Fahdi Chehne

Quitting cigarette smoking results in a fast improvement of in vivo oxidation injury (determined via plasma, serum and urinary isoprostane).

Isoprostanes (IP) have been identified as reliable markers of in vivo oxidation injury. Recently, in vascular tissue and blood as well as urine of cigarette smokers, increased IP values have been discovered. We examined 47 adults (26 males, 21 females; aged 30-66 years), admitted to a cardiovascular unit on an outpatient basis, with various risk factors but without any sign of manifestation of atherosclerosis. Refraining from cigarette smoking for a few days resulted in a significant drop of plasma, serum, and urinary 8-epi-PGF(2alpha). Thereafter, a further continuous decrease was monitored, reaching a steady state after about 4 weeks after quitting cigarette smoking. Prevalues of 8-epi-PGF(2alpha) were higher, depending on the type and number of risk factors; the decrease after quitting, however, was comparable. These results indicate that exsmokers may rapidly recover from their enhanced in vivo oxidation.

Isoprostane 8-epi-PGF2α is frequently increased in patients with muscle pain and/or CK-elevation after HMG-Co-enzyme-A-reductase inhibitor therapy

Background: Muscle pains with or without CK‐elevation are among the most frequently observed side‐effects in patients with hyperlipoproteinemia on various statins. The pathophysiological background, however, remains obscure.

Oxidation Injury in Patients Receiving HMG-CoA Reductase Inhibitors

AbstractBackground: Myopathy in its severe forms including rhabdomyolysis is a very rare adverse effect occurring during monotherapy with the HMG-CoA reductase inhibitors (‘statins’) and is associated with pronounced signs of oxidation injury. This has been found at a local (muscle) as well as at a systemic level (blood). Several lines of evidence indicate that even mild forms of myopathy during statin treatment may be associated with in vivo oxidation injury. In contrast, statin therapy has been shown to be associated with a decrease in oxidation injury. Objective: The aim of this study was to investigate whether patients with heterozygous familial hypercholesterolaemia who did not exhibit any symptoms or abnormalities in safety parameters during 6 months of treatment with various statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) did exhibit a change in oxidation injury as assessed by the isoprostane levels. Methods: Blood (plasma and serum) as well as urine was tested before and 1, 3 and 6 months after starting statin therapy. Results: Out of 111 treated patients (63 males, 48 females; aged 19 to 58 years) who did not experience any adverse effects during statin treatment, 11 (seven males, four females; aged 24 to 51 years) showed a pronounced increase in 8-epi-prostaglandin (PG) F2α in all the compartments examined. In the remaining 100 patients (56 males, 44 females; aged 19 to 58 years) there was either no change in or even an apparent decrease in 8-epi-PGF2α. This increase was monitored with all the statins administered. If elevated, the increase in 8-epi-PGF2α remained without change throughout the entire follow-up period. No sex difference or differential response between smokers and nonsmokers was observed. Discussion: These findings indicate that in the absence of other clinically observable adverse effects, in some of the patients, for an as yet unknown reason, statin therapy may be associated with increased oxidation injury. The fact that changing to another statin is apparently not necessarily associated with an identical response raises the question of a specific predisposition for certain compounds in a given patient. These data add a further piece of evidence that mild adverse effects of statins that are difficult to assess might be much more prevalent than widely considered. The clinical relevance and consequence of these findings still remains to be assessed.

Increased lipid peroxidation in a patient with CK-elevation and muscle pain during statin therapy

Muscle pains, CK-elevation and, rarely, rhabdomyolysis may occur during HMG-Co-enzyme-A-reductase inhibitor therapy. The underlying pathogenetic mechanisms are not yet identified. Recently, we reported a patient who showed symptoms of muscle pains during statin therapy which improved when he received vitamin E [1]. After submitting that manuscript, Holt et al. described an increase in lipid peroxidation in patients with rhabdomyolysis [2] using 8-epi-prostaglandin (PG)F2a as a determinant for in-vivo oxidation injury [3,4]. Recently, in our clinical practice we identified a patient suffering from severe familial hypercholesterolemia (male; GH, 54 a; 184 cm/180 kg) without any other risk factor who experienced severe muscle pain on lovastatin 40 mg/day with CK-elevation (329 U/l). We proceeded to measure the isoprostane 8-epi-PGF2a in plasma, serum and urine as a measure of in-vivo oxidation injury at the time of onset of pain, after withdrawal of the drug (Fig. 1), and throughout the following 3 months. 8-epi-PGF2a in plasma, serum and urine was increased strikingly. Withdrawing the drug resulted in a stepwise decrease in the respective values, almost normalizing within 2, and completely normalizing within 4 weeks. CK rapidly normalized as well. Changing to atorvastatin had no adverse effect on 8-epi-PGF2a, which has continued to remain normal until now (\6 months). Our findings show for the first time that during the symptomatic period of muscle pains with CK-elevation during statin therapy, 8-epi-PGF2a is severely increased indicating a significant in-vivo oxidation injury. As lipid lowering drugs are known to improve 8-epi-PGF2a either directly or indirectly via lipid lowering [5], the effect described cannot be due to the drug itself. The extent of the increase was clearly associated with the extent of symptoms seen in the patient. There is no information available yet as to whether the individual antioxidant status is relevant for the development of muscular side effects [6]. These findings, however, explain the benefit of vitamin E-therapy seen in one patient with similar side effects [1]. The role of antioxidant status and antioxidants thus needs to be assessed in detail in patients suffering from various side effects under statin treatment.

Iso) Prostaglandins in saliva indicate oxidation injury after radioiodine therapy.

UNLABELLED As salivary glands concentrate radioiodine the radiation injury associated with 131I-therapy may result in sialoadenitis and xerostoma leading to a lasting impaired quality of life. Recently we reported about prostaglandin concentration changes as biochemical markers for radiation injury. Isoprostanes, a new family of prostaglandin-like compounds, have been demonstrated to be reliable markers for oxidation injury in vivo. PATIENTS AND METHODS In this study we examined the levels of 8-epi-PGF2alpha, the major member of the isoprostane family in 24 patients undergoing 1311 treatment in different doses for hyperthyroidism and differentiated thyroid cancer. 6 healthy sex and age-matched volunteers were monitored in parallel. Saliva(iso)prostaglandins were determined before 131I treatment, as well as 1, 3, 7, 14, 21, and 28 days, and 2, 3, and 6 months after therapy. RESULTS 8-epi-PGF2alpha showed a significant 1311 dose-dependent temporary increase. The alterations were comparable in all investigated patients and significantly higher in cigarette smokers. TXB2 and 6-oxo-PGF, showed a dose-dependent increase too. TXB2 was higher in cigarette smokers and 6-oxo-PGF1alpha lower as compared to non-smokers. CONCLUSION These results clearly demonstrate a dose- and time-dependent tissue (TXB2, 6-oxo-PGF1alpha) and oxidation in-jury (8-epi-PGF2alpha) after 131I-therapy in the salivary glands.

Increased Isoprostane 8-epi-PGF2A in Statin-Induced Myopathy

The most prevalent side effect of statins are muscle pains occurring in presence but also in absence [1] of elevated creatine phosphokinase (CK). In one patient statin-induced muscular pains improved significantly after vitamin E [2]. Thereafter, examining another patient we found for the first time a pronounced increase in 8-epi-PGF2α, disappearing after withdrawal of the respective statin. Earlier it has been reported that rhabdomyolysis is associated with an increase in isoprostane (IP) formation [3]. Therefore, we assessed the IP 8-epi-PGF2α in plasma, serum, and urine after extraction and purification using a specific immunoassay.