer,
and Dennis S. Charney

Chapter 14 Pharmacology of Amyotrophic Lateral Sclerosis: Old Strategies

and New Perspectives........................................................................261
Tiziana Petrozziello, Valentina Tedeschi, Alba Esposito,
and Agnese Secondo
Contents vii

Chapter 15 Repositioning Clinic-Ready Compounds for the Treatment

of Spinal Muscular Atrophy..............................................................275
Faraz Farooq

Chapter 16 Rescuing Ischemic Brain Injury by Targeting the Immune

Response through Repositioned Drugs.............................................287
Diana Amantea and Giacinto Bagetta
Index.......................................................................................................................303
Preface
A better understanding of many nervous system disorders and their effective treat-
ment represents an important scientific challenge and an increasing concern for
health systems worldwide, due to the chronic nature of some of these conditions
and their high incidence especially in the increasing aging population. In spite of
significant financial and professional investments, and great advances made during
the past two decades, the fundamental etiology and pathophysiology of many dis-
eases affecting the nervous system remain unclear, and effective disease-modifying
therapies are still lacking. The reasons for such a failure in developing new effective
therapeutics for nervous system disorders are several and of different nature. The
intricate biology of the nervous system itself, together with the complexity and slow
progression of these specific pathologies, made it difficult to understand the basic
disease mechanisms and to identify appropriate end points and biomarkers, essen-
tial in achieving an accurate stratification of patients’ populations. Indeed, patients’
heterogeneity, lack of reliable biomarkers for both diagnosis and treatment, and
slow progression are some of the factors responsible for the failure of many clinical
trials. Furthermore, limitations related to the uncertain predictive validity of animal
models seem to have interfered with the successful identification of safe and/or
effective new candidate drugs, and contributed to the high rate of late-stage clinical
trial failures, for instance in the case of drugs acting on the central nervous system.
In addition to the existing biological reasons, regulatory barriers seem to have
contributed to make de novo drug discovery and development for nervous system
diseases a lengthy, costly, and risky process. Although this is particularly true for
drug development in the field of neuroscience, in recent years it has become more
and more clear that, in general, the whole traditional paradigm of R&D needed some
rethinking. Over the last decade, increasing pharma R&D costs were not paralleled
by increased productivity. On the contrary, the relationship between the investments
to develop new innovative drugs and the outcome in terms of the resulting medical
and financial benefits dramatically decreased, and only very few new drugs were
approved.
Among the possible alternative approaches to de novo drug discovery, drug repo-
sitioning seems to be one of the most promising strategies to develop therapeutic
options for currently unmet medical needs. Drug repositioning or repurposing or
reprofiling (the terms are sometimes used interchangeably) refers to a designed way
to identify new applications for existing drugs, at any stage of their long develop-
mental or clinical path. This also includes drugs that have been shown to be safe but
not effective for the indication they were originally developed for or, to the extreme,
drugs investigated but not further developed or even removed from the market for
safety reasons (drug rescue).
Thanks to the most recent advancements in technologies, including in vitro/in
vivo screening approaches and computational tools such as bioinformatics, chemoin-
formatics, network biology, and system biology, the drug repositioning concept has
flourished and moved from casual discoveries to targeted strategies.

ix
x Preface

Repositioning shows several advantages over traditional de novo drug discovery,

such as reduced development costs and shorter time to approval and launch, and
is emerging as a particularly attractive approach for several pathologies including
rare and neglected diseases. Although with some challenges, the recovery of failed
compounds for new indications clearly represents an interesting business opportu-
nity for the industry, as also shown by the creation of ad hoc partnerships between
big pharma, academia, and governments. Also from a social standpoint, conveying
existing data and knowledge toward new therapeutic applications stands as a highly
ethical way to maximize the use of patient information, and several nonprofit orga-
nizations have launched programs specifically aimed to support drug repurposing
projects and initiatives.
It is clear that collaboration between different entities is key to the success of this
attractive and complex new strategy in improving and accelerating therapeutic devel-
opment for nervous system disorders.
Renowned experts from different settings (academia, industry, nonprofit organi-
zations) will discuss all these aspects in the present volume of the series Frontiers
in Neurotherapeutics. The book aims to provide an overview of drug repositioning
applications specific to neurotherapeutics and is organized in three sections, each
composed of several chapters. Section I introduces the concept and rationale of drug
repositioning, illustrates the different possible challenges in repurposing by analyz-
ing the cases of Alzheimer’s and Parkinson’s diseases, and describes the contribu-
tion of nonprofit research organizations. Section II illustrates the evolution of drug
repositioning from a serendipitous advance to a precise strategy, providing some
examples of techniques and tools used for the identification of new applications for
existing compounds. Section III focuses on drug repositioning relevance specifi-
cally for nervous system diseases, providing some historical examples and analyz-
ing in individual chapters the status of some of the main nervous system conditions
(Alzheimer’s, Parkinson’s, and Huntington’s diseases; amyotrophic lateral sclerosis;
spinal muscular atrophy; ischemic stroke; and psychiatric disorders).
We thank all the authors for their participation and their valuable contributions
and the reviewers for their critical comments. We are particularly grateful to Hilary
LaFoe for her constant support, to Natasha Hallard for her skilled help, and to all
CRC Press and Taylor & Francis Group staff for their professional assistance during
all phases of book production.
Editors
Dr. Joel Dudley is associate professor of genetics and genomic sciences and director
of biomedical informatics at Mount Sinai School of Medicine, New York (NY, USA).
Prior to Mount Sinai, he held positions as cofounder and director of informatics at
NuMedii, Inc., and consulting professor of systems medicine in the Department of
Pediatrics at Stanford University School of Medicine (CA, USA), where he partici-
pated in leading research to incorporate genome sequencing into clinical practice.
Dr. Dudley’s current research is focused toward solving key problems in genomics
and precision medicine through the development and application of translational and
biomedical informatics methodologies. His publications cover the areas of bioinfor-
matics, genomic medicine, personal and clinical genomics, as well as drug and bio-
marker discovery. He received a BS in microbiology from Arizona State University
and an MS and a PhD in biomedical informatics from Stanford University School of
Medicine (CA, USA).

Dr. Laura Berliocchi is associate professor of pharmacology at the Department of

Health Sciences, Magna Græcia University (Catanzaro, Italy). She is leading the
Pain Unit at the Center of Preclinical and Translational Pharmacology (University
of Calabria, Italy), whose research activity is focused on a better understanding of
the neurobiology of pain for more effective clinical treatments. Her latest research
activity is focused on the role of autophagy in neuronal dysfunction and on the iden-
tification of new strategies for pain management. She received a BSc (Hons) in biol-
ogy from the University of Rome “Tor Vergata” (Italy), a specialization degree in
biotechnologies from the same university, and a PhD in molecular toxicology from
the University of Konstanz (Germany). She was a research associate at the Medical
Research Council (MRC; Leicester, UK), working on the effects of synaptic and
axonal damage on neuronal function and survival, then a London Pain Consortium
(LPC) senior research fellow and a scientific visitor at University College London
(UCL; London, UK), where she trained in experimental models of pain and worked
on mechanisms of pain control. She is a Deutscher Akademischer Austauschdienst
(DAAD) alumna.

xi
Contributors
Cecilio Álamo Aleksandra Caban
Department of Biomedical Sciences Creativ-Ceutical
(Pharmacology Area) Kraków, Poland
University of Alcalá
Madrid, Spain David Cavalla
Numedicus Limited
Cambridge, United Kingdom
Diana Amantea
Department of Pharmacy, Health and
Silvia Cerri
Nutritional Sciences
Center for Research in
University of Calabria
Neurodegenerative Diseases
Rende, Italy
Casimiro Mondino National
Neurological Institute
Giulia Ambrosi Pavia, Italy
Center for Research in
Neurodegenerative Diseases Alexander W. Charney
Casimiro Mondino National Department of Neuroscience
Neurological Institute and
Pavia, Italy Department of Psychiatry
Icahn School of Medicine at Mount
Christos Andronis Sinai
Biovista Inc. New York, New York
Charlottesville, Virginia
Dennis S. Charney
Department of Psychiatry
Giacinto Bagetta Icahn School of Medicine at Mount
Department of Pharmacy, Health and Sinai
Nutritional Sciences New York, New York
University of Calabria
Rende, Italy John R. Ciallella
Melior Discovery Inc.
Fabio Blandini Exton, Pennsylvania
Center for Research in
Neurodegenerative Diseases Spyros N. Deftereos
Casimiro Mondino National Biovista Inc.
Neurological Institute Charlottesville, Virginia
Pavia, Italy
Maria P. del Castillo-Frias
Bruce Bloom Manchester Institute of Biotechnology
Cures within Reach The University of Manchester
Chicago, Illinois Manchester, United Kingdom

xiii
xiv Contributors

Andrew J. Doig Christopher A. Lipinski

Manchester Institute of Biotechnology Melior Discovery Inc.
The University of Manchester Exton, Pennsylvania
Manchester, United Kingdom
Francisco López-Muñoz
Alba Esposito Faculty of Health Sciences and Chair of
Department of Neuroscience, Genomic Medicine
Reproductive and Camilo José Cela University
Odontostomatological Sciences and
“Federico II” University of Naples Faculty of Medicine and Health
Naples, Italy Sciences
University of Alcalá
Faraz Farooq and
Molecular Biomedicine Program Neuropsychopharmacology Unit
Children’s Hospital of Eastern Ontario Hospital 12 de Octubre Research
Research Institute Institute (i+12)
Ottawa, Ontario, Canada Madrid, Spain
and
Christine M. Macolino-Kane
Mathematics & Science Department Melior Discovery Inc.
Emirates College for Advanced Exton, Pennsylvania
Education
Abu Dhabi, United Arab Emirates Hermann Mucke
H.M. Pharma Consultancy
Francesca Romana Fusco Vienna, Austria
Laboratory of Neuroanatomy
Santa Lucia Foundation Francesco Napolitano
Rome, Italy Systems and Synthetic Biology
Laboratory
Silvia E. García-Ramos Telethon Institute of Genetics and
Hospital Pharmacy Service Medicine
Principe de Asturias University Hospital Pozzuoli, Italy
Madrid, Spain
Nichole Orr-Burks
Szymon Jarosławski Department of Infectious Disease
Public Health Department University of Georgia
Aix-Marseille University Athens, Georgia
Marseille, France
Emanuela Paldino
Anna Kapuśniak Laboratory of Neuroanatomy
Creativ-Ceutical Santa Lucia Foundation
Kraków, Poland Rome, Italy

Eftychia Lekka Andreas Persidis

Biovista Inc. Biovista Inc.
Charlottesville, Virginia Charlottesville, Virginia
Contributors xv

Aris Persidis Agnese Secondo

Biovista Inc. Department of Neuroscience,
Charlottesville, Virginia Reproductive and
Odontostomatological Sciences
Olivia Perwitasari “Federico II” University of Naples
Department of Infectious Disease Naples, Italy
University of Georgia
Athens, Georgia
Byoung-Shik Shim
Tiziana Petrozziello Immunology and Microbial Sciences
Department of Neuroscience, The Scripps Research Institute
Reproductive and Jupiter, Florida
Odontostomatological Sciences
“Federico II” University of Naples
Valentina Tedeschi
Naples, Italy
Department of Neuroscience,
Reproductive and
Andrew G. Reaume Odontostomatological Sciences
Melior Discovery Inc. “Federico II” University of Naples
Exton, Pennsylvania Naples, Italy

Cecile Rémuzat
Creativ-Ceutical Mondher Toumi
Paris, France Public Health Department
Aix-Marseille University
Douglas M. Ruderfer Marseille, France
Department of Medicine, Psychiatry
and Biomedical Informatics
Ralph A. Tripp
Vanderbilt University School of Medicine
Department of Infectious Disease
Nashville, Tennessee
University of Georgia
Athens, Georgia
Joseph R. Scarpa
Department of Genetics and Genomic
Sciences Vassilis Virvillis
Icahn School of Medicine at Mount Sinai Biovista Inc.
New York, New York Charlottesville, Virginia
Section I
The Rationale and Economics
of Drug Repositioning
 1 Scientific and
Commercial Value of
Drug Repurposing
David Cavalla

CONTENTS
1.1 Introduction .......................................................................................................3
1.2 Case Histories ...................................................................................................4
1.3 Advantages of Drug Repurposing .....................................................................8
1.3.1 Attritional Risk .....................................................................................8
1.3.2 Cost .....................................................................................................10
1.3.3 Time ....................................................................................................11
1.4 Disadvantages .................................................................................................12
1.4.1 Off-Label Medicine ............................................................................13
1.5 Variants ...........................................................................................................14
1.5.1 Repurposing of Generic Drugs ...........................................................15
1.5.2 Repurposing of Abandoned Assets .....................................................15
1.6 Off-Target versus On-Target ...........................................................................16
1.6.1 Rare Diseases ......................................................................................17
1.7 Conclusion ......................................................................................................19
References.................................................................................................................19

1.1 INTRODUCTION
Drug repurposing is a directed strategy to identify new uses for existing drugs, to be
embarked upon at any stage in their developmental or clinical life. For pharmaceutical
R&D, the benefits are clear: alongside reduced risk of developmental failure, there is
demonstrable reduced cost and time of development. While historically many examples
of repurposing arose from serendipitous clinical findings, modern repurposing has other
skills in its toolbox; it may also derive from literature-based methods, deliberate in vitro
or in vivo screening exercises, or in silico computational techniques to predict function-
ality based on a drug’s gene expression effects, interaction profile, or chemical structure.
From the earliest times of medicine, doctors have sought further uses for avail-
able treatments. Traditional folk medicines are often proposed for the treatment of a
bewilderingly wide range of purposes. The keystone in the process of new uses for
existing drugs is the physician; they approach the issue using the principle of “clini-
cal relatedness,” whereby if a drug is useful for condition A, it is likely to be useful
for a related condition B.

3
4 Drug Repositioning: Approaches and Applications for Neurotherapeutics

As distinct from the historical interest in new use for existing medicines, the mod-
ern strategy of drug repurposing involves a much fuller evaluation of a drug-like
compound, including its chemistry, its medical use, and the biological target through
which its effect is derived. This diverges from the traditional discovery approach,
which is focused on a particular disease-related target. Instead, drug repurposing
starts with the drug, looks at its complete biological profile, and ends with the identi-
fication of a number of new diseases for which it might be useful. These hypotheses
are then tested experimentally, in preclinical and clinical trials.
The nomenclature in the field of drug repurposing has been rather confusing: other
terms such as drug repositioning, reprofiling, and therapeutic switching have been
suggested by some authors to relate to subtly different aspects. In this chapter, they
will be taken to mean the same thing, broadly, the “concept of branching the develop-
ment of an active pharmaceutical ingredient, at any stage of the life cycle and regard-
less of the success or misfortune it has encountered so far, to serve a therapeutic
purpose that is significantly different from the originally intended one” (Mucke 2014).
There are three main categories of drug repurposing: the identification for a new indi-
cation of a developmental compound, a launched proprietary product, and a generic drug.
In addition, relative to the primary indication, repurposing may involve a different dose, a
different route of administration, a different formulation, or none of these, in which case it
may represent more of a product line extension. Each of these alternatives differs substan-
tially from the other in terms of developmental, regulatory, and commercial prospects.
The change of indication may also involve further optimization of the active principle,
on the basis that a very good way of discovering a new drug is to start with an old drug.

1.2 CASE HISTORIES
Recent attention to the deliberate strategy of drug repurposing has arisen partly
because of the observed frequency with which this has happened by chance in the
past. In other words, as success in pharmaceutical R&D becomes evermore chal-
lenging, investigators have been attracted to this strategy because pharmaceutical
products with secondary uses are known from previous, serendipitous experience.
These findings, although serendipitous, have revealed more than just another use for
an existing drug. Their frequency has also revealed that a single biological mediator
is usually involved in many different diseases, and this pleiotropy makes repurposing
(of a modulator of such a mediator) a promising strategy.
The discovery of the use of thalidomide for the treatment of leprosy is an instruc-
tive example. Before it was banned by WHO (World Health Organization) for its
teratogenicity in 1962, and withdrawn from the market in Europe and Canada, tha-
lidomide was used for the treatment of insomnia and morning sickness. By 1964,
almost no one believed that it might be reintroduced after its infamous history.
But at this time, a critically ill patient with erythema nodosum leprosum (ENL),
a complication of multibacillary leprosy, was referred to Dr. Jacob Sheskin, who
was at Hadassah University in Jerusalem. The patient was originally from Morocco
and was being treated by the University of Marseilles, France. Leprosy (Hansen’s
disease) is a chronic, infectious human disease caused by a bacillus similar to that
which causes tuberculosis.
Scientific and Commercial Value of Drug Repurposing 5

The patient was on the verge of death—for months, the pain of his condition
had prevented him from sleeping for more than 2 or 3 hours in any 24-hour period.
Sheskin had no available therapy for his patient and as a last resort administered
thalidomide because he thought that its original indication for insomnia would allow
him to sleep better. Rather to Sheskin’s surprise, one day after administering two
pills of thalidomide, the patient slept continuously for about 20 hours. After 2 days,
the pain, which had been so severe, had disappeared almost entirely. After another
3 days, Sheskin decided to withdraw treatment, and the condition rapidly worsened.
Sheskin was unable to replicate his discovery in Israel, because leprosy was almost
unknown. So he traveled to Venezuela, where leprosy was endemic and thalidomide
was still available. In clinical trials in subsequent years, he treated 173 patients and
symptomatically cured over 90%. The development was taken up by the U.S. phar-
maceutical company Celgene, who engaged with the FDA and finally secured their
approval in 1997 to use thalidomide for the treatment of erythema nodosum lepro-
sum; in due course, it was also approved for multiple myeloma.
The case of thalidomide represents perhaps the most remarkable of all examples
of drug repurposing. If a product that is globally recognized as having terrible effects
when prescribed for a certain indication can induce an almost Lazarus-like effect in
a life-threatening disease, and then become approved for such use from one of the
world’s most exacting regulatory agencies, surely are there effectively no existing
drugs for which an alternative use cannot be posited? The constraint in this analysis
is revealed by the following thought experiment: if thalidomide can be approved for
these serious conditions despite its appalling safety record in the context of the origi-
nal indications, it must equally be the case that an existing drug, deemed safe in an
original serious indication, is not necessarily acceptably “safe” in a much less serious
secondary indication. The product needs to be subjected to a new regulatory review,
and a new safety/efficacy assessment, specifically for this new indication. Thus, it is
difficult to countenance the new use of, say, an existing cancer chemotherapeutic for
a condition significantly less severe than cancer (unless there are ameliorating fac-
tors, such as a lower dose).
It is surprising how new uses can be found even for well-known drugs long after
their therapeutic birth. Think of aspirin, which derives from the bark of the willow
tree; its use to relieve headaches, pains, and fevers was known to Hippocrates in
ancient Greece around 2500 years ago. It was isolated in the early nineteenth century
and introduced as a pharmaceutical by Bayer in 1899. It took a further 70 years for
the British pharmacologist and Nobel Laureate John Vane to discover that aspirin
could disrupt a pathway needed for platelet aggregation (Vane 1971). Further studies
in the 1980s showed that this effect could be used for the prevention of heart attacks
and stroke; low-dose aspirin is now widely used for this effect. A further 30 years
passed while its role in cancer was unraveled, and in December 2010 important clini-
cal information was reported supporting the ability of aspirin to prevent colorectal
and other cancers (however, crucially, this preventative effect on colorectal cancer
is based on data from 25,000 patients but is published with the caveat that “further
research is needed”) (Rothwell et al. 2011). Over a century has passed since aspirin
was first commercialized as a painkiller, which goes to show how long it can take
for therapeutic uses to be discovered even in modern scientific times and with a
6 Drug Repositioning: Approaches and Applications for Neurotherapeutics

well-known drug. The main reason for this very long time interval is the lack of com-
mercial incentive to develop a generic drug for a new indication, since the existence
of a generic substitution removes any commercial exclusivity that might reward a
successful innovator. Clinical trials of aspirin in cancer are currently being financed
from the public purse, which results in far longer time frames than if commercial
investment were available.
The widespread adoption of a deterministic approach to the identification of new
indications for developmental drugs followed the approval of the use of sildenafil for
erectile dysfunction in 1998. The commercial success of this product introduction by
a large pharmaceutical company, and the prospective identification and pursuit of a
secondary indication of an incompletely developed drug, attracted significant interest
in drug repurposing as a business strategy.
The discovery of sildenafil began in 1985 at Pfizer in a discovery program focused
on inhibitors of cGMP phosphodiesterase type V (PDE5) enzyme as novel antihyper-
tensives. The project changed direction toward angina after test compounds, which
were shown to inhibit PDE5 activity, resulted in vasodilatation and platelet inhibi-
tion. Human trials began in the United Kingdom, which were disappointing for their
primary end point, but some patients reported the unexpected side effect of penile
erections, which ultimately led to the development of sildenafil (Viagra™) as a treat-
ment for erectile dysfunction. However, research continued into pulmonary hyperten-
sion; as the role of PDE5 within this condition became better understood, sildenafil
was repurposed again. Pulmonary hypertension is the general term for a progressive
increase in pressure in the vessels supplying the lungs, particularly the pulmonary
artery. It can be idiopathic, familial, or secondary to conditions such as rheumatoid
arthritis or HIV. Symptoms often include right heart failure, shortness of breath, dizzi-
ness, fainting, and leg swelling. With a median survival of 2–3 years from the time of
diagnosis, it is a life-threatening disease, unlike erectile dysfunction. In its idiopathic
form, pulmonary arterial hypertension is a rare disease with an incidence of about
2–3 per million per year; however, it is far more common as a condition secondary to
other diseases.
Sildenafil works by relaxing the arterial wall, which leads to a reduction in pulmo-
nary arterial resistance and pressure. This, in turn, reduces the workload of the right
ventricle of the heart and improves symptoms of right-sided heart failure. Pfizer con-
ducted three trials on sildenafil in pulmonary arterial hypertension, the largest being
an international, multicenter, randomized, blinded, controlled study involving 278
patients with the disease. Conclusions were drawn from the data produced, which
showed improvements in exercise capacity, and the company submitted an additional
registration for this indication of sildenafil to the FDA, for which it was approved in
2005. The dose of sildenafil required to treat pulmonary hypertension was as low as
one-fifth of the dose for erectile dysfunction.
Finally, we have an example of a determinate development of a product for a new
use in modern times, which came to fruition in 2013, when a compound we had
known for 200 years was approved for the treatment of relapsing multiple sclerosis
(MS) in both Europe and the United States. The product manufacturer was the large
biotech company Biogen-Idec, who had licensed it from a small German company
called Fumapharm.
Scientific and Commercial Value of Drug Repurposing 7

The product, codenamed BG-12, is more commonly called dimethyl fumarate, known
since the early days of organic chemistry and first synthesized as early as 1819. It there-
fore took nearly two centuries for the use in MS to be approved. For at least 150 years,
dimethyl fumarate was considered as an organic chemical without conceivable therapeu-
tic effects, rather than as a pharmaceutical. For a long while, its primary function was as a
mould inhibitor and accordingly was added to leather items such as sofas during storage.
However, at very low concentrations (down to 1 part per million), it is an allergic sensi-
tizer: it produces extensive, pronounced eczema that is difficult to treat. This came to the
fore in 2007, when 60 Finnish users of leather sofas into which dimethyl fumarate had
been incorporated suffered serious rashes; as a consequence, the importation of products
containing dimethyl fumarate has been banned in the European Union since 2009.
As a pharmaceutical, dimethyl fumarate (and other fumarate esters) was first used
to treat psoriasis, and a product called Fumaderm™ had been approved in Germany
for this use since 1994. Biogen was interested in these wider uses of this product in
conditions similar to psoriasis. Given that the pathophysiology of psoriasis is based
on various immune and inflammatory mechanisms that are shared with other condi-
tions, Biogen undertook an investigation of the product’s biochemical pharmacology,
during which it was discovered that the mechanism of action involves upregulation
of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein, followed by induction of
an antioxidant response. This is achieved through modification of the cysteine groups
of a protein called KEAP1, which normally tethers Nrf2 in the cytoplasm. Once
modified by fumarate, the KEAP1/Nrf2 complex dissociates and Nrf2 migrates to
the nucleus, where it activates various antioxidant pathways. Armed with this knowl-
edge, Biogen chose to develop dimethyl fumarate for MS.
While Fumaderm was commonly prescribed for psoriasis within Germany under
Fumapharm, its use was geographically constrained. Once licensed to Biogen-Idec, far
greater funds and priority were allocated to the longer-term studies necessary for MS.
They sponsored two main trials to prove the efficacy of the product involving 1200 and
1430 patients, respectively, with relapsing remitting MS and conducted over 2 years.
The extra resources at the campaign’s disposal were not wasted; they culmi-
nated in the regulatory approval of an oral product, Tecfidera™, which contained a
slightly different composition of fumarate esters at a higher dose than Fumaderm.
As many of the existing products for MS required intramuscular or subcutaneous
injection, Tecfidera as an oral product offers distinct advantages; in addition, when
measuring up to other oral MS products, it poses a lower risk of adverse cardiac
events relative to fingolimod and a lower risk of liver toxicity compared to teriflu-
nomide. It is now approved in both the United States and Europe and has recently
been allocated 10 years of regulatory exclusivity in the latter territory. This remark-
able story, concerning the introduction of a valuable new therapeutic option in a
very serious disease, that had lain unappreciated for nearly 200 years, should not
be underestimated: it proves that major improvements in therapy can derive from
evaluating existing compounds in ways that had not previously been anticipated.
From the patient’s perspective, therefore, drug repurposing offers huge benefits.
An extensive list of 92 drug repurposing examples of drugs that have been approved
or orphan designated for a secondary use can be found at http://drugrepurposing.info/
index.php.
8 Drug Repositioning: Approaches and Applications for Neurotherapeutics

1.3 ADVANTAGES OF DRUG REPURPOSING

The 505(b)(2) process is a regulatory pathway applicable in the United States for
exactly this situation: it applies to previously approved drugs that have undergone small
modifications, for instance, either as a new formulation or in terms of a new use. It
stands in comparison to the 505(b)(1) pathway, which applies to new chemical entities.
In recent years, the proportion of FDA approvals that are based on the 505(b)(2) regula-
tory pathway has been increasing markedly. In 2014, compared to the 41 FDA approv-
als via 505(b)(2), there were only 35 via the 505(b)(1) route (Camargo Pharmaceutical
Services 2015). However, not all of the 505(b)(2) approvals relate to drug repurposing.
Another, slightly earlier, statistic provides that 20% of the 84 new marketed drug prod-
ucts in 2013 derive specifically from repurposing (Graul et al. 2014). It has been esti-
mated that repurposed drugs now reap $250 billion per year, constituting around 25%
of the annual revenue of the pharmaceutical industry (Naylor et al. 2015b; Tobinick
2009). Some of the most prominent commercial examples are shown in Table 1.1. The
last row in Table 1.1 represents a structural variant of the famous repurposing example,
thalidomide, a strategy which is dealt with at the end of the chapter. These commercial
successes have fuelled and ratified increased adoption of the repurposing strategy.
It would be a mistake to assume that repurposing overwhelmingly produces
incremental advances. Beyond the commercial successes in Table 1.1, repurposing
has also produced noteworthy advances in healthcare as a whole. Examples of drug
repurposing products that have been effective in serious and intractable conditions
are described in Table 1.2. In some cases, such as pirfenidone and espindolol, the
products are first-in-class approaches to the new therapeutic indication.
Defined as a modern prospective strategy of R&D, as distinct from the historical
approach reliant on clinical serendipity, drug repurposing started to be used widely
in the first few years of the new millennium. The most notable reason for this is an
attempt to solve the poor, and declining, drug R&D productivity in the pharmaceutical
industry over the past 20–30 years. It has been estimated that the cost of developing
a new drug de novo may be over $1800 million. In addition, due to stringent regula-
tions regarding safety, efficacy, and quality, the time required has been estimated to
be 10–17 years (Paul et al. 2010). The expected value of a drug discovery program at
its inception has been estimated as less than zero for a small molecule drug discovery
campaign, as a direct result of the time and cost of development and risk of failure;
according to an analysis from 2009, the estimated net present value (NPV) for an
average small molecule is −$65 million with an internal rate of return (IRR) of 7.5%
(David et al. 2009).

1.3.1 Attritional Risk
Around 10 drug candidates need to enter into human investigation in order to pro-
duce one new molecular entity product launch (DiMasi and Grabowski 2007) and,
before that, many thousands of molecular library members may need to be screened,
structurally optimized and tested for effects in animal toxicology studies in order
for the preclinical candidates themselves to enter first-in-human studies. The risk of
R&D failure is therefore reduced if one starts with a product that has already been
Another random document with
no related content on Scribd:
of Man, p. 29; Avebury, Prehistoric Times, p. 401; and De Mortillet,
Le Préhistorique, p. 621.
121 : 17. Schenck, p. 190, says concerning Switzerland: “There were
three [cultural] stages, stone, bronze, and iron.... On the other hand,
from the anthropological point of view, this subdivision can also be
made. In the first stage [Neolithic Lacustrian], we find only
brachycephalic crania; in the second there are an almost equal
number of brachycephalic and dolichocephalic; in the third there is a
predominance of dolichocephalic” (that is, Schenck divides the
Neolithic into three periods according to skulls, and the last runs into
the age transitionary to bronze).
See also G. Hervé, Les populations lacustres, p. 140; His and
Rütimeyer, Crania Helvetica, pp. 12, 34, etc.; and the note on p. 275
of Rice Holmes’s Cæsar’s Conquest of Gaul. Ripley gives useful and
concise discussions on pp. 120, 471, 488 and 501.
121 : 19. See both Keller and Schenck for the numbers of dwellings.
121 : 22. There were, of course, the caves and rock shelters used
during a large part of the year, but probably no other regularly
constructed dwellings served as permanent, all-the-year-round
places of abode prior to the lake dwellings, and it is doubtful if these
were inhabited in winter. It is generally believed that the custom of
building pile villages arose from considerations of safety. This
protection would be absent when the lakes were frozen over, and at
the same time the huts would be exposed on all sides, including the
floor, to the wintry blasts sweeping the lakes. They would in this
way be rendered practically uninhabitable during the winter
season.
Keller declares that the same type of dwelling is found in the whole
circle of countries which were formerly Celtic. (Introduction, p. 2.)
The Crannoges of Scotland and Ireland continued in use until the age
of iron in those countries. In Switzerland the lake dwellings
disappeared about the first century (p. 7). The population was
numerous (p. 432), large enough to have to depend upon cattle and
agriculture (p. 479).
This type of dwelling is found from Ireland to Japan, and even in
South America. Many lake dwellings exist at the present day. The
Welsh, Scotch and Irish Crannoges are related in structure to the
European fascine types (Keller, p. 684 and Introduction). Others are
built somewhat differently, and are, of course, of independent origin.
An ancient site was unearthed at Finsbury, on the outskirts of
London not long since, where there used to be a marsh. The
inhabitants of this lake-dwelling were native outcasts during
Romano-British times.
121 : 26. See Schenck, and Keller, p. 6. On p. 140 of Keller we read:
“The Pile Dwellings of eastern Switzerland ceased to exist before the
bronze age or at its beginnings; those of western Switzerland came to
their full development during this period.” On p. 37, describing the
settlement of Mooseedorfsee Keller says: “A very striking
circumstance ought to be mentioned, namely, that even heavy
implements, such as stone chisels, grinding or sharpening stones,
etc., were found quite high in the relic bed, while lighter objects, such
as those made out of bone, were met with much deeper.” It is known
that the Mooseedorfsee settlement is very old. No metal has been
found here, but a bone arrowhead is described by Keller on p. 38. He
remarks that the bones of very large animals were uncommonly
numerous. It seems as if the earlier inhabitants were users of bone
rather than of stone implements.
122 : 1. Herodotus, V, 16 describes them. He also is the source of
our information regarding the keeping of cattle, although
archæological finds have proved the location of stables out on the
platforms between the houses. His interesting account is given
herewith: “Their manner of living is the following. Platforms
supported upon tall piles stand in the middle of the lake, which are
approached from land by a single narrow bridge. At the first the piles
which bear up the platforms were fixed in their place by the whole
body of the citizens, but since that time the custom which has
prevailed about fixing them is this: they are brought from a hill called
Orbêlus, and every man drives in three for each wife that he marries.
Now the men all have many wives apiece; and this is the way in
which they live. Each has his own hut, wherein he dwells, upon one
of the platforms, and each has also a trap door giving access to the
lake beneath; and their wont is to tie their baby children by the foot
with a string, to save them from rolling into the water. They feed
their horses and their other beasts upon fish, which abound in the
lake to such a degree that a man has only to open his trap door and
to let down a basket by a rope into the water and then to wait a very
short time, when he draws it up quite full of them. The fish are of two
kinds, which they call the paprax and the tilon.”
122 : 3. In the Introduction, p. 2, and elsewhere Keller says
regarding cattle: “Cattle were kept, not on land, as in the Terramara
region, but on the platforms themselves, out in the lakes. Many
charred remains of stables and stable refuse have been taken from
the lakes, but only from certain parts of the sites, between those of
the houses.” See also Schenck, p. 188.
Rice Holmes, pp. 89–90 of Ancient Britain, says of that country
that agriculture was limited in the Neolithic, but flourished in the
Bronze Age.
122 : 14. The Terramara Period. Keller, pp. 378 seq. As related to
Switzerland, pp. 391, 393. For swamp and river bank sites, pp. 391,
397 seq. For bronze in Terramara settlements, p. 386. For the Upper
Robenhausian, see Schenck, p. 190, and Montelius, La civilisation
primitive en Italie. Peet, The Stone and Bronze Ages in Italy, and
Munro, The Lake Dwellings of Europe and Palæolithic Man and the
Terramara Settlements must also be read in this connection.
Schwerz, Völkerschaften der Schweiz, gives, for the average cranial
indices of the Lake Dwellers, 79 during the Stone Age, 75.5 in the
Copper Age, and 77 in the Bronze Age. Of these last 14 per cent only
were brachycephalic, 20 per cent were extremely long-headed. In the
Iron Age 46 per cent were brachycephalic. Consult also Deniker, 2, p.
316.
122 : 21. Ripley, pp. 502–503; Sergi, 2; Robert Munro, 2; Peet, 2.
122 : 27–123: 4. See the note to p. 117 : 18.
123 : 5. On the Kitchen Middens, see especially Madsen, Sophus
Müller and others in Affaldsdynger fra Stenaldern i Danmark.
123 : 12. Salomon Reinach, 3 and 5; Deniker, 2, p. 314; and Peake,
2, p. 156, where we find the following: “Over the greater part of
Sweden,—all, in fact, except a strip of coastline on the western side of
Scania,—and all along the shore of the Baltic from the Gulf of
Bothnia southwards and westwards as far as a point midway between
the Vistula and the Oder, there are found abundant remains of a
primitive civilization which dates from the Neolithic Age, and indeed,
from early in that age. This civilization, known as the East
Scandinavian or Arctic culture, extended, perhaps later, over the
whole of Norway.”
Consult the notes to pp. 125: 4 seq. for western trade.
123 : 20. Sergi, 4; Beddoe, 4, pp. 26, 29; Fleure and James, pp. 122
seq.
123 : 23. Paleolithic Population. Fleure and James,
Anthropological Types in Wales, p. 120. Rice Holmes, Ancient
Britain, p. 380, says they were confined to the South. No Paleolithic
implements were found north of Lincoln, or at least of the East
Riding of Yorkshire.
123 : 26. John Munro, The Story of the British Race, p. 45; Rice
Holmes, Ancient Britain, p. 68; and Fleure and James, pp. 40, 69–
74, 122 seq.
124 : 4. For the Alpines see pp. 134 seq. of this book.
124 : 9. Consult the note to p. 143 on this subject.
124 : 15. On the Nordics see pp. 167 seq. and 213 seq. On the
Scandinavian blonds see the note to p. 20 : 5.
124 : 20. See the notes to pp. 168 seq.
125 : 1. G. Elliot Smith, The Ancient Egyptians, especially pp. 146
and 149 seq.; Breasted, 1, 2 and 3; Keane, Ethnology, pp. 72 seq.;
Sophus Müller, L’Europe préhistorique, p. 49; Hall, Ancient History
of the Near East, p. 3.
125 : 4. Deniker, 2, pp. 314–315: “The great trade route for amber,
and perhaps tin, between Denmark and the Archipelago is well
known at the present day; it passes through the valley of the Elbe, the
Moldau and the Danube. The commercial relations between the
north and the south explain the similarities which archæologists find
between Scandinavian bronze objects and those of the Ægean
district.”
See also E. H. Minns, Scythians and Greeks, for trade in the East,
via the Vistula, Dnieper and Danube, pp. 438–446, 458, 459, 465,
493, etc.; and Déchellette, Manuel d’Archéologie, t. I, p. 626, and II,
p. 19. Herodotus IV, 33, gives the trade route from the Hyperboreans
to Delos. Félix Sartiaux, Troie, La Guerre de Troie, pp. 162, 181, also
discusses the trade routes for amber.
 125 : 7. Amber. Tacitus, Germania: “They [the tribes of the Æstii]
ransack the sea also and are the only people who gather in the
shallows and on the shore itself the amber which they call in their
tongue ‘glæsum.’ Nor have they, being barbarians, inquired or
learned what substance or process produces it; nay, it lay there long
among the rest of the flotsam and jetsam of the sea, until Roman
luxury gave it a name. To the natives it is useless; it is gathered
crude, it is forwarded to Rome unshaped; they are astonished to be
paid for it. Yet you may infer that it is the exudation of trees: certain
creeping and even winged creatures are continually found
embedded; they have been entangled in its liquid form and as the
material hardens, are imprisoned. I should suppose, therefore, that,
just as in the secluded places of the East, where frankincense and
balsam are exuded, so in the islands and lands of the West, there are
groves and glades more than ordinarily luxuriant,” etc.
Amber, if rubbed, has magnetic qualities and develops electricity.
Our word “electricity” is derived from its Greek name, “electron.”
Tacitus says: “If you try the qualities of amber by setting fire to it, it
kindles like a torch and soon dissolves into something like pitch and
resin.”
125 : 13. Gowland, Metals in Antiquity, pp. 236, 252 seq.
125 : 15 seq. Copper. Reisner’s opinion that the pre-dynastic
Egyptians invented the use of copper (Naga-ed-Dêr, I, p. 134) which
is followed by Elliot Smith (Ancient Egyptians, p. 3), is not the view
held by all scholars. Hall believes that the knowledge of the use of
metal came to the prehistoric southern Egyptians (Ancient History
of the Near East, p. 90), toward the end of the pre-dynastic age from
the north. But he counts the Mount Sinai and Cyprus deposits as
northern centres of origin from which a knowledge of the working of
the metal radiated.
The mines of the Sinaitic peninsula were worked for copper at the
time of Seneferu, about 3733 B. C., and probably much earlier
(Gowland, p. 245, and elsewhere), “but long before the actual mining
operations were carried on, how long it is impossible to say, the
metal must have been obtained by primitive methods from the
surface ore. It is hence not unreasonable to assume that at least as
early as about 5000 B. C. the metal copper was known and in use in
Egypt.” The same writer believes “that an earlier date than 5000 B.
C. should be assigned to the first use of copper in the Chaldean
region.” In this he bases himself on the discovery of copper figures
associated with bricks and tablets bearing the name of King Ur-Nina
(about 4500 B. C.), and the fact that the upper Tigris region is known
to contain rich deposits of the mineral. Jastrow, Jr., assigns the date
of 3000 B. C. to Ur-Nina, which may be more correct. Gowland dates
copper in Cyprus at 2500 B. C., or even 3000, judging by the finds at
Crete dated 2500 B. C. In the Troad he thinks it was used not later
than in Cyprus. For China the date is unknown, but if we accept
2205, given in the Chinese annals as the time when the nine bronze
caldrons were cast, which are often mentioned in the historical
records, then copper may have been in use as early as 3000, or even
earlier. De Morgan dates copper at 4400 B. C. in Egypt, where it was
found in the supposed tomb of Menes.
See also Lord Avebury, Prehistoric Times, pp. 71–72, who gives
3730 for copper-working in Sinai, and its first appearance about
5000 B. C. Montelius, 1, p. 380, gives copper in Cyprus as about
2500 B. C., hardly 3000; and for Egypt 5000; he regards it as having
been known in Babylon at about the same time. Breasted, Ancient
Times, assigns the date of the earliest copper as at least 4000 in
Egypt.
125 : 27. Eduard Meyer, 1, p. 41. But cf. Reisner, Naga-ed-Dêr, I, p.
126, note 3. Also Hall, Ancient History of the Near East, p. 28.
126 : 1. Elliot Smith, 1, p. 8: “Most serious scholars who concern
themselves with the problems of the ancient history of Egypt and
Babylonia have now abandoned these inflated estimates of the
lengths of the historical periods in the two empires; and it is now
generally admitted that Meyer’s estimate of 3400±100 B. C. is a close
approximation to the date of the union of Upper and Lower Egypt
and that the blending of Semitic and Sumerian cultures in Babylonia
took place shortly after the time of this event in the Nile valley.” See
also Hall, Ancient History of the Near East, p. 3.
126 : 7. Bronze. Rice Holmes, 1, p. 125: “The oldest piece of bronze
that has yet been dated was found at Medûm, in Egypt, and is
supposed to have been cast about 3700 B. C. But the metal may have
been worked even earlier in other lands; for a bronze statuette and a
bronze vase, which were made twenty-five centuries before our era
have been obtained from Mesopotamia and the craft must have
passed through many stages before such objects could have been
produced. Yet it would be rash to infer that either the Babylonians or
the Egyptians invented bronze for neither in Egypt nor in Babylonia
is there any tin. The old theory that it was a result of Phœnician
commerce with Britain has long been abandoned and British bronze
implements are so different from those of Norway and Sweden,
Denmark and Hungary, that it cannot have been derived from any of
these countries. German influence was felt at a comparatively late
period, but from first to last British bronze culture was closely
connected with that of Gaul and through Gaul with that of Italy.”
126 : 9. Gowland, p. 243: “It has been frequently stated that the
alloy used by the men of the Bronze Age generally consists of copper
and tin in the proportions of 9 to 1. I have hence compared the
analyses which have been published with the following results:
 EARLY WEAPONS AND IMPLEMENTS. 57 ANALYSES

In 25 the tin ranges from about 8 to 11 per cent.

„ 6 „ „ „ „ „ 11 „ 13 „ „
„ 26 „ „ „ „ „ 3 „ 8 „ „

LATER PALSTAVES AND SOCKETED AXES. 15 ANALYSES

In 13 the tin ranges from about 4.3 to 13.1 per cent.

„ 2 „ „ was about 18.3 per cent.

SPEAR AND LANCE HEADS

In 5 the tin ranges from about 11.3 to 15.7 per cent.

STILL LATER. SWORDS. 33 ANALYSES

In 14 the tin ranges from about 8 to 11 per cent.

„ 12 „ „ „ „ „ 12 „ 18 „ „
„ 7 „ „ is less than 9 per cent.

“It is obvious, therefore, that these statements do not accurately

represent the facts. And if we consider the different uses to which the
implements or weapons were put, it is evident that no single alloy
could be equally suitable for all.... It is worthy of note that these
proportions (i. e., different hardnesses for different implements)
appear to have been frequently attained, and for this the men of the
later Bronze Age are deserving of great credit as metallurgists and
workers in metal.”
On the percentages of tin with copper for bronze see also
Montelius, 1, pp. 448 seq.
126 : 12. Schenck, p. 241, describes a copper axe exactly like those
of polished stone, and another of bronze, of very primitive pattern,
showing that these were copied from the earlier stone models.
Some authorities think that iron, in Egypt at least, came in about
the same time as bronze, or even earlier. Certain peoples missed
altogether one or another of these stages, as the absence of remains
indicates. For instance, the central Africans had, as far as is known,
no bronze age, but passed directly from the use of stone to that of
iron. (See Rice Holmes, Ancient Britain, p. 123.) See the notes to p.
129 on the value of iron. Occasional implements of any material
better than that ordinarily in use, which had been introduced by
trade or acquired by fighting, were very highly prized. Any books on
primitive peoples contain references to the value of such “foreign
tools.”
126 : 24. Diodorus Siculus, V. Consult Crania Britannica, by Davis
and Thurnam, the chapter on the “Historical Ethnology of Britain,”
for evidence that the Phœnicians did have intercourse with Britain.
For a full discussion of this disputed question see pp. 483–514 in
Rice Holmes’s Ancient Britain. Herodotus and other early writers
allude to the fleets of the Phœnicians, and of course the voyage of
Pythias about the last half of the fourth century B. C. was undertaken
to discover the source of the Phœnician tin. See Holmes’s Britain,
pp. 217–226; D’Arbois de Jubainville, Les premiers habitants de
l’Europe, vol. I, chap. V; Hall, Ancient History of the Near East, pp.
158, 402–403; and G. Elliot Smith, Ancient Mariners, on the
Phœnicians.
On pp. 251–252 of Ancient Britain, Rice Holmes makes the
suggestion that the export of tin from Britain may have died down by
Roman times.
127 : 9 seq. G. Elliot Smith, 1, p. 178, and map 3. Deniker, 2, p. 315,
says: “It is generally admitted that the ancient Bronze Age
corresponds with the ‘Ægean Civilization’ which flourished among
the peoples inhabiting, between the thirtieth and twentieth centuries
B. C., Switzerland, the north of Italy, the basin of the Danube, the
Balkan peninsula, a part of Anatolia, and lastly, Cyprus. It gave rise,
between 1700 and 1100 B. C., to the ‘Mycenæan Civilization,’ of
which the favorite ornamental design is the spiral.”
Myers, in Ancient History, pp. 134–135, states that in Crete the
metal development began as early, at least, as 3000 B. C., and was at
its height in the island about 1600 or 1500 B. C. Articles of Cretan
handiwork found in Egypt point to intercourse with that country as
early as the sixth dynasty, which he makes about 2500 B. C. See also
G. Elliot Smith, 1, pp. 147, 179–180, and the authorities quoted on
bronze.
127 : 26–128 : 1 seq. G. Elliot Smith, 1, pp. 178–180. Rice Holmes,
1, p. 123, gives in a footnote the sixth dynasty as about 3200 B. C. (cf.
above), when Elliot Smith says the movement first began (ibid., pp.
169, 171). They do not agree on the date of this dynasty. See also Rice
Holmes (ibid., p. 125), and Breasted, 3, p. 108. Montelius assigns
2100 B. C. for the small copper daggers of northern Italy.
128 : 2. The Eneolithic period. G. Elliot Smith, 1, pp. 20 seq., 37
and 163 seq. Professor Orsi is responsible for the introduction of this
term. See T. E. Peet, The Stone and Bronze Ages in Italy, and G.
Sergi, Italia, pp. 240 seq., on the Eneolithic period in Italy.
128 : 13. Oscar Montelius, The Civilization of Sweden in Heathen
Times, and Kulturgeschichte Schwedens von den ältesten Zeiten;
Sophus Müller, Nordische Alterthumskunde. The latter gives 1200 B.
C. See also Rice Holmes, 1, pp. 64, 127, 424–454; Beddoe, 4, p. 15;
Haddon, 3, p. 41. According to Gjerset, in his History of the
Norwegian People, the Bronze Age in Norway began about 1500 B.
C., the Iron Age at 500 B. C. Lord Avebury, pp. 71–72; Read, Guide to
the Antiquities of the Bronze Age; and Deniker, 2, p. 315, give 1800
B. C. for Britain, and for northern Europe Avebury assigns 2500 B. C.
1800 is the generally accepted date for the beginning of the Bronze
Age in Britain.
128 : 16. Alpines in Ireland. Beddoe, 4, p. 15; Fleure and James,
pp. 128–129, 135, 139; Rice Holmes, 1, p. 432; Ripley, pp. 302–303;
Abercromby, pp. 111 seq.; Crawford, pp. 184 seq. But Fleure and
James say, p. 138, that other Alpines without brow ridges are to be
found at the present time in considerable numbers on the east coast
of Ireland. Ripley’s strong assertion that no Alpines have remained in
the British Isles has been proved by more recent study to require
modification.
128 : 17. See in this connection Fleure and James, p. 127.
128 : 26. Cf. Elliot Smith, 1, pp. 20–21, 163, 181; Peet, 2; Reisner,
Early Dynastic Cemeteries of Naga-ed-Dêr; and Rice Holmes, 1, p.
65 seq.
 129 : 2–8. The megaliths were not erected by Alpines, for there are
practically none in central Europe, according to Keane, Ethnology,
pp. 135–136, and Dr. Robert Munro, in a discussion published in the
Jour. Roy. Anth. Inst., 1889–1890, p. 65. On the other hand, Peet, 1,
pp. 39, 64, says they are being discovered in the interior—a few in
Germany. He does not mention bronze among the finds in the
megaliths of France, but there was a little gold. Bronze was, however,
found in Spain. Consult Fleure and James, pp. 128 seq.; Rice
Holmes, 2, pp. 8–9; and, for an exhaustive archæological study,
Déchellette, Manuel d’archéologie, vol. I, chap. III, especially
paragraph v, pp. 393 seq., for dolmens in Brittany. Concerning the
contents of these we may quote the following:
“Polished hatchets, often enough of rare stone, beads from
necklaces, and pendants of Callais or of divers materials, implements
of flint, knives, arrow points which are wing-shaped, scrapers,
nodules, grinding stones, pottery, vases, grains of baked earth, some
rare jewels of gold, collars and bracelets, such is, in general, the
composition of the contents of the neolithic dolmens of Brittany,
contents different, as we shall see, from those of the sepulchres of the
Bronze Age in the same region. These vast Armorican crypts belong
certainly to the end of the Neolithic period, in spite of the absence of
copper, the habitual forerunner of bronze objects. The smallness of
the crypt, the size of the tumulus, the mixture of construction in huge
blocks and in walls seem to indicate, as M. Cartailhac has observed, a
more recent age than that of ordinary dolmens. In the pure Bronze
Age the monolithic supports are replaced by the walls of unmortared
stones.
“Moreover, we shall see that there have been found in certain
covered alleys in Brittany, pottery of a very characteristic type called
calciform vases, pottery belonging in the south of France and
southern Europe with the first objects of copper and bronze. Jewels
of gold confirm, on the other hand, these chronological
determinations.” On p. 397: “The dolmen sepulchres of the Bronze
Age in Brittany, and notably in Finisterre, are distinguished more
often by the type of their construction from those of the Stone Age.”
“The dolmens of Normandy and Isle de France contain some stone
objects, fragments of vases, and numerous debris of human
skeletons.” The end of the pure Neolithic is the date of the megaliths
in Armorica, as we read on p. 407. The first metals, imported from
the south, penetrated into northern Gaul a little later than in the
southern provinces. That is why certain typical objects of the end of
the pure Neolithic in Armorica, such as Callais and the calciform
vases, are associated with the first objects of copper or bronze in the
funerary crypts of Provence and Portugal.
G. Elliot Smith and W. H. R. Rivers claim that there is a close
connection throughout the eastern hemisphere between the
distribution of megalithic monuments and either ocean or fresh-
water pearls, but this appears to the author to be far-fetched. Two
very recent articles dealing with megaliths are “Anthropology and
Our Older Histories,” by Fleure and Winstanley, and “The Menhirs of
Madagascar,” by A. L. Lewis.
129 : 8. Rice Holmes, Cæsar’s Conquest of Gaul, p. 9.
129 : 12. Earliest iron in the north. See the notes to pp. 131 : 1 and
131 : 9 on the La Tène period. Also Montelius, 2, and Sophus Müller,
2, pp. 145 and 165 seq.
129 : 13. Mound burials among the Vikings. Montelius, 2.
129 : 15. Iron in Egypt. Some authorities think that iron in Egypt
came in about the same time as bronze, or even earlier. A piece of
worked iron was found in the Great Pyramid, to which a date of
about 3500 B. C. has been assigned. But, according to the
archæological investigations of Professor Flinders Petrie, iron came
into general use only about 800 B. C.
Myres, in The Dawn of History, is quoted from p. 60 for the
following neat summary, although any of the authorities on Egypt,
such as Petrie, Maspero, Hall, Breasted, Elliot Smith, Reisner,
Meyer, etc., should be consulted as original investigators: “The
presence of iron, rare though it is, as far back as the first dynasty,
puts Egypt into a position which is unique among metal-using lands;
for, apart from these rare, but quite indisputable finds, Egypt
remains for thousands of years a bronze-using, and for long, a merely
copper-using, country.... In Egypt iron was known as a rarity, worn
as a charm and an ornament, and even used, when it could be gotten
ready made, as an implement; and it does not seem to have been
worked in the country, and probably its source was unknown to the
Egyptians. In historic times they still called it the ‘metal of heaven’ as
if they obtained it from meteorites; and it looks at present as though
their earliest knowledge of it was from the south; for central Africa
seems to have had no bronze age but direct and ancient transition
from stone to iron weapons. Yet when they conquered Syria in the
sixteenth century, they found it in regular use and received it in
tribute. At home, however, they had no real introduction to an ‘Age
of Iron’ until they met an Assyrian army in 668 B. C. and began to be
exploited by Greeks from over sea.” In this connection see also
Ridgeway, The Early Age of Greece, pp. 613–614. The same author,
pp. 154 seq., discusses the value of iron in these early times.
Deniker, p. 315 of his Races of Man, says Italy had iron as early as
1200 B. C.
Montelius assigns 1100 for iron in Etruria.
129 : 19. Hallstatt iron culture. See Baron von Sacken, Das
Grabfeld von Hallstatt; Dr. Moritz Hoernes, Die Hallstattperiode;
Bertrand and Salomon Reinach, Les Celts dans les vallées du Pô et
du Danube; and Ridgeway, The Early Age of Greece, pp. 407–480
and 594 seq. There is a brief summary by Ridgeway which it will
serve to quote: “Everywhere else the change from iron weapons to
bronze is immediate but at Hallstatt iron is seen gradually
superseding bronze, first for ornament, then for edging cutting
implements, then replacing fully the old bronze types and finally
taking new forms of its own. There can be no doubt that the use of
iron first developed in the Hallstatt area and that thence it spread
southwards into Italy, Greece, the Ægean, Egypt and Asia, and
northwards and westwards in Europe. At Noreia, which gave its
name to Noricum, less than forty miles from Hallstatt, were the most
famous iron mines of antiquity, which produced the Noric swords so
prized and dreaded by the Romans. (See Pliny, Hist. Nat., XXXIV,
145; Horace, Epod., 17 : 71.) This iron needed no tempering and the
Celts had found it ready smelted by nature just as the Eskimos had
learned of themselves to use telluric iron embedded in basalt.... The
Hallstatt culture is that of the Homeric Achæans (see Ridgeway,
Early Age of Greece, pp. 407 seq.), but as the brooch (along with
iron, cremation of the dead, the round shield and the geometric
ornament), passed down into Greece from central Europe, and as
brooches are found in the lower town at Mycenæ, 1350 B. C., they
must have been invented long before that date in central Europe. But
as they are found here in the late bronze and early iron age, the early
iron culture of Hallstatt must have originated long before 1350 B. C.,
a conclusion in accordance with the absence of silver at Hallstatt
itself.”
Keller, p. 160, describes an iron sword modelled after the same
pattern as those of bronze; Schenck, p. 341, mentions a copper axe
exactly like those of stone, and another of bronze of very primitive
pattern. These and numerous other examples show the gradual
growth of each age.
The generally accepted date for Hallstatt is about 900 or 1000 B.
C. Even Rice Holmes approves of this. (See 2, p. 9.) But if we believe
that iron spread from Hallstatt, and it was in Etruria at 1200–1100
B. C., and in Greece, in the form of swords like those of Hallstatt, at
1400 B. C. (according to Ridgeway), together with pins and various
other objects which originated in the Tyrol, it is certainly very
conservative to place the appearance of iron in Austria at 1500 B. C.
Iron weapons were found in the remains of Troy from the war of
1184 B. C. See Ridgeway, op. cit., and Lartiaux, p. 179.
We may quote from Hoernes as follows regarding the dates: “The
temporal limits of the Hallstatt period are uncertain, according to the
districts which one includes and the phenomena which one
considers. It is now known that the Hallstatt relics for the most part
belong to the first half of the last millennium B. C. But while some
assign these relics as from the time of perhaps 1200 to perhaps 500,
others are satisfied with the period from 900 to 400, or bring them
even farther forward. It is certain that one must differentiate in these
questions between the west and the east of the Hallstatt culture
areas; in the one the particular Hallstatt forms would come nearer to
the close than in the other. One or perhaps more centuries lie
between the first appearance of the La Tène forms in Western
Germany and in the eastern Alps. Also the beginning varies
according to the locality and the criteria which one takes for a guide,
that is to say, according to whether the phenomena of the time about
1000 B. C. are considered as belonging still in the pure Bronze Age,
to a transition period, or indeed to the first Iron Age.”
129 : 26. Ridgeway, speaking of the Achæans, says: “They brought
with them iron which they used for their long swords and cutting
implements.... The culture of the Homeric Achæans” (these are dated
about 1000 B. C., about the time of the Dorians, according to Bury, p.
57) “corresponds to a large extent with that of the early Iron Age of
the Upper Danube (Hallstatt) and to the early Iron Age of Upper
Italy (Villanova).”
Myres, Dawn of History, p. 175, says that there was a gradual
introduction of iron, first for tools and then for weapons. It had been
known as “precious metal” in the Ægean since the late Minoan third
period, or even the late Minoan second period, which is usually dated
with the XVIIIth Egyptian dynasty as about 1500–1350. Most other
writers, however, including Bury, p. 57, Myers, Anc. Hist., p. 136, and
Deniker, Races of Man, p. 315, ascribe the general use of iron to a
much later invasion, namely that of the Dorians, about 1100 B. C.
129 : 29. Iron swords of the Nordics. Ridgeway, 1, pp. 407 seq.:
“Their chief weapon was a long iron sword; with trenchant strokes
delivered by these long swords the Celts had dealt destruction to
their foes on many a field. They used not the thrust, as did the
Greeks and Romans of the classical period. This is put beyond doubt
by Polybius (II, 30) who in his account of the great defeat suffered by
the combined tribes of Transalpine Gæsatæ, Insubres, Boii and
Taurisci, when they invaded Italy in 225 B. C., tells us that the
Romans had the advantage in arms ‘for the Gallic sword can only
deliver a cut but cannot thrust.’ Again in his account of the great
victory gained over the Insubres by the Romans in 223 B. C., the
same historian tells us that the defeat of the Celts was due to the fact
that their long iron swords easily bent, and could only give one
downward cut with any effect, but that after this the edges got so
turned and the blades so bent, that unless they had time to straighten
them out with the foot against the ground, they could not deliver a
second blow.
“‘When the Celts had rendered their swords useless by the first
blows delivered on the spears the Romans closed with them and
rendered them quite helpless by preventing them from raising their
hands to strike with their swords, which is their peculiar and only
stroke, because their blade has no point. The Romans, on the
contrary, having excellent points to their swords, used them not to
cut but to thrust; and by thus repeatedly smiting the breasts and
faces of the enemy, they eventually killed the greater number of
them.’ (II, 33 and III.)”
 Further evidence in support of our contention that iron was in use
much earlier than is generally admitted, comes from an unexpected
quarter. J. N. Svoronos, in a recent book on ancient Greek coinage,
entitled L’Hellénism primitif de la Macédoine, prouvé par la
numismatique, p. 171, remarks: “In the first place, indeed, it is
forgotten that some of this information, that which is derived from
people of ‘mythical’ times, can be referred not only to the invention
of the first money struck in precious metal (gold, electrum, or silver),
but even to obelisks of iron, or to cast plinths in the form of copper
axes, which, of a determined weight, and legally guaranteed by the
state, constituted, already before the XVth century, as we positively
know at the present time, the first legal money.”
130 : 2. Keary, The Vikings in Western Christendom, chap. XIII;
Steenstrup, Normannerne.
130 : 4. “Furor Normanorum.” On account of the suffering inflicted
by the Vikings and other northern raiders in Europe, a special
prayer, A furore Normanorum libera nos was inserted in some of
the litanies of the West.
130 : 5. Rome was sacked by Alaric in 410 A. D., and during the
forty years following the German tribes seized the greater part of the
Roman provinces and established in them what are known as the
Barbarian Kingdoms. Consult Villari, The Barbarian Invasions of
Italy.
130 : 8 seq. See chap. XIII, pp. 242 seq., of this book.
130 : 13 seq. Ripley, pp. 125–126. The discovery of the Alpine type
was the work of Von Baer.
130 : 24. The Iron Age in western Europe. Deniker, 2, p. 315, says:
“So also, according to Montelius, the introduction of iron dates only
from the fifth or third century B. C. in Sweden, while Italy was
acquainted with this metal as far back as the twelfth century B. C.
The civilization of the ‘iron age,’ distributed over two periods,
according to the excavations made in the stations of Hallstatt
(Austria) and La Tène (Switzerland), must have been imported from
central Europe into Greece through Illyria. The importation
corresponds perhaps with the Dorian invasion of the
Peloponnesus.... The Hallstattian civilization flourished chiefly in
Carinthia, southern Germany, Switzerland, Bohemia, Silesia, Bosnia,
the southeast of France and southern Italy (the pre-Etruscan age of
Montelius). The period which followed, called the second, or iron age
or the La Tène period, was prolonged until the first century B. C. in
France, Bohemia and England. In Scandinavian countries the first
iron age lasted until the sixth century, and the second iron age until
the tenth century A. D.” Referring to the La Tène period in a
footnote, Deniker says: “This term, first used in Germany, is accepted
by almost all men of science. The La Tène period corresponds pretty
nearly with the ‘Âge Marmien’ of French archæologists and the ‘Late
Celtic’ of English archæologists. Cf. M. Hoernes, Urgeschichte d.
Mensch., chapters VIII and IX.”
Rice Holmes, 1, p. 231, remarks: “Iron in Britain is hardly older
than 500 B. C. (i. e. the earliest products of the British iron age were
traded in. See p. 229). In Gaul the Hallstatt period is believed to have
lasted from about 800 to about 400 B. C.” On p. 126: “It is certain
that in the southeastern districts iron tools began to be used not later
than the fourth century B. C.”
See also Sir John Evans, Ancient Bronze Implements, pp. 470–
472. Consult especially Déchellette, Manuel d’archéologie, t. II, pp.
152 seq., on iron in western Gaul during the La Tène period.
130 : 28. La Tène Period. M. Wavre and P. Vouga, Extrait du
Musée neuchatelois, p. 7; V. Gross, La Tène, un oppidum helvète; E.
Vouga, Les Helvètes à La Tène; and F. Keller, The Lake Dwellings of
Switzerland.
131 : 3. Montelius suggests this date. Lord Avebury, in Prehistoric
Times, even goes so far as to suggest 1000 B. C.
131 : 5. Rice Holmes, 2, the footnote to p. 9; Déchellette, Manuel
d’archéologie, t. II, p. 552.
131 : 9. La Tène culture and the Nordic Cymry. This is also in
Britain termed the “Late Celtic period.” See Rice Holmes, 2, p. 318.
For the expansion of the Celtic empire and La Tène see Jean
Bruhnes, p. 779. G. Dottin, in his Manuel celtique, devotes a whole
chapter to the Celtic empire.
Cymry. See the note to p. 174 : 22 of this book. As to the Nordic
characters of these people, see Rice Holmes, 1, P. 234.
131 : 12. Nordic Gauls and Goidels as users of bronze. Rice Holmes,
1, pp. 126, 229, and elsewhere.
 131 : 15. Haddon, Wanderings of People, p. 49.
131 : 19. S. Feist, Europa im Lichte der Vorgeschichte, p. 9, etc.
131 : 23. Tacitus, Germania.
131 : 26. Tacitus, Germania, 4: “Personally I associate myself with
the opinion of those who hold that in the peoples of Germany there
has been given to the world a race untainted by intermarriage with
other races, a peculiar people and pure, like no one but themselves;
whence it comes that their physique, in spite of their vast numbers, is
identical;—fierce blue eyes, red hair, tall frames,” etc.
See Beddoe, 4, pp. 81–82; Fleure and James, pp. 122, 126, 151–
152; and Ripley, passim, for remarks on the increasing brunetness of
Britain and other parts of Europe which were formerly more blond.
The recent article by Parsons entitled “Anthropological
Observations on German Prisoners of War,” contains an interesting
reference, on p. 26, to the resurgence of Alpine types in central
Europe.

CHAPTER IV. THE ALPINE RACE

134 : 1. There seem to have been at least three distinct types of

Alpines, one with a broad head and developed occiput typical of
western Europe, a second with a flat occiput and a high crown,
represented by such peoples as the Armenoids of Asia Minor, and a
third, of which little notice has been taken, except by such men as
Zaborowski (2) and Fleure and James, pp. 137 seq. This third type is
encountered here and there in nests which “stretch at least from
southern Italy to Ireland, by way of the Straits of Gibraltar and
across France by the dolmen line.” Fleure and James may be quoted
for the following discussion. “Questions naturally arise as to the
homologies of this type, and its distribution beyond the line here
mentioned. If we had the type in Britain, by itself, we should be
inclined to connect it with the general population of Central Europe,
the dark, broad-headed Alpine type. We should, however, retain a
little hesitation about this, as our type is sometimes of extraordinary
strength of build and, while often fairly short, it is occasionally
outstandingly tall; moreover, the hair is frequently quite black, and
this is not on the whole an Alpine character. But, when we note the
coastal distribution of this type, our hesitation is much increased, for
the Alpine type has spread typically along the mountain flanks and
its characteristic rarity in Britain is evidence of how little it has
followed the sea.
“We cannot but wonder also whether what Deniker calls the
Atlanto-Mediterranean type is not a result of averaging these dark
broad-heads with the true Mediterranean type.
“Seeking further distributional evidence, we find that the dark
broad-heads are highly characteristic of Dalmatia and may be an old-
established stock, but it would appear that this region is famous for
the height of the heads there, and our type is not specially high-
headed. Broad-head brunets do, however, occur farther east in Asia
Minor, the Ægean, and Crete, for example. Many are certainly
hypsicephalic, but in others it seems that the brow and head are
moderate and the forehead rather rectangular, as in our type....
“It is interesting that there should be evidence of our dark broad-
heads beyond the Irish end of the line now discussed, the line of
intercourse which Déchellette thinks must be older than the Bronze
Age. The chief evidences for the type beyond Ireland are:
“1. Ripley (p. 309) shows that a dark, broad-headed element is
present in Shetland, West Caithness, and East Sutherland. This is
sometimes called the Old Black Breed.
“2. Arbo finds the coast and external openings of the more
southerly Norwegian fjords have a broad-headed population,
whereas the inner ends of the fjords and the interior are more
dolichocephalic. The broad-heads stretch from Trondhjemsfjord
southward, and from their exclusively coastwise distribution he
supposes them to have come across from the British Isles.
“The population is darker than the rest of Norway and its area of
distribution, as Dr. Stuart Mackintosh has kindly pointed out to us,
is, like that of the same type in the British Isles, characterized by a
pelagic climate.”
Von Luschan has fully discussed the Armenoid type in his Early
Inhabitants of Western Asia, and with E. Petersen, in Reisen in
Lykien, Milyas, und Kibyratis. A special study was made by Chantre
in his Recherches anthropologiques dans l’Asie occidentale.
 The first type, then, the western European, has a short, thick
stature, round head, and rather light pigmentation; the second,
Armenoid, a rather tall stature, square, high head, flat occiput, and
dark pigmentation. The third, the Old Black Breed, is rather small
and dark.
In addition to these we have a fourth type, which has been called
the Bronze Age race, or, better, the Beaker Maker type (Borreby).
This has been discussed by Greenwell and Rolleston, Beddoe, and
Keith, especially as to their possible survivors at the present day; by
Abercromby, in Bronze Age Pottery; by Crawford, The Distribution
of Early Bronze Age Settlements in Britain; and by Peake, in a
discussion of the last work in the same number of the Geographical
Journal. Fleure and James describe it also. See the note to p. 138 : 1
of this book.
Further anthropological studies may simplify the problem
somewhat, but the author is now inclined to believe that the above-
mentioned third brachycephalic type, the “Old Black Breed,”
represents the survivors of the earliest waves of the round-head
invasion—in Britain antedating the arrival of the Neolithic
Mediterraneans, while the first type mentioned above represents the
descendants of the last great Alpine expansion. This type in southern
Germany has been so thoroughly Nordicized in pigmentation that
these blond South Germans are sometimes discussed as though they
were a distinct Alpine subspecies. The type is scantily represented in
England, and when found may be partly attributed to ecclesiastics
and other retainers brought over by the Normans.
The second of the above types, the Armenoids, are virtually absent
from Europe, and seem to be characteristic of eastern Anatolia and
the immediately adjacent regions.
The author regards the fourth, Borreby or Beaker Maker type of
tall, round heads as distinct from the three preceding types. The
distribution of their remains would indicate they entered Britain
from the northeast. We have no clew as to their origin. A similar type
is found in the so-called Dinaric race of Deniker (which Fleure and
James mention in connection with the third type but hesitate to class
with it), which extends from the Tyrol along the mountainous east
coast of the Adriatic into Albania. Further study of the Tripolje
culture (see note to p. 143 : 15) and the mixture of population north