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 Computer Aided
Chemical Engineering
Quantitative Systems
Pharmacology
Models and Model-Based Systems
with Applications

Volume 42

Edited by

Davide Manca
Process Systems Engineering Laboratory,
Dipartimento di Chimica,
Materiali e Ingegneria Chimica “Giulio Natta”,
Politecnico di Milano, Milano, Italy
Elsevier
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Contents
Contributors .............................................................................................................xv
Preface ....................................................................................................................xix
Acknowledgments ..................................................................................................xxi

SECTION 1 INTRODUCTION TO QUANTITATIVE

SYSTEMS PHARMACOLOGY
CHAPTER 1 Quantitative Systems Pharmacology: Extending
the Envelope Through Systems Engineering ...................3
Clara Hartmanshenn, Rohit T. Rao, Seul-A. Bae,
Megerle L. Scherholz, Alison Acevedo, Kamau K. Pierre,
Ioannis P. Androulakis
1. Introduction .....................................................................................3
2. The Emergence of QSP Modeling .................................................4
2.1. Multiscale Modeling: Beyond the Drug Target.....................5
2.2. Modeling the Disease State ....................................................6
3. Modeling Drug Exposure and Drug Response
at the Systemic Level .....................................................................9
4. Modeling Biological and Drug Interactions
at the Molecular Level..................................................................11
4.1. Omics Data ...........................................................................11
4.2. Genomics ..............................................................................11
4.3. Transcriptomics ....................................................................12
4.4. Proteomics ............................................................................13
4.5. Metabolomics........................................................................13
4.6. Omics Network Using Pathway Enrichment .......................14
4.7. Case Study: Pathway Enrichment for
Synthetic MPL ......................................................................15
5. Summary of the Model Development Process.............................17
6. QSP in Context .............................................................................18
6.1. Case Study: Cortisol Regulation in the Context
of Environmental Clues: Next Challenges...........................20
7. How Systems Engineering Can Enable QSP ...............................22
8. Final Comments ............................................................................23
Acknowledgments ............................................................................. 24
References.......................................................................................... 24

v
vi Contents

SECTION 2 MODELING AND APPLICATIONS

OF SYSTEMIC PHARMACOKINETICS
AND PHARMACODYNAMICS
CHAPTER 2 An Engineering Oriented Approach to
Physiologically Based Pharmacokinetic and
Pharmacodynamic Modeling ...............................................37
Roberto A. Abbiati, Adriana Savoca, Davide Manca
1. Introduction ...................................................................................37
2. Classic Compartmental Pharmacokinetic Models........................39
3. Physiologically Based Pharmacokinetic Models .........................40
3.1. Individualization of the Pharmacokinetic Prediction...........44
3.2. Model Identification .............................................................44
4. Introduction to Pharmacodynamics ..............................................49
5. Mathematical Formulation of a PBPK Model .............................49
5.1. The PBPK Model .................................................................50
6. Mathematical Formulation of PD Models....................................55
6.1. Direct Effect Model: Hill Equation......................................56
6.2. Indirect Response Models ....................................................58
6.3. Irreversible Effect Models....................................................60
7. Conclusions ...................................................................................60
References.......................................................................................... 61

CHAPTER 3 Advanced Techniques for the Optimal Design

of Experiments in Pharmacokinetics ...............................65
Federico Galvanin, Fabrizio Bezzo
1. Introduction ...................................................................................65
2. Identifying a Physiological Model: The Need for
Experimental Design.....................................................................66
3. Design of Experiments Under Constraints for
Physiological Models....................................................................67
3.1. Design Procedure..................................................................69
3.2. Design of Experimental Protocols Under
Uncertainty............................................................................69
4. Case Study I: Identification of a PK–PD Model .........................71
5. Case Study II: Design of More Effective Clinical Tests
for the Study of VWD ..................................................................76
6. Conclusions ...................................................................................81
References.......................................................................................... 82
 Contents vii

CHAPTER 4 On the Identifiability of Physiological Models:

Optimal Design of Clinical Tests .......................................85
Fabrizio Bezzo, Federico Galvanin
1. Introduction ...................................................................................85
2. The Concept of Identifiability ......................................................87
3. Identifiability Tests .......................................................................88
3.1. A Priori Tests for Parametric Identifiability........................88
3.2. A Posteriori Tests for Parametric Identifiability .................89
3.3. Practical Identifiability of Parametric Models.....................92
4. Identifiability in the Development of Compartmental
Models...........................................................................................93
5. Optimal Design of Clinical Tests for Guaranteed
Identifiability.................................................................................95
6. Case Study: Identification of Physiological Models
of VWD.........................................................................................97
6.1. Structural Identifiability of Candidate
VWD Models......................................................................101
6.2. Practical Identifiability From Clinical Tests
and Information Analysis ...................................................103
7. Conclusions .................................................................................107
References........................................................................................ 108

CHAPTER 5 Bayesian Hierarchical Modeling of Gabapentin

Absorption and Disposition with Application
to Dosing Regimen Assessment .......................................111
Stephen D. Stamatis, Linas Mockus, Lee E. Kirsch,
Gintaras V. Reklaitis
1. Introduction .................................................................................111
2. Methods.......................................................................................113
3. Model Description ......................................................................115
3.1. Absorption Model...............................................................116
3.2. Disposition Model ..............................................................118
3.3. Initial Conditions ................................................................121
3.4. Statistical Model .................................................................121
4. Implementation ...........................................................................125
5. Results and Discussion ...............................................................128
6. Conclusions .................................................................................133
7. Future Directions ........................................................................134
References........................................................................................ 134
viii Contents

CHAPTER 6 Computational Tools in the Assistance

of Personalized Healthcare ...............................................139
Maria M. Papathanasiou, Melis Onel, Ioana Nascu,
Efstratios N. Pistikopoulos
1. Introduction .................................................................................139
1.1. Disease Dynamics...............................................................139
1.2. Patient Variability...............................................................140
1.3. Data Availability.................................................................141
2. Mathematical Approaches in Biomedical
Systems .......................................................................................142
2.1. Big Data Analytics .............................................................142
2.2. Metabolic Networks and Other Modeling
Approaches .........................................................................145
2.3. Dynamic, Quantitative Mathematical
Modeling .............................................................................146
3. Control in Biomedical Systems ..................................................153
4. The PAROC Framework and Software Platform ......................157
4.1. High-Fidelity Modeling and Analysis................................158
4.2. Model Approximation ........................................................158
4.3. Multiparametric Programming and Control.......................159
4.4. Moving Horizon Estimation (MHE) ..................................159
5. PAROC Application to Biomedical Systems.............................161
5.1. AML....................................................................................161
5.2. The Anesthesia Process ......................................................170
5.3. Diabetes ..............................................................................180
6. Conclusions .................................................................................187
Acknowledgments ........................................................................... 188
Appendix A.1. Mathematical Model for AML ...................................................188
A.1.1. Treatment Inflow ............................................................188
A.1.2. Pharmacokinetic Model ..................................................188
A.1.3. Pharmacodynamic Model ...............................................189
A.1.4. Cancer Cell Cycle Model ...............................................189
A.1.5. Normal Cell Cycle Model ..............................................190
A.1.6. Drug Subcutaneous Route ..............................................191
Appendix A.2. Mathematical Model for Intravenous
Anesthesia ...................................................................................191
Appendix A.3. Mathematical Model for Volatile
Anesthesia ...................................................................................193
Appendix A.4. Mathematical Model for Diabetes ..............................................195
References........................................................................................ 198
 Contents ix

SECTION 3 TRANSPORT AND DISTRIBUTION

OF DRUGS TO TARGET SITES
CHAPTER 7 Multiscale Models for Transport and
Biodistribution of Therapeutics in Cancer ...................209
Arturas Ziemys, Milos Kojic, Miljan Milosevic,
Bernhard Schrefler, Mauro Ferrari
1. Introduction .................................................................................209
2. Computational Models of Payload Release From
Drug Vectors ...............................................................................210
3. Computational Models of Biodistribution in Tissue
Microenvironment.......................................................................217
4. Biodistribution Models for the Entire Tumor ............................221
4.1. Pipe 1D Vessel Network ....................................................224
4.2. Smeared 3D Model Data ....................................................224
4.3. Time Steps ..........................................................................224
5. Tumor Response Model..............................................................227
6. Concluding Remarks...................................................................233
Acknowledgement ........................................................................... 233
References........................................................................................ 234

CHAPTER 8 Quantitative Systems Pharmacology on Cancer

Drug Delivery to Target Sites: Application of
Chemical Engineering Tools .............................................239
Roberto A. Abbiati, Jessie L.-S. Au
1. Introduction .................................................................................240
1.1. Purpose of Quantitative Systems Pharmacology ...............240
1.2. Unique Challenges for Cancer Therapeutics .....................240
1.3. Application of Chemical Engineering Tools in QSP ........241
1.4. Content Overview...............................................................241
2. Kinetic Processes in Delivering Therapeutics to Their
Intended Targets .........................................................................242
2.1. Transport From the Injection Site to the Tumor
Interstitium..........................................................................242
2.2. Transport From the Interstitial Space to Molecular
Targets on Cell Membrane or Inside the Cell ...................242
3. Transport Barriers .......................................................................244
3.1. Reduced Transport Due to Abnormality in Tumor
Blood and Lymphatic Systems...........................................244
3.2. Extravasation ......................................................................245
3.3. Interstitial Transport ...........................................................245
x Contents

4. Additional Considerations for

Nanotherapeutics.........................................................................245
4.1. Nanotechnology ..................................................................245
4.2. Delivery of Nanoparticles From the Injection Site
to Targets ............................................................................246
4.3. NP Biocorona......................................................................246
4.4. Delivery of Nanotherapeutics to Extracellular
and Intracellular Targets.....................................................246
4.5. Endocytic Transport and Recycling ...................................247
4.6. Release of NP Cargo into the Cytosol ...............................247
5. Mathematical Basis of Individual Transport Processes
and Available Chemical Engineering Tools ..............................247
5.1. Mathematics of the Therapeutic Transport
in Blood From the Injection Site to Tumor
Interstitium..........................................................................248
5.2. Mathematics of Extravasation ............................................249
5.3. Mathematics of Interstitial Transport.................................249
5.4. Mathematics of Intracellular Transport..............................250
5.5. Mathematics of Interactions Between a Therapeutic
and Components of Biologic Milieu..................................251
6. Computational Models of Delivering a Cancer Therapeutic
to its Targets ...............................................................................251
6.1. Multiscale Models ..............................................................251
6.2. Compartmental Open Body Models
and Physiologically Based PK Models ..............................252
6.3. Modeling Spatial-Dependent PKs
in Tumors............................................................................254
7. Examples of Successful Use of Computational
Models to Describe and Predict Outcomes in Biological
Systems .......................................................................................258
7.1. Modeling Cellular Processing and Transport of an
Agent Targeting a Molecule...............................................258
7.2. Predictive Models of Interstitial Diffusive
Transport Based on Nanoparticle–Cell Interaction
Parameters...........................................................................259
7.3. Predictive Multiscale Models to Capture Tumor Spatial
Heterogeneities and to Predict In Vivo Spatiokinetics
of Therapeutics ...................................................................260
7.4. Predictive Models of Delivery–Exposure–Response
in Human Patients ..............................................................263
 Contents xi

8. Perspectives on QSP Research ...................................................266

Acknowledgments ........................................................................... 267
References........................................................................................ 268

CHAPTER 9 Systems Engineers’ Role in Biomedical Research.

Convection-Enhanced Drug Delivery ..............................271
Darian R. Esfahani, Kevin M. Tangen, Morteza Sadeh,
Akop Seksenyan, Brandon L. Neisewander, Ankit I. Mehta,
Andreas A. Linninger
1. Introduction .................................................................................271
2. In Vitro Models...........................................................................272
2.1. The Catheter Backflow Problem ........................................272
2.2. Brain Phantom Models .......................................................273
2.3. Catheter Backflow Studies in Phantom Models ................276
2.4. The Future of CED Models................................................278
3. In Vivo Models ...........................................................................279
3.1. CED Targets .......................................................................279
3.2. CED Carriers and Vectors..................................................283
4. Clinical Trials .............................................................................286
4.1. Brain Tumors ......................................................................291
4.2. Neurodegenerative Diseases...............................................292
4.3. Metabolic Disorders ...........................................................293
5. Future Directions and Challenges ..............................................293
5.1. Catheter Design ..................................................................294
5.2. Computational Modeling....................................................294
5.3. Real-Time Imaging.............................................................294
5.4. Nanoparticles ......................................................................295
6. Conclusions .................................................................................295
References........................................................................................ 295

SECTION 4 MODELING OF DRUG DELIVERY SYSTEMS

CHAPTER 10 On the Modeling of Oral Drug Delivery ..........................305
Luke E.K. Achenie, Naresh Pavurala
1. Introduction .................................................................................305
1.1. Polymer Matrix Tablet .......................................................306
1.2. Polymers for Oral Drug Delivery.......................................306
2. Customization of Oral Drug Dosage Form: Innovation
in Tablet Design..........................................................................308
2.1. Some Results ......................................................................309
xii Contents

3. How the Polymer in the Customized Dosage Form

May be Designed ........................................................................311
3.1. Problem Formulation..........................................................312
3.2. Mixed Integer Nonlinear Optimization:
Outer Approximation Algorithm........................................315
4. Results and Discussion ...............................................................316
4.1. Ranking Polymer Candidates Using the Desirability
Function ..............................................................................317
4.2. Solubility Parameter Analysis ............................................319
5. Conclusions .................................................................................321
References........................................................................................ 321
Further Reading ............................................................................... 324

CHAPTER 11 Drug Delivery From Polymeric Matrices .......................325

Gianluca Chiarappa, Michela Abrami, Rossella Farra,
Barbara Dapas, Gabriele Grassi, Mario Grassi
1. Introduction .................................................................................325
2. Drug Delivery Systems...............................................................328
2.1. Matrices ..............................................................................329
3. Matrices Characterization ...........................................................332
3.1. Rheology .............................................................................333
3.2. Swelling Test ......................................................................334
3.3. Small-Angle Neutron Scattering ........................................335
3.4. Release Test........................................................................335
3.5. Low-Field NMR .................................................................336
3.6. Crioporosimetry ..................................................................339
3.7. Considerations ....................................................................341
4. Drug Delivery Mechanisms........................................................341
5. Mathematical Modeling..............................................................343
6. Conclusions .................................................................................350
References........................................................................................ 351
Further Reading ............................................................................... 356

CHAPTER 12 Modeling the Mechanics and the Transport

Phenomena in Hydrogels ...................................................357
Diego Caccavo, Antonella Vietri, Gaetano Lamberti,
Anna Angela Barba, Anette Larsson
1. Introduction .................................................................................358
1.1. Importance of Hydrogels and of Modeling Approaches,
Chapter Outline...................................................................358
1.2. Viscoelastic and PE Behaviors...........................................360
 Contents xiii

1.3. A Brief Introduction to Continuum Mechanics .................361

1.4. Modeling Approaches.........................................................363
2. The Hydrogel Free Energy (ATOT) and Free Energy
Density (A) ..................................................................................364
2.1. The Elastic Contribution ....................................................364
2.2. The Mixing Contribution....................................................367
2.3. The Change of Reference Frame: From Dry
to Swelling-Free State ........................................................368
3. The PE Model .............................................................................370
3.1. Mass Balance ......................................................................370
3.2. Momentum Balance............................................................370
3.3. Volumetric Constraint ........................................................370
3.4. The Dissipation Inequality .................................................371
3.5. The Constitutive Equations (P,̿ μ1, h̿ 1 )...............................371
3.6. Initial and Boundary Conditions ........................................372
4. The PVE Model ..........................................................................372
4.1. Upgrading the Constitutive Equations Adding
a Rheological Model ..........................................................373
4.2. The Initial and Boundary Conditions.................................377
5. The Multicomponent PVE Model .............................................377
References........................................................................................ 381

Index.......................................................................................................................385
This page intentionally left blank
Contributors
Roberto A. Abbiati
Institute of Quantitative Systems Pharmacology, Carlsbad, CA; Department of
Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health
Sciences Center, Oklahoma City, OK, United States; Process Systems
Engineering Laboratory, Dipartimento di Chimica, Materiali e Ingegneria Chimica
“Giulio Natta”, Politecnico di Milano, Milano, Italy
Michela Abrami
Department of Engineering and Architecture, Trieste University, Trieste, Italy
Alison Acevedo
Department of Biomedical Engineering, Rutgers, The State University of New
Jersey, Piscataway, NJ, United States
Luke E.K. Achenie
Department of Chemical Engineering, Virginia Tech, Blacksburg, VA,
United States
Ioannis P. Androulakis
Department of Chemical and Biochemical Engineering; Department of
Biomedical Engineering, Rutgers, The State University of New Jersey,
Piscataway, NJ, United States
Jessie L.-S. Au
Institute of Quantitative Systems Pharmacology; Optimum Therapeutics LLC,
Carlsbad, CA; Department of Pharmaceutical Sciences, College of Pharmacy,
University of Oklahoma Health Sciences Center, Oklahoma City, OK; Ohio State
University, Columbus, OH, United States; College of Pharmacy, Taipei Medical
University, Taipei, Taiwan, ROC
Seul-A. Bae
Department of Chemical and Biochemical Engineering, Rutgers, The State
University of New Jersey, Piscataway, NJ, United States
Anna Angela Barba
Department of Pharmacy, University of Salerno, Fisciano, Italy
Fabrizio Bezzo
CAPE-Lab—Computer-Aided Process Engineering Laboratory, Department of
Industrial Engineering, Universitá di Padova, Padova, Italy
Diego Caccavo
Department of Industrial Engineering, University of Salerno, Fisciano, Italy
Gianluca Chiarappa
Department of Engineering and Architecture, Trieste University, Trieste, Italy
Barbara Dapas
Department of Life Sciences, Cattinara University Hospital, Trieste University,
Trieste, Italy

xv
xvi Contributors

Darian R. Esfahani
Department of Neurosurgery, University of Illinois at Chicago, Chicago, IL,
United States
Rossella Farra
Department of Engineering and Architecture, Trieste University, Trieste, Italy
Mauro Ferrari
Houston Methodist Research Institute, Houston, TX, United States
Federico Galvanin
Department of Chemical Engineering, University College London, London,
United Kingdom
Gabriele Grassi
Department of Life Sciences, Cattinara University Hospital, Trieste University,
Trieste, Italy
Mario Grassi
Department of Engineering and Architecture, Trieste University, Trieste, Italy
Clara Hartmanshenn
Department of Chemical and Biochemical Engineering, Rutgers, The State
University of New Jersey, Piscataway, NJ, United States
Lee E. Kirsch
College of Pharmacy, University of Iowa, Iowa City, IA, United States
Milos Kojic
Houston Methodist Research Institute, Houston, TX, United States;
Bioengineering Research and Development Center BioIRC Kragujevac,
Kragujevac; Serbian Academy of Sciences and Arts, Belgrade, Serbia
Gaetano Lamberti
Department of Industrial Engineering, University of Salerno, Fisciano, Italy
Anette Larsson
Pharmaceutical Technology, Department of Chemical Engineering; SuMo
BIOMATERIALS, A VINNOVA VINN Excellence Center at Chalmers University of
Technology, Gothenburg, Sweden
Andreas A. Linninger
Department of Neurosurgery; Laboratory for Product and Process Design,
Department of Bioengineering, University of Illinois at Chicago, Chicago, IL,
United States
Davide Manca
Process Systems Engineering Laboratory, Dipartimento di Chimica, Materiali e
Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, Milano, Italy
Ankit I. Mehta
Department of Neurosurgery, University of Illinois at Chicago, Chicago, IL,
United States
 Contributors xvii

Miljan Milosevic
Bioengineering Research and Development Center BioIRC Kragujevac,
Kragujevac, Serbia
Linas Mockus
Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN,
United States
Ioana Nascu
Artie McFerrin Department of Chemical Engineering, Texas A&M University,
College Station, TX, United States
Brandon L. Neisewander
Department of Neurosurgery, University of Illinois at Chicago, Chicago, IL,
United States
Melis Onel
Artie McFerrin Department of Chemical Engineering, Texas A&M University,
College Station, TX, United States
Maria M. Papathanasiou
Department of Chemical Engineering, Centre for Process Systems Engineering
(CPSE), Imperial College London, London, United Kingdom; Artie McFerrin
Department of Chemical Engineering, Texas A&M University, College Station, TX,
United States
Naresh Pavurala
Department of Chemical Engineering, Virginia Tech, Blacksburg, VA,
United States
Kamau K. Pierre
Department of Biomedical Engineering, Rutgers, The State University of New
Jersey, Piscataway, NJ, United States
Efstratios N. Pistikopoulos
Artie McFerrin Department of Chemical Engineering, Texas A&M University,
College Station, TX, United States
Rohit T. Rao
Department of Chemical and Biochemical Engineering, Rutgers, The State
University of New Jersey, Piscataway, NJ, United States
Gintaras V. Reklaitis
Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN,
United States
Morteza Sadeh
Department of Neurosurgery, University of Illinois at Chicago, Chicago, IL,
United States
Adriana Savoca
Process Systems Engineering Laboratory, Dipartimento di Chimica, Materiali e
Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, Milano, Italy
xviii Contributors

Megerle L. Scherholz
Department of Chemical and Biochemical Engineering, Rutgers, The State
University of New Jersey, Piscataway, NJ, United States
Bernhard Schrefler
Houston Methodist Research Institute, Houston, TX, United States; Centre for
Mechanics of Biological Materials, University of Padova, Padova, Italy
Akop Seksenyan
Department of Neurosurgery, University of Illinois at Chicago, Chicago, IL,
United States
Stephen D. Stamatis
Eli Lilly and Company, Lilly Research Labs, Indianapolis, IN, United States
Kevin M. Tangen
Laboratory for Product and Process Design, Department of Bioengineering,
University of Illinois at Chicago, Chicago, IL, United States
Antonella Vietri
Department of Industrial Engineering, University of Salerno, Fisciano, Italy
Arturas Ziemys
Houston Methodist Research Institute, Houston, TX, United States
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 GENERAL CATARRHAL STOMATITIS.
BUCCAL INFLAMMATION.
Mature animals most subject: Causes in horse, mechanical, chemical, microbian
irritants—alkalies, acids, caustics, hot mashes, ferments, fungi, rank grasses,
excess of chlorophyll, clover, alfalfa, acrid vegetables, bacterial infection secondary,
acrid insects in food; symptomatic of gastritis, pharyngitis, diseased teeth, specific
fevers. Symptoms: Congestion and tumefaction of buccal mucosa, lips and salivary
glands; Epithelial desquamation; fœtor; salivation; froth; papules; vesicles.
Prognosis. Treatment: Cool soft food; antiseptics; wet applications to skin;
derivatives.
This is much more common in the adult than in suckling domestic
animals. None of the domestic mammals or birds can be considered
immune from it, but as its causes and manifestations differ
somewhat it seems well to consider it separately in the different
genera.
 GENERAL CATARRHAL STOMATITIS IN
SOLIPEDS.

Causes. These may be classed as mechanical, chemical, microbian

and other irritants. In the horse it is often due to the reckless
administration of irritant liquids as remedies. Owing to the length of
the soft palate the horse can refuse to swallow any liquid as long as
he chooses, and some of the worst cases of stomatitis I have seen
resulted from the retention in the mouth of caustic alkaline liquids
given under the name of “weak lye.” Strong acids and caustic salts
dissolved in too little water or other excipient, or suspended in
liquids in which they cannot dissolve, or made into boluses which are
crushed between the teeth are not infrequent conditions. Too hot
mashes given to a hungry horse is another cause of this trouble.
Fermented or decomposed food is often most irritating. Coachmen
will sometimes induce it by attaching to the bit bags of spicy or
irritant agents, to cause frothing and make the animal appear
spirited.
Fungi in fodders are among the common causes. The rust of wheat
(puccinia graminis), the caries of wheat (tilletia caries), the blight
(erysiphe communis), ergot (claviceps purpurea), the fungus of rape
(polydesmus excitiosus) and the moulds (penicillium and puccinia)
have all been noticed to coincide with stomatitis, and charged with
producing it. On the other hand, at given times, one or other of these
cryptogams has been present extensively in the fodder without any
visible resultant stomatitis. The apparent paradox may be explained
by the fact that these fungi vary greatly in the irritant or harmless
nature of their products according to the conditions under which
they have grown, and the stage of their development at which they
were secured and preserved. Ergot notoriously differs in strength in
different years, on different soils, under various degrees of sunshine,
shade, cloud, fog, etc. In different States in the Mississippi valley it is
not uncommon to find stomatitis in horses in winter, fed on ergoted
hay, while cattle devouring the same fodder have dry gangrene of
feet, tail and ears. Yet in other seasons the ergot fails to produce
these lesions. Rank grown, watery vegetation, especially if it contains
an excess of chlorophyll is liable to cause stomatitis. Red and white
clover, trefoil, hybrid and purple clover, and alfalfa have all acted
more or less in this way, though in many cases, the food has become
musty or attacked by bacterial ferments. Some of the strongly
aromatic plants, and those containing acrid principles (cicuta virosa,
œnanthe crocata, mustard, etc.) cause buccal inflammation and
salivation.
The irritation in many such cases is not due to one agent only, the
vegetable or other irritant may be the starting point, acting but as a
temporary irritant, the action of which is supplemented and
aggravated by the subsequent attacks of bacterial ferments on the
inflamed, weakened or abraded tissues. The bacteria present in the
mouth, food or water would have had no effect whatever upon the
healthy mucosa, while they make serious inroads on the diseased. On
the other hand the vegetable, mechanical or chemical irritant would
have had but a transient effect, but for the supplementary action of
the bacteria.
In horses that have the bad habit of retaining masses of half
masticated food in the cheeks the growth of cryptogams is greatly
enhanced and such food often becomes violently irritating.
Among other mechanical causes may be named pointed or barbed
hairs or spines (barley awns, spikes, thorns, etc.) which, lodging in a
gland orifice, or in a wound of the gum or mucosa, form a source of
irritation or a centre for bacterial growth and abscess.
Again, irritants of animal origin must be named. These are not
taken by choice, but when lodged in fodder, or in the pastures they
are taken in inadvertently with the food. In this way poisonous
insects, and especially hairy caterpillars, cantharides, potato bugs,
etc., gain access to the mouth.
It must not be overlooked that stomatitis occurs as an extension,
sympathetic affection or sequel of diseases of other organs. Gastritis
is usually attended by redness and congestive tenderness of the
tongue, especially of the tip and margins, and other parts of the
buccal mucosa, notably the palate just back of the incisors, are often
involved. In other cases it appears as a complication of pharyngitis,
laryngitis, of affections of the lower air passages, of the teeth and
periodontal membrane or of the salivary glands.
It appears also in a specific form in certain fevers, as in horsepox,
pustulous stomatitis, aphthous fever and even in strangles. Mercurial
stomatitis, rarely seen at the present time, is one of the worst forms
of the disease, and like the infectious forms will be treated
separately.
Lesions and Symptoms. At the outset and in the slighter forms of
congestion there is merely heat and dryness of the buccal mucosa.
Redness may show on the thinner and more delicate portions of the
membrane, as under the tongue, on the frænum, and on the
sublingual crest. But elsewhere it is hidden by the thickness of the
epithelium, and the manifestations are merely those of suppressed
secretion with local hyperthermia.
As the congestion is increased there is seen, even at this early
stage, a slight thickening or tumefaction of the mucosa, especially on
the gums, lips, the sublingual area, the orifices of the salivary glands,
and the palate back of the upper incisors. On the dorsum of the
tongue, the cheeks and lips, generally the lack of loose connective
tissue tends to prevent the swelling.
With the advance of the inflammation the redness of the mucosa
extends, at first in points and circumscribed patches, and later over
the entire surface. The epithelium drying and degenerating in its
surface layers forms with the mucus a sticky gummy film on the
surface, which, mingling with decomposing alimentary matters gives
out a heavy, offensive or even fœtid odor.
The different parts of the mouth are now tender to the touch, and
this, with the fœtor and even bitterness of the bacterial products
combine with the general systemic disturbance in impairing or
abolishing appetite. In any case mastication becomes slow and
infrequent, and morsels of food are the more likely to be retained, to
aggravate the local condition by their decomposition.
The dry stage is followed by the period of hypersecretion, and in
this the salivary glands take a prominent part, so that ptyalism
(slobbering) becomes the most marked feature of the disease. The
saliva mixed with the increasing secretion of mucus and the
abundance of proliferating and shedding epithelium, escapes from
the lips and falls in stringy masses in the manger and front of the
stall. When there is much motion of the jaws and tongue it
accumulates as a froth around the lips.
A careful examination of the mucosa will sometimes detect slight
conical elevations with red areolæ, representing the tumefied orifices
of the obstructed mucous follicles, and later these may show as
minute erosions. Even vesicles have been noticed (Weber,
Dieckerhoff, Kosters), but when these are present one should
carefully exclude the specific stomatites such as horsepox, contagious
pustular stomatitis, aphthous fever, etc.
Erosions of the mucosa and desquamation of the epithelium have
been noticed in horses fed on purple (hybrid) clover, buckwheat or
ergot, and in some of these cases the inflammation has extended (in
white faces especially) to the skin of the face, the mucosa of the nose,
and the adjacent glands, and as complications icterus, constipation,
colics, polyuria, albuminuria and paresis of the hind limbs have been
observed. These latter are common symptoms of cryptogamic
poisoning.
Prognosis. In uncomplicated cases the disease is not a grave one,
lasting only during the continued application of the local irritant, and
recovering more or less speedily when that has been removed.
Complications are dangerous only when due to some specific disease
poison (glanders, actinomycosis, strangles, etc.), and even poisoning
by the usual cryptogams of leafy or musty plants is rarely persistent
in its effects.
Treatment. This resolves itself into the removal of the irritant
cause and the soothing of the irritation. When the cause has been
definitely ascertained the first step is easy.
In the direction of soothing treatment, a careful selection of diet
stands first. Fibrous hay and even hard oats, barley or corn may have
to be withheld, and green food, or better still, bran mashes, gruels,
pulped roots or fruits allowed. Scalded hay or oats, ensilage, sliced
roots, or ground feed may often be taken readily when the same
aliments in their natural condition would be rejected or eaten
sparingly.
 Medicinal treatment may often be given in the drinking water
which should always be allowed in abundance, pure and clean. In the
way of medication chlorate of potash, not to exceed one-half to one
ounce per day according to the size of the animal, may be added,
together with an antiseptic (carbolic acid, borax, permanganate of
potash, common salt, naphthol, creolin, hyposulphite of soda). In
case of severe swelling, a cap made to fit the head with strips wet in
alum and vinegar or other astringent solution maintained against the
intermaxillary space may be desirable. Support for the tongue may
be necessary as mentioned under glossitis.
In case of complications on the side of the bowels, liver or kidneys,
laxatives, diuretics and antiseptic agents may be called for.
 GENERAL CATARRHAL STOMATITIS IN
CATTLE.
Dense resistant mucosa protective: Affection usually circumscribed. Action of
violent irritants, and toxins of specific fevers. Mechanical irritants. Symptoms:
Salivation; congestion; eruptions; erosions; ergot; acrid vegetables; caustics.
Treatment: Astringents; antiseptics; refrigerants; derivatives; tonics. Removal of
foreign bodies. Lesions and symptoms in sheep.
The mouth of the ox as Cadeae well says has a cuticular epithelium
too thick and resistant to be easily attacked by microbes. It follows
that infected inflammations are far more frequently circumscribed
than in the thinner and softer buccal mucosa of the horse. The more
general buccal inflammations come more particularly from the use of
food that is too hot or that contains strongly irritant agents. The
thickness of the buccal epithelium however, is no barrier to the local
action of poisons operating from within as in rinderpest, or aphthous
fever, or in malignant catarrh, nor is it an insuperable barrier to the
local planting of the germs of cow pox, anthrax, actinomycosis, or
cryptogamic aphtha (muguet). The wounds inflicted by fibrous food
make infection atria for such germs, hence the great liability to such
local inflammations, in winter when the animals are on dry feeding.
For the same reason, perhaps, the prominent portions of the buccal
mucosa,—the papillæ—are sometimes irritated themselves while
serving as protectors for the general mucous surface, and hence they
become specially involved in inflammation, which constituted the
“barbs” of the old farriers. Utz records a buccal inflammation
occurring in herds fed on green trefoil, first cutting, showing that
even in cattle this agent may determine a general stomatitis.
Symptoms. These do not differ from those of the horse, and
resemble, though often in a milder form, the buccal manifestations of
aphthous fever. There is the difficulty of mastication and
indisposition to take in fibrous aliment, the drivelling of saliva from
the mouth, or its accumulation in froth around the lips, the frequent
movement of the tongue and jaws, and the congestive redness,
papular eruption, vesication, or even erosion of the affected mucous
membrane. It is always necessary to guard against confounding the
simple stomatitis, and the slighter infected inflammations, from the
more violent infections above referred to. The special diagnostic
symptoms must be found under the respective headings. The
aphthous fever is not to be expected in American herds, but the
stomatitis which is associated with ergot in the food is met more
particularly in winter and spring, and must not be confounded with
the specific disease, on the one hand nor with the simpler forms of
buccal inflammation on the other. In the case of ergoted fodder the
signs of ergotism in other situations will be found, in the affected
animals, such for example as necrotic sloughs and sores around the
top of the hoof, sloughing of the hoof or of one or more digits, or of
the metatarsus, of the tip of the tail or ear; abortions, convulsions,
delirium, lethargy or paralysis. If not seen in the same animals some
of these forms may be observed in other members of the herd. Then
the buccal lesions are in themselves characteristic: soft, whitish,
raised patches of the epithelium (rarely blisters) are followed by
desquamation and exposure of the red, vascular surface beneath, and
this tends to persist if the ergoted fodder is persisted in.
Treatment. Simple stomatitis of the ox generally tends to
spontaneous and early recovery. The simplest astringent and
antiseptic treatment is usually sufficient to bring about a healthy
action. Borax given in the drinking water, not to exceed four ounces
per day, or the same amount mixed with syrup or honey and
smeared occasionally on the tongue, or hyposulphite or sulphite of
soda, or weak solutions of carbolic acid will usually suffice, after the
irritant cause has been removed. Vinegar, or highly diluted mineral
acids may be used but are somewhat hurtful to the teeth. Decoctions
of blackberry bark or solutions of other vegetable astringents may be
used as alternatives. When there is evidence of irritant matters in the
stomach or bowels, a saline laxative will be advisable to be followed
by vegetable bitters or other tonics. Thorns and other foreign bodies
imbedded in the tongue or other part of the mouth must be
discovered and removed.
 CATARRHAL STOMATITIS IN SHEEP.
The more delicate buccal mucosa in these animals would render
them more subject to inflammations, but this is more than
counterbalanced by the mode of prehension of aliments, not by the
tongue, but by the delicately sensitive lips, and further by the
daintiness and care with which these animals select their food. The
treatment would not differ materially from that prescribed for the
ox.
 GENERAL CATARRHAL STOMATITIS IN
DOGS.
Causes: burns; spiced food; bones; sepsis; ferments; pin caterpillar; dental and
gastric troubles. Symptoms: careful prehension and mastication; congestion;
swelling; eruption; erosion; furred tongue; stringy salivation; fœtor; swelling of
lips, cheeks, intermaxillary space, and pharynx. Treatment: demulcent foods;
antiseptics; derivatives; tonics; care of teeth and gums.
Causes. Hot food is a common cause in hungry dogs. Spiced food
in house dogs fed scraps from the table tend to congestion of mouth
and stomach alike. Irritation through wounds with bones, especially
in old dogs with failing teeth, and in exceptional cases the impaction
of a bone between the right and left upper molars are additional
causes. Putrid meat must also be recognized as a factor, the septic
microbes seizing upon the wounds and spreading from this as an
infecting centre. Lactic acid and other irritant products developed
through fermentation of particles of food retained about the gums
and cheeks soften the epithelium and irritate the sub-epithelial
tissue, causing congestion. Megnin draws attention to the fact that
the pin caterpillar (bombyx pinivora) found on the stalks of couch
grass (Triticum repeus) produces buccal irritation when chewed and
swallowed to induce vomiting. As in other animals more or less
buccal congestion attends on gastric congestion and inflammation.
Dental troubles are often sufficient causes.
Symptoms. The animal becomes dainty with regard to his food,
picking up the smaller or softer pieces and rejecting the larger or
harder. Mastication is painful and selection is made of moist or soft
articles which can be swallowed without chewing or insalivation. The
mouth is red and hot, and at times the mucous membrane eroded, or
blistered, the lesions concentrating especially on the gums and
around the borders of the tongue. The dorsum of the tongue is
furred, whitish, yellowish or brownish. Saliva collects in the mouth
and escapes in filmy strings from its commissures, and the odor of
the mouth becomes increasingly foul. Swelling of the lips, cheeks or
intermaxillary space marks the worst cases.
 Treatment. Withdraw all irritant and offensive aliments. Give
soups, mushes, scraped or pounded lean meat in small quantities,
washing out the mouth after each meal with a 20 per cent. solution of
permanganate of potash or borax or a two per cent. solution of
carbolic acid. Cadeac advises against chlorate of potash on account of
its known tendency to bring about hæmoglobinæmia in dogs. A
laxative and bitters may be called for in case of gastritis or
indigestion, and any morbid condition of the teeth must be attended
to. Decayed teeth may be removed. Tartar especially must be cleaned
off by the aid of a small wooden or even a steel spud and a hard
brush with chalk will be useful. A weak solution of hydrochloric acid
is usually employed to loosen the tartar, but this is injurious to the
structure of the teeth and had best be avoided if possible. Tincture of
myrrh is especially valuable both as a gum-tonic and as a deodorant
and antiseptic. This may be rubbed on the irritated gums as often as
the mouth is washed.
 GENERAL CATARRHAL STOMATITIS IN
SWINE.

Causes: Irritants; ferments; noose on jaw; specific poisons. Symptoms: Careful

feeding; thirst; frothy lips; champ jaws; redness; swelling; fœtor. Treatment:
Cooling, astringent, antiseptic lotions; mushy food; derivative; tonics.

Causes. Swine suffer from simple stomatitis when exposed to

thermal, mechanical or chemical irritants. Food that is too hot, or
that which is hard and fibrous, or that which contains spikes and
awns, capable of entering and irritating gland ducts or sores, or food
which is fermented or putrid, food or medicine of an irritant
character. The habit of catching and holding swine with a running
noose over the upper jaw, and the forcing of the jaws apart with a
piece of wood in search of the cysticercus cellulosa are further
causes. In several specific infectious diseases inflammation of the
mucous membrane with eruption or erosion is not uncommon. Thus
aphthous fever is marked by vesicular eruption, muguet by epithelial
proliferation and desquamation, hog cholera and swine plague by
circumscribed spots of necrosis and erosion. Patches of false
membrane are not unknown, and local anthrax, tubercle and
actinomycosis are to be met with. Inflammation may start from
decaying teeth.
Symptoms are like as in other animals, refusal of food, or a
disposition to eat sparingly, to select soft or liquid aliments, to
swallow hard materials half chewed or to drop them, to champ the
jaws, and to seek cold water. Accumulation of froth around the lips is
often seen, and the mouth is red, angry, dry, and hot, and exhales a
bad odor.
Treatment does not differ materially from that adopted in other
animals. Cooling, astringent, antiseptic lotions, honey and vinegar,
and in case of spongy or eroded mucosa, tincture of myrrh daily or
oftener. Soft feeding, gruels, pulped roots, or well kept ensilage may
be used, and clean, cool water should be constantly within reach. In
case of overloaded stomach or indigestion a laxative followed by
bitter tonics will be in order.
 CATARRHAL STOMATITIS OF BIRDS. PIP.

Causes: hurried breathing; local irritants; exposure; filthy roost. Symptoms:

gaping; roupy cry; epithelial pellicle on tongue, larnyx. or angle of the bill.
Treatment: pick off pellicle; smear it often with glycerized antiseptic. Remove
accessory and exciting causes.

This form of inflammation of the tongue of birds is characterized

by the increased production and desiccation of the epithelium so that
it takes on a horny appearance. According to Cadeac it may
accompany various inflammatory affections of the air passages,
which cause hurried breathing with persistently open bill, and thus
entail evaporation of the moisture. More commonly it has its primary
cause in local inflammation of the surface in connection with damp,
cold, draughty hen-roosts, and above all, the accumulation of
decomposing manure and the exhalation of impure gas. Even in such
cases the abnormal breathing with the bill open is an accessory cause
of the affection.
Symptoms. The breathing with open bill should lead to
examination of the tongue, but above all if at intervals the bird with a
sudden jerk of the head emits a loud shrill, raucous sound, which
reminds one of the cough of croup. The tip and sides of the tongue
are found to be the seat of a hard, dry, and closely adherent epithelial
pellicle, which suggests a false membrane.
Treatment. The common recourse is to pick or scrape off the
indurated epithelial mass, leaving a raw, bleeding surface exposed.
This is then treated with a solution of borax, or chlorate of potash.
Cadeac deprecates this treatment as useless and dangerous, and
advises the disintegration of the dry epithelial mass with a needle
taking care not to prick nor scratch the subjacent sensitive tissue,
and to wash with a 5 per cent. solution of chlorate of potash. A still
more humane and effective method is to make a solution of
hyposulphite of soda in glycerine and brush over the affected surface
at frequent intervals. This may be conveniently applied through the
drinking water.
In case of implication of the lower air passages or lungs, the
treatment must be directed to them, and soft, warm, sloppy food and
the inhalation of water vapor will prove of great advantage. Secure
clean, sweet, dry pens, pure air, and sunshine. (See pseudo
membranous enteritis.)
 LOCAL STOMATITIS.

Division of circumscribed buccal inflammations: palatitis; gnathitis gingivitis;

glossitis. Causes: injuries; acrid; venomous or caustic agents; diseased teeth;
foreign bodies in gland ducts; malformed jaws; infections, etc. Symptoms:
salivation; difficult prehension and mastication; dropping half masticated morsels;
distinctive indications of different caustics; abrasion; abscess; slough; infective
disease lesions. Treatment: for palatitis, massage by hard corn ears, scarification,
laxatives; for gnathitis, care for teeth and ducts, astringent washes, eliminate
mercury; for glossitis, remove cause, use antidote to venom, or to chemical irritant,
astringent, antiseptic lotions or electuaries, evacuate abscess, soft, cool diet,
elevate the head, suspend the tongue.

Localized inflammations in the buccal cavity are named according

to the portion of the lining membrane attacked;—palatitis if seated
in the roof of the mouth; gnathitis if restricted to the cheeks;
gingivitis if to the gums; and glossitis if to the tongue.
Palatitis. Lampas. Congestion of the hard palate behind
the upper front teeth. This is usually seen in young horses during
the period of shedding the teeth and is caused by the irritation and
vascularity consequent on teething. The red and tender membrane
projects beyond the level of the wearing surfaces of the upper
incisors, and may materially interfere with the taking in of food. A
common practice in such cases is to feed unshelled Indian corn, the
nibbling of which seems to improve the circulation in the periodontal
membrane and by sympathy in the adjacent palate. Superficial
incisions with the lancet or knife will usually relieve, and may be
followed by mild astringent lotions if necessary. If apparently
associated with costiveness or gastric or intestinal irritation a dose of
physic will be demanded. Nothing can excuse the inhuman and
useless practice of burning the parts with a hot iron.
 Gnathitis. Inflammation of the Cheeks. Usually resulting as
a distinct affection from irregular or overgrown teeth, or the entrance
of vegetable spikes into the gland ducts, these cause local swelling
and tenderness, slow imperfect mastication, dropping of food half
chewed, accumulation of food between the cheeks and teeth,
thickening, induration and sloughing of the mucous membrane with
excessive fœtor.
Treatment. Consists in correcting the state of the teeth and ducts
and using one of the washes recommended for glossitis.
Gingivitis. Inflammation of the gums. This is either
connected with the eruption of the teeth in young animals and to be
corrected by lancing the swollen gums and giving attention to the
diet and bowels; or it is due to scissor-teeth or to the wear of the
teeth down to the gums in old horses; or it is dependent on diseased
teeth, or mercurial poisoning, under which subjects it will be more
conveniently considered. Barley awns or other irritants must be
extracted.
Glossitis, Inflammation of the Tongue. Causes. Mostly the
result of violence with bits, ropes, etc., with the teeth, or with the
hand in giving medicine; of scalding food, of acrid plants in the food:
of irritant drugs (ammonia, turpentine, croton, lye, etc.), or of sharp,
pointed bodies (needles, pins, thorns, barley and other barbs, etc.)
which perforate the organ. In exceptional cases leech and snake bites
are met with especially in cattle, owing to the tongue being exposed
when taking in food. Local infections and those of the specific forms,
determine and maintain glossitis.
Symptoms: Free flow of saliva, difficulty in taking in food or
drinking, and red, swollen, tender state of the tongue, which in bad
cases hangs from between the lips. The mucous membrane may be
white, (from muriatic acid, alkalies, etc.), black, (from oil of vitriol,
lunar caustic, etc.), yellow, (from nitric acid, etc.), or of other colors
according to the nature of the irritant. It may be raised in blisters,
may present red, angry sores where the epithelium has dropped off;
may become firm and indurated from excessive exudation; may swell
and fluctuate at a given point from the formation of an abscess; or
may become gangrenous in part and drop off. Breathing is difficult
and noisy from pressure on the soft palate. There is usually little
fever and death is rare unless there is general septic infection.
 Treatment will depend on the cause of injury. In all cases seek for
foreign bodies imbedded in the organ and remove them. If snake
bites are observed use ammonia or potassium permanganate locally
and generally, or cholesterin as a local application. If the irritation
has resulted from mineral acids, wash out with calcined magnesia
lime water, or bicarbonate of soda or potash. If from alkalies (lye)
use weak vinegar. If from caustic salts employ white of egg,
vegetable-gluten, boiled linseed, slippery elm, or other compound of
albumen or sheathing agent. In ordinary cases use cold astringent
lotions, such as vinegar and water; vinegar and honey; borax, boric
or carbolic acid, chlorate of potash, alum or tannin and honey.
Poultices applied around the throat and beneath the lower jaw are
often of great value. The bowels may be relieved if necessary by
injections, as it is usually difficult to give anything by the mouth. If
ulcers form touch them daily with a stick of lunar caustic or with a
fine brush dipped in a solution of ten grains of that agent in an ounce
of distilled water. For sloughs use a lotion of permanganate of
potash, one drachm to one pint of water, or one of carbolic acid, one
part to fifty of water. If an abscess forms give a free exit to the pus
with the lancet, and afterward support the system by soft nourishing
diet, and use disinfectants locally. As in all cases of stomatitis, the
food must be cold gruels or mashes, or finely sliced roots will often
be relished.
The mechanical expedient of supporting the tongue in a bag is
essential in all bad cases, as if allowed to hang pendulous from the
mouth inflammation and swelling are dangerously aggravated.
 APHTHOUS STOMATITIS. FOLLICULAR
STOMATITIS.
Causes: in horse, ox, dog; rough, fibrous food, blistering ointments, bacteria.
Symptoms: general stomatitis, and special; papules with grayish centres and red
areolæ, vesiculation, ulceration. Treatment: Astringent, antiseptic, derivative,
tonic, stimulant.
This is a rare affection in ruminants where the thickness of the
epithelial covering appears to be a barrier to infection or injury,
while it is common in the more delicate and sensitive buccal mucosa
of the horse and dog. In the horse the ingestion of irritant plants with
the food and the penetration of vegetable barbs into the mucous
follicles may be charged with causing the disease, while in both horse
and dog the licking of blistering ointments and the local action of
fungi and bacteria are factors in different cases.
Symptoms. With the ordinary symptoms of stomatitis, there
appear minute firm, whitish, circular elevations representing the
openings of the inflamed mucous or salivary follicles, having a
reddish areola, and grayish white vesicular centre. They may amount
to a line or more in diameter, and on bursting leave red cores or
ulcers. The whole mouth may be affected or the disease may be
confined to the lips, gums or tongue.
Treatment. Beside the general astringent washes, this affection is
greatly benefited by the local use of antiseptics, as sulphite or
hyposulphite of soda, 2 drachms in a quart of water. Borax,
permanganate of potash, carbolic acid or other antiseptic in suitable
solution may be substituted. Saline laxatives are often useful to
remove sources of irritation in stomach and intestines, and iron salts
(chloride or nitrate) in full and frequently repeated doses may be
given internally. Ulcers may be cauterized and soft food and pure
water given from an elevated manger.
 ULCERATIVE STOMATITIS. GANGRENOUS
STOMATITIS.
Causes: specific disease poisons; debility; rachitis; cancer; chronic suppuration;
irritation—mechanical, chemical, thermic, venomous, etc. Symptoms: difficult,
imperfect prehension and mastication, salivation, bleeding, swollen, puffy
epithelium, blisters, extending erosions, deep or spreading. Duration. Treatment:
correct constitutional fault, tonics, soft, digestible food, antiseptics, mild caustics.
This is characterized by the formation of necrotic spots and
patches of the buccal epithelium, with desquamation, and the
formation of more or less rodent ulcers of the sub-epithelial mucosa.
Like other ulcerative processes it is usually due to microbic invasion,
and in this way it may supervene on other and simpler forms of
stomatitis. It also varies in its manifestations and nature according to
the genus of animal, and the specific microbe present.