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Pharmaceutical inhalation aerosol technology Third Edition Hickey
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Library of Congress Cataloging‑in‑Publication Data
/ [edited by] Anthony J. Hickey, Sandro R.P. da Rocha. implementing game mechanics, art, design and programming / Penny de Byl. Description: Third edition. | Boca Raton, Florida : CRC Press, [2019] | Drugs and the pharmaceutical sciences | Includes bibliographical references and index
Identifiers: 2018044344| ISBN 9781138063075 (hardback : alk.paper)
LC record available at https://lccn.loc.gov/2018044344
Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com
and the CRC Press Web site at http://www.crcpress.com
Anthony J. Hickey and Sandro R.P. da Rocha
Anthony J. Hickey and David C. Thompson
Peter A. Crooks, Narsimha R. Penthala, and Abeer M. Al-Ghananeem
5.
Myrna B. Dolovich
6.
Stefanie K. Drescher, Mong-Jen Chen, Jürgen B. Bulitta, and Günther Hochhaus
7.
Thomas D. Roper
8.
Ajit S. Narang, Mary E. Krause, Shelly Pizarro, and Joon Chong Yee
Jeremy Clarke and S. van den Ban
Helen N. Strickland and Beth Morgan
Section IV Particle Engineering/Processing
11. Milling and Blending: Producing the Right Particles and Blend Characteristics for Dry Powder Inhalation ................................................................................................................
Bernice Mei Jin Tan, Lai Wah Chan, and Paul Wan Sia Heng
12. Engineering Stable Spray-Dried Biologic Powder for Inhalation ............................................291
John N. Pritchard, Dirk von Hollen, and Ross H.M. Hatley
21. Soft Mist Inhalers
Stefan Leiner, David Cipolla, Joachim Eicher, Wilbur de Kruijf, and Herbert Wachtel
Section VII Drug Product Testing
22. Quality by Design Considerations
William Craig Stagner and Anthony J. Hickey
23. Solid State Testing of Inhaled Formulations 523
Philip Chi Lip Kwok and Hak-Kim Chan
24. Aerodynamic Particle Size Testing 541
Jolyon Mitchell
Section VIII Regulatory Considerations
25. Scanning the Intricate Regulatory Landscape and Trying to Peek Over the Horizon 591
Stephen T. Horhota, Stefan Leiner, and Allen Horhota
26. Pharmacopeial and Regulatory Guidances on Product Quality and Performance 601
Anthony J. Hickey
27. The European Union Regulatory Scene ...................................................................................... 611
Steven C. Nichols and Dennis Sandell
Section IX Preclinical Testing
28. Reconstituted 2D Cell and Tissue Models ................................................................................. 627
Nicole Schneider-Daum, Patrick Carius, Justus C. Horstmann, and Claus-Michael Lehr
29. 3D In Vitro/Ex Vivo Systems........................................................................................................ 653
Bethany M. Young, Alexandria Ritchie, Laleh Golshahi, and Rebecca L. Heise
30. Preclinical Models for Pulmonary Drug Delivery 669
Jibriil P. Ibrahim, Robert J. Bischof, and Michelle P. McIntosh
Section X Clinical Testing
31. Bioequivalence of Orally Inhaled Drug Products: Challenges and Opportunities 687
Jayne E. Hastedt and Elise Burmeister Getz
32. General Conclusions 719
Anthony J. Hickey and Sandro R.P. da Rocha Index 721
Preface
Two previous editions of the book Pharmaceutical Inhalation Aerosol Technology (PhIAT) were published in 1993 and 2004. The first edition appeared at a time when few books on aerosol technology were available, notably those of WC Hinds (Aerosol Technology, Wiley) and PC Reist (Introduction to Aerosol Science) that had only been available for a decade. There were few general texts on medical aerosols, and those were in specialized areas, notably several volumes by Stephen Newman. With this background, the original PhIAT book was intended to broadly cover all aspects of the field from lung biology (pharmacology, physiology, and anatomy) to drug product manufacturing, performance, and clinical applications. In the intervening decades many new volumes have appeared and much more has been published on aerosol physics, formulation and device development, and therapeutic strategies, supported by the commercialization of many new drug products.
This edition of PhIAT not only provides an update on many topics addressed in the 2nd edition, but also expands the “technology” focus of the original volumes to address the title more directly. Since the major purpose of any book should be its utility to the reader, it is logical to look at the topic from the perspective of clear unmet needs. The new text covers all aspects of product development and manufacturing encompassing the important areas of preformulation, formulation, device selection, and drug product evaluation. In order to expand the scope to consider previously unaddressed aspects of pharmaceutical inhalation aerosol technology, considerations of the patient interface have been restricted to those aspects of aerosol delivery, lung deposition, and clearance that are used as measures of effective dose delivery.
The introduction of Dr. Sandro da Rocha as co-editor of the new edition reflects the intention to bring engineering principles to bear on this important topic and to stress the importance of pharmaceutical engineering as a foundational element of all inhaler products and their application to pulmonary drug delivery.
We are grateful to the publishing staff, in particular, Hilary LaFoe and Jessica Poile for their assistance in navigating the manuscript through the process.
This book is dedicated in memory of Professor Paul Myrdal, outstanding scientist, educator, family man, and friend. He is missed by all.
Anthony J. Hickey Chapel Hill, NC
Sandro R.P. da Rocha Richmond, VA September 2018
Editors
Anthony J. Hickey is Distinguished RTI Fellow at the Research Triangle Institute, Emeritus Professor of Molecular Pharmaceutics of the Eshelman School of Pharmacy (2010–present, Professor 1993–2010), and Adjunct Professor of Biomedical Engineering in the School of Medicine at the University of North Carolina at Chapel Hill. He obtained PhD (1984) and DSc (2003) degrees in Pharmaceutical Sciences from Aston University, Birmingham, United Kingdom. Following postdoctoral positions, at the University of Kentucky (1984–1988), Dr. Hickey joined the faculty at the University of Illinois at Chicago (1988–1993). In 1990 he received the AAPS Young Investigator Award in Pharmaceutics and Pharmaceutical Technology. He is a Fellow of the Royal Society of Biology (2000), the American Association of Pharmaceutical Scientists (2003), the American Association for the Advancement of Science (2005), and the Royal Society of Biology (2017). He received the Research Achievement Award of the Particulate Presentations and Design Division of the Powder Technology Society of Japan (2012), the Distinguished Scientist Award of the American Association of Indian Pharmaceutical Scientists (2013); the David W. Grant Award in Physical Pharmacy of the American Association of Pharmaceutical Scientists (2015); Thomas T. Mercer Joint Prize for Excellence in Inhaled Medicines and Pharmaceutical Aerosols of the American Association for Aerosol Research and the International Society for Aerosols in Medicine (2017). He has published numerous papers and chapters (over 250) in the pharmaceutical and biomedical literature, one of which received the AAPS Meritorious Manuscript Award in 2001. He has edited five texts on pharmaceutical inhalation aerosols and co-authored three others on “pharmaceutical process engineering,” “pharmaceutical particulate science,” and “pharmaco-complexity.” He holds 25 United States patents on a variety of inhaler device technologies, pulmonary, and oral drug delivery formulation technologies. He is founder (1997, and formerly President and CEO, 1997–2013) of Cirrus Pharmaceuticals, Inc., which was acquired by Kemwell Pharma in 2013; founder (2001, and formerly CSO, 2002–2007) of Oriel Therapeutics, Inc, which was acquired by Sandoz in 2010; founder and CEO of Astartein, Inc. (2013–present); member of the Pharmaceutical Dosage Forms Expert Committee of the United States Pharmacopeia (USP, 2010–2015, Chair of the Sub-committee on Aerosols); and formerly Chair of the Aerosols Expert Committee of the USP (2005–2010). Dr. Hickey conducts a multidisciplinary research program in the field of pulmonary drug and vaccine delivery for treatment and prevention of a variety of diseases.
Sandro R.P. da Rocha is a full professor in the Department of Pharmaceutics in the School of Pharmacy and director for Pharmaceutical Engineering—School of Pharmacy at Virginia Commonwealth University (VCU). He also holds a joint appointment in Chemical and Life Science Engineering and is a full member of the Massey Cancer Center at VCU. He obtained his BSc and MSc in Chemical Engineering at USFM and UFSC, respectively, in Brazil, and a PhD in 2000 from the University of Texas at Austin in Chemical Engineering. After a postdoctoral position in Chemistry and Biochemistry also at the University of Texas at Austin, Dr. da Rocha joined the faculty at Wayne State University in Detroit, MI, where he worked until 2015. Professor da Rocha has contributed extensively to the area of pulmonary drug delivery, particularly through the development of novel pressurized metered dose inhaler formulations and of nanotherapeutics for pulmonary drug delivery, both areas having potential applications in the treatment of a variety of pulmonary disorders. Professor da Rocha has received numerous awards and recognition for his work, including visiting appointments at foreign institutions where he has developed collaborative efforts and taught in the area of nanomedicine and pulmonary drug delivery. Professor da Rocha has delivered a number of lectures nationally and internationally in the area of pulmonary nanotherapeutics and has written manuscripts and book chapters with his collaborators that include visiting faculty, postdoctoral fellows, PhD, undergraduate, graduate, and high-school students, who now hold key positions in the industry, academia, and government in various areas including pulmonary pharmaceutics.
Contributors
Ana Aguiar-Ricardo LAQV-REQUIMTE Department of Chemistry Faculty of Science and Technology
NOVA University of Lisbon Caparica, Portugal
Abeer M. Al-Ghananeem Department of Pharmaceutical Sciences Sullivan University Louisville, Kentucky
Balaji Bharatwaj Merck & Co., Inc., Rahway, New Jersey
Elizabeth R. Bielski Department of Pharmaceutics School of Pharmacy
Virginia Commonwealth University Richmond, Virginia
Robert J. Bischof Hudson Institute of Medical Research Melbourne, Victoria, Australia and
Allergenix Pty Ltd. Melbourne, Victoria, Australia
Jürgen B. Bulitta Department of Pharmaceutics University of Florida Gainesville, Florida
Elise Burmeister Getz Oriel Therapeutics, Inc., a Novartis Company Clinical Department Emeryville, California USA
Patrick Carius Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)
Helmholtz Center for Infection Research (HZI)
Saarland University
Saarbrücken, Germany and Department of Pharmacy
Saarland University
Saarbrücken, Germany
Nicholas Carrigy Department of Mechanical Engineering University of Alberta Edmonton, Alberta, Canada
Hak-Kim Chan
Sydney Pharmacy School Faculty of Medicine and Health The University of Sydney Camperdown, NSW, Australia
Lai Wah Chan Department of Pharmacy National University of Singapore Singapore
Mong-Jen Chen Department of Pharmaceutics University of Florida Gainesville, Florida
Jeremy Clarke GlaxoSmithKline Pharma Supply Chain Ware, United Kingdom
Joon Chong Yee
Bristol-Myers Squibb, Co. New York City, New York
David Cipolla Aradigm Hayward, California
Eunice Costa
Inhalation, R&D Drug Product Development Hovione FarmaCiencia Lisboa, Portugal
Gabriella Costabile Department of Pharmacy Ludwig-Maximilians-Universität München Munich, Germany
Peter A. Crooks University of Arkansas for Medical Sciences Little Rock, Arkansas
Sandro R.P. da Rocha Department of Pharmaceutics Center for Pharmaceutical Engineering Virginia Commonwealth University Richmond, Virginia
Wilbur de Kruijf Medspray Enschede, the Netherlands
Anne H. de Boer Department of Pharmaceutical Technology and Biopharmacy University of Groningen Groningen, the Netherlands
Myrna B. Dolovich Faculty of Health Sciences Department of Medicine McMaster University Hamilton, Ontario, Canada
Stefanie K. Drescher Department of Pharmaceutics University of Florida Gainesville, Florida
Joachim Eicher Boehringer Ingelheim Pharma GmbH and Co. KG HP Supply Germany Ingelheim am Rhein Germany
Warren H. Finlay Department of Mechanical Engineering University of Alberta Edmonton, Alberta
Laleh Golshahi Department of Mechanical Engineering
Virginia Commonwealth University Richmond, Virginia
Floris Grasmeijer PureIMS
Roden, the Netherlands University of Groningen Groningen, the Netherlands
Ailin Guo Pharmaceutical Sciences South Dakota State University Brookings, South Dakota
Jayne E. Hastedt JDP Pharma Consulting, LLC San Carlos, California
Ross H.M. Hatley Respironics Respiratory Drug Delivery (UK) Ltd. A business of Philips Electronics UK Limited Chichester, West Sussex, United Kingdom
Rebecca L. Heise Department of Biomedical Engineering
Virginia Commonwealth University Richmond, Virginia
Paul Wan Sia Heng Department of Pharmacy National University of Singapore Singapore
Rodrigo S. Heyder Department of Pharmaceutics
Virginia Commonwealth University Richmond, Virginia
Anthony J. Hickey
University of North Carolina Chapel Hill, North Carolina and
RTI International Research Triangle Park, North Carolina
Günther Hochhaus Department of Pharmaceutics University of Florida Gainesville, Florida
Susan Hoe
AstraZeneca Pharmaceuticals LP South San Francisco, California Cambridge, United Kingdom
Allen Horhota
Moderna Therapeutics
Greater Boston Area Boston, Massachusetts
Stephen T. Horhota
BIND Therapeutics Westford, Massachusetts
Justus C. Horstmann
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)
Helmholtz Center for Infection Research (HZI)
Saarland University
Saarbrücken, Germany and Department of Pharmacy
Saarland University
Saarbrücken, Germany
Jibriil P. Ibrahim
Monash Institute of Pharmaceutical Sciences Parkville, Victoria, Australia
Mary E. Krause
Bristol-Myers Squibb, Co. New York City, New York
Philip Chi Lip Kwok
Sydney Pharmacy School
Faculty of Medicine and Health
The University of Sydney Camperdown, NSW, Australia
David Lechuga-Ballesteros
AstraZeneca Pharmaceuticals LP South San Francisco, California
Claus-Michael Lehr
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)
Helmholtz Center for Infection Research (HZI)
Saarland University
Saarbrücken, Germany and Department of Pharmacy
Saarland University
Saarbrücken, Germany
Stefan Leiner
Boehringer Ingelheim Pharma GmbH and Co. KG
Quality & Records Management
Ingelheim am Rhein Germany
Benjamin W. Maynor
Liquidia Technologies Research Triangle Park, North Carolina, USA
Michelle P. McIntosh
Monash Institute of Pharmaceutical Sciences Parkville, Victoria, Australia
Bernice Mei Jin Tan
Department of Pharmacy
National University of Singapore Singapore
Olivia M. Merkel
Department of Pharmacy
Ludwig-Maximilians-Universität München Munich, Germany
Jolyon Mitchell
Inhaler Consulting Services Inc. London, Ontario, Canada and Affiliate Professor University of Hawai’i, College of Pharmacy Hilo, Hawai’i
Beth Morgan
AstraZeneca Pharmaceuticals Research Triangle Park, North Carolina
Ajit S. Narang
Small Molecule Pharmaceutical Sciences
Genentech, Inc. San Francisco, California
Steven C. Nichols Director
OINDP Consultancy Rugby, Warwichshire, UK
Narsimha R. Penthala
Department of Pharmaceutical Sciences University of Arkansas for Medical Sciences Little Rock, Arkansas
Shelly Pizarro
Genentech, Inc.
San Francisco, California
John N. Pritchard
Respironics Respiratory Drug Delivery (UK) Ltd.
A business of Philips Electronics UK Limited Chichester, West Sussex, United Kingdom
Joshua J. Reineke Pharmaceutical Sciences
South Dakota State University Brookings, South Dakota
Alexandria Ritchie Department of Biomedical Engineering Virginia Commonwealth University Richmond, Virginia
Thomas D. Roper Department of Chemical and Life Science Engineering Virginia Commonwealth University Richmond, Virginia
Dennis Sandell S5 Consulting Blentarp, Sweden
William Craig Stagner Department of Pharmaceutics Campbell University Buies Creek, North Carolina
Nicole Schneider-Daum Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Center for Infection Research (HZI) Saarland University Saarbrücken, Germany
Martina Steinmaurer Department of Pharmacy Ludwig-Maximilians Universität München Munich, Germany
Helen N. Strickland GlaxoSmithKline Zebulon, North Carolina
David C. Thompson Department of Clinical Pharmacy University of Colorado Health Sciences Center Denver, Colorado
S. van den Ban GlaxoSmithKline Global Manufacturing and Supply Ware, United Kingdom
Reinhard Vehring Department of Mechanical Engineering University of Alberta Edmonton, Alberta, Canada
Dirk von Hollen Respironics, Inc. A Philips Healthcare Company Murrysville, Pennsylvania
Herbert Wachtel
Boehringer Ingelheim Pharma GmbH and Co. KG Analytical Development Ingelheim am Rhein Germany
Lin Yang Aurobindo Pharma USA Inc. Durham, North Carolina
Hao Yin Medical Research Institute Wuhan University Wuhan, China
Bethany M. Young Department of Biomedical Engineering Virginia Commonwealth University Richmond, Virginia
Ying Zhang Medical Research Institute Wuhan University Wuhan, China
1 Introduction
Anthony J. Hickey and Sandro R.P. da Rocha
A number of outstanding texts on foundational elements of the topics discussed in this book exist, and the reader is encouraged to familiarize themselves with these materials, as they describe basic principles (Finlay, 2001), specific (Purewal and Grant, 1997, Srichana, 2016 and Zeng et al, 2000) and general dosage forms (Colombo et al., 2013, Hickey, 2007, Newman, 2009, Smyth and Hickey, 2011), and analytical methods (Tougas et al., 2013).
The advances in pharmaceutical inhalation aerosol technology occurring since the turn of the millennium have increased the potential of pulmonary drug delivery substantially. While some of the new developments had their origins in earlier work, we have seen the appearance of new propellants and new regulations considering the phase out of what we still consider new propellants, new dry powder inhalers, nebulizers, and a new category of product, soft mist inhalers.
In parallel with these new products, the breadth of application has increased to include the treatment of chronic obstructive pulmonary disease, a range of infectious diseases, diabetes, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension. Pre-clinical studies and clinical trials covering yet a range of other potential applications of orally inhaled products include the use of a broader range of biologics and also nanomaterials that may help further advance the pulmonary drug delivery market.
Successful aerosol therapy has given research and development a boost, and the prospects of even greater opportunities for disease management is emerging from patient compliance, adherence tools, and new classes of drugs for local and systemic delivery through the lungs.
This text is focused on the active pharmaceutical ingredient, formulation development, device design, process and product engineering, and analytical methods to assess critical quality attributes underpinning safe and efficacious dosage forms.
Figure 1.1 depicts the sequence in which these topics will be presented, which follows the product development pathway. The conclusion of the volume is a discussion of bioequivalence testing and the interface between the dosage form and the patient. This reflects the point at which design and engineering controls, which are embedded in a regulated environment of quality by design, give way to biological factors.
It is intended that the materials covered in subsequent sections familiarize the reader with the underlying science and engineering associated with the design and characterization of complex dosage forms required to deliver orally inhaled aerosols. The platform of knowledge will be useful in considering options for specific applications and is a point from which to launch new technologies that will frame future developments in the field as described in a companion text (Hickey and Mansour, in press).
FIGURE 1.1 P roduct development themes in pharmaceutical inhalation aerosol technology.
REFERENCES
Colombo P, Traini D, Buttini F. Inhaled Drug Delivery: Techniques and Products. New York: Wiley-Blackwell; 2013.
Finlay W. The Mechanics of Inhaled Pharmaceutical Aerosols: An Introduction. New York: Academic Press; 2001.
Hickey A. Inhalation Aerosols, Physical and Biological Basis for Therapy. 2nd ed. New York: Informa Healthcare; 2007.
Hickey A J, Mansour H H, Eds. Inhalation Aerosols, Physical and Biological Basis for Therapy, Third Edition. Boca Raton, FL: CRC Press; in press.
Newman S. Respiratory Drug Delivery: Essential Theory and Practice. Richmond, VA: RDD Online; 2009.
Purewal T, Grant D. Metered Dose Inhaler Technology. Boca Raton, FL: CRC Press; 1997.
Smyth H, Hickey A. Controlled Pulmonary Drug Delivery. New York: Springer; 2011.
Srichana T. Dry Powder Inhalers: Formulation, Device and Characterization. Hauppauge, NJ: Nova Science Publishers; 2016.
Tougas T, Mitchell J, Lyapustina S, Eds. Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products. New York: Springer; 2013.
Zeng X, Martin G, Marriott C. Particulate Interactions in Dry Powder Formulations for Inhalation New York: CRC Press; 2000.
Section I Discovery
Physiology of the Airways
Anthony J. Hickey and David C. Thompson
2.3.3
2.2.1.4
The airways represent a unique organ system in the body, their structure allowing air to come into close contact with blood, is one of the principal adaptions permitting the existence of terrestrial life. This adaptation also makes the airways a useful route of administration of drugs in the inhaled or aerosol form. This chapter provides an overview of the physiology of the airways excluding that of the nasopharyngeal regions of the airways. Aspects considered relevant to the practical and theoretical application of inhaled substances are emphasized.
2.2 Anatomy of the Airways
The airways (constituting the lungs) may be viewed as a series of dividing passageways originating at the trachea and terminating at the alveolar sac. In the context of aerosol design and delivery, such a “static” overview represents a satisfactorily simple model. However, many factors beyond the anatomy of the airways are relevant to the therapeutic use of aerosols.
2.2.1 Structure
The airways are often described as the pulmonary tree in that their overall form resembles a tree. The tree trunk is analogous to the trachea of the airways that bifurcates to form main bronchi. These divide to form smaller bronchi that lead to individual lung lobes: three lobes on the right side and two on the left side. Inside each lobe, the bronchi undergo further divisions to form new generations of smaller caliber airways: the bronchioles. This process continues through the terminal bronchioles (the smallest airway not involved with an alveolus), the respiratory bronchioles (which exhibit alveoli protruding from their walls), alveolar ducts, and terminates with the alveolar sacs. In the classic model of the airways, as described by Weibel (1963), each airway divides to form two smaller “daughter” airways (Figure 2.1), and, as a result, the number of airways at each generation is double that of the previous generation. The model proposes the existence of 24 airway generations in total, with the trachea being generation 0 and the alveolar sacs being generation 23. In passing from the trachea to the alveolar sac, two physical changes occur in the airways that are important in influencing airway function. Firstly, the airway caliber decreases with increasing generations, for example, tracheal diameter ≈ 1.8 cm versus alveolar diameter ≈ 0.04 cm ( Figure 2.2). This permits
FIGURE 2.1 Model of airway. (With kind permission from Taylor & Francis: Morphometry of the Human Lung, Berlin, Germany, Springer-Verlag, 1963, Weibel, E.)
FIGURE 2.2 Graph of airway diameter and cross-sectional are as a function of airway generation.
adequate penetration of air to the lower airways for a given expansion of the lungs. Secondly, the surface area of the airways increases with each generation to the extent that the total area at the level of the human alveolus is in the order of 140 m 2 (Gehr et al., 1978). The alveolus is the principal site of gas exchange in the airways, a function compatible with the increased surface area that promotes extensive and efficient diffusional gas exchange between the alveolar space and the blood in alveolar capillaries (vide infra). The relatively small change in cross-sectional area that occurs over the 19 generations of airways between the trachea and the terminal bronchiole (from 2.5 cm 2 to 180 cm 2) (Bouhuys, 1974) fosters the rapid, bulk flow of inspired air down to the terminal bronchiole. By contrast, the cross-sectional area increases greatly in the four generations between the terminal bronchiole and the alveolar sac (from 180 cm 2 to 10,000 cm 2) (Bouhuys, 1974), which results in a significant decrease in the velocity of airflow to the extent that the flow velocity fails to exceed that of diffusing oxygen molecules (Weibel, 1984). Accordingly, diffusion assumes a greater role in determining the movement of gases in these peripheral airways.
The various levels of the airways may be categorized functionally as being either conducting or respiratory airways. Those airways not participating in gas exchange constitute the conducting zone of the airways and extend from the trachea to the terminal bronchioles. This region is the principal site of airway obstruction in obstructive lung diseases, such as asthma. The respiratory zone includes airways involved with gas exchange and comprises respiratory bronchioles, alveolar ducts, and alveolar sacs. As such, conducting and respiratory zones of the airways may be distinguished simply by the absence or presence of alveolar pockets (which confer gas exchange function). Regions within each zone may be classified further on a histological basis. For example, the contribution of cartilage to the airway wall is one means of differentiating the trachea from bronchi and bronchioles because cartilage exists as incomplete rings in the trachea, regresses to irregularly shaped plates in bronchi, and is absent from bronchioles. Also, respiratory bronchioles may be discriminated from terminal bronchioles by the presence of associated alveoli.
Other histological changes are evident downward throughout the pulmonary tree, and the cellular profile of each region has distinctive effect on functional aspects of the airways under physiological and pathophysiological conditions.
2.2.1.1
Epithelium
The epithelium of the airways is a continuous sheet of cells lining the lumenal surface of the airways. It separates the internal environment of the body (i.e. subepithelial structures) from the external environment (i.e. airway lumen). The lumenal surface of the epithelium is, therefore, exposed to inhaled substances, such as gases, particulates, or aerosols. Connecting adjacent epithelial cells are specialized tight junctional processes (Inoue and Hogg, 1974; Williams, 1990) that limit the penetration of inhaled substances by the intercellular route of administration. Under normal or physiological conditions, larger molecules must past through the epithelial cell. Therefore, the epithelium serves the important function of limiting access of inhaled substances to the internal environment of the body. Under pathophysiological conditions, the epithelium may be damaged, enhancing penetration of substances present in the airway lumen (Godfrey, 1997).
The airway epithelium comprises a variety of cell types (Table 2.1), the distribution of which confers different functions on the airways region. The lumenal surface of the airways are lined by ciliated cells from the trachea to the terminal bronchus. Mucus, a viscous fluid containing mucin glycoproteins and proteoglycans, floats on a watery layer of periciliary fluid (or sol) and covers the lumenal surface of the epithelium. The secretions fulfill four important functions. Firstly, it protects the epithelium from becoming dehydrated. Secondly, the water in the mucus promotes saturation of inhaled air. Thirdly, the mucus contains antibacterial proteins and peptides, such as defensins and lysozyme that suppress microbial colonization of the airways (Finkbeiner, 1999; Schutte and McCray, 2002). Fourthly, the mucus is involved in airway protection from inhaled xenobiotics or chemicals. Coordinated beating of the epithelial cilia propels the blanket of mucus towards the upper airways and pharynx where the mucus may either be swallowed or ejected. The rate of mucus propulsion varies according to the airway region such that movement in the smaller airways is slower than in the larger airways, a situation that arises from the proportionally larger number of ciliated cells in the larger airways and the higher ciliary beat frequency in the larger airways (Gail and L’enfant, 1983). Syllogistically, this process is advantageous, given that many small airways converge on the larger, more central airways whose mucus clearance rate would have to be greater to accommodate the large volumes of mucus being delivered by the smaller distal airways. This process of
TABLE 2.1
Cells of the Airway Epithelium
Cell
Ciliated columnar
Mucous (goblet)
Serous
Clara (nonciliated epithelial)
Brush
Basal
Putative Function
Mucus movement
Mucus secretion
Periciliary fluid; mucus secretion
Xenobiotic metabolism; surfactant production
Transitional form of ciliated epithelial cell
Progenitor for ciliated epithelial and goblet cells
Dendritic Immunity
Intermediate
Neuroendocrine (Kultschitsky or APUD)
Alveolar type I
Alveolar type II
Alveolar macrophage
Mast
Transitional cell in differentiation of basal cell
Chemoreceptor; paracrine function
Alveolar gas exchange
Surfactant secretion; differentiation into type I cell
Pulmonary defense
Immunoregulation
Sources: Holt, P. et al., Clin. Exp. Allergy, 19, 597–601, 1989; Jeffrey, P., Am. Rev. Respir. Dis., 128, S14–S20, 1983; Scheuermann, D., Microsc. Res. Tech., 37, 31–42, 1997.
the movement of mucus up the pulmonary tree, known as the mucociliary escalator, serves the defensive function of clearing inhaled particles that become trapped in the mucus from the lung.
The significance of mucus trapping of aerosolized particles is emphasized by the fact that radiolabeled aerosols have been used in the measurement of mucociliary transport (Morrow, 1973). Coughing increases clearance of mucus from the airways, which rapidly propels the mucus towards the pharynx. Failure to clear mucus from the airways resulting from ciliary dysfunction or mucus hypersecretion (as may occur in cystic fibrosis or chronic bronchitis) can result in airway obstruction and infection. Such a situation may adversely affect the therapeutic activity of an inhaled drug by increasing the thickness of the mucus layer through which the drug must diffuse to reach its site of action and retard penetration of the aerosolized particles throughout the airways resulting from mucus plugging of the airway lumen. Goblet cells (and mucous glands) are not present in airways distal to the bronchi (Tyler, 1983), and, therefore, a mucus layer does not line the peripheral airways.
Alveolar type I cells represent the principal cell type lining the lumenal surface of the alveoli (Crapo et al., 1983; Gail and L’enfant, 1983), and it is through these cells that gases must diffuse for oxygen and carbon dioxide exchange to occur with blood in the pulmonary capillaries. Alveolar type II cells are also present in the alveoli. Cuboidal in nature, these cells possess microvilli and serve the important function of secreting surfactant (Gail and L’enfant, 1983), a mixture of carbohydrates, proteins, and lipids essential in reducing alveolar surface tension, which diminishes the work of alveolar expansion during inspiration. In addition, type II cells serve as progenitor cells in the regeneration of the alveolar epithelium. For example, type II cells differentiate into type I cells after type I cell damage (Gail and L’enfant, 1983; Voelker and Mason, 1989).
Epithelium of the central and peripheral airways have the capacity to produce and release pro-inflammatory mediators, such as arachidonic acid metabolites, nitric oxide, cytokines, and growth factors, and thereby modulate the progression of airway diseases (Mills et al., 1999). In addition, substances released from central airway epithelium can influence the ability of adjacent smooth muscle to contract (Spina, 1998).
2.2.1.2
Smooth Muscle Cells
Smooth muscle is separated from the epithelium by the lamina propria, a region of connective tissue containing nerves and blood vessels. In the trachea, the smooth muscle connects the open ends of the incomplete cartilage rings and, therefore, constitutes only a fraction of the circumference of this component of the airways. Further down the pulmonary tree, through the bronchi and bronchioles, the contribution of the smooth muscle to the airway wall increases to the point of completely encircling the airway. Contraction or relaxation of the smooth muscle has a direct influence on airway caliber and, thereby, affects airflow in the airways. Bronchoconstriction is the result of smooth muscle contraction and is the principal cause of airway obstruction in reversible obstructive airway diseases, such as asthma. The tone or state of contraction of airway smooth muscle is subject to control by neurotransmitters released from innervating nerves, hormones, or mediators released from activated inflammatory cells.
2.2.1.3
Gland Cells
Located in the submucosa of cartilage-containing airways and in the lamina propria of the trachea are glands that secrete mucus into the airway lumen (Reid, 1960). Each mucous gland consists of four regions: the ciliated duct, collecting duct, mucous tubules, and secretory tubules (Meyrick et al., 1960). The ciliated duct opens to the lumen of the airways and is lined by ciliated epithelial cells. It merges with the collecting duct, the walls of which comprise columnar cells. Mucous cells line the mucous tubules that lead from the collecting duct. Serous cells (which contribute to the more liquid component of mucus) line the blind-ended serous tubules that are located at the distal ends of the mucous tubules. Several secretory tubules feed into the collecting duct. Mucus is secreted via the collecting and ciliated ducts into the lumen of the airways. Goblet cells, located in the epithelium of the larger central airways, secrete mucus directly into the airway lumen (Rogers, 1994). Mucus hypersecretion results from an increase in the number and/or size of mucous glands and goblet cells in disease states, such as chronic bronchitis (Finkbeiner, 1999; Rogers, 1994).
2.2.1.4
Nerves
In the central nervous system regulation of airway function, afferent and efferent nerves serving sensory and effector functions, respectively, innervate the airways ( Table 2.2 , Figure 2.3) (Widdicombe, 2001). Slowly adapting receptors (or pulmonary stretch receptors) are located in the smooth muscle of the central airways (trachea to larger bronchi), respond to airway stretch, and are thought to be involved in the reflex control of ventilatory drive. Rapidly adapting receptors (or irritant receptors) ramify within the epithelium of the central airways and are sensitive to chemical or irritant stimuli (e.g. inflammatory mediators), mechanical stimuli, and interstitial edema. Activation of these receptors results in an increase in the rate or depth of breathing and in bronchoconstriction mediated through a central nervous system reflex in efferent cholinergic nerve activity. Inhalation of foreign substances, such as particulates, can activate these receptors to elicit reflex bronchoconstriction. Afferent C-fibers are tachykinin-containing nerves that ramify within the epithelium and between smooth muscle cells (Lundberg et al., 1984). Chemical (e.g. inflammatory mediators), particulate, and mechanical stimuli activate afferent C-fibers to cause rapid, shallow breathing or apnoea and to evoke central reflex bronchoconstriction through increased efferent cholinergic nerve activity (Coleridge and Coleridge, 1984; Widdicombe, 2001).
Under conditions of cholinoceptor blockade, central reflex bronchodilation through activation of efferent nonadrenergic noncholinergic nerves may be observed (Michoud et al., 1088). Stimulation of afferent C-fibers can result in the release of tachykinins at the site of stimulation and alter airway function independently of the central nervous system, e.g. by inducing mucosal edema (McDonald et al., 1996). These nerves are thought to be important sensory modalities for conveying retrosternal discomfort induced by inhaled irritants. Neuroepithelial bodies are located in the epithelium of the central airways and are intimately associated with the endings of nerves, which are primarily afferent in nature (McDonald et al., 1996; Widdicombe, 2001). Each neuroepithelial body comprises groups of neuroendocrine cells that contain biogenic amines, such as serotonin, and peptides, such as calcitonin gene-related peptide (cGRP) (Cutz and Jackson, 1999). Hypoxia induces the release of these biologically active substances which can then activate the sensory nerve endings to elicit a central reflex or act locally on adjacent tissues, such as blood vessels or airway smooth muscle (Cutz and Jackson, 1999; Widdicombe, 2001). Cholinergic nerves are carried to the airways in the vagus nerve and innervate airway smooth muscle and submucosal glands. The neurotransmitter, acetylcholine, released from cholinergic nerves promotes bronchoconstriction (Widdicombe, 1963) and mucus secretion (Baker et al., 1985; Ueki et al., 1980).
Nonadrenergic noncholinergic inhibitory nerves, also carried in the vagus nerve, are the sole bronchodilator innervation of airway smooth muscle (Diamond and Altiere, 1989). These nerves may also inhibit airway mucus secretion (Rogers, 2000). Adrenergic nerves do not innervate human airway smooth muscle (Richardson, 1977) and have little effect on mucus secretion in human airways (Baker et al., 1985; Richardson, 1977).
Breuer-Hering reflex (inhibition of inspiration; prolongation of expiration)
Responds to airway irritants, mechanical stimuli, Interstitial edema
Responds to airway irritants, mechanical stimuli
Responds to hypoxia
Vasoconstriction
Bronchoconstriction, mucus secretion
Bronchodilation, mucus secretion
FIGURE 2.3 Role of afferent and efferent nerves in altering airway function. Stimulation of afferent (or sensory) nerves, such as afferent C-fibers, rapidly adapting receptors, or slowly adapting receptors, results in an increase in electrical impulse traffic to the central nervous system. Depending on the afferent nerve activated, processing and integration in the central nervous system may result in an increase in the activity of: (1) efferent motor nerves governing muscles that regulate breathing (i.e. affect the rate and depth of ventilation) or (2) efferent autonomic nerves, such as cholinergic and nonadrenergic noncholinergic inhibitory nerves, that modify mucus secretion or airway caliber through changes in smooth muscle tone. Afferent C-fibers may also serve an efferent function insofar as impulses can spread throughout the C-fiber network from the size of C-fiber stimulation to result in the release of tachykinins (such as substance P and neurokinin A). These released substances may then act on blood vessels to increase permeability or on smooth muscle to increase vascular permeability and elicit bronchoconstriction, respectively.
2.2.1.5
Defensive Cells
Alveolar macrophages are migrating mononuclear cells present in the interstitium and lumenal surface of the alveoli (Crapo et al., 1982). These cells phagocytize (envelop and, when possible, enzymatically degrade) foreign substances, particles, or microorganisms in the alveoli, after which they remain in the alveolus or migrate to the mucociliary escalator or into lymph tissue. Upon activation, macrophages release a variety of enzymes and biologically active mediators (Laskin and Laskin, 2001; Sibile and Reynolds, 1990) that may influence airway function. The synthesis and release of matrix metalloproteinases (MMPs) by activated alveolar macrophages can contribute to lung tissue remodeling (Parks and Shapiro, 2001; Shapiro, 1999).
Mast cells are located in the walls of the central and peripheral airways and may be found free in the lumen of the airways (Cutz and Orange, 1977). Activation by antigen cross-bridging of surface antibodies elicits cellular degranulation of the mast cell and the release of biologically active preformed and newly generated mediators. Also released are proteases, including chymase and tryptase, which can modify airway function by degrading biologically active proteins and peptides (Caughey, 1991). In addition,
tryptase activates protease-activated receptors, leading a variety of unanticipated biological actions, such as induction of airway smooth muscle proliferation (Abraham, 2002; Cocks and Moffatt, 2001). Mast cells serve an important role in the response of the airways to challenge by antigens (or allergens).
2.2.1.6 Blood Supply
The cardiovascular system can be divided into two components (as shown in Figure 2.4): the pulmonary circulation and the systemic circulation. The pulmonary circulation carries deoxygenated blood from the right ventricle to the lungs and returns oxygenated blood from the lungs to the left atrium. Emerging from the right ventricle is the main pulmonary artery, which branches to form smaller pulmonary and intrapulmonary arteries. This pulmonary arterial tree undergoes further rapid subdivision in parallel with the pulmonary tree to form pulmonary capillaries, a fine network of blood vessels in intimate contact with the alveolus. The capillaries drain into postcapillary venules that unite to form small veins and, distally, larger veins. These drain into the pulmonary vein, which returns blood from the lungs to the left atrium. The systemic circulation carries oxygenated blood from the left ventricle to the tissues of the body and returns deoxygenated blood from the body to the right atrium. Arteries and arterioles carry
FIGURE 2.4 Cardiovascular system in the body. Oxygen diffuses from the oxygen-rich environment of the alveolus into the deoxygenated blood of the pulmonary circulation. The newly oxygenated blood returns by the pulmonary vein to the left atrium and ventricle: contraction of the latter provides the driving force for circulation of oxygen-rich blood to the organs and tissues of the body. Cells of the body use oxygen for energy-producing processes that result in the formation of carbon dioxide. Depleted of oxygen and richer in carbon dioxide, blood leaving the tissues returns by the venous circulation to the right atrium. The right ventricle pumps the carbon dioxide-rich blood into the pulmonary circulation from whence the carbon dioxide may diffuse into the alveolus. Arrows indicate the direction of blood flow.
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BOOK X.
CONCERNING PARTITION, LIMITATION, AND BOUNDARIES.
TITLE I. CONCERNING PARTITION, AND LANDS CONVEYED BY CONTRACT.
I. A Partition Once Made, shall Remain Forever in Force
II. No Partition Made Between Brothers shall be Revoked, Even if it was not Made in Writing, but Only in the Presence of a Competent Witness.
III. Where a Partition is Made Among Many Persons by the Majority, and those Entitled to the Larger Share, it shall not be Changed by any Act of the Minority.
IV. One Heir shall have the Right to Act for all the Others, either as Plaintiff or Defendant.
V. Where Anyone Violates a Contract Establishing a Partition, and Seizes a Portion of the Property.
VI. Where an Heir Plants a Vineyard, or Erects a House, on Land Belonging to his Co-Heirs.
VII. Where one Person Plants a Vineyard on the Land of Another, to which he has no Title
VIII. Concerning the Division of Lands Made Between Goths and Romans
IX. Concerning Forests Still Undivided Among Goths and Romans
X. Whatever Acts a Slave may Perform, without the Order of his Master, shall be Void, except when Otherwise Provided by Law
XI. Whoever Enters upon Land, under a Lease, must Comply with his Contract.
XII. Where Lands are Leased, by a Written Contract, for a Term of Years.
XIII. Where he who Rents Land under Contract, Cultivates a Greater Area than he has a Right to do, under the Conditions of the Same.
XIV. Where a Dispute Arises Between Landlord and Tenant, Concerning Arable Lands, or Forests, which are Leased.
XV. Both Tenants must Pay the Rent for Land which has been Sublet.
XVI. Where Goths have Appropriated any of the Third Part of Land Belonging to Romans, they shall Restore the Entire Amount to the Romans, under Order of Court
XVII. Concerning the Partition of Property Among the Blood-Relatives of Slaves, and the Distribution of their Personal Estates
XVIII. All Personal Property shall be Classed under One Title
XIX. Where a Contract is not Complied with, according to its Terms
I. A Partition Once Made, shall Remain Forever in Force.
A just partition once made, shall always remain in force, and, for no reason, shall it ever be altered thereafter.
II. No Partition made Between Brothers shall be Revoked, Even if it was not Made in Writing, but Only in the Presence of a Competent Witness.
We hereby decree that a partition made between brothers, even though it be not evidenced by an agreement in writing, shall remain in force, provided it can be proved by competent testimony; and, when this has been done, said partition shall have full validity in law.
III. Where a Partition is Made Among Many Persons by the Majority, and those Entitled to the Larger Share, it shall not be Changed by any Act of the Minority.
Where several heirs are interested in a partition of property, whatever is determined upon, as equitable, by a majority of the same, shall prevail, and shall not be interfered with thereafter by the minority.
FLAVIUS CHINTASVINTUS, KING.
IV. One Heir shall have the Right to Act for all the Others, either as Plaintiff or Defendant.
It was established by a former law that, where a cause is heard in court, one person shall not have the right to answer for another, unless the latter, who is equally interested, should be present, and should consent; and, for this reason, we consider it superfluous to make further provision in such matters, in cases where litigation arises, and each person must plead his own cause. However, lest through the artifice of an adversary, where a party interposes delay on behalf of one joined with him in the case, the term of thirty years may run against the complainant; after due deliberation, we hereby decree, that no excuse for delay shall be allowed in behalf of any party; and that any party to a suit may appear for all others joined with him, in the same manner as if he alone were interested. If, however, an heir should lose the suit either through corruption, or by his own negligence, the rights of none of his co-heirs shall be
prejudiced thereby; and should any of them desire to reopen the case, they shall be permitted to do so. The law hereinbefore mentioned, which relates to this subject, is hereby abrogated; and we enjoin the observance of the present one upon all the people of our realm. And we hereby decree, that the same rule shall be observed where one of several parties interested in the prosecution of a claim thinks that a suit ought to be brought to collect it.
V. Where Anyone Violates a Contract Establishing a Partition, and Seizes a Portion of the Property.
Whoever violates the provisions of a partition made between heirs, and seizes any property belonging to a co-heir, shall forfeit as much of his own share as he attempted to take from the other
VI. Where an Heir Plants a Vineyard, or Erects a House, on Land Belonging to his Co-Heirs.
Where anyone plants a vineyard, or builds a house, upon the land of any of his co-heirs, whether the owner of the same is ignorant of the fact, or consents to it, (even if he who planted said vineyard, or built said house, was ignorant of what part of said land belonged to his co-heirs), when he shall establish this, either by his own oath, or by the testimony of witnesses, he shall give to the owner upon whose premises he planted the vineyard, an equal quantity of land of the same value, and shall remain secure in the possession of the vineyard which he planted. If, however, he should plant said vineyard against the consent of the owner, he shall forfeit all right to the same. The same rule shall apply to buildings of every description. We also decree that if anyone should sell, give away, or exchange, land belonging to another; as soon as it shall be discovered that he had no title to the same, and if he who received said land should have built a house upon it, or should have planted a vineyard, olive-grove, garden, or orchard therein; or should have added anything to the value of said land by his labor; and the party to whom said land belongs should delay to claim it; or should be ignorant that it had been so disposed of; or should be unwilling to assert his rights to the same, in order to thereafter reap the benefit of
the additional value it has acquired from the labor of another; when the said owner shall establish his title to said land in court, he shall receive another similar tract, double in value, from the party who made the illegal sale or transfer, and he who improved said land shall under no circumstances lose the fruits of his toil.
VII. Where one Person Plants a Vineyard on the Land of Another, to which he has no Title.
Whoever plants a vineyard upon the land of another, who is not his co-heir, without the permission of said owner, either by force, or when said owner was ignorant of the fact, or absent (even if he should not have been forbidden to do so), shall lose the vineyard that he planted; for the reason that he ought to know that whoever appropriates the property of another should not profit twofold by his illegal act.
VIII. Concerning the Division of Lands Made Between Goths and Romans.
A division of arable lands or forests made between Goths and Romans, shall under no circumstances be interfered with, provided said division shall be proved to have been publicly made, and no Roman shall take, or claim for himself, any part of the two thirds of said land allotted to a Goth in said division; nor shall any Goth dare to seize, or claim for himself, any of the third part of said land allotted to a Roman, unless it should have been bestowed upon him by our generosity; and any division made between parents or neighbors shall not be disturbed by their posterity.
IX. Concerning Forests Still Undivided Among Goths and Romans.
In the case of forests which are still undivided, where any Goth or Roman has appropriated a portion of the same, and placed it under cultivation, we hereby decree that if any woodland of equal value belongs to the party bound under the law to make compensation, the person entitled to receive said compensation shall not refuse to accept the woodland aforesaid. If, however, the former should have
no woodland of equal value, the tract which is under cultivation shall be divided between the two parties.
X. Whatever Acts a Slave may Perform, without the Order of his Master, shall be Void, except when Otherwise Provided by Law.
Wherever a slave makes a division of any property, or does any other act without the order of his master, except where authorized by law, we declare said act to be invalid, unless the master of said slave should be willing to sanction the same.
XI. Whoever Enters upon Land, under a Lease, must Comply with his Contract.
Whoever rents land under the terms of a legal contract, for a fixed annual rental, shall have possession of said premises, and must pay the rent at the end of each year, according to the terms of the lease; because no contract should be violated. Where the tenant neglects to pay the rent at the end of each year, the owner shall be entitled to the possession of his land; and he who did not comply with his contract shall, through his own fault, lose all the profit which might accrue to him under said contract.
XII. Where Lands are Leased, by a Written Contract, for a Term of Years.
Where the use of land is granted by an instrument in writing, for a certain term of years, he who received said land shall restore the same to the owner, at the expiration of said term, and shall do so without unnecessary delay, according to the conditions of the contract.
XIII. Where he who Rents Land under Contract, Cultivates a Greater Area than he has a Right to do, under the Conditions of the Same.
Whoever rents land under a lease, shall occupy as much of said land as the owner permits him to use, and no more. If, however, he should cultivate more land than he is entitled to under his contract, or
should bring in others for that purpose, or his sons and grandsons, inmates of his house, should cultivate lands not included in his lease; or he should occupy any fields without the permission of the owner; or should, without authority, cut down any grove, for the purpose of having tillable land, or meadows, or to build fences out of the timber; he shall lose everything which he has appropriated without permission; and it shall rest in the discretion of the owner whether he shall increase the rent, or shall at once take possession of the land not included in the lease. And where only arable land is rented to any person and no woodland or pasture is included, no lessee shall have the right to use said woodland or pasture without the consent of the owner thereof.
XIV. Where a Dispute Arises Between Landlord and Tenant, Concerning Arable Lands, or Forests, which are Leased.
Where any dispute arises between the parties to a lease, concerning the quantity of land granted under said lease the lessor, if he is living, and if he is dead, his heirs, shall make oath that said lessor did not lease a larger tract of land than is designated by them. And after they have made oath as aforesaid, they shall attach their seals to the same in the presence of witnesses, to the end that no cause for dispute may arise thereafter If, however, said parties should not be worthy of credit, or should be unwilling to make oath as aforesaid, or should have any doubt concerning the amount of land so leased, they shall not make oath and imperil their souls, but they shall divide each of the whole number of aratra received by themselves, as heirs of their parents, into fifty arepennes: so that every portion occupied or cultivated shall include said fifty arepennes; nor shall they presume to occupy any more than said portion measured and allotted to them, unless with the consent of the owner or owners of said land. Any tenant who occupies more than said quantity of land, shall pay double the amount of rent of the tract he illegally entered upon.
XV. Both Tenants must Pay the Rent for Land which has been Sublet.
Where a landlord receives a tenant on his land, and it afterward happens that the latter sublets a third of the same to another party, both shall be considered tenants of the landlord, and shall pay rent to him in proportion to the amount of land they occupy.
XVI. Where Goths have Appropriated any of the Third Part of Land Belonging to Romans, they shall Restore the Entire Amount to the Romans, under Order of Court.
Judges, governors, and other authorities, in all cases where Romans have been deprived of their lands, shall take them from those who occupy them, and restore them to the Romans, in order that the royal treasury may sustain no loss; provided, however, that the period of fifty years shall not have elapsed, so that, by limitation of time, the rights of the Romans to said lands may not have been lost.
FLAVIUS CHINTASVINTUS, KING.
XVII. Concerning the Partition of Property Among the BloodRelatives of Slaves, and the Distribution of their Personal Estates.
It is the just province of the law to amend or repeal by new decrees, any former statutes which may be devoid of reason or equity; and the cause of abuses must first be determined, before laws can be enacted for their correction. As a son is born of both parents, why should he follow the condition of his mother, while he owes his being equally to his father. It is, therefore, but reasonable that we decree that where one slave has married a slave owned by another person, any issue of said marriage shall belong equally to the masters of both slaves. Where, however, there is but one son born to said parents, since he cannot serve both masters at once, he shall remain with his mother until his twelfth year, at which age he will be able to work. The master of the female slave shall then pay to the master of her husband one half of the value of the child, after said value shall have been appraised by men of respectability. A similar rule shall be observed in the cases of other children of slaves, where said children are not of even number. All personal property which said male and female slave has accumulated, while living
under one roof, shall belong to both masters. And if said slaves should have accumulated any property on land belonging to a third person, or any building, or any real estate of any description, or any personal property that is not portable, the masters of said slaves shall have a right to the division of said property among themselves, in the same manner as if it had been acquired through relationship by blood. If one of the said masters should be opposed to the marriage of the slaves aforesaid, he may straightway separate them, under this condition: that, after said marriage shall have come to the knowledge of said masters, and they should not desire its continuance, they must dissolve it within a year. If, through their negligence, this reasonable time prescribed by law should have elapsed, whatever issue said slaves may have after that time, shall be equally divided between their masters; the sex, number, and ages of said children being taken into consideration. If more than a year should elapse without one or both of their masters being aware of said marriage, all issue of the same shall be divided between them, as aforesaid.
THE GLORIOUS FLAVIUS RECESVINTUS, KING.
XVIII. All Personal Property shall be Classed under One Title.
We often see wicked persons, for the purpose of contention, pervert the meaning of the law; and, in order to prevent such conduct, as far as possible, we desire to simplify matters whenever this can be done. Therefore, we decree that no difference shall exist in the classification of all kinds of personal property, whether said property be tangible, or merely held in trust by one for another; in order that the subtle distinctions which have arisen in the classification of said property may be abolished.
THE GLORIOUS FLAVIUS RECESVINTUS, KING.
XIX. Where a Contract is not Complied With, according to its Terms.
Whenever any person obtains possession of land, vineyards, or any other real estate, under a lease for the tenth part of its annual yield, or for any other payment, or consideration, whether said lease
is in writing, or verbal, provided he who leases it does so under some contract for rent, the lessee shall, without demand or solicitation from the lessor, pay his rent regularly; nor shall the right of the landlord to said rent be affected, in any way, should he not do so. For wherever the provisions or covenants of a lease are not fulfilled, the right of the owner shall not be affected; because the controversy has not arisen through the act of the landlord, but through the fraud of the tenant. If the tenant should refuse to fulfil his contract, or to comply with any of its provisions, he shall pay double the amount to the landlord which he agreed to pay him under the terms of the lease. And if the tenant, alleging various pretexts, should not comply with his contract for such a time that the rights of the owner are lost by the limitation of the law, that is, for fifty years, he shall forfeit said property, with all the increase in value of the same resulting from his labors thereon.
TITLE II. CONCERNING THE LIMITATIONS OF FIFTY AND THIRTY YEARS.
I. After the Lapse of Fifty Years, Neither Goths nor Romans can Assert a Claim to Property.
II. No Fugitive Slave shall Again be Reduced to Servitude, after the Lapse of Fifty Years.
III. No Suit at Law shall be Brought Thirty Years After the Cause of Action has Arisen.
IV. The Limitation of Thirty Years shall Run in all Cases Excepting those where Slaves of the Crown are Concerned
V. Concerning Claims made within Thirty Years
VI. The Limitation of Thirty Years shall not Run while Persons are Exiled
VII. Within what Time Slaves Belonging to the Crown can Again be Reduced to Slavery
I. After the Lapse of Fifty Years, Neither Goths nor Romans can Assert a Claim to Property.
Lands apportioned between Goths and Romans, which have not been claimed within fifty years, can under no circumstances be claimed afterwards.
II. No Fugitive Slave shall Again be Reduced to Servitude, after the Lapse of Fifty Years.
Fugitive slaves who have not been found within fifty years, shall not, after that time, be returned to servitude.
III. No Suit at Law shall be Brought Thirty Years After the Cause of Action has Arisen.
All suits at law, whether well founded or not, and also all criminal cases, which shall not have been brought or determined in thirty years; or any disputes relating to the ownership or possession of slaves, which have not been settled within that time, shall under no circumstances be prosecuted afterwards. Where any person attempts to bring a suit thirty years after the cause of action has arisen, he shall be barred by the limitation aforesaid, and shall be compelled to give a pound of gold to whomever the king may direct.
THE GLORIOUS FLAVIUS RECESVINTUS, KING.
IV. The Limitation of Thirty Years shall Run in all Cases, Excepting those where the Slaves of the Crown are Concerned.
Want of care and resolution in an owner often disturbs the rightful possession of property, and what vigilance was not exerted to preserve, illegal license appropriates. The passage of the aforesaid period of thirty years is seen to occur so constantly in human affairs, that now it does not seem to have originated in the institutions of man, but rather to have arisen, in the course of nature, from the affairs themselves; and for this reason, therefore, we hereby decree, for all time hereafter, that if any beneficiary of the king, or any employee of the Crown, except royal slaves, should have held any property belonging to anyone for the space of thirty years, he shall have the right to claim and retain said property for himself, forever; and the demand of no one shall avail against said limitation, after it shall have been legally established.
Royal slaves whose servile origin is publicly known, who are at large, and wandering from place to place, even though they should pay no taxes, and should lie concealed in hiding places, or remain under the protection of any person for the space of thirty years, as aforesaid, shall not thereby escape the restraints of slavery, but shall be restored to their original condition without regard to lapse of time. Those only shall be excepted from the operation of this law who have received their freedom from the king.
V.
Concerning
FLAVIUS CHINTASVINTUS, KING.
Claims made within Thirty Years.
Long continued possession frequently transfers the ownership of property from one person to another; for whatever anyone has held for thirty years without molestation, can never be lost through the claims of another To the end, however, that the rights of claimant as well as those of possessor may be properly protected, we hereby decree that the following law shall be observed by all, to wit: that wherever any property has been held by any person for from twentyfive to thirty years, and another person should claim said property; and the possessor should be notified of said claim either by the judge or the claimant, and should fail to make restitution, or to
answer within a reasonable time; or should interpose delay under any pretext; or should assert his claim while the possessor of said property is absent, that is to say, while he is in another province, or in the army; under such circumstances, the judge shall deliver said property into the possession of the claimant in the presence of three witnesses, in order that the limitation of time may not run against said claim. And if the judge should order the property in dispute to be delivered into the possession of the claimant by a bailiff, he shall issue a writ directed to said bailiff, signed by his own hand, and according to the form hereinafter specified; and if there should be other property than that claimed in the place where the latter is situated, in order that no dispute may arise, the doors or gates of the enclosure where said property is situated shall be sealed with the signet of the judge or of the bailiff, and shall remain sealed for eight days; and the claimant shall retain possession of it for only eight days; but he must not waste, spoil, or dispose of said property, in any way, but must care for the same to the best of his ability. After the expiration of that time he must leave the property intact, in the possession of him who originally held it, and no responsibility whatever shall attach to him who had possession of it for the eight days aforesaid. And he himself, or any of his family or descendants, shall have the right to assert their claim to said property, at any time within thirty years from the day when the claimant made the demand as aforesaid. And if said person should not be able to establish the justice of his claim, he shall render satisfaction to the owner of the property, as a person making an unjust demand for something to which he was not entitled. If he should damage said property, or dispose of it, in any way, while in his possession, he shall be compelled to restore fourfold its value; and neither he, nor any of his family or posterity, shall have a right to make any claim for said property at any time thereafter.
We also hereby decree that if the property in dispute should consist of different articles, and should be situated in different places, an order issued by the judge relating to any one of said articles shall have the same force as if it related to all. The form of the order issued by the judge shall be as follows:—
WRIT OF INFORMATION THE JUDGE TO THE BAILIFF
We inform you that such-and-such a person claims property in the possession of so-and-so, and we hereby order you to place said property in the possession of said claimant, in the presence of two or three witnesses; to be left in his possession for the space of eight days only, according to the provisions of the law; and if you should find any property to which the seal of the owner thereof is not attached, you will attach your own seal thereto, to remain unbroken for the aforesaid term of eight days, in order to remove all cause of dispute or opportunity for fraud; and none of said property shall be removed by you.
FLAVIUS RECESVINTUS, KING.
VI. The Limitation of Thirty Years shall not Run while Persons are Exiled.
The more humanity is oppressed by misfortune, the more we should provide by our clemency for the evils with which it is afflicted. Wherefore, whenever any person of noble rank, or any freeman, or even a slave, is confined in prison, or sent into exile, by order of the king; and should afterwards be liberated, or pardoned, and return to his country, and anyone should have claimed any of his property during his absence; the time which he passed in confinement or exile shall not be counted as a part of the thirty or fifty year limitation barring a claim, or action at law; but the time during which he was imprisoned, or absent from the country, and unable to assert his rights, shall be excepted from the period of limitation aforesaid. In all other cases the laws which have already established periods of limitation relating to claims and actions at law, shall remain in force hereafter.
FLAVIUS EGICA, KING.
VII. Within what Time Slaves Belonging to the Crown can Again be Reduced to Slavery.
We hereby repeal the former law by which slaves belonging to the Crown could be reduced to their former condition of servitude,
without consideration of the lapse of time, and, in the place thereof, issue the following decree, to wit: that whoever has had in his possession any slaves of the Crown for the space of thirty years, and said slaves have not been transferred to the possession of any other person during that time; or if any such slaves should wander from place to place, without paying any tax for the space of fifty years; said slaves shall under no circumstances be reclaimed by the Crown. But those persons under whose control such slaves were, for either the thirty or the fifty year period aforesaid, must make suitable compensation for their services to the royal treasury; to the end that one and the same law may prevail concerning the slaves of both prince and people.
TITLE III. CONCERNING BOUNDARIES AND LANDMARKS.
I. How Boundaries and Landmarks shall be Preserved.
II. Concerning the Destruction and Removal of Landmarks.
III. What is to be Done when a Dispute Arises Concerning Boundaries.
IV. Where One Person makes a Claim to Land Included within the Boundaries of Another.
V. Where any Change was made in the Boundaries of Land During the Time of the Romans, no Claim Based upon Other Boundaries shall Prevail
I. How Boundaries and Landmarks shall be Preserved.
We hereby decree that all ancient landmarks and boundaries shall stand as established in former times, and that they shall not be disturbed or removed.
II. Concerning the Destruction and Removal of Landmarks.
Whoever levels any landmarks for the purpose of travel, or dares to remove any established landmarks, for every landmark so fraudulently disturbed, if he is a freeman, he shall pay twenty solidi; and if he is a slave he shall receive fifty lashes, and shall restore said landmark. If any person while plowing land, or planting a vineyard, should involuntarily disturb a landmark, he shall restore the same in the presence of the neighbors, and shall not, thereafter, be liable to any damage or penalty for removing the same.
III. What is to be Done when a Dispute Arises Concerning Boundaries.
Whenever a dispute arises concerning the boundaries of land, search shall be made for the old landmarks; that is to say, the mounds of earth, or squared stones, which, in ancient times, were made or placed in order to define the boundaries of lands; or for any stones which have been buried, and are carved to show that they were intended as landmarks. Should any of said landmarks be wanting, search must then be made for such trees as might have been marked in former times, to define the boundaries between different tracts of land.
THE GLORIOUS FLAVIUS RECESVINTUS, KING.
IV. Where One Person makes a Claim to Land Included within the Boundaries of Another.
Where anyone inherits or acquires land within the boundaries of another person, or, during the absence, or without the knowledge of the owner of the same, obtains possession of such land for a long period of time, or for more than the term of fifty years, even though his occupation of said property was public and notorious, he shall have no permanent title thereto; and as soon as the boundaries of said land shall have been established by the discovery of the ancient landmarks, by persons appointed to find the same, he shall restore said land so appropriated to the owner thereof. Nor shall any obligation of the owner, nor undisputed possession for a long period of time, avail against the ancient landmarks, when they are discovered. But it must be proved, if it can be ascertained, whether said land was acquired by one of the contesting parties or by the ancestors of either of them; for if such time should have elapsed that neither of said parties, nor any of their ancestors, knew who first obtained the title to or possession of said property, and the party in possession is unable to show by an instrument in writing, or by witnesses, whence the title to said premises was derived, because the fact of original possession is in doubt; whoever of said claimants is in possession of said land at the time shall have an irrevocable right to retain it. Where, however, one person seems to have been in possession of said land without the other claimant asserting any right to the same, and such possession shall be public, and apparently established by existing landmarks, and no evidence of fraud be disclosed; it is not reasonable that the title of the owner should be lost by reason of its occupation for a protracted period by another.
Where one person has obtained possession of land by force or fraud, this shall in no wise affect the rights of another claimant. If, however, one person should attempt to gain possession of property occupied by another, not through fraud or insolence, but by a judicial proceeding, if his claim is just, he shall be entitled to possession of said property. But if, unknown to the owner, he should unexpectedly attempt to gain possession of the land of the latter, the owner of the
same shall have the right to accuse him of being a trespasser with violence, and, by legal proceedings, compel him to surrender said property.
V. Where any Change was made in the Boundaries of Land During the Time of the Romans, no Claim Based upon Other Boundaries shall Prevail.
Where real property, in which any person claims an interest, was disposed of before the coming of the Goths, and was transferred to the possession of another party either by sale, donation, partition, or any other transaction, whatever title or right to said property shall be proved to have been formerly conveyed by the Romans shall remain inviolable. But where a title to real property cannot be established by any certain landmarks or boundaries, the following proceeding must be observed, to wit: an examination of the premises must be made by persons selected by the consent of all parties; and the judge, for his own information, shall cause the oldest residents of the neighborhood to be sworn, that they will, without fraud, show where the boundaries of the land in question are situated; and no one shall establish a new boundary without the presence of the other party, or in the absence of one of the inspectors appointed by common consent, as aforesaid. If a freeman should violate this provision, he shall be liable for the penalty of forcible entry, as prescribed by law. Where a slave commits this offence, without the knowledge of his master, he shall receive two hundred lashes in public, but his master shall incur no liability for his act.[50]
BOOK XI.
CONCERNING THE SICK AND THE DEAD, AND MERCHANTS WHO COME FROM BEYOND SEAS.
TITLE I. CONCERNING PHYSICIANS AND SICK PERSONS.
I. No Physician shall Presume to Bleed a Woman, in the Absence of her Relatives.
II. No Physician shall Visit Persons Confined in Prison.
III. Where a Physician Treats Disease under a Contract.
IV. Where a Sick Person Dies, while a Physician is Treating him under a Contract.
V. Where a Physician Removes a Cataract from the Eye.
VI. Where a Freeman or a Slave Dies from Being Bled
VII. Concerning the Compensation to be Received for the Instruction of a Student in Medicine
VIII. No Physician shall be Imprisoned without a Hearing
I. No Physician shall Presume to Bleed a Woman, in the Absence of her Relatives.
No physician shall presume to bleed a freeborn woman without the presence of her father, mother, brother, son, uncle, or some other relative, except urgent necessity should demand it; and where it happens that none of the above-named persons can be present, the woman must be bled in the presence of respectable neighbors or slaves, of either sex, according to the nature of her illness. If a physician should do this without the presence of any of the aforesaid persons, he shall be compelled to pay ten solidi to the husband or the relatives of said woman; for the reason that it is not at all improbable that, on such an occasion, wantonness may sometimes occur.[51]
II. No Physician shall Visit Persons Confined in Prison.
No physician shall presume to enter a prison when governors, tribunes, or deputies, are excluded therefrom, without being accompanied by the jailer, lest the prisoners, influenced by fear, may
