Stahl N, Baldwin MA, Teplow DB, Hood L, Gibson BW, Burlingame AL, Prusiner SB. Structural analysis of the scrapie prion protein using mass spectrometry and amino acid 
sequencing. Biochemistry . 1993;32:1991–2002. 27. Gu Y , Singh N. Doxycycline and protein folding agents rescue the abnormal phenotype 
of familial CJD H187R in a cell model. Brain Res Mol Brain Res . 2004;123:37–44. 28. T atzelt J, Prusiner SB, Welch WJ. Chemical chaperones interfere with the formation of 
scrapie prion protein. EMBO J . 1996;15(23):6363–6373. 29. Shak ed GM, Fridlander G, Meiner Z, Taraboulos A, Gabizon R. Protease-resistant and 
detergent-insoluble prion protein is not necessarily associated with prion infectivity. J Biol Chem. 1999;274(25):17981–17986. 30. Nakano KK, Da wson DM, Spence A. Machado disease. A hereditary ataxia in Portuguese 
emigrants to Massachusetts. Neurology. 1972;22(1):49–55. 31. Y oshida H, Yoshizawa T, Shibasaki F, Shoji S, Kanazawa I. Chemical chaperones reduce 
aggregate formation and cell death caused by the truncated Machado-Joseph disease 
gene product with an expanded polyglutamine stretch. Neurobiol Dis . 2002;10(2):88–99. 32. Cheng F , Liang J, Tao Z, Chen J. Functional materials for rechargeable batteries. Adv Mater . 2011;23(15):1695–1715.13 Chemistry of DMSO
 33. Xu D, Wang ZL, Xu JJ, Zhang LL, Zhang XB. Novel DMSO-based electro -
lyte for high performance rechargeable Li-O2 batteries. Chem Commun  (Camb). 2012;48(55):6948–6950. 34. Peng Z, Freunber ger SA, Chen Y , Bruce PG. A reversible and higher-rate Li-O2 battery. Science . 2012;337(6094):563–566. 35. McGann LE, Walterson ML. Cryoprotection by dimethyl sulfoxide and dimethyl sul -
fone. Cryobiology. 1987;24(1):11–16. 36. Cox MA, Kastrup J, Hrubišk o M. Historical perspectives and the future of adverse reac -
tions associated with haemopoietic stem cells cryopreserved with dimethyl sulfoxide. Cell Tissue Bank . 2012;13(2):203–215. 37. Benekli M, Anderson B, Wentling D, Bernstein S, Czuczman M, McCarthy P. Severe 
respiratory depression after dimethyl sulphoxide-containing autologous stem cell infu -
sion in a patient with AL amyloidosis. Bone Marrow Transplant. 2000;25(12):1299–1301. 38. Petropoulou AD, Bellochine R, Norol F, Marie JP, Rio B. Coronary artery spasm after infu -
sion of cryopreserved cord blood cells. Bone Marrow Transplant . 2007;40(4):397–398. 39. Martino M, Morabito F , Messina G, Irrera G, Pucci G, Iacopino P. Fractionated infu -
sions of cryopreserved stem cells may prevent DMSO-induced major cardiac complica -
tions in graft recipients. Haematologica. 1996;81(1):59–61. 40. F ahmy MD, Almansoori KA, Laouar L, Prasad V , McGann LE, Elliott JA, Jomha 
NM. Dose-injury relationships for cryoprotective agent injury to human chondrocytes. Cryobiology . 2014;68(1):50–56. 41. Gonella S, Berchialla P , Bruno B, Di Giulio P. Are orange lollies effective in prevent -
ing nausea and vomiting related to dimethyl sulfoxide? A multicenter randomized trial. Support Care Canc . 2014;22:2417–2424. 42. Imaizumi K, Nishishita N, Muramatsu M, Yamamoto T, Takenaka C, Kawamata S, 
Kobayashi K, Nishikawa S, Akuta T. A simple and highly effective method for slow-
freezing human pluripotent stem cells using dimethyl sulfoxide, hydroxyethyl starch 
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Europe. J Geophys Res . 1999;104:8113–8152. 44. Berresheim H, Tanner DJ, Eisele FL. Real-time measurement of dimethyl sulfoxide in 
ambient air. Anal Chem . 1993;65(1):84–86. 45. A vgoustidi V , Nightingale P, Joint I, Steinke M, Turner S, Hopkins F, Liss PS. Decreased 
marine dimethyl sulfide production under elevated CO2 levels in mesocosm and in vitro 
studies. Environ Chem . 2012;9:399–404. 46. Bates TS, Lamb BK, Guenther A, Dignon J, Stoiber RE. Sulfur emissions to the atmo -
sphere from natural sources. J Atoms Chem . 1992;14:315–337. 47. Schneider SH. The greenhouse effect: Science and policy. Science . 1989;243:771–781. 48. Lucas DD, Prinn RG. Parametric sensitivity and uncertainty analysis of dimethyl -
sulfide oxidation in the clear-sky remote marine boundary layer. Atmos Chem Phys . 2005;5(6):1505–1525. 49. Harv ey GR. Dimethylsulfoxide and dimethylsulfone in the marine atmosphere. Geophys 
Res Lett . 1986;13:49–53.15
2DMSO in Basic 
Pharmacology
ABSORPTION, FATE, AND EXCRETION OF DMSO
Pharmacokinetics is the branch of pharmacology that deals with what the body does 
to administered drugs. The opposite of pharmacokinetics is pharmacodynamics, which deals with what the drug does to the body. Pharmacokinetics of a drug can be examined by administering the drug to animals or humans and obtaining blood, urine, and feces specimens for the quantitative analysis of the drug’s adsorption, metabolism, and excretion patterns. The rate of appearance and elimination of the drug in the bloodstream as well as the drug’s transformation into other compounds as it passes through the liver and excretion of the drug’s metabolites can then be recorded. The pharmacokinetics of dimethyl sulfoxide (DMSO) following its topical appli -
cation has been well studied. Findings show that DMSO has a wide distribution in tissue and body fluids. DMSO and its metabolite dimethyl sulfone are excreted in the urine and feces, while its second metabolite, dimethyl sulfide, is eliminated through the breath and skin and is responsible for the characteristic garlic  odor that 
is noticed after DMSO application. Dimethyl sulfone can persist in serum 2 weeks after a single intravesical instillation. No residual accumulation of DMSO occurs after its prolonged use. 1
Human volunteers were given DMSO orally and dermally at a dose of 1 g/kg as 
a 70% aqueous solution. DMSO was quickly absorbed when administered dermally. Peak serum levels occurred after 4–8 h. Orally administered DMSO was rapidly absorbed, reaching a peak serum level after 4 h. Unchanged DMSO and its metabo -
lite dimethyl sulfone appeared in the serum after about 48 h and persisted for as long as 2 weeks. Urinary excretion of DMSO after dermal and oral administration was approximately 13% and 30%–68% of the dose, respectively. Renal clearance of DMSO was about 14 mL/min. 2
Topical application of radioactive 35S-DMSO in humans can be observed in blood 
after 5 min and in bones 1 h later.3
Radioactive 35S-DMSO was orally administered to rats. Animals were killed 
at specific times, and the tissues were assayed for total radioactivity.4 All tissues 
showed radioactivity after 30 min. Plasma, kidney, spleen, lung, heart, and testes seemed to have higher levels than liver, fat, small intestine, brain, skeletal muscle, and red cells. Concentrations in the testes, skeletal muscle, heart, and brain increased 
after 30 min but remained virtually constant in other tissues. Levels of DMSO had 
declined to minimal values in all tissues after 24 h.
4 The ratio of dimethyl sulfone to 
DMSO 4 h after oral administration of 35S-DMSO was found to be virtually constant 16 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
in liver, testes, kidney, spleen, small intestine, heart, and plasma.4 The lowest levels 
of 35S-DMSO were found in the lens of the eye. The half-life of 35S-DMSO was 
prolonged in hard tissues, and virtually no radioactive DMSO is found in any tissue 
1 week after the last dose of a single or repeated administration.4
Rhesus monkeys were given daily oral doses of 3 g DMSO/kg for 14 days, and 
its major metabolite, dimethyl sulfone, was measured in serum, urine, and feces by gas–liquid chromatography. 5 DMSO was quickly absorbed and reached a steady-
state blood level after 24 h and then was cleared from blood within 72 h after treat -
ment ended. Serum DMSO declined in a linear fashion as described by second-order kinetics. 5 Dimethyl sulfone half-life in serum was calculated to be 38 h and appeared 
in blood within 2 h, reaching a steady-state concentration after 4 days of treatment. Following DMSO administration, dimethyl sulfone was cleared from serum after 120 h. Urinary excretion of unmetabolized DMSO and dimethyl sulfone accounted for about 60% and 16%, respectively, of the total ingested dose. 5 The absorption of 
DMSO by monkeys appears similar to that for humans, but its conversion to dimethyl sulfone and its urinary elimination are more rapid in monkeys. 5
PENETRATION
There are four principal variables that influence the penetration of a solute through any given membrane: (1) the diffusion coefficient through the membrane, (2) the con -
centration of the agent in the vehicle, (3) the partition coefficient between the mem -
brane and the vehicle, and (4) the thickness of the membrane barrier. 6 Penetration 
agents are designed to affect one or more of these variables without causing perma -
nent structural or chemical modification of the physiological barrier. Alteration of membrane thickness is less practical for drug delivery (it is difficult to conceive of nontoxic agents that could reversibly decrease the thickness of the stratum corneum), so most penetration agents, including DMSO, attempt to reversibly alter variables 1–3 given earlier. There is some evidence to suggest that DMSO can increase diffusion through the 
stratum corneum by disruption of the barrier function. 7 This probably occurs through 
aprotic interactions with intercellular lipids and may also include reversible distor -
tion of lipid head groups that produce a more permeable packing arrangement.8,9 
DMSO may play a role in partitioning as well by forming solvent microenvironments within the tissue that can effectively extract solute from vehicle. Finally, DMSO can have a profound solubilizing effect on less soluble agents in a variety of vehicles, increasing penetration simply by delivering a higher concentration to the membrane barrier. 10
CHEMICAL CHAPERONES
The actions of DMSO as a chemical chaperone are discussed in Chapter 1. Chemical 
chaperones such as DMSO, glycerol, trimethylamine n-oxide, and other small mol -
ecules have been found to stabilize and help in the folding of proteins.11
Chemical chaperones differ from molecular chaperones, which are small molecules 
found in the endoplasmic reticulum. These chemical chaperones also differ from 17 DMSO in Basic Pharmacology
pharmacological chaperones, which are small synthetic molecules that can induce 
 correct  folding by binding to the hydrophobic domains of a given protein in an adenos -
ine triphosphate (ATP)-dependent fashion.12 The older the cell, the more difficult it is 
to cope with protein misfolding.13 Whether DMSO can also act as a pharmacological 
chaperone has not been determined. Although DMSO has not been used extensively 
in misfolded protein diseases, it may offer some hope as a treatment due to its osmo -
lytic activity in preventing aggregate formation in neurotoxic gain  disorders such as 
Alzheimer’s disease (deposition of amyloid-β  peptide in brain tissue and neurofibril -
lary tangles within neurons), Parkinson’s disease (deposition of aggregated α -synuclein 
in Lewy bodies), scrapie or mad cow disease (pathological prion protein production), and Huntington’s disease (excessive number of CAG repeats in the huntingtin gene). It follows that if DMSO is successful in treating neurotoxic gain disorders, it could 
also be useful in loss-of-function  diseases such as nephrogenic diabetes mellitus, 
Gaucher’s disease, Fabry’s disease, and cystic fibrosis. 14 Loss-of-function disorders 
are generally caused by missense point mutations. Examples of point mutation disor -
ders are sickle-cell disease and amyotrophic lateral sclerosis. Loss-of-function muta -
tions can alter the normal folding proteins and lead to their degradation, a process that could be blocked by DMSO and by the cell’s ability to try and stay healthy. 14 
Toxic gain disorders involve proteins that fail to fold into their normal configuration, and in their misfolded state, they can become toxic in some way and quickly aggre -
gate, leading to the formation of inclusion bodies that eventually result in cell death. 15
DMSO AS A PAIN MEDICATION
Many ancient cultures believed that pain was a test of faith or a punishment by the gods for human folly. The remedy for pain was to appease the wrath of gods with magic, rituals, or sacrifice of animals and humans. Ancient philosophers considered pain to be an emotion. Aristotle in his 
Nicomachean Ethics  saw pain not as an internal noxious sensation but as spirits 
entering the injured body to affect the soul. This explanation that pain was an exter -
nal force that entered the body and could be treated by prayer endured for centuries. This thinking was partly replaced by the seventeenth-century discoveries of a mech -
anistic theory to explain pain. One of the earliest expositions of pain mechanics were the descriptive 1644 writings of the French philosopher and mathematician René Descartes, who proposed a more pragmatic approach to pain. Descartes correctly believed that pain did not come from the outside but rather within the body where it traveled through nerves to the brain. Pain is the most common reason for people to seek medical help and is a major 
presenting complaint in a multitude of medical conditions and disorders. It has been common knowledge for thousands of years that acute or chronic pain can signifi -
cantly interfere with a person’s quality of life and normal daily function. Woolf
16 has described three types of pain. First, there is nociceptive  pain, which 
acts as an early warning, protective system that can feel a harmful stimulus, such as an object that is too hot or cold, or too sharp, and react to minimize the pain. The second type of pain is inflammatory  and occurs when there is tissue injury, for 
example, with an inflamed joint, a local or systemic infection, or following surgery. 18 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
This type of pain is adaptive in the sense that the individual limits the movement of 
the body part in pain in order to shorten the duration or the degree of the pain and accelerate its eventual recovery. The third type of pain is pathological. Pathological pain is not adaptive or pro -
tective  as in types 1 and 2 but results from tissue damage affecting the nervous 
system. 16 This type of pain can occur in the absence of inflammation or noxious 
stimuli and may persist for a long duration when stimuli are excessively intense or prolonged. The quality of pathological pain can be severe or moderate and may inter -
fere with sleep or daily function. At the same time, pain can downgrade the health and psychological well-being of the individual. 17
Pain killers, particularly opioid drugs, are the leading cause of unintentional over -
dose deaths in teens and adults, and according to the Centers for Disease Control and Prevention (CDC), such deaths have reached epidemic proportions in the United States. The number of unintentional drug poisoning deaths exceeds either motor vehicle accidents or suicides, two of the leading causes of death in the United States. 18 
One of the reasons for easily overdosing and dying from narcotics is their powerful action as central nervous system (CNS) depressants, especially when the narcotic is combined with alcohol or another pain medication. 19
For these reasons, an analgesic medication with a high margin of safety, which 
lacks CNS depressant activity and is void of the danger of unintentional overdose and death, has been an elusive Golden Fleece quest by the pharmaceutical industry and by academic and government-sponsored research. These pharmacological properties in an analgesic agent and avoidance of death 
by overdose appeared to have been solved in 1964 when Jacob et al. 20 first reported 
on the local analgesic potential of DMSO in humans. The use of DMSO as a pain medication in humans is discussed in detail in Chapter 3. The basic biological actions of DMSO as a pain medication using animals will be 
reviewed here. Although there is extensive literature on the pain mechanisms exerted by DMSO in animal models, its physiological and pharmacological properties are incompletely understood. It should be pointed out that there is considerable difficulty in using methods 
that can accurately characterize pain sensibility more so in animals than humans with respect to its quality, intensity, and duration, and this fact makes it challenging to discover treatments that truly improve the outlook of patients with pain. A case in point is the thousands of papers written on brain endorphins in the past three decades where great hope for controlling pain was overshadowed by the fact that not one effective treatment emerged from this vast field of research. In experimental pain research, there are two common techniques used in 
rodent models to evaluate potential analgesic agents, the tail flick test and the hot plate test. The tail flick test measures a rodent’s pain response to a light beam focused on the animal’s tail and the time for the tail to flick that is recorded as the pain threshold. 21 In the hot plate test, the rodent is placed on a warm plate, 
and temperature is increased until a thermal nociceptive response is observed, indicated by the animal rapidly licking or flicking its hind paws. 22 In these tests, 
a baseline latency response without the analgesic agent is first obtained and com -
pared to the latency following administration of the agent to be tested.19 DMSO in Basic Pharmacology
Following clinical reports on the action of DMSO to relieve pain in humans,20,23–28 
animal research was begun to answer multiple questions regarding whether DMSO 
was an analgesic agent and, if so, how it worked. One early study to address some of these questions was reported by Haigler and 
Spring.29
Using the tail flick and hot plate tests, these investigators applied two criteria to 
determine (1) if DMSO had analgesic properties and, if so, (2) whether the analgesic effect observed with DMSO was related to opiate receptors. It was found that animals given DMSO IV and IP at high doses (5.5 g/kg), and 
administered topically on the tail, produced a profound analgesia on both the hot plate and tail flick tests. 29
The analgesic effect obtained with DMSO was apparently not due to a general 
anesthetic effect because the rats were not ataxic and did not lose their righting reflex. By contrast, morphine given 10 mg/kg intraperitoneally produced an anal -
gesic effect as frequently as DMSO on the hot plate, but the duration of morphine analgesia was typically less than 2 h both on the hot plate and on tail flick. The anal -
gesic time course for DMSO was longer than that for morphine and, in several rats, lasted over 24 h. Additionally, the analgesic effect by morphine, but not by DMSO, was blocked with the opioid antagonist naloxone indicating that the analgesic action on pain receptors by DMSO and morphine differed significantly. 29
If the analgesic action of DMSO was not achieved by blocking morphine recep -
tors, how was pain relieved in animals or humans? The answer remained unsettled until 1993, when Evans et  al.30 reported 
their findings in a study where 2%, 9%, and 15% DMSO was applied directly to exposed cat sural nerves. These unmyelinated sural nerves mediate somatic pain from C-fibers that terminate on the skin, muscle, and joint capsules. 31 It was 
found that C-fiber conduction velocity was slowed by 5% DMSO and was con -
centration dependent. At 9% concentration, DMSO completely blocked C-fiber conduction, and at 15% concentration, the onset of nerve block was virtually immediate
30 (Figure 2.1). The study by the Evans et  al.30 was an extension of 
previous findings by Sawada and Sato,32 who had reported that the mechanism 
involved in the nerve conduction block induced by DMSO appeared to be due to potassium channel blockade. These investigators observed that DMSO caused a rapid membrane depolarization and decrease in membrane conductance of Aplysia  neurons, a finding consistent with the blockade of potassium leak chan -
nels. 32 These leak potassium channels function to set the negative membrane 
potential of neurons. They differ from voltage-gated channels because they are always open to the passage of sodium and potassium ions across the membrane whereas voltage-gated channels open and close in response to specific changes in the membrane potential. How DMSO specifically affects potassium channel depolarization has not been made 
clear, but Davis et al. 33 found that 50% DMSO was necessary to block muscle twitch 
in a frog sciatic nerve-gastrocnemius muscle preparation. Interestingly, Becker et al.34 
found that 75% DMSO blocked both myelinated A-delta and unmyelinated C-nerve fibers (Figure 2.1). In a study of small fiber afterdischarge in spinal cord, medulla, and tegmentum following stimulation of the superficial radial and sural nerves, Shealey
35 20 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
also found blocking of pain impulses by exposing the peripheral nerve to 5%–10% 
DMSO, a result that they concluded might be due to blockade of C-fibers. The effects of DMSO and a DMSO-containing saline solution were used on 
 thermal- and chemical-induced nociception and inflammation, and the locomotor 
activity after treatment was evaluated in CD1 mice.36 This mouse type is a multi -
purpose research animal model that can be used in such fields as toxicology to test safety and efficacy of drug products, and on in vivo  nerve preparations. Centrally or orally administered DMSO was shown to display anti-  n ociception 
to thermal (hot plate and tail flick test) and chemical (formalin test) stimuli.36 
Additionally, oral and central, but not local, administrations of DMSO were seen to improve locomotor activity in the CD1 mice. 36
Thus, the collective evidence on the analgesic effects of DMSO in reducing pain 
sensation differs from that of complete anesthesia since it appears to involve block -
ade or partial blockade of A-delta fibers that mediate acute sharp pain as well as C-fibers that mediate somatic signals involving temperature, sensual touch, and muscle and joint pain. This evidence implies that DMSO could be useful in mus -
culoskeletal aching pain and sharp arthritic pain impulses, which are conveyed by lightly myelinated A-delta fibers, and somatic pain mediated by C-fibers. The merit of this conclusion will be further examined in Chapter 3. The effects of DMSO on these experimental pain-related conditions offer the potential by DMSO to reduce or abolish pain by mechanisms ostensibly distinct from the opioids and the dangers posed by narcotic prescriptive agents. Another possible mechanism exerted by DMSO on pain receptors may be its 
effect on the excitotoxic expression of voltage-gated sodium channels and glutamate, NMDA ( N-methyl- d-aspartate), and AMPA ( α-amino-3-hydroxy-5-methylisoxazole-
4-propionate)
37 as suggested by Hoang et al.38
Sodium channels are located in all sensory neurons, and some sodium chan -
nels that are sensitive to tetrodotoxin are found only on nociceptive-related sensory 
DMSO action in pain relief
DMSO bl ocks conduction
Spinothalamic
Anterior spinothalamic 
tractC-fiberA-delt a
fiber
Lateral 
spinothalamic trac tFree nerve 
ending: 1° afferent
terminals in skin
FIGURE 2.1  (See color insert. ) DMSO topical application can block both myelinated 
A-delta and unmyelinated C-pain fibers.30,34 See text for details.21 DMSO in Basic Pharmacology
neurons implicated in pathological pain states.38 Lidocaine, for example, is a widely 
used local anesthetic that functions through the blockade of sodium channels, a 
mechanism distinct from the opioids.39
Since DMSO is reported to have an effect on blocking sodium and calcium ion entry 
into cells40,41 and several research groups have shown that cancer-related neuropathic 
pain42,43 has an underlying mechanism involving membrane hyperexcitability due to 
overexpression of sodium channels and glutamate buildup stemming from the upregula -
tion of NMDA/AMPA pathways, it has been suggested that DMSO could be used as a primary or adjuvant analgesic agent in controlling pain in advanced cancer patients. 38
ANTI-INFLAMMATORY
Inflammation is a localized and complex protective reaction by the organism to remove damaging stimuli by removing offending factors and mobilizing molecules responsible for the healing process. The damaging stimuli can involve, but are not limited to, adhesion molecules, neutrophils, complement, IgG, irritants, dying cells, or pathogens. Inflammation is implicated in the pathogeneses of arthritis, cancer, and stroke, as well as in neurodegenerative and cardiovascular diseases. The acute phase of inflammation is characterized by the rapid influx of blood granulocytes, typically neutrophils, followed swiftly by monocytes that mature into inflammatory macrophages that can subsequently proliferate and cause tissue damage. When the inflammation occurs at or just under the skin, the characteristic signs of inflamma -
tion are pain (dolor), heat (calor), redness (rubor), and swelling (tumor), responses that can lead to scarring and loss of organ function. A classical and popular model of inducing experimental inflammation and hyper -
algesia from edema formation is the carrageenan-induced inflammation in the rat paw. This model has been used extensively in the development of nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 (COX-2) inhibitors. 44
Evidence indicates that the COX-2-mediated increase in prostaglandin E2 (PGE2) 
and prostaglandin I2 (PGI2) production contributes to the severity of the inflamma -
tory and pain responses in this rat paw model.45
Carrageenan-induced inflammation in the rat paw was used by Formanek and 
Kovak46 and later by Görög and Kovács47 to demonstrate the anti-inflammatory 
action of DMSO applied to the edematous rat paw. These investigators showed a significant reduction in paw and limb edema after topical DMSO application, but no biochemical explanation was available to explain how DMSO exerted its action. The anti-inflammatory actions of DMSO generated suspicion that its therapeutic benefit could be explained by its activity on prostaglandin pathways since it was well known that prostaglandins play a key role in the generation of the inflammatory response. PROSTAGLANDINS
It remained for Panganamala and his research team48 in 1976 to show that 
DMSO had an effect on prostaglandin biosynthesis. Using a liver microsomal preparation, DMSO was seen to stimulate PGE
1 and inhibit PGF2α by blocking 
arachidonic-acid-induced platelet aggregation, a reaction involving endoperoxide 22 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
metabolites, PGE2, thromboxane A2 (TXA2), and PGI2.48 These authors concluded 
that anti-  i nflammatory properties shown by DMSO in these studies were likely due 
to its hydroxyl radical–scavenging ability and inhibition of prostaglandin synthesis.48
Prostaglandins and TXA2 are collectively called prostanoids, which form when 
arachidonic acid, a 20-carbon unsaturated fatty acid, is released from the plasma 
membrane by phospholipases and metabolized by the sequential actions of pros -
taglandin G/H synthase or cyclooxygenase (COX).40 Prostaglandin production 
remains very low in uninflamed tissues, but when acute inflammation occurs, it increases immediately prior to the recruitment of leukocytes and the infiltration of immune cells. The presence of TXA
2 in blood will cause strong vasoconstriction and platelet 
aggregation, while the formation of PGF2α, or PGE2, will also negatively affect the 
vascular and platelet systems, but the reaction will not be as severe as with TXA2.49
There is presently considerable evidence that the resulting inhibition of PGF2α, 
PGE2, and TXA2 synthesis has the effect of reducing inflammation, as well as pro -
moting antipyretic, antithrombotic, and analgesic effects. The effects of PGE1 and 
PGE2 on platelet function are believed to be mediated through prostanoid receptors 
that are linked to the control of intracellular levels of cAMP. The outer cell membranes of bovine corpora lutea are reported to contain discrete 
and specific receptors for PGE1 and PGF2α.50 Preincubation of membranes for 1 h  
at 4°C with increasing concentrations of DMSO resulted in a progressive inhibition of [
3H]PGF2α binding but had no effect on [3H]PGE1 binding.51 It should be noted 
that PGE1 and PGE2 are known to modify platelet function. PGE1 has been shown 
in many studies to inhibit platelet aggregation in a concentration-dependent man -
ner.52,53 In contrast, the effects of PGE2 are less consistent and have been reported 
to either stimulate or inhibit platelet aggregation depending on the concentration of PGE
2 and the conditions used.54
The action by DMSO on PGI2, PGE1, and PGF2α led de la Torre55 to theorize that 
DMSO may play an important clinical role in neutralizing tissue injury by acting on prostaglandin pathways (Figure 2.2). Assuming the tissue injury is of sufficient mag -
nitude, one of the initial molecular reactions to occur in the body is an immediate reduction of oxygen delivery to the tissue. As this happens, mitochondrial oxidative phosphorylation is negatively affected and results in a reduction of ATP, the major source of cellular energy. As ATP concentration decreases, sequestered calcium is released to activate mitochondrial and microsomal phospholipases. The phospholipases chemically attack long-chain phospholipids, thus uncoupling 
esterified free fatty acids. At the same time, inhibition of mitochondrial oxidation results in hypoxia and further buildup of free fatty acids. Polyunsaturated free fatty acids provide the substrate for conversion to prostaglandins. PGI
2 (prostacyclin) and, 
to a lesser extent, PGE1 act as vasodilators and platelet deaggregators. The antiplate -
let aggregation activity by  PGI2, and PGE1, results from its increase in cAMP levels 
in platelets (Figure 2.2).56,57
Therapeutic use of PGE1 has been shown to have anti-ischemic and anti-  
inflammatory effects on patients with cardiovascular disease, such as in peripheral arterial occlusive disease. 58,59 Also, it has recently been proposed that naturally 
occurring PGE1 may have a modulatory role in the development of atherosclerosis.60 23 DMSO in Basic Pharmacology
By contrast, studies in mice have revealed that PGE2 is released from inflamed ves -
sels and atherosclerotic plaques,61 and evidence indicates that PGE2 is involved in 
platelet thrombus formation,62 making this prostaglandin a possible therapeutic tar -
get for stroke or cardiac thrombosis prevention. One of the first observations that noted DMSO’s anti-inflammatory properties 
used ultraviolet light (PUVA) to produce an inflammatory reaction that killed or 
reduced proliferation of epidermal melanocytes whose role is to protect the skin against ultraviolet radiation. In a mice skin model exposed to prolonged PUVA known to induce a strong inflammatory reaction, DMSO application to the skin increased the numerical density of pigmented cells, thus allowing better recovery of the inflammatory response. 63
Epithelial cell injury under hyperinflammatory conditions is critical in the 
development of septic acute lung injury (ALI). A model of ALI using the human alveolar epithelial cell line A549 was created to test the cytoprotective effects of 
anti- i nflammatory agents, including DMSO.64 It was found that 0.02% DMSO acted 
as a powerful antioxidant, attenuating a cocktail of cytotoxic mediators made up of IL-1β/TNF- α/IFN- γ exerted from the A549 cancer cell line. 64
The effects of DMSO on inflammatory cytokines have been reported in intesti -
nal cells exposed to a variety of inflammatory cytokines in vitro .65 DMSO at 0.5% 
was shown to significantly decrease mRNA levels of inflammatory proteins, includ -
ing IL-6, IL-1 α, IL-1 β, and dose dependently reduced COX-2-derived PGE2.65 In 
addition, DMSO decreased the production of IL-6 and macrophage chemoattrac -
tant protein-1 (MCP-1) secretions, both in a dose-dependent manner in the intestinal cells. 65 MCP-1 is a major chemokine responsible for inducing macrophage migration 
and appears to play several roles in tumor growth and metastasis.Eﬀects of DMSO on prostaglandin pat hways
DMSO
Prosta cyclin synthesis
cAMP
Incre ases
Vasodila tionPGI2, PGE1 Platel ets TXA2, PGE2, PGF2αDeaggregation Aggregation/T_hrom boxane synthesis
VasoconstrictionStimulatesInhibits
FIGURE 2.2  Presumed actions of DMSO based on experimental evidence derived from 
experiments on the prostaglandin–thromboxane (PG–TX) and platelet systems. DMSO stim -
ulates prostacyclin synthase to form prostacyclin (PGI2), a powerful platelet deaggregator and 
vasodilator. DMSO has been shown to antagonize the synthesis or release of TXA2, PGF2α, 
and PGE2 to counteract their effect of platelet aggregation and vasoconstriction in model 
systems. The antiplatelet aggregation activity by PGI2 and PGE1 is reported to result from a 
stimulating increase in platelet cAMP levels by DMSO. See text for details.24 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
Plasma cholesterol and bile acid metabolism were significantly reduced by 2% 
DMSO treatment in the drinking water for 9  days, a finding consistent with the 
reduced CH-7 alpha-hydroxylase activity, the rate-limiting enzyme of bile acid bio -
synthesis in the treated rat group.66 Although the exact mechanism for this action by 
DMSO on cholesterol and bile production is unclear, it did not affect either micro -
somal cholesterol content or hepatic glutathione content.66
These actions by DMSO on toxic cytokines could be a major clue as to its action 
as a pain reliever and powerful anti-inflammatory agent. In addition, the complex interactions of DMSO in prostaglandin biosynthesis and production have important implications in cerebral and cardiac physiology. CARDIAC DISEASE
The human heart receives about 1/20th of cardiac output under basal conditions, and when this blood flow delivery is reduced or compromised, cardiac damage or death can occur. Several intriguing studies have examined the effects of DMSO on experi -
mental myocardial infarction and cardiac hemodynamics. One early study 
reported that DMSO provided significant protection of rat heart exposed to 
 reoxygenation-induced cell injury.67 This model of anoxic injury to cardiac cells 
involves perfusing the heart with an anoxic perfusate followed by reoxygenation 
with an oxygen perfusate, a technique that induces a rapid release of oxygen–  
creatine kinase (CK), causing reduced coronary flow and severe cardiac con-traction with the formation of contraction bands. Prior to reoxygenation, 10% DMSO was given by mixing it with the anoxic perfusate, an action that resulted in increased coronary flow rate, a marked reduction of the oxygen–CK release, and a significant decrease in the number of contraction bands from 43% in con -
trol hearts to 23% using DMSO. 67 This study indicated that DMSO has the poten -
tial to protect cardiac tissue from a hypoxic insult, an ability that could be useful in cardiac ischemia or heart failure. One of the actions of DMSO in the ischemic myocardium is to aid in the diffusion 
of oxygen into the thick myocardial tissue, thus aiding the myocyte protection from anoxia or ischemia. 68
The effects of DMSO infusion on a canine model of myocardial ischemia and 
systemic hemodynamics were reported by Levett et al.69 Hourly measurements of 
cardiac output, pulmonary wedge pressure, pulmonary artery pressure, heart rate, mean arterial pressure, cerebral blood flow, intracranial pressure, and blood gases were monitored before and after the ligation of the left descending coronary artery. After 15 min of coronary artery ligation, control saline or 500 mg/kg of a 50% DMSO solution was injected as an intravenous (IV) bolus. 69 By the third hour after 
ligation, cardiac output increased significantly, and both systemic and cerebrovas -
cular resistances decreased in the DMSO-treated animals as compared to controls. CBF also increased after DMSO but not in controls, and there were no significant 
differences in heart rate, mean arterial pressure, pulmonary artery wedge pres -
sure, or cerebral or pulmonary resistances in the control as compared to the DMSO group. 69 This study concluded that DMSO infusion in a canine model of myocardial 25 DMSO in Basic Pharmacology
ischemia has protective activity and merits further evaluation by extending the time 
course after infarction to a more realistic clinical setting.69
The study by Levett et al.69 recently received confirmation using a rat model of 
acute myocardial infarction caused by left anterior descending coronary artery liga -
tion.70 Before myocardial infarction was induced, 500 µL/kg of DMSO was given 
intraperitoneally daily for 3 days with the last dose given 15 min before ligation.70 
After 90 min of occlusion, postmortem examination showed markedly less cardiac damage reflected by a reduction of mean necrotic volume in the infarcted left ven -
tricular wall area and by significantly lowered levels of the cardiac injury markers troponin I and myoglobin, as compared to controls. The mechanism by DMSO in protecting cardiac tissue from ischemic injury remains unsettled but appears to be similar to its protection of focal ischemic brain tissue following occlusion of the middle cerebral artery in rats. 71
A review of the experimental cardiac effects of DMSO may provide some clues.72 
For example, DMSO can produce either positive or negative inotropic effects on car -
diac tissue depending on the dose used and animal species and specific cardiac tissue studied. 73 Myocardial tissue preparations using 70 mM DMSO concentration or less 
will increase positive inotropic contractile response, while using more than 70 mM concentration, the inotropic effect will be species dependent. 74 Moreover, none of the 
contractile effects of DMSO is antagonized by blocking beta-adrenergic receptors or by blocking other classical myocardial receptors at doses that do not intrinsi -
cally alter cardiac contractility. 75 In isolated atrial preparations, DMSO decreases 
contractile rate without appreciably altering cardiac rhythm. However, when the DMSO concentration is above 140 mM, a concentration not likely to be used in vivo , 
both rate and rhythm are decreased possibly by DMSO’s effect on acetylcholinergic response to slow down conduction via the atrioventricular node. 74 However, these 
effects on the myocardium are reversible when DMSO exposure stops. A reduction of systemic vascular resistance and an increase in cardiac output 
were found after slow DMSO infusion at a dose of 2 g/kg 50% solution in canine myocardium. 76 These values were temporary and returned to normal 10 min after 
DMSO infusion had been completed although cardiac output remained high for sev -
eral hours when compared to saline control infusions.76 These findings were consid-
ered to result from a possible transient expansion of plasma volume that increased cardiac preload and cardiac output and could be relevant in treating hypovolemic patients with clinical brain injury or cardiac ischemia. 76
The case for using DMSO as a primary agent in the clinical treatment of myo -
cardial infarction and coronary artery ischemia or hypoxia can be argued by not -
ing some of the specific properties reported for this drug. These cardiac conditions diminish blood flow to the heart either by coronary vessel narrowing due to platelet aggregation on vessel walls or by atherosclerotic epicardial plaque-related stenosis. Present treatments for these conditions include coronary vasodilators such as rano -
lazine and nitrate preparations, platelet deaggregators such as aspirin or clopidogrel 
bisulfate, coronary artery balloon angioplasty or stenting, and coronary artery bypass 
surgery. Other pharmacological treatments such as calcium channel blockers, beta blockers, angiotensin-converting enzyme inhibitors, cholesterol-lowering drugs, and angiotensin receptor blockers may be useful in long-term therapy, but they do not 26 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
reverse coronary artery ischemia or myocardial infarction acutely. DMSO addresses 
an important aspect related to the pathology seen in coronary artery ischemia. First, DMSO, as we have reviewed earlier, is a powerful platelet deaggregator. A report by Pace et al.77 showed that when DMSO was used as a solubilizing agent 
to test the potential of cardiac anti-aggregatory drugs in experimental coronary artery stenosis, it was discovered that the active agent was DMSO, not the drugs that were tested. When used alone, DMSO was observed to reverse the reduction of coronary blood flow induced by a critical stenosis on the canine circumflex coronary artery without changing other hemodynamic measures in the animals tested. 77 These findings suggested that DMSO acted a platelet deaggregator in 
reversing the coronary artery stenosis that allowed platelet aggregation and low -
ered coronary blood flow. The findings by Pace et al.77 were confirmed by Dujovny 
et  al.,78 who reported scanning electron microscopic examination of rat carotid 
artery–induced occlusion induced by arteriotomy and suture closure where the formation of heavy platelet deposits, fibrin, and red blood cell clumps at the arteri -
otomy site collected. The administration of DMSO 2 g/kg slowly infused intrave -
nously resulted in minimal signs of fibrin clumping and platelet deposition at the carotid artery suture line. 78 The platelets appeared spherical with no pseudopod 
formation, while the adjacent endothelium appeared intact in contrast to control non-DMSO-treated animals who showed heavy platelet deposits and fibrin and erythrocyte clumping. 78
We have discussed the antiplatelet action of DMSO from the studies of 
Panganamala et al.,48 who showed that DMSO inhibited arachidonic-acid-induced 
platelet aggregation possibly by inhibiting prostaglandin biosynthesis, particularly PGE
2. Holtz and Davis79 and Harrison et al.80 have suggested that DMSO is a sulf -
hydryl inhibitor and that this action prevents platelet-to-platelet bonding, whereas Wieser et al. 81 showed that DMSO could increase cyclic AMP by inhibiting phos -
phodiesterase in a non platelet system (Figure 2.2). DMSO was found to inhibit the cardiac hypertrophy, anemia, and depression in a model of copper deficiency of the heart. This finding suggests that the hydroxyl radical–scavenging ability by DMSO may contribute to the protection of cardiovascular defects caused by dietary copper deficiency. 82
The second property DMSO possesses that may be useful in coronary artery 
pathology is its hydroxyl radical–scavenging action and its ability to function as an antioxidant and inhibitor of superoxide anion formation. 83–86
Oxygen-derived free radicals, such as the superoxide anion, hydrogen perox -
ide, and the hydroxyl radical, are implicated as mediators in myocardial injury and ischemia during reoxygenation of ischemic tissue. 87–89 The naturally occurring anti -
oxidant enzymes, superoxide dismutase and catalase, are reported to prevent the formation of the cytotoxic hydroxyl radical during physiological conditions but may not be able to cope with the free radical generation that follows ischemia and reperfusion. 90
The third property by DMSO that may be useful in cardiac ischemia serves as 
a sodium channel blocker. Heart muscle homeostasis depends on the optimal flux of Na
+ and Ca+ for its proper rhythmic contractions, and when an equilibrium of 
myocyte influx and efflux of these two ion species fails, it results in rhythm and 27 DMSO in Basic Pharmacology
contractile dysfunction (Figure 2.3). Drugs that prevent abnormal sodium influx into 
heart tissue provide an effective protection against Na+ and Ca+ overload. It has been 
reported that DMSO has an effect on blocking Na+ and Ca+ entry into cells.48,91 Since 
substantial Na+ and Ca+ entry into myocytes typically occurs after cardiac arrhyth -
mias and myocardial infarction, DMSO administration may prevent this inward cellular ion flux while preserving K
+ outflux from cardiac tissue. The mechanisms 
exerted by DMSO on Na+ and Ca+ channels need to be further investigated in mam -
malian models since the results of such studies could produce an extremely use -
ful and relatively safe agent for a variety of cardiac disorders affected by changes involving these cations. The fourth property shown by DMSO as a potential cardiac agent is its protective 
activity against tissue factor (TF) expression in human endothelial cells in response to tumor necrosis factor- α (TNF- α) or thrombin exposure
91 (Figure 2.3). There 
is general agreement that TF is a key protein in the activation of coagulation and thrombus formation. 92 This activation of thrombus formation and coagulation is a 
cause of acute coronary syndromes and myocardial infarction.93
High levels of TNF- α may result in acute coronary disease where it can induce 
increasing levels of TF in coronary vessels.92
DMSO was found to suppress, in a concentration-dependent manner, TF  e xpression 
and activity in response to TNF- α or thrombin exposure in human endothelial cells, 
monocytes, and vascular smooth muscle cells (VSM) in vitro .91 Moreover, it was 
additionally observed that DMSO prevented proliferation and migration of VSM from human aorta, an outcome that could have important clinical application in treating coronary thrombosis and myocardial infarction. 91
DMSO cardiac actions
Prevents VSM migr ation and proliferation
Inhibits  platelet agg regation af ter LAD oc clusio n
Blocks abnormal Na+ and Ca+ cell entr yBlocks tissue factor expressionRestores cardiac output and cerebral bl ood ﬂow
after LAD oc clusion
FIGURE 2.3  Cardiac actions reported following administration of DMSO. DMSO prevents 
the migration and proliferation of vascular smooth muscle cells (VSM) following cardiac ischemia, a common occurrence seen after heart attacks and stroke. Restoration of cardiac output is reported following occlusion of the lateral anterior descending (LAD) coronary artery, which mimics a heart attack. Tissue factor, a powerful cardiac thrombogen, is sup -
pressed by DMSO. DMSO may have salutary effects on injured cardiac tissue by blocking abnormal Na
+ and Ca+ influx into cardiac myocytes, preventing myocardial ischemia. See 
text for details.28 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
In vivo , DMSO treatment significantly suppressed TF activity and prevented 
thrombotic occlusion in the mouse carotid artery model subjected to a photochemi -
cal injury91 (Figure 2.3). In summary, DMSO combines four important properties that could be beneficial 
in cardiac disease: platelet deaggregation , sodium channel blocker , TF antagonist , 
and free radical scavenger and antioxidant . There is no drug therapy at the present time that combines these four properties 
shown by DMSO, thus giving this agent a novel therapeutic advantage as a potential 
treatment of coronary syndromes. As an antiplatelet agent, DMSO could have ben -
eficial effects in coronary artery disease by inhibiting blood clot formation and thus prevent vascular ischemic events involving atherosclerosis in the periphery as well as in the heart and brain vasculature. As a sodium channel blocker, DMSO may show usefulness in the treatment of cardiac arrhythmias. 94,95
DMSO’s antagonism of TF could prevent or treat clot formation in coronary 
syndromes as well as other disorders associated with TF elevation, such as hyper -
tension, diabetes, and dyslipidemia.93 Since these cardiac conditions involve tissue 
injury to cardiac cells, the formation of oxygen and hydroxyl radical formation is to be expected. DMSO, as a powerful free radical scavenger, may be pivotal as a primary or adjuvant therapeutic agent in controlling cytotoxic damage from radical formation. ULCERATIVE COLITIS
Current use of DMSO in inflammatory bowel disease is limited, and few studies are available in experimental intestinal disorders. Ulcerative colitis is a nonspecific inflammatory disease of unknown origin, aris -
ing in the colonic mucosa and clinically characterized by recurrent attacks of bloody diarrhea interspersed with asymptomatic intervals. Pathologically, the disease begins by a diffuse inflammation of the rectosigmoid area and may extend proximally to the entire colon. Crypt abscesses, mucosal ulceration, and epithelial necrosis eventually develop. There is no cure for ulcerative colitis, and treatment usually aims at the inflammatory aspect of the disease and the use of corticosteroids as immune system suppressants and with aminosalicylate preparations  as the main anti-inflammatory 
drugs. Free radicals such as DMSO have been tried for ulcerative colitis on the theory 
that oxygen-derived free radicals may be involved in the mechanism of this disorder and that removing these free radicals may result in the treatment of attacks and in protecting the colon against the recurrence of attacks. In a mouse model of colitis induced by dextran sodium sulfate, 500 µL of DMSO was reported to suppress the 
aggravation of the inflammatory response when given daily via the rectum to the mice for 7 days. 96 Inflammatory suppression by DMSO of experimental colitis may 
be due to its inhibition of superoxide radical formation generated by inflammatory 
cells.97 The damaging process could involve reactive oxygen metabolites generated 
intracellularly by either NADPH oxidase in the neutrophils or by xanthine oxidase, 
which is present in gut mucosa.98 This pathway seems to be a major source of oxygen 
free radicals in ischemic/reperfusion injury of the gut.9929 DMSO in Basic Pharmacology
SKIN PENETRANT
DMSO has been reported to enhance drug penetration, promote membrane transport, 
stabilize membrane integrity, improve percutaneous penetration, and accelerate drug absorption and drug effects. 100 The ability of DMSO to quickly and safely cross the 
dermal barrier when topically applied to the skin has been used in clinical medicine using DMSO alone or as a percutaneous carrier of other drug molecules. 101,102
Penetration of the skin by an active agent is dependent on the barrier function of 
the stratum corneum.103 Four variables influence the penetration of an active agent 
through any given membrane: (1) the relative diffusion coefficient through the mem -
brane, (2) the concentration of the agent, (3) the partition coefficient between the membrane and the agent, and (4) altering the thickness of the membrane barrier. 104 
Agents that penetrate the stratum corneum may affect one or more of these variables and, except for the fourth variable, can do so without causing permanent structural or chemical modification of the dermal barrier. Alteration of membrane thickness is less practical for drug delivery because of the damage it would cause to the stratum corneum, so most penetration agents, including DMSO, do so by relative diffusion coefficient through the membrane or by variables 1–3. 105
There is some evidence to suggest that DMSO can increase diffusion through the 
stratum corneum by the disruption of the barrier function.106 This probably occurs 
through aprotic interactions with intercellular lipids and may also include reversible distortion of lipid head groups that produce a more permeable packing arrangement. DMSO may also play a role in partitioning as well by forming solvent microenviron -
ments within the tissue that can effectively extract solute from vehicle. 107
WOUND HEALING
Matrix metalloproteinases, especially metalloproteinase-9 (MMP-9), degrade vari -
ous proteins of the extracellular matrix, including collagen type IV, the major com -
ponent of basement membranes that also separate the epidermis from the dermis. Limited activity of MMP-9 is essential, while excessive activity is deleterious to the healing process. The antioxidant effects of DMSO have been reported to be useful as a topical 
agent in the treatment of chronic wounds. The effects of DMSO on MMP-9 were studied in disordered wound healing using TNF- α to induce MMP-9 from human 
keratinocytes. 108 Results showed that DMSO inhibited the production of both MMP-9 
levels and MMP-9 mRNA expression when TNF- α-stimulated keratinocyte cells in 
a concentration-dependent manner. Inhibition of MMP-9 levels was statistically sig -
nificant at DMSO concentrations of 0.75% and higher.108 These findings suggest that 
DMSO may reduce the harmful effects of MMP-9 through downregulation at the transcription level and may be useful to prevent TNF- α-induced proteolytic activity 
in cutaneous inflammatory reactions. A systematic review looked at the efficacy of topical DMSO on wound healing 
of decubitus ulcers and its use as a topical anti-inflammatory drug. 109 The collec -
tive evidence reported indicates that the use of DMSO in these conditions was ben -
eficial, both for wound healing and for analgesia, while the toxicity was deemed to 30 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
be low. The most frequent outcome measures were reduction of erythema and rapid 
healing of ulcers, along with decreased signs of inflammation, such as rubor, dolor, calor, and tumor. DMSO was found to be dramatically effective for healing severe skin necrosis caused by accidental extravasation of the anticancer drug mitomycin C during IV administration. 110 This involved using 90% DMSO combined with a 
10% alpha-tocopheryl acetate applied prophylactically on the skin after extrava -
sation into the tissue of antineoplastic agents but before ulceration.110 This same 
combination of DMSO–alpha-tocopherol has been found to universally prevent severe ulceration and tissue breakdown in patients sustaining extravasation by a cytotoxic drugs, in most cases preventing skin ulceration induced by anthracy -
clines and mitomycin. 111
BURNS AND SCAR TISSUE
Partial-thickness burn wounds on rat abdominal skin were treated using 1% metro -
nidazole or 1% norfloxacin using a petrolatum base with 0.25% w/w DMSO. These formulations with DMSO as a base appeared more effective for wound contraction of the partial-thickness burn wound and against aerobic and anaerobic bacteria than a marketed formulation composed of 1% silver sulfadiazine cream. 112 Histopathology 
of the burn wound tissue confirmed the effectiveness of these preparations in treat -
ing the partial-thickness burn wound.112
As an antimicrobial applied topically to thermal burn wounds in rats, 1% w/vol 
DMSO mixed with 1% silver sulfadiazine showed better response than when 1% silver sulfadiazine was used alone possibly by potentiating the absorption of silver sulfadiazine across the mucosal membrane in the treated animals. 113
Antimicrobial photodynamic therapy (PDT) is able to photoinactivate microor -
ganisms produced by a light-activated photosensitizer (PS). PDT mediated by meso-mono-phenyl-tri( N-methyl-4-pyridyl)-porphyrin (PTMPP) to treat burn wounds in 
mice was used with 25% of 500  µM DMSO in mice with third-degree burn wounds 1 
day after being infected with bioluminescent Staphylococcus aureus . When a PDT–
DMSO–PTMPP mixture was used,
114 a substantial fluence-dependent reduction of 
the luminescence signal was obtained, indicating that more than 98% of the bacteria were eradicated. By contrast, PDT alone or light alone had no antimicrobial effect, and 500 μ M PTMPP in PBS had only a small light dose-dependent effect on reduc -
ing the luminescence signal and did not appear to have significant antimicrobial activity against S. aureus . 114 The effect of DMSO in this preparation was thought to 
have been to disaggregate the PS molecules and to increase the antimicrobial PDT efficiency by the light-activated PS. 114
Chemical burns have been treated with DMSO. Subcutaneous injections of 
20% calcium gluconate in a solution of 25% DMSO significantly slowed the progress of hydrochloric acid burn in rat hindquarters during the first 24  h, markedly reduced damage, and enhanced tissue recovery for the remainder of 
the observation period. 115 Subcutaneous injections of calcium gluconate–DMSO 
were found to be more effective in this chemical burn model than topical applica-
tion of this preparation.11531 DMSO in Basic Pharmacology
The anti-inflammatory and antioxidant effects of DMSO were tested in rats 
exposed to alkali-acid burns of the esophagus. The resulting corrosive esophagitis 
was treated with 10 mL/kg of a 10% DMSO solution given intraperitoneally 15 min following the corrosive esophagitis. 115a DMSO treatment was continued every 12 h for 
4 days, and the esophagi were removed postmortem after 7 days. Histopathological examination revealed that the alkali burn group treated with DMSO showed signifi -
cantly reduced inflammation than the control alkali burn group. When alkali and acid burn groups treated with DMSO were compared, there was more inflammation in the DMSO-treated acid burn group, but histological analysis still showed signifi -
cantly less damage than the acid control group. DMSO treatment also resulted in a significant decrease in the immunoreactivity of the oxidative stress marker nuclear factor-kappa B (NF- κB) in both the acid and alkali groups. 115a This study suggested 
that DMSO is a promising agent in the treatment of experimental corrosive esopha -
gitis possibly by suppressing NF- κB from rapidly activating transcription factors that 
express genes critical in the acute phase inflammatory response. Corneal alkali injury was induced in rabbits and treated with daily topical appli -
cations of 20% DMSO. Corneal opacification at day 3 and corneal ulceration were significantly lower in the treatment group than in the control group, but this effect was not sustained during the rest of the study period. 116
Not many studies have been reported on the effects of DMSO in scar formation. A study by Erk et al.117 reported that incubation of human scar with 99% DMSO 
showed disruption of collagen fibers and dramatic loss of periodic cross-striations when examined by electron microscopy. Scar tissue incubated with 50% DMSO showed only moderate loss of the periodic striations in the collagen fibers and no fiber fraying. 117 These findings have intriguing implications to limit or abolish unde -
sirable scar tissue in the clinical setting. DMSO treatment administered intraperitoneally to rats for 35  days decreased 
experimentally induced intestinal adhesions by 80% over controls as compared to saline, cortisone acetate, or a combination of cortisone and DMSO administered separately. 118
When administered next to a wound incision but not at the incision site itself in 
rabbits, 70% DMSO appeared to increase the development of wound tensile strength over controls. 119 Although 70% topical DMSO administered peripherally will also 
reduce local pain from the wound, effective pain analgesia with intrawound adminis-tration of very minute amounts of DMSO may be as effective or more so than periph -
eral wound administration. This intrawound application approach will be reviewed in detail later (see Section “Intrawound Administration of DMSO”). In 1968, McFarlane et al. 120 reported that DMSO could prevent necrosis in experi -
mental skin flaps by increasing blood perfusion to the ischemic region. This observa -
tion was followed by many articles since then, which have confirmed this finding.121 
The mechanism for the protective effect on skin flaps by DMSO remains to be clari -
fied, but one possibility may be the stimulation by DMSO of histamine, a strong 
vasodilator that could counter the vasoconstriction seen in dying skin flaps.122,123 
Another possibility is DMSO’s action as an antioxidant and free radical scavenger 
that would likely worsen the skin flap necrosis.32 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
Survival of skin flaps in surgery by preventing tissue necrosis is an important 
aspect of patient recovery. In one study, experimental skin flaps were elevated in 
rat abdomen, and the epigastric vein was occluded by a microvascular clamp for 8 h.
124 DMSO 1.5 g/kg was injected intraperitoneally only once at reperfusion or 
administered every day for 5  days. DMSO did not increase percent flap survival when given as a single dose at reperfusion compared with saline solution, but when given for 5 days at reperfusion and postoperatively, DMSO significantly increased flap survival. 124
In plastic surgery, a direct relationship between heavy smoking and flap necro -
sis is well known. As an antioxidant and vasodilator, DMSO was given orally at 2 mL/kg to rats with random skin flaps that had been exposed to nicotine. 125 
DMSO was shown to reduce the serum and skin levels of malondialdehyde, an indicator of oxidative stress in cells and tissues and a marker of lipid peroxidation, and to lessen the necrotic vasculopathy observed in controls following nicotine exposure. 125
The topic of scarification after physical injury of CNS tissue and the use of DMSO 
in scar formation will be further examined in Chapter 8. RESPIRATORY STIMULATION
The effects of DMSO and two analeptics, doxapram and ethamivan, were tested for their activity on respiratory minute volume (RMV) and respiratory rate in monkeys and rats. 126 These tests were inspired by the dramatic respiratory response of rhe -
sus monkeys given IV DMSO following experimental traumatic brain injury, which produced a short period of apnea due to severe brain swelling
127 (see Chapter 8 for 
details). In a subsequent experiment, 10 rhesus monkeys were lightly anesthetized with sodium pentobarbital (a respiratory depressant), intubated, and given an IV injection of 0.09% saline; DMSO, 2 g/kg in a 50% solution; doxapram, 0.8 mg/kg; or ethamivan, 5 mg/kg. Doxapram is a stimulant of central respiratory centers used clinically at low IV doses in patients with respiratory depression due to ingestion of excessive doses of narcotics. Doxapram is also indicated in preterm infants with prolonged periods of apnea 
that can lead to hypoxemia and neurological damage. 128 Doxapram is also used 
in pets presenting with acute respiratory problems associated with perioperative respiratory depression and neonatal hypoxia. Although not presently used any -
more, ethamivan is a respiratory stimulant drug related to nikethamide and was mainly used in the treatment of barbiturate overdose and chronic obstructive pul -
monary disease. 129
Adverse effects of these and other respiratory stimulants include hypertension, 
skeletal muscle hyperactivity, tachycardia, and generalized CNS excitation, includ -
ing seizures. One minute after DMSO injection in the monkey experiment, RMV and RR 
showed a sharp rise in RMV of 295% together with a rise in RR of 49% of the preinjection levels. The stimulating effects of DMSO on RMV and RR remained high for 25 min and reached preinjection levels after 50 min. Some animals treated with DMSO urinated copiously during this time. 127 Injections of doxapram also 33 DMSO in Basic Pharmacology
increased RMV to 300%, while RR rose 37% of baseline levels. Ethamivan injec -
tion stimulated RMV and RR only slightly, and the effect lasted only 2 min. These 
changes by ethamivan were accompanied by severe convulsions, arousal, and nys -
tagmus.126 No changes were observed on RMV or RR when physiological saline 
was injected. The results of respiratory stimulation by DMSO led to a second experiment to 
examine the effects of DMSO on experimental hypoxemia in rats. Rats were treated with intraperitoneal (IP) injections of DMSO 2 g/kg, doxapram 25 mg/kg, and etha -
mivan 10 mg/kg and were then exposed precisely for 210 s to pure nitrogen in a closed chamber. Each treated rat was paired with a saline control while in the nitro -
gen chamber. The results of this study are shown in Table 2.1. Survivors of nitrogen exposure experiencing acute hypoxia treated with DMSO were 18 of 20, with doxa -
pram 18 of 20, and with ethamivan 6 of 20. Saline-treated rats’ average for survival was 3 of 20 rats. 126
The effect of DMSO on hypoxemic rats revealed that this treatment was 
superior in keeping animals alive when compared to the well-known respira -
tory stimulant ethamivan and had similar effects as doxapram. When nitrogen exposure was increased to 215 s, DMSO-treated rats showed more resistance and better survival rate to hypoxic death than did doxapram-treated rats. The results of these studies on rhesus monkeys and rats undergoing either narcotic-induced respiratory depression or nitrogen-induced hypoxia indicate that DMSO admin -
istration may reverse respiratory distress in humans. This aspect is discussed further in the text. ACUTE RESPIRATORY DISTRESS SYNDROME
These experiments indicated that DMSO has the potential to quickly stimulate respi -
ratory centers in rats and nonhuman primates. These data were the basis for a study in humans presenting with acute respiratory distress syndrome (ARDS).
Dimethyl_Sulfoxide_(DMSO)_in_Trauma_and_Disease_[2015].txt
Summarize the following text section accurately and concisely. Maintain specific details and numerical information, and use anti-repetition mechanisms:

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Pharmacodynamics
What is the opposite of pharmacokinetics in pharmacology?
To examine the body's response to the drug and the drug's effects on the body
What is the purpose of pharmacokinetics in the study of a drug?
Inhibition of prostaglandin biosynthesis
What is the primary mechanism of DMSO's anti-inflammatory effects?
Inhibition of superoxide radical formation
What is the primary mechanism of DMSO's antioxidant effects?
To reverse respiratory distress in humans
What is the potential use of DMSO in treating respiratory distress syndrome?