Re: Re: Re: Re: Re: Clinical trials of antioxidants 18 February 2005
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James J Whitehead,
Researcher Getting Better
40A Josephine Avenue London SW2 2 LA

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Re: Re: Re: Re: Re: Re: Clinical trials of antioxidants

Dear Nicholas Bennett,

Once again thank you for your kind support ,interest and imput into large scale clinical trials of antioxidants. To be honest thats my sole reason for taking part in this debate.

In Reply to: "Speaking of which: the necessary steps involved in organising a clinical study of the kind proposed are relatively simple, providing one has the infrastructure in place. Superficially it looks likely to get through an Institutional Review Board and then all you would need would be funding and a patient base. Mostly likely, for statistical power, it would have to be a multicenter study, which significantly complicates the matter (especially with regard to funding). It would be very important too to properly design the study to have enough power to detect and control for any differences between various arms."

I greatley appreciate your imput here and appreciate your good will and spirit in this project. Personaly I feel it would be very interesting and theraputic for all "sides" perhaps in an joint effort to establish scientificaly the true theraputic potential of antioxidants to work together in designing clinical trials of these antioxidant, mineral, amino acid, micro nutrient agents.

Such a joint effort would benefit patients worldwide in establishing what is and what is not effective. I feel it would also benefit all "sides" Doctors/scientists who have taken time and effort in participating in this debate which I am aware has or can be frustrating for all "sides". Although all the "sides" may not be able to agree on everything it would be fantastic if something constructive and positive could come out of this for all "sides" patients and doctors.

Although at times it looks like all the different "sides" have no common ground, I feel that by looking at things in another way I can see that there is some common ground between the "sides" and feel it would be in the best interests of patients/doctors and science to work together both in clinical trial designe/investigation and experimentational models in order to establish greater understanding.

Despite having opposing views or differing views I am sure that actually we are all on the same side. That is I think all the "sides" all want to help patients live longer , healthier more productive lives. To this end I salute Nicholas Bennett for his good spirit and encourage others from all "sides" to do the same.

In Reply to Nicholas Bennett :

"In fact, the type of immunosuppressive therapy used differs for renal transplant and liver transplant recipients. In our study, the majority of liver transplant recipients did not receive corticosteroids, whereas all renal transplant recipients were treated with cortisone. It was recently demonstrated in vitro that hydrocortisone acts directly on the activation of the lytic cycle of HHV-8 in latently infected cells." [1] "

Your quite right, I have been looking into this as well for quite some time and it is interesting. I was even reading only a day or two ago a paper that claimed to link increased KS occurance in people using corticosteriod creams. With reference to this I found the following studies interesting.

""Corticosteroid use in transplant recipients increases the incidence and severity of Kaposi's sarcoma (KS), a disease associated with KS- associated herpesvirus (KSHV) infection. Recently, the prototypic corticosteroid, hydrocortisone, was shown to directly induce lytic cycle reactivation of KSHV in latently-infected BCBL-1 cells." (1)

" Patients undergoing chronic steroid therapy for organ transplantation are at increased risk for development of human herpes virus 8(HHV-8)-associated Kaposi's sarcoma (KS). It has also been reported that following steroid withdrawal, KS lesions often undergo partial or complete regression. METHODS: We have examined the effect of corticosteroid treatment on HHV-8 replication, gene expression, and lytic protein expression in BCBL-1 cells in vitro. BCBL-1 cells were collected after culture for 24-72 hr with hydrocortisone (HC) 1-5 microM, phorbol ester 20 ng/ml (positive control), and culture medium only (negative control). HHV-8 genomic conformation was examined by Gardella gel analysis. mRNA expression of viral cyclin (v-Cyc), viral Bcl-2 (v-Bcl-2), viral macrophage inflammatory protein-I (v-MIP-I), viral interferon regulatory factor-1(v-IRF-1), and viral tegument protein (TP) was examined by RT-PCR Southern blot. Viral protein expression within the cells was examined by indirect immunofluorescence using 5 different HHV-8 positive antisera from 4 renal transplant recipients and 1 patient with classic KS. RESULTS: Gardella gel analysis revealed that HC induced an accumulation of the linear replicative genomic form of the virus in a time-dependent fashion. Southern blot analysis of the RT-PCR products revealed that HC induced increased expression of v-IRF-1, v-Bcl-2, and TP mRNA, with little discernible effect on v-Cyc, and v-MIP-I. Immunofluorescence revealed that HC induced increased numbers of cells expressing lytic antigens. CONCLUSIONS: These data indicate that hydrocortisone acts directly on BCBL -1 cells to activate the lytic cycle of HHV-8 and provide further support for the hypothesis that HHV-8 is activated in corticosteroid-treated immunocompromised patients. " (2)

"Liver tissue is one of the principal targets of glucocorticoids, therefore changes in the balance between hepatic oxidative and reductive capacity may greatly influence adverse effects of glucocorticoid therapy. In this study, effects of glucocorticoid on the activities of hepatic antioxidant defence enzymes were examined by using developing chick embryos.

After the administration of 0.25 micromol hydrocortisone sodium succinate, a typical glucocorticoid, to 15-day-old chick embryos, glutathione peroxidase, glutathione reductase, catalase and superoxide dismutase in the liver generally began to decrease at around 4 h, reaching 60-70% of control levels between 24 and 48 h.

These changes were observed much earlier than the elevation of the hepatic thiobarbituric acid reacting substance (TBARS) level which began to increase from 20h, reaching about six times the control level at 48 h after hydrocortisone administration. Conversely, the elevated TBARS level decreased back to the normal level with the recoveries of these enzyme activities. Furthermore, it was found that the aniline hydroxylase activity, measured as a marker of oxidative activity, began to increase after around 12 h.

These results suggested that TBARS levels were possibly produced by the suppression of antioxidant defence abilities and the significant induction of oxidative activity in the liver by glucocorticoid.

As the elevated TBARS in the liver can be distributed to tissues, TBARS will be involved in the occurrence of some of the glucocorticoid- induced adverse effects such as cataract formation." (3)

"In developing chick embryos, hydrocortisone induces cataract formation following a decrease in lens glutathione content but an increase in lipid peroxide content in lens, blood and liver.

The preventive effects of ascorbic acid 2-O-alpha-glucoside (AA-2G) on these parameters were compared on cataract formation with those of ascorbic acid (AsA) and ascorbic acid 2-O-phosphate (AA-2P). In these tissues, AA-2G inhibited a decrease in glutathione content and an increase in lipid peroxide content more effectively than either AsA or AA-2P.

Various tissues including lens and liver have alpha-glucosidase activity, strongly suggesting that AsA is enzymatically liberated from AA- 2G in these tissues. In summary, these results suggest that AA-2G exerts a potent anti-cataract activity via a reduction in oxidative damage through AsA release." (4)

"he aim of this work was to determine the effects of dietary intake vitamin E and selenium (Se) on lipid peroxidation as thiobarbituric acid reactive substances (TBARS) and on the antioxidative defense mechanisms in the liver of rats treated with high doses of prednisolone.

Two hundred fifty adult male Wistar rats were randomly divided into five groups. The rats were fed a normal diet, but groups 3, 4, and 5 received a daily supplement in their drinking water of 20 mg vitamin E, 0.3 mg Se, and a combination of vitamin E and Se, respectively, for 30 d. For 3 d subsequently, the control group (group 1) was treated with a placebo, and the remaining four groups were injected intramuscularly with 100 mg/kg body weight (BW) prednisolone. After the last administration of prednisolone, 10 rats from each group were killed at 4, 8, 12, 24, and 48 h and the activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) enzymes and the levels of glutathione (GSH) and TBARS in their livers were measured.

GSH-Px, SOD, and CAT enzyme activities and GSH levels in prednisolone -treatment group (group 2) began to decrease gradually at 4 h, falling respectively to 38%, 55%, and 40% of the control levels by 24 h, and recovering to the control levels at 48 h.

In contrast, prednisolone administration caused an increase in the hepatic TBARS, reaching up to four times the levels of the control at 24 h. However, supplementation with vitamin E and Se had a preventive effect on the elevation of the hepatic TBARS and improved the diminished activities of the antioxidative enzymes and the levels of GSH.

Therefore, the present study demonstrates the effectiveness of vitamin E and Se in reducing hepatic damage in glucocorticoid- treated rats and suggests that reductions in increased TBARS as a result of prednisolone may be an important factor in the action of vitamin E and Se." (5)

I have also posted some more studies on cortisol here Stress -Cortisol-drugs-infections-cancer-immune-suppression

While reading today as a result of what Nicholas Bennett said I found some very interesting papers on the above subject which I will be adding to the above post shortley which answered one or two long standing questions I had for which again I thank him.

Best Wishes

James J Whitehead

Clinical trials volunteer Member and


1.J Med Virol. 2002 Mar;66(3):378-83. Minimal reactivation of Kaposi's sarcoma-associated herpesvirus by corticosteroids in latently infected B cell lines. Zoeteweij JP, Rinderknecht AS, Davis DA, Yarchoan R, Blauvelt A. Dermatology Branch, National Cancer Institute, Bethesda, Maryland 20892-1908, USA.

2.Transplantation. 1999 Mar 15;67(5):648-52. Hydrocortisone activation of human herpesvirus 8 viral DNA replication and gene expression in vitro. Hudnall SD, Rady PL, Tyring SK, Fish JC. Department of Pathology, University of Texas Medical Branch, Galveston 77555-0741, USA.

3.Pharm Pharmacol. 1998 Jun;50(6):655-60. Alteration of activities of hepatic antioxidant defence enzymes in developing chick embryos after glucocorticoid administration--a factor to produce some adverse effects? Lee JW, Iwatsuru M, Nishigori H. Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa, Japan. 4. Ocul Pharmacol. 1994 Fall;10(3):537-42. Related Articles, Links Effect of ascorbic acid 2-O-alpha-glucoside on hydrocortisone-induced cataract formation in developing chick embryos: II. Influence on glutathione and lipid peroxide contents in the lens. Nagata M, Hikida M, Mibu H, Muto N, Yamamoto I. Central Research Laboratories, Santen Pharmaceutical Co., Ltd., Osaka, Japan. 5.Biol Trace Elem Res. 2003 Mar;91(3):231-41. Effects of dietary vitamin E and selenium on antioxidative defense mechanisms in the liver of rats treated with high doses of glucocorticoid. Beytut E, Aksakal M. Department of Physiology, Veterinary Faculty of Kafkas University, Kars, Turkey.

Competing interests: Clinical trials volunteer