Aspirin and methylsulfonylmethane (MSM): a search for common mechanisms, with implications for cancer prevention.

Anticancer Res. 2003 Jan-Feb;23(1A):453-8.

Ebisuzaki K.

Departments of Microbiology and Immunology and of Biochemistry, University of Western Ontario, London, Ontario, N6A-5C1, Canada. kebisuza@julian.uwo.ca

BACKGROUND: Aspirin (acetylsalicylic acid), a prototypic nonsteroidal anti-inflammatory drug (NSAID), and MSM, a "nutritional supplement", are both used in the treatment of arthritis and described as cancer chemopreventive agents. Initial experimentation indicating that aspirin and MSM also induced the differentiation of murine erythroleukemia (MEL) cells led to a search for common mechanisms involving these two agents. MATERIALS AND METHODS: Since the major mechanism of action attributed to aspirin is the inhibition of cyclooxygenase (COX), prostaglandin (PG) production was examined under differentiation-inducing conditions in MEL cells. RESULTS: Aspirin at low, nontoxic concentrations induced differentiation leading to terminal cell division. Aspirin had no effect on PGE2 production and minimal inhibitory effect on COX activity. Furthermore, salicylate, a major metabolite of aspirin and an ineffective COX inhibitor, induced differentiation at concentrations comparable to aspirin. Similar experiments with MSM indicated that MSM had no effect on PGE2 production or on COX activity under differentiation--inducing conditions and at concentrations reported in other studies. CONCLUSION: These experiments indicated that aspirin and MSM induced differentiation by a COX-independent mechanism(s) and suggested that a common mechanism for the chemopreventive action invoked by both agents might be the activation of gene functions leading to differentiation and thereby dismantling the cellular capacity for proliferation.

PMID: 12680248 [PubMed - indexed for MEDLINE]

Methylsulfonylmethane observed by in vivo proton magnetic resonance spectroscopy in a 5-year-old child with developmental disorder: effects of dietary supplementation.

J Comput Assist Tomogr. 2002 Sep-Oct;26(5):818-20.

Cecil KM, Lin A, Ross BD, Egelhoff JC.

Department of Radiology/MC 5031, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. cecil@athena.chmcc.org

Proton magnetic resonance spectroscopy (MRS) revealed a distinct resonance at 3.15 ppm in the brain of a 5-year-old male diagnosed with autism. The resonance assignment is attributable to ingestion of methylsulfonylmethane (MSM) as a dietary supplement. Glucosamine with MSM is marketed as a source of dietary sulfur and treatment of joint pain. Recognition of this chemical on brain proton MRS as an exogenous compound is necessary to avoid confusion as a pathologic metabolite of pediatric metabolic disease.

PMID: 12439321 [PubMed - indexed for MEDLINE]

Sulfur in human nutrition and applications in medicine.

Altern Med Rev. 2002 Feb;7(1):22-44.

Parcell S.

American Institute for Biosocial and Medical Research (AIBMR), Tacoma, WA, USA. steveparcell@attbi.com

Because the role of elemental sulfur in human nutrition has not been studied extensively, it is the purpose of this article to emphasize the importance of this element in humans and discuss the therapeutic applications of sulfur compounds in medicine. Sulfur is the sixth most abundant macromineral in breast milk and the third most abundant mineral based on percentage of total body weight. The sulfur-containing amino acids (SAAs) are methionine, cysteine, cystine, homocysteine, homocystine, and taurine. Dietary SAA analysis and protein supplementation may be indicated for vegan athletes, children, or patients with HIV, because of an increased risk for SAA deficiency in these groups. Methylsulfonylmethane (MSM), a volatile component in the sulfur cycle, is another source of sulfur found in the human diet. Increases in serum sulfate may explain some of the therapeutic effects of MSM, DMSO, and glucosamine sulfate. Organic sulfur, as SAAs, can be used to increase synthesis of S-adenosylmethionine (SAMe), glutathione (GSH), taurine, and N-acetylcysteine (NAC). MSM may be effective for the treatment of allergy, pain syndromes, athletic injuries, and bladder disorders. Other sulfur compounds such as SAMe, dimethylsulfoxide (DMSO), taurine, glucosamine or chondroitin sulfate, and reduced glutathione may also have clinical applications in the treatment of a number of conditions such as depression, fibromyalgia, arthritis, interstitial cystitis, athletic injuries, congestive heart failure, diabetes, cancer, and AIDS. Dosages, mechanisms of action, and rationales for use are discussed. The low toxicological profiles of these sulfur compounds, combined with promising therapeutic effects, warrant continued human clinical trails.

PMID: 11896744 [PubMed - indexed for MEDLINE]

Toxicity of methylsulfonylmethane in rats.

Food Chem Toxicol. 2002 Oct;40(10):1459-62.

Horvath K, Noker PE, Somfai-Relle S, Glavits R, Financsek I, Schauss AG.

Pharmaceutical Control and Development Laboratory Ltd, Budapest, Hungary.

Methylsulfonylmethane (MSM) is a popular dietary supplement used in a variety of conditions including pain, inflammation, allergies, arthritis, parasitic infections and the maintenance of normal keratin levels in hair, skin and nails. Despite its popularity, there is little published toxicology data on MSM. The objective of this study was to evaluate the acute and subchronic toxicity of MSM in rats at a dose five to seven times the maximum recommended dose in humans. MSM administered in a single gavage dose of 2 g/kg resulted in no adverse events or mortality. MSM administered as a daily dose of 1.5 g/kg for 90 days by gavage resulted in no adverse events or mortality. Necropsy did not reveal any gross pathological lesions or changes in organ weights. Renal histology of treated animals was normal. It is concluded that MSM is well tolerated in rats at an acute dose of 2 g/kg and at a subacute chronic dose of 1.5 g/kg.

PMID: 12387309 [PubMed - indexed for MEDLINE]

A multicentered, open-label trial on the safety and efficacy of methylsulfonylmethane in the treatment of seasonal allergic rhinitis.

J Altern Complement Med. 2002 Apr;8(2):167-73.

Barrager E, Veltmann JR Jr, Schauss AG, Schiller RN.

GENESIS Center for Integrative Medicine, Graham, WA, USA.

BACKGROUND: Seasonal allergic rhinitis (SAR) affects more than 23 million Americans annually, and current epidemiologic studies indicate that its prevalence within the United States is increasing. Numerous clinical observations and case studies have led researchers to hypothesize that methylsulfonylmethane (MSM) may help ameliorate the symptoms associated with SAR. OBJECTIVE: The primary goal of this study was to evaluate the efficacy of MSM in the reduction of SAR-associated symptoms. This study also examined possible adverse reactions associated with methylsulfonylmethane supplementation. Finally, this study attempted to elucidate the method of action by which MSM elicits its effect on allergy symptoms. DESIGN: Fifty-five (55) subjects were recruited for the study. All met the criteria for participation in the study. 50 subjects completed the study. Those subjects completing the study consumed 2,600 mg of MSM orally per day for 30 days. Clinical respiratory symptoms and energy levels were evaluated by a Seasonal Allergy Symptom Questionnaire (SASQ) at baseline and on days 7, 14, 21, and 30. Immune and inflammatory reactions were measured by plasma immunoglobulin E (IgE) and C-reactive protein at baseline and on day 30. An additional inflammatory biomarker, plasma histamine, was measured in a subset of subjects (n = 5). RESULTS: Day 7 upper and total respiratory symptoms were reduced significantly from baseline (p < 0.01 and p < 0.005, respectively). Lower respiratory symptoms were significantly improved from baseline by week 3 (p < 0.001). All respiratory improvements were maintained through the 30-day visit. Energy levels increased significantly by day 14 (p < 0.0001); this increase continued through day 30. No significant changes were observed in plasma IgE or histamine levels. The results of this study are promising. It would be worthwhile to conduct a larger, randomized, double-blind, placebo-controlled study to establish further if MSM would be a useful agent in the treatment of symptoms associated with SAR. CONCLUSION: The results of this study suggest that MSM supplementation of 2,600 mg/day for 30 days may be efficacious in the reduction of symptoms associated with SAR. Furthermore, few side effects are associated with the use of this compound. Recent acute and subacute chronic toxicologic data on the same source of MSM as used in this study, further validate the safety of this product.

PMID: 12006124 [PubMed - indexed for MEDLINE]

Accumulation of methylsulfonylmethane in the human brain: identification by multinuclear magnetic resonance spectroscopy.

Toxicol Lett. 2001 Sep 15;123(2-3):169-77.

Lin A, Nguy CH, Shic F, Ross BD.

MR Spectroscopy Unit, Huntington Medical Research Institutes, 660 South Fair Oaks Avenue, Pasadena, CA 91105, USA.

Methylsulfonylmethane (MSM) is a widely available 'alternative' medicine. In vivo magnetic resonance spectroscopy (MRS) was used to detect and quantify MSM in the brains of four patients with memory loss and in three normal volunteers all of who had ingested MSM at the recommended doses of 1-3 g daily. MSM was detected in all subjects at concentrations of 0.42-3.40 mmole/kg brain and was equally distributed between gray and white matter. MSM was undetectable in drug-naive normal subjects (N=25), patients screened for 'toxic exposure' (N=50) or patients examined with 1H MRS for the diagnosis of probable Alzheimer Disease (N=520) between 1991 and 2001. No adverse clinical or neurochemical effects were observed. Appearance of MSM in significant concentrations in the human brain indicates ready transfer across the intact blood-brain barrier, of a compound with no known medical benefits.

PMID: 11641045 [PubMed - indexed for MEDLINE]

Calcium, sulfur, and zinc distribution in normal and arthritic articular equine cartilage: a synchrotron radiation-induced X-ray emission (SRIXE) study.

J Exp Zool. 1995 Sep 1;273(1):82-6.

Rizzo R, Grandolfo M, Godeas C, Jones KW, Vittur F.

Dipartimento di Biochimica, Universita di Trieste, Italy.

Calcium, sulfur, and zinc content in normal and arthritic equine cartilage have been studied by synchrotron radiation-induced X-ray emission (SRIXE). Ranging from the superficial to the columnar zone of the normal tissue, calcium and zinc concentrations are increasingly higher, whereas sulfur is at its highest concentration in the transitional zone. In the arthritic tissue, calcium concentration is at its maximum in the transitional zone, whereas zinc and sulfur distributions are relatively homogeneous. Sulfur concentration in arthritic cartilage is reduced to about one-third with respect to that in normal tissue. The possibility that zinc concentration reflects the distribution of the zinc-containing enzyme alkaline phosphatase is presented.

PMID: 7561728 [PubMed - indexed for MEDLINE]

Pharmacodynamic effects of inhaled dry powder formulations of fenoterol and colforsin in asthma.

Clin Pharmacol Ther. 1993 Jan;53(1):76-83

Bauer K, Dietersdorfer F, Sertl K, Kaik B, Kaik G.

Department of Internal Medicine, University of Vienna Medical School, Austria.

The airway and tremor response and cardiovascular and hypokalemic effects of single doses of inhalative fenoterol dry powder capsules (0.4 mg) were compared with the fenoterol metered dose inhaler (0.4 mg) and colforsin (forskolin) dry powder capsules (10.0 mg), a direct activator of the adenylate cyclase system, in 16 patients with asthma. Subjects (FEV1 < or = 60% predicted) were investigated in a randomized, double-masked, placebo-controlled, four-period, crossover trial for a 120 minute period. All active drugs caused a significant increase in specific airway conductance (p < 0.05); the order of potency (mean +/- SEM maximum increase from baseline) was fenoterol metered dose inhaler (0.51 +/- 0.06 sec-1 x kPa-1), fenoterol dry powder capsules (0.49 +/- 0.07), and colforsin dry powder capsules (0.30 +/- 0.03). A marked increase in finger tremor amplitude resulted after fenoterol metered dose inhaler only (62.93% +/- 10.21%; p < 0.05) in contrast to fenoterol dry powder capsules (15.84% +/- 4.35%; p < 0.05) and colforsin dry powder capsules (12.87% +/- 10.44%; p > 0.05). A decrease in plasma potassium was found after fenoterol (metered dose inhaler > dry powder capsules; p < 0.05). In conclusion, fenoterol dry powder capsules caused less tremor response and hypokalemic effects than the metered dose inhaler, although the bronchodilator capacity was similar. Colforsin dry powder capsules resulted in a measurable bronchodilatation in patients with asthma.

PMID: 8422745 [PubMed - indexed for MEDLINE]

Dimethylsulfoxide (DMSO) blocks conduction in peripheral nerve C fibers: a possible mechanism of analgesia.

Neurosci Lett. 1993 Feb 19;150(2):145-8.

Evans MS, Reid KH, Sharp JB Jr.

Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield.

Dimethylsulfoxide (DMSO) is readily absorbed through skin, and relieves musculoskeletal pain when applied topically to painful areas. We studied the effects of DMSO on C-type nerve fibers, which mediate pain sensation. DMSO was applied directly to exposed cat sural nerves. C fiber conduction velocity was slowed by DMSO, even in low concentrations (5-7% v/v). Higher concentrations completely blocked C fiber conduction, with a minimum blocking concentration of 9%. Onset of nerve block was almost immediate with 15% DMSO or higher concentrations. C fiber blockade may account for analgesia with DMSO.

PMID: 8469412 [PubMed - indexed for MEDLINE]

Prolongation of response to DMSO by heparin maintenance.

Urology. 1993 Jan;41(1 Suppl):64-6.

Perez-Marrero R, Emerson LE, Maharajh DO, Juma S.

Department of Urology, Queen's University, Kingston, Ontario.

Dimethylsulfoxide (DMSO) is an effective treatment of symptomatic patients with detrusor mastocytosis but it is associated with frequent relapses. A group of patients (N = 25) followed for twelve months showed a relapse rate of 59 percent. Our experience with a combination of DMSO and heparin has suggested that the relapse rate may be lower. Heparin is a glycosaminoglycan that may afford protection to the urothelium and may reduce the relapse rate. It is better tolerated than DMSO or a combination of DMSO and heparin and does not produce garlic halitus. It is not associated with coagulation anomalies when administered intravesically. To determine whether or not maintenance therapy with intravesical heparin may reduce relapses we have treated a similar cohort of 25 patients with monthly instillations of 10,000 IU of heparin over a twelve-month period. Both groups were comparable in age, duration of symptoms, severity of symptoms, and response to DMSO. At twelve months only 20 percent of the heparin-treated group had relapsed versus 52 percent of the control group. Furthermore 6 patients (24%) in the follow-up group failed to respond to retreatment with DMSO while all of the heparin maintenance group continued to respond to one or more treatments with DMSO. Thus, it seems that heparin maintenance produces a significant reduction in the relapse rate of patients who respond to DMSO and reduces the number of patients requiring alternative therapy.

PMID: 8420097 [PubMed - indexed for MEDLINE]

Effect of dimethyl sulfoxide and dimethyl sulfone on a destructive process in the joints of mice with spontaneous arthritis

Patol Fiziol Eksp Ter. 1991 Mar-Apr;(2):37-9.

Murav'ev IuV, Venikova MS, Pleskovskaia GN, Riazantseva TA, Sigidin IaA.

The authors used the blind method for evaluation of the morphological picture of the joints and the level of circulating immune complexes to study the effect of prolonged oral administration of dimethyl sulfoxide (DMSO) and its main metabolite dimethyl sulfone on the development of spontaneous arthritis in 36 Mrl/Mn/lnr female mice. It was found that DMSO and dimethyl sulfone lessen the destructive changes in the joints, while DMSO also inhibits the manifestation of immune disorders, i. e. produces a "basal" effect on the course of spontaneous chronic arthritis in experimental animals.

PMID: 1881708 [PubMed - indexed for MEDLINE]

Dimethyl sulfoxide modulation of diabetes onset in NOD mice.

Klandorf H, Chirra AR, DeGruccio A, Girman DJ.

Diabetes. 1989 Feb;38(2):194-7.

Department of Medicine, University of California, Los Angeles School of Medicine.

Dimethyl sulfoxide (DMSO), a hydroxyl radical scavenger, is known as an immunosuppressive agent and can reduce autoantibody levels in experimental autoimmune diseases. Because classic diabetogens damage the DNA and membrane of the beta-cell by the generation of free radicals, the purpose of these investigations was to determine whether the intake of DMSO or its derivatives methylsulfonylmethane (MSM) and dimethylsulfide (DMS) could prevent the expression of autoimmune diabetes in the spontaneously diabetic NOD mouse. DMSO (2.5%), MSM (2.5%), and DMS (0.25%) were added to the drinking water of female NOD mice immediately after weaning. Control animals were maintained on regular drinking water. The presence of overt diabetes was monitored from the age of 2 mo by weekly urinary glucose testing until the animals either became overtly glucosuric or were greater than 240 days of age. In contrast to what we expected, DMSO (2.5%) markedly increased the rate at which the animals expressed overt diabetes (P less than .0004, log-rank test). MSM had no effect, whereas DMS reduced the incidence and rate of diabetes onset. When DMSO (2.5%) was administered to male NOD mice and control strains of mice (BALB/c and ICR), the control group did not develop glucosuria or insipidus, whereas DMSO increased the incidence of diabetes in the male NOD mice from 21 to 79%. In contrast, when DMSO was fed to female NOD mice on a purified AIN-76 diet, diabetes onset was reduced to 36%. We conclude that DMSO accelerates the uptake of dietary diabetogens into the beta-cell of genetically susceptible animals (NOD mice). The protective effect of the purified diet in such animals may be due to a lack of putative diabetogens in purified diet, or alternatively, the diet itself contains factor(s) that protect the beta-cell from autoimmune attack and/or destruction.

PMID: 2914623 [PubMed - indexed for MEDLINE]

A controlled study of dimethyl sulfoxide in interstitial cystitis.

J Urol. 1988 Jul;140(1):36-9.

Perez-Marrero R, Emerson LE, Feltis JT.

Department of Urology, Queen's University, Kingston, Ontario, Canada.

To evaluate the effectiveness of dimethyl sulfoxide in the treatment of patients with biopsies suggestive of interstitial cystitis, 33 patients underwent a controlled crossover trial. Patients were allocated randomly to receive 50 per cent dimethyl sulfoxide or placebo (saline). The medication was administered intravesically every 2 weeks for 2 sessions of 4 treatments each. Response was assessed urodynamically and symptomatically. Thirty women and 3 men (mean age 48 years and mean duration of symptoms 5.5 years) were entered into the study. No significant side effects to dimethyl sulfoxide were noted. When assessed subjectively, 53 per cent of dimethyl sulfoxide treated patients were markedly improved compared to 18 per cent of the placebo treated patients. Of the dimethyl sulfoxide group 93 per cent had objective improvement versus 35 per cent of the placebo group. Thus, dimethyl sulfoxide proved to be superior to placebo in the objective and subjective improvement of patients with interstitial cystitis.

PMID: 3288775 [PubMed - indexed for MEDLINE]

Growth inhibitory effects of dimethyl sulfoxide and dimethyl sulfone on vascular smooth muscle and endothelial cells in vitro.

In Vitro Cell Dev Biol. 1987 Jun;23(6):422-8.

Layman DL.

The growth of bovine aortic smooth muscle and endothelial cells was studied after exposure to dimethyl sulfoxide (DMSO) or its major metabolite, dimethyl sulfone (DMSO2). Both compounds caused a dose-dependent inhibition of cell growth as determined by [3H]thymidine incorporation and by counting the number of cells with time of exposure in culture. The IC50 of DMSO (concentration which produces 50% inhibition of growth) was 1% for smooth muscle cells and 2.9% for endothelial cells. Similarly, the IC50 of DMSO2 was also 1% for smooth muscle cells, but was 1.8% for endothelial cells. After a 4-d exposure to either compound, the growth inhibition of smooth muscle cells was completely reversible at 1%, partially reversible at 2 to 3% and completely irreversible at 4%. By comparison, inhibition of endothelial cell growth was completely reversible up to 4% of either compound. It is concluded that the growth of smooth muscle cells was similarly inhibited by DMSO and DMSO2, but that smooth muscle cells were more susceptible than endothelial cells to the growth inhibitory effects of these compounds. In addition, DMSO2 was a more potent inhibitor of cell growth than DMSO and its growth inhibition was less reversible than that produced by DMSO.

PMID: 3597282 [PubMed - indexed for MEDLINE]

Effects of oral dimethyl sulfoxide and dimethyl sulfone on murine autoimmune lymphoproliferative disease.

Proc Soc Exp Biol Med. 1986 Nov;183(2):227-30.

Morton JI, Siegel BV.

The results from several studies examining the effects of DMSO on autoimmune phenomena have been inconclusive, possibly because of differences in experimental models, treatment regimens and doses employed. In the present investigation, autoimmune strain MRL/lpr, C3H/lpr, and male BXSB mice were placed on a continuous treatment regimen with 3% DMSO or 3% DMSO2 in the drinking water, ad libitum, commencing at 1 to 2 months of age, before spontaneous disease development could be detected. This represented doses of 8-10 g/kg/day of DMSO and 6-8 g/kg/day of DMSO2. Both compounds were observed to extend the mean life span of MRL/lpr mice from 5 1/2 months to over 10 months of age. All strains showed decreased antinuclear antibody responses and significant diminution of lymphadenopathy, splenomegaly, and anemia development. Serum IgG levels and spleen IgM antibody plaque formation, however, did not differ from control values. There was no indication of involvement of systemic immunosuppressive or antiproliferative effects, and treated animals were observed to remain healthy and vigorous with no signs of toxicity. These results demonstrate that high doses of both DMSO and its major in vivo metabolite, DMSO2, provide significant protection against the development of murine autoimmune lymphoproliferative disease. Possible mechanisms of protection are discussed.

PMID: 3489943 [PubMed - indexed for MEDLINE]

Pharmacology of DMSO.

Cryobiology. 1986 Feb;23(1):14-27.

Jacob SW, Herschler R.

A wide range of primary pharmacological actions of dimethyl sulfoxide (DMSO) has been documented in laboratory studies: membrane penetration, membrane transport, effects on connective tissue, anti-inflammation, nerve blockade (analgesia), bacteriostasis, diuresis, enhancement or reduction of the effectiveness of other drugs, cholinesterase inhibition, nonspecific enhancement of resistance to infection, vasodilation, muscle relaxation, antagonism to platelet aggregation, and influence on serum cholesterol in experimental hypercholesterolemia. This substance induces differentiation and function of leukemic and other malignant cells. DMSO also has prophylactic radioprotective properties and cryoprotective actions. It protects against ischemic injury.

PMID: 3007027 [PubMed - indexed for MEDLINE]

Incorporation of methylsulfonylmethane sulfur into guinea pig serum proteins.

Life Sci. 1986 Jul 21;39(3):263-8.

Richmond VL.

Methionine, an essential amino acid, and cysteine are the major sulfur-containing amino acids in the body and both are thought to be synthesized predominantly in plants and micro-organisms. Methylsulfonylmethane (MSM) is a natural constituent of the environment in which it is found in plants, in milk and urine of both bovines and humans, is a normal oxidation product of dimethyl sulfoxide (DMSO) also in the natural environment and may be part of the natural global sulfur cycle. To determine whether sulfur from methylsulfonylmethane (MSM) is incorporated into sulfur amino acids, I fed 35S-MSM to guinea pigs. 35S was incorporated into peptidyl methionine and cysteine of guinea pig serum proteins. The specific activity of 35S-methionine was 30% greater than for 35S-cysteine, suggesting a precursor-product relationship. Total specific activity of serum proteins was increased by only 30% with a 100% increase of administered 35S-MSM, suggesting a limiting step in synthesis. Approximately 1% of the radioactivity was recovered in serum proteins, none in the feces and most was excreted in the urine. Microorganisms of intestinal lumen may be responsible for the incorporation of the 35S of MSM into sulfur amino acids. MSM may provide a source of sulfur for essential animal methionine by mechanisms not yet elucidated in either animals or micro-organisms.

PMID: 3736326 [PubMed - indexed for MEDLINE]