DMSO : Biological Actions of Dimethyl Sulfoxide DMSO - New York Academy of Sciences

516 Pages·1967·88.73 MB·English

by  Chauncey Depew Leake , Stanley W Jacob MD

ANNALS OF VOLUME 243
THE NEW YORK ACADEMY
OF SCIENCES
BIOLOGICAL ACTIONS OF
DIMETHYL SULFOXIDE
StanleyW.Jacob
Robert Herschler
PUBLISHED BY THE NEW YORK ACADEMY OF SCIENCES
ANYAA9 243 1-508 (1975)
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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
Volume 243
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Volume 243
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January27, 1975
BIOLOGICAL ACTIONS OF DIMETHYL SULFOXIDE* _^
Stanley W. Jacob and Robert Herschl^r
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LIBRARY
CONTENTS
Opening Remarks. By Chauncey D. Leake 5
Part I. Mechanismof Actionof Dimethyl Sulfoxide
Pharmacologicand BiochemicalConsiderationsofDimethylSulfoxide. By DonC. Wood
and Julianne Wood 7
Physical Properties ofDimethyl Sulfoxide and its Function in Biological Systems. By H.
Harry Szmant 20
InfluenceofNonionic Organic Solutes on Various ReactionsofEnergyConservation and
Utilization. By Thomas E. Conover 24
EffectsofDimethyl Sulfoxide on Subunit Proteins. By Thomas R. Henderson, Rogene
F. Henderson, andJ. LyndalYork 38
TheEffectofDimethyl Sulfoxideon a Lysosomal Membrane. By DonaldW. Mischand
Margaret S. Misch 54
Specific ModificationsoftheNa". K"-Dependent AdenosineTriphosphataseby Dimethyl
Sulfoxide. ByJoseph D. Robinson 60
Altered Mitogenic Responsiveness of Chronic Leukemic Lymphocytes and Normal
Human LymphocytesTreatedwith DimethylSulfoxide. ByAnthonyJ. Dennisand
Henry E. Wilson 73
Cell-Mediated Immunity: Its Modulation by Dimethyl Sulfoxide. By Harry Bartfeld
AND Andrew Goldstein 81
Antiarthritic and Antithrombotic Effects of Topically Applied Dimethyl Sulfoxide. By
PeterGorogand Iren B. Kovacs 91
Part II: Toxicology, Fate, and Metabolism
ToxicityofDimethylSulfoxide, AloneandinCombination. By LionelF. Rubin 98
Biological Effects of the Metabolites of Dimethyl Sulfoxide. By J. J. Kocsis, S.
HarkAWAY,andR.Snyder 104
Pharmacological Effects of Dimethyl Sulfoxide on the Mammalian Myocardium. B\
Marshal ShlaferandArvland M. Karow,Jr 110
The Influence of Dimethyl Sulfoxide on Cellular Ultrastructure and Cytochemistry. By
Edmund B. Sandborn, HeatherStephens, and Moise Bendayan 122
Metabolism and Excretion of Dimethyl Sulfoxide in Cows and Calves after Topical and
Parenteral Application. By J. Tiews, E. Scharrer, N. Harre, L. Flogel, and W.
Jochle ' 139
The Penetration and Clearance of Dimethyl Sulfoxide from the Rat Eye After Topical
Application. By W. J. Weaver, R. V. Hill, F. S. Weber, andS. W.Jacob 151
*Thisseriesofpapersisthe resultofaconferenceentitledConferenceon Biological ActionsofDimethyl
Sulfoxide,heldbvTheNewYorkAcademyofSciencesonJanuary9, 10.and 11, 1974.
PartIII. Effectsof Dimettiyl SulfoxideonTumorSystems
Stimulation by Dimethyl Sulfoxide of Erythroid DiflFerentiation and Hemoglobin Syn-
thesis in Murine Virus-Induced Leukemic Cells. By Charlotte Friend and
William Scher 155
EffectofDimethyl Sulfoxideand Dimethylformamideon theGrowth and Morphologyof
TumorCells. Bv E. Borenfreund, M.Steinglass,G. Korngold,andA. Bendich
'. 164
Studies on the Intracisternal A-Type Particlesin Mouse PlasmaTumorCells: Induction
ofMaturation ofthe Particles. ByS. E. Stewart, G. Kasnic,Jr.,C. Urbanski, M.
Myers, andT. Sreevalsan 172
Effect of Dimethyl Sulfoxide on the Hepatic Disposition of Chemical Carcinogens. Bv
Walter G. Levine '.. 185
PotentiationofAntineoplasticCompoundsbyOral DimethylSulfoxideinTumor-Bearing
Rats. By Joel Warren, Miriam R. Sacksteder, Harriet Jarosz, Bruce
Wasserman, and Peter E. Andreotti 194
Studies on the Modifying Effect of Dimethyl Sulfoxide and Other Chemicals on Experi-
mentalSkinTumor Induction. By FrejStenbackandHumbertoGarcia 209
Part IV. Dimethyl Sulfoxidein Agriculture
Fate and Metabolism of Dimethyl Sulfoxide in Agricultural Crops. By Bernard C.
Smale, NeilJ. Lasater,and BruceT. Hunter 228
Accumulation and Persistence of Sulfur^"^ in Peach Foliage and Fruit Sprayed with Ra-
diolabeled Dimethyl Sulfoxide. By Harry L. Keil 237
Use of Dimethyl Sulfoxide to Control Aflatoxin Production. Bv George A. Bean and
George W. Rambo .' 238
PartV. Dimethyl Sulfoxide: Basic Considerations
Current Concepts Concerning Radioprotective and Cryoprotective Properties of
Dimethyl SulfoxideinCellularSystems. By M.J.Ashwood-Smith 246
The Effect of Dimethyl Sulfoxideon Forelimb Regeneration ofthe Adult Newt, Triturus
viridescens. ByGeraldG. Slattery andAnthonyJ.Schmidt 257
In vivo and in vitro Effects ofDimethyl Sulfoxideon Streptomycin-Sensitive and-Resis-
tant Escherichia coli. By William E. Feldman, James D. Punch, and PatriciaC.
Holden 269
The Effect of Dimethyl Sulfoxide on Pneumocystis carinii. By John W. Smith and
WalterT. Hughes 278
The Effects of Dimethyl Sulfoxide on Neurite Development in vitro. By Fred Jerrold
Roisen 279
Dimethyl Sulfoxide: A Tool in the Study of Sperm Motility Control. By Leonard
Nelson 297
Discussion Paper: Dimethyl Sulfoxide as a Cryoprotective Agent for Platelet Pres-
ervationby Freezing. By MarioG. Baldini 306
Part VI. Effectsof Dimethyl Sulfoxidein LowerAnimal Models
Production ofInterferon in theWhite Mouseby DimethylSulfoxide. ByMichaelKunze
308
OrallyAdministeredDimethylSulfoxide: ItsEffectsonBloodConcentrationsonSalicylic
Acid, Sulfanilamide, and Warfarin. ByG. Thomas Passananti,CarolA. Shively,
and Elliot S. Vesell 311
A Comparison ofGlycerol and Dimethyl Sulfoxide as Cryoprotective Agents for an Ex-
perimentalTumor: A PilotStudy. ByWilliam P.Graham, III 317
Effect of Dimethyl Sulfoxide and Hydrogen Peroxide on Tissue Gas Tensions. By M.
Bert Myers andWilliam Donovan 320
The Effect of Dimethyl Sulfoxide on Hypothalamic-Pituitary-Adrenal Functions in the
Rat.ByJohnP. AllenandCatherine F.Allen 325
PartVII. Effectsof Dimethyl SulfoxideontheCentral NervousSystem
The Effect of Dimethyl Sulfoxide on the Neuronal Excitability and Cholinergic Trans-
mission in AplysiaGanglion Cells. By Masashi Sawada and MakotoSato 337
Enhancement of Resistance ofGlial Cells by Dimethyl Sulfoxide against Sonic Disrup-
tion. By Ramon Lim andSean Mullan 358
Dimethyl Sulfoxide in Central Nervous System Trauma. By J. C. de la Torre, H. M.
Kawanaga, D. W. Rowed, C. M. Johnson, D. J. Goode, K. Kajihara, and S.
Mullan 362
,
PartVIII. DimethylSulfoxide:Clinical Concepts
Design ofTherapeuticTrials for Dimethyl Sulfoxide. ByThomasG. Kantor 390
The Present and Potential RoleofDimethyl Sulfoxidein ConnectiveTissueDisorders. By
John Baum 391
Discussion Paper: Methodology and Techniques in the Evaluation ofDimethyl Sulfoxide
forConnectiveTissue Disorders. By RaulFleischmajer 393
Dimethyl SulfoxideTherapy in Various Dermatological Disorders. Bv LazaroSehtman
395
;
Experimental and Clinical Evaluation ofTopical DimethylSulfoxidein Venous Disorders
ofthe Extremities.ByA. Kappert 403
DimethylSulfoxideTherapyinChronicSkin Ulcers.By Rene Miranda-Tirado 408
Dimethyl Sulfoxide Therapy as Toxicity-Reducing Agent and Potentiator ofCyclophos-
phamide in the Treatment of Different Types ofCancer. By Jorge Cornejo Gar-
RiDO and Raul Escobar Lagos 412
DimethylSulfoxideTherapyin SevereRetardationin MongoloidChildren. By ManuelJ.
AspiLLAGA, Ghislaine Morizon, Isabel Avendano, Mila Sanchez, and Lucila
Capdevile 421
Dimethyl Sulfoxide Therapy in Nonmongoloid Infantile Oligophrenia. By Ana Giller
AND Maria E. M. de Bernadou 432
Oral Dimethyl Sulfoxide in Mental Retardation. By Jeanne Gabourie, Janis W.
Becker, Barbara Bateman, Michael Dunn, andStanleyJacob 449
Dimethyl SulfoxideTherapyin Bronchiolitis. ByAristidesZuniga, Rodolfo Burdach,
AND Santiago Rubio 460
Dimethyl Sulfoxide Therapy in Subjective Tinnitus of Unknown Origin. By Aristides
ZunigaCaro 468
Evaluation of Dimethyl Sulfoxide Therapy in Chronic Respiratory Insufficiency of
BronchopulmonaryOrigin. ByRenato EulufI Marin 475
Dimethyl Sulfoxidein theTreatmentofRetinal Disease. By RobertV. Hill 485
Dimethyl SulfoxideTherapy inSterility DuetoTubalObstruction. By HugoVenegas .... 494
Experiencein the UseofDimethyl Sulfoxidein the DiseasesoftheSupporting MotorAp-
paratus and General Suppurative Surgery. By Michael B. Dubinsky and Andrew
A. Skager 497
The HumanToxicologyofDimethyl Sulfoxide. By Richard D. Brobyn 500
SummaryoftheDimethylSulfoxideConference. ByArthur L. Scherbel 510
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NOTE TO READER
DMSO
Although the abbreviation is not acorrectdefinition,wedecidedtouseit
throughout this monograph, simply because dimethyl sulfoxide has been generally
known as DMSO for some time, and we felt that to introduce a more correct but
less well-known designation, such as MczSO, might produce some confusion. We
have, however, used the full term dimethyl sulfoxidein the titlesofallpapers, andof
the monograph itself, in order to further the conceptofemploying the full chemical
nameforbiological agentsor substances.
StanleyW. Jacoband Robert Herschler
Thismonograph wasaidedby contributionsfrom:
Acoustical and FireproofingCompany Mrs. Elizabeth Kinsman
Portland, Oregon Portland, Oregon
Amato Brothers Fred Meyer Foundation
Portland, Oregon Portland, Oregon
Mr. Thomas Autzen Mrs. EleanorOoten
TheAutzen Foundation Oregon City, Oregon
Portland, Oregon
Mr. William J. Polits
Mrs. Eleanor H. Cole Portland, Oregon
NewYork, NewYork
Mrs. Harrison Ring
Mrs. Eunice L. Gaido Portland, Oregon
Conroe, Texas
Miss Mozelle M. Wilson
JohnC. Higgins Foundation Portland, Oregon
Portland, Oregon
^
OPENING REMARKS
Chauncey D. Leake
UniversityofCalifornia
San Francisco, California94143
This is the third international conference convened during the past decade on
thatremarkablesubstance, dimethyl sulfoxide(DMSO). Thefirst was a comprehen-
sive conference, organized by The New York Academy of Sciences in 1966, under
the direction of Drs. Stanley Jacob and Edward E. Rosenbaum, of the University
ofOregon. These keen clinicians had discovered the extraordinarily useful poten-
DMSO
tial of inthetreatmentofvariouspainful pathologicalconditions.
The second wasconvened in Viennain 1966, under the auspicesofSchering A. G.
ofWest Berlin. Organized under the skilled direction ofDr. Gerhard Laudahn, this
DMSO
second conferencedealtlargely with clinical reports.
The third conference on DMSO, now convening here, was again arranged by Dr.
Stanley Jacob. This is to be oriented toward broad biological and clinical applica-
tions of the demonstrated and verified properties of DMSO. It will also include
reportson its clinical usefulness.
In the decade since the first hesitant reports on DMSO came from Dr. Jacob
and his colleagues, there have been many thousands ofpublished reports on its bio-
logical actions and its clinical usefulness in human and veterinary medicine. These
reportshavecomefrom allovertheworld.
In the U.S.S.R., where bureaucratic control ofdrug preparation and use is even
DMSO
tighter than in the United States, the clinical usefulness of has been
considered sufficiently verified to make it available for use in accordance with the
judgmentofphysicians.
The mostinformativepublicationson DMSO are:
1. the reports anddiscussions at theNew York Academy ofSciences conference
in 1966.^ Thiswas separately summarized by Leake.
2. the reports and discussions ofthe Viennaconferencein 1966.^Thiswas sump-
tuously published and distributed by Schering AG ofWest Berlin. The book wasdis-
tinguished by fine color photographs, especially ofreversiblelenschangesin theeyes
ofsomeexperimental animals.
3. the sharp journalistic book prepared for popular distribution by Pat
McGrady."* This gives much detail on the efforts of our Food and Drug Adminis-
tration tojustify its rulingson theuseofDMSO.
4. the carefully prepared summaries of the properties, biological actions, and
usesofDMSO, edited sowell byJacobandcolleagues.^
5. the cautious, officialized report of an ad hoc committee of the National
AcademyofSciences.®
DMSO
It is significant that there is a great deal ofpublished material on from
all parts of the world. Many are listed in the reports given at the New York
Academy of Sciences conference in 1966. The Vienna Symposium listed 395. The
volume edited by Jacob and colleagues^ lists over 2,000 references on chemistry,
cryobiology, and pharmacology alone. Thereareprobably morethan thisnumberof
clinical reports on DMSO in both human and veterinary medicine. The National
Academy of Sciences ex cathedra Committee referred specifically to 230 reports,
andlisted a"bibliography" ofabout 300.
5
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6 Annals NewYork Academy ofSciences
It is increasingly difficult to obtain bureaucratic permission to study newdrugs.
Itisdifficult forphysicianstousetheirownjudgmentany moreinprescribingdrugs.
They are the people licensed by our governments to use drugs in accordance with
theirjudgment as to their safety andeffectiveness for individual patients, takinginto
account the relation of risk to benefit in the widely differing conditions of their
differentpatients.
Our Food and Drug Administration, however, operates under the terms of a
detailed Act ofour Congress. This Act seems to imply that nodrugis to beused by
aphysicianunlessitisdemonstratedto beabsolutely safeand absolutelyeffective.
There is no such drug: not even tap water or table salt is absolutely safe and
effective. Gaussian distribution inevitably occurs in the response to any chemical
agent. Ifenough people areinvolved, it will alwaysbefoundthatwith thesamedose,
strictly quantitated on a weight basis, some few persons will show practically no
effect, while some few others may show a very strong response, evendeath. Itis the
professional responsibility of physicians in actual practice tojudge this relation of
risk tobenefitfortheirindividual patients.
In my opinion, it is the responsibility of our governments and of our drug in-
dustry to furnish physicians with the verified scientific facts about drugs: their
chemical composition and physicochemical properties; their ratesofabsorption and
distribution; the character and rates oftheir changes in our bodies; their rates and
modesofexcretion; theirbiological actions overtherangeoforganizationallevelsof
living material (from molecules, subcellular units, cells, organs, tissues, and indi-
viduals to societies and ecologies); their toxicities upon single or repeated adminis-
tration; the untoward reactions likely to be encountered; and the preparations
available. Then it is up to thejudgment oflicensed physicians to decidehow and for
whatpurposetheywillusethem.
DM
With regard to SO, the relevant scientific facts have been clearlyestablished
by many competent scientists in many different places. This scientific information
on DMSO has been well and widely applied in many appropriateclinical conditions
ofanimalsandhumans.
Our conference will add furtherdetail to this scientific knowledgeofDMSO and
ofits clinical usefulness. As I said when summarizing the first DMSO conference,
*'Thewell-known legal principleofres ipsaloquitur might well apply tothesituation
involving DMSO." I concluded then, as I do now, that **rarely has anewdrug come
so quickly to thejudgment ofthe members ofthe health professions with so much
verifiable data from so many parts ofthe world, both experimentally and clinically,
asto safety andefficacy."
So, let thedeliberations and discussions ofthis Conference result in the wisdom
beinggained that may allow DMSO to finds its placein alleviating someofthepains
andpathologicaldistresswhichcan afflictusall.
References
1 Jacob,S.&E. E. Rosenbaum. 1967.Ann.N.Y.Acad.Sci. 141: 1-671
2. Leake,C.D. 1966.Science152: 1646-1649.
3. Laudahn, G. & K. Gertich. 1966. DMSO Internationales Symposium, 219 pp.
Saladruck. Berlin,WestGermany.
4. McGrady, p. 1973. The Persecuted Drug: The Story of DMSO, 372 pp. Doubleday &
Company,Inc.GardenCity,N.Y.
5. Jacob, S., E. E. Rosenbaum & D. C. Wood. 1971. Dimethyl-Sulfoxide. Vol. 1. Basic
Concepts,479pp. Marcel Dekker.NewYork,N.Y.
6. National Academy of Sciences. 1973. Dimethyl sulfoxide as a therapeutic agent.
Report, 119p.
Part Mechanism of Action of Dimethyl Sulfoxide
I.
PHARMACOLOGIC AND BIOCHEMICAL CONSIDERATIONS
OF DIMETHYL SULFOXIDE
Don C. Wood andJulianneWood
Medlab ComputerServices
Salt Lake City, Utah84102
I
A broad spectrum of the primary pharmacological properties of DMSO have
been reported. Concurrently with pharmacologic studies in laboratoryexperimental
models, there have been evaluations of its clinical therapeutic efficacy, and an
equally broad spectrum offavorable therapeutic claims have also been made. It has
been perplexing to all serious students ofthis drug that the basic and clinical studies
have produced conflicting reports. Controversial claims, however, are usually
associated with the development and refinement ofany new drug. In many respects
the case of DMSO is unique, in that it appears to palliate such a large number of
different clinical conditions and also to evidence such a wide range of pharmaco-
logical properties. As we gain more experience with DMSO, a greater degree of
standardization will result, and many ofthe areas ofcontroversy will be resolved. In
comparing published reports, the reader should be careful to review comparableex-
perimental design, common stages ofdisease in patients, similar dosings, routes of
therapy, frequency of therapy, methods of measuring results, and inherent experi-
mental error, and so on. Few studies have been reported in which identical models
havebeen used bydifferentinvestigators toevaluate DMSO.
In addition to experimental design, patient selection, and methodology, other
physical or chemical characteristics may affect the results obtained in DMSO
studies. These factors often appear unique to DMSO, and may or may not have
been published. Some DMSO investigators have "grown up" with a trial-and-error
understanding ofthese potential experimental problems. A property ofDMSO that
has caused considerable difficulty in the interpretation oflaboratory findings is the
degree of ionization it may impose upon the constituents of an aqueous buffer
system. If an aqueous phosphate buffer is prepared to a specific pH value, then is
subsequently diluted with DMSO, not only will the concentration of buffer change
with the dilution, but the pH value will change as well. Ifthe DMSO-buffer mixture
is not checkedjust before use, erroneous interpretations ofdata can result. Enzyme
activities, metabolic studies, tissue or cell cultures, in vitro microbiology, and nu-
merous other test systems could be seriously modified, yielding results that relate
simply to a buffer pH change, rather than to an effect of DMSO on the primary
physiologicorpharmacologicproperty beingexamined.
Investigators have been concerned that enzymes fail to respond in a predictable
fashion when mixed with DMSO solutions. There are enzymes that appear to be
unaffected by high concentrations of DMSO. Other enzymes are potentiated in
catalytic activity. A third group ofenzymes are inhibited in relatively dilute DMSO
solutions. Do these studies reflect pH changes or modifications of protein con-
formation, or in the case of enzyme inhibition, is the catalytic activity related to
chemical changes in functional groups? This very complex matter has been dis-
cussedelsewhere.^"*
It is known that DMSO is reduced to dimethyl sulfide (DMS) when mixed in
vitro with glutathione or cysteine.^ DMSO will interfere with many laboratory
procedures commonly used to measure constituents in biological fluids such as
DMSO
blood glucose, ascorbic acid, and so on.^ The concentration of in the test
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8 Annals NewYork Academy ofSciences
system is important to the degree ofinterference. Most in vivo experiments would
probably beunaffected by theseproblems, but manyin vitro studies are affected.
Numerous other examples could be sited, with particular reference to
pharmacologic and therapeutic studies in clinical testing,in which the DMSO con-
centration and frequency of treatment are extremely critical to success. Most
clinicians who have had extensive experience with DMSO now have an under-
standing of this therapeutic problem. Frequency of treatment and the concentra-
DMSO
tions of used in clinical evaluations are extremely critical to the results that
will be obtained. The fact that some ofthis information is not clear has been one of
theimportant factorsleadingtodifferencesin publishedexperimentalfindings.
This paper will attempt to bring together not only pharmacological laboratory
experimental models, but also some clinical studies which might lend support to a
better understanding of DMSO and its action. As one attempts to understand the
mechanism ofDMSO in a disease process, one must consider the fact that multiple
pharmacological properties can be expressed in a single clinical problem. It is likely
that some of the drug characteristics would be favorable in a particular clinical
situation, whileother properties mightwork to thepatient'sdisadvantage.
MembranePenetration
DMSO
in varying concentrations has been shown to cross body membranes in
animals. The process is reversible. The integrity of most membranes is unaffected;
except where extremely concentrated (90-100%) doses of DMSO come into direct
contact with the membrane. In clinical therapeutic conditions, such concentration
levels would rarely be reached. Exceptionsto the rapid penetration ofthe membrane
are nails and the enamel of the teeth, where little penetration, if any, can be
demonstrated.
Numerous studies on the fate and metabolism of labelled DMSO have
confirmed the rapid movement and generalized distribution of the labelled
component in nearly every tissue of the body. Extraction and analysis of the label
fromvarious tissues showsthepresenceofDMSOoroneofits metabolites.^~*'
Klingman^^'^^ mixed dyes, antiperspirants, and steroids with varying concentra-
tions of DMSO. He reported enhanced penetration through human skin, as com-
pared with controls that did not contain DMSO, and claimed that theenhancement
of penetration was not dependent on irreversible damage to the stratum corneum.
Maibach and Feldman^'' reported a threefold increase in the penetration of
percutaneous steroid when mixed with DMSO. Maximum urinary excretion of
testosterone and hydrocortisoneoccurred in man within 36 hoursaftertreatmentof
theskin.
Sulzberger and colleagues^^ used iron dyes, iodine, and methylene blue as visual
DMSO
markers ofpenetration following dermal application of dye mixtures. They
found in biopsies that there was essentially no penetration ofthe marker below the
stratum corneum. The stratum corneum was completely invaded, however.
Stroughton^^"^* also transported hydrocortisone and hexachlorophene into the
stratum corneum. He found that the deposit remained for as long as 16 days, and
was resistanttowashingwith alcoholor soap and water.
Perlman and Wolfe^^ found that solutions of allergen of low molecular weight
would penetrate intact human skin when mixed with 90% DMSO. Allergens that
had molecular weights of more than 3,000 failed to penetrate the skin. Smith and
Hegre^° reported, however, that specific antibodies did form in rabbits treated with
DMSO
dermal applicationsof and bovine serum albumin.