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, Amy J. North, Lieselotte B. Wells,

Employing [35S] DMSO, Kolb et al, evaluated the absorption and distribution of DMSO in lower animals and man. Ten minutes after the cutaneous application in the rat, radioactivity was measured in the blood. In man radioactivity appeared in the blood 5 minutes after cutaneous application. One hour after application of DMSO to the skin, radioactivity could be detected in the bones.

When the theorectical basis of DMSO action is described, we can list literally dozens of primary pharmacologic actions. This relatively brief summary will touch on only a few:

 / ; North, Amy J.; Wells, Lieselotte B.

/ North, Amy J.; Wells, Lieselotte B.; Campbell, William B.

In a recent landmark study, Dutch researchers studied more than 1600 subjects with hip OA and 635 with knee OA. The researchers evaluated radiographs of the hip and knee at baseline and follow-up. The researchers assessed the associations between different types of NSAIDs and the progression of OA. The mean follow-up period was 6.6 years. They found that long-term use of the NSAID diclofenac was associated with a more than twofold increase in radiologic progression of hip osteoarthritis and a threefold increase in progression observed in the knee. Ibuprofen use was also shown to be associated with a statistically significant increase in progression of the users’ knee and hip OA.119 The interesting point of this study is that the study population was healthy. The authors noted that this may have resulted in an underestimation of the reported associations. Their conclusion noted,“…these data suggest that diclofenac may induce accelerated progression of hip and knee OA. Whether this occurs because of a true deleterious effect on cartilage or because of excessive mechanical loading on a hip or knee following pain relief, remains to be investigated.” Another study comparing diclofenac with placebo, as seen in Figure 17, accelerated OA in knees as evidenced by a greater decline in joint space width on X-rays compared to placebo.120

What actually happens to patients who take NSAIDs on a regular basis? If NSAIDs, by inhibiting pain and inflammation in osteoarthritic joints, cause people with OA to overuse a damaged joint, this should result in accelerating joint degeneration and joint replacements at an earlier time or, alternatively, if treatment with NSAIDs alters cartilage metabolism and inhibits joint healing, an acceleration of articular cartilage degeneration should be seen. Numerous studies have shown that non-steroidal anti-inflammatory drugs, particularly indomethacin, increase the rate of progression of osteoarthritis of the hip and knee.112-117 Statistically significant progression of hip radiographs in osteoarthritic patients can be seen within one year of those patients taking NSAIDs. In one study, the authors noted, “…a statistically significant correlation between the NSAID consumption score and changes in the radiological parameter (p=0.0001). This statistically significant difference was retained when the percentage of days taking NSAIDs was added (p = 0.0004).”118

JO - Journal of Clinical Investigation

There were more than twice as many patients showing deterioration in the indomethacin group as the placebo. The difference between the two groups was highly statistically significant (p=0.009). The authors noted that the risk of deterioration within a one year period in patients taking indomethacin relative to placebo was 2.1 (risk ratio).111 The authors concluded firmly, “Our study confirms beyond a reasonable doubt that indomethacin increases the rate of radiological deterioration of osteoarthritic knees.”

By the third year of the study, the results were so dramatic demonstrating the acceleration of the degeneration of the articular cartilage in the knee osteoarthritic patient treated with indomethacin that this part of the study had to be stopped.

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T2 - Journal of Clinical Investigation


D. H. Hechtman, , M. A. Gimbrone, A. I. Schafer

The suggestion that indomethacin accelerates the bone destruction in osteoarthritis of the hip was first made by Coke in 1967;103 subsequent reports have been numerous that provide further clinical evidence of the damaging effects of non-steroidal anti-inflammatory drugs on osteoarthritic hips.104-107 In one retrospective investigation of the relationship between the use of non-steroidal anti-inflammatory drugs on hip destruction in primary osteoarthritis of the hip, 70 hips were studied in 64 patients. Cranial acetabular migration, a measure of acetabular destruction, was present in 37 hips and absent in 33. Regular intake of NSAIDs was noted for 31 of the 37 migrating hips. In regard to the other six, three took NSAIDs on and off and only three of the 37 did not take NSAIDs. Those patients with serious hip destruction when compared with those who did not have the acetabular destruction did not differ in sex, age, pain grading, or walking ability. The only significant difference was the amount of NSAIDs taken. According to the researchers, NSAID use was associated with progressive formation of multiple small acetabular and femoral subcortical cysts and subchondral bone thinning. They concluded, “The association of acetabular bone destruction with regular NSAID intake in patients with osteoarthritis of the hip adds further evidence to the clinical and experimental observations on the powerful and potentially harmful effects of these drugs on cartilage and bone.”108 In this study the NSAIDs used regularly and associated with acetabular migration in this series were indomethacin (14 hips); ibuprofen (8 hips); naproxen (3 hips); sulindac, aspirin, and piroxicam (2 hips each); flurbiprofen, azapropazone, diclofenac, fenclofenac, and ketoprofen (1 hip each). The authors noted, “This study suggests caution in the widespread use of NSAIDs for osteoarthritis of the hip…”

JF - Journal of Clinical Investigation

Since normal articular chondrocytes produce very little PGE2 and osteoarthritic chondrocytes produce a lot of it through the COX-2 enzyme, it would make sense from a traditional medical point of view to attack arthritis pain from this angle. This is especially true since the over expression of the COX-2 protein (and thus increased PGE2 levels) plays an important role in many pathophysiolgic states, including systemic inflammation, fever, cancer, angiogenesis, Alzheimer’s disease, and inflammatory arthritis.96 Yes, in certain conditions inflammation is harmful, but it is a big leap to assume everywhere there is PGE2 it is harming tissue. The articular chondrocytes make PGE2 in response to injury to stimulate healing. Osteoarthritic cartilage spontaneously releases PGE2 in levels at least 50-fold higher than normal cartilage and 18-fold higher than normal cartilage stimulated with cytokines and endotoxin.97-100 The inflammation that occurs through PGE2 when a normal or osteoarthritic joint is injured is the body’s immune system response to try and get the joint injury repaired.101 When a person uses medications that block this response, while pain may be improved, the repair mechanisms for the joint are inhibited. The long-term consequences, of course can be an acceleration of the degenerative osteoarthritic process. (See Figure 16.) Long-term NSAID treatment not only blocks PGE2 production by direct inhibition of COX-2 activity but by down-regulating COX-2 synthesis.102

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Source: Received September 9, 1985. Accepted September 16, 1985 by the Academic Press, Inc. Printed 1985 (pp. 14-27). DMSO Organization wishes to thank the Academic Press, Inc., for allowing us to place this article on our World Wide Web site. Academic Press retains all copyright. To copy any portion of this article, please obtain permission from the publisher.

KW - hypoxic pulmonary hypertension

To see if these sort of damaging changes occurred with NSAID use on osteoarthritic knees the Longitudinal Investigation of Nonsteroidal Anti-inflammatory Drugs in Knee Osteoarthritis (LINK) study group was formed in England. They did a large study to compare the rate of radiographic progression in knee osteoarthritis comparing indomethacin (NSAID) with placebo. The study involved 20 rheumatology clinics in the United Kingdom. Patients received indomethacin 25mg three times daily or a placebo. The average person in each group was around 60 years of age and had osteoarthritis in the knee for over five years. The study involved 85 clients in the indomethacin group and 85 in the placebo group. Radiographic analysis was done yearly and the radiographic grade was judged by two observers using a six point scale. The average length of follow-up was three years. By the third year of the study, the results were so dramatic demonstrating the acceleration of the degeneration of the articular cartilage in the knee osteoarthritic patient treated with indomethacin that this part of the study had to be stopped.

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