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Call number: LD2668 .T4 1952 C6 / Master of Science

Call number: LD2668 .T4 1953 R62 / Master of Science

published_or_final_version / Biochemistry / Master / Master of Philosophy

The influence of vitamin C on the pharmacokinetics of caffeine was investigated in ten elderly males, age 66 to 86 years. Caffeine (4 mg kg⁻¹) was administered intravenously on three different occasions over a seven-week period: before vitamin C restriction, after approximately four weeks of vitamin C restriction (15 mg dietary intake per day), and after two weeks of vitamin C supplementation (500 mg orally, twice daily). Blood and urine samples were collected over a 48-hour period following each caffeine administration. The plasma half-life (t₁/₂), rate constant of elimination (K), apparent volume of distribution (V), total body clearance (TBC), renal clearance (RC), and metabolic clearance (MC) of caffeine were determined. Simultaneous plasma (PVC), whole blood (WBVC), and leukocyte (WBCVC) vitamin C concentrations were obtained. All of the mean vitamin C values determined at the first kinetic trial (KT-1) were within the normal ranges for the respective biologic fluid or tissue. All of the mean vitamin C values changed significantly during the study; decreasing to below the normal ranges by the second kinetic trial (KT-2) following dietary vitamin C restriction, and increasing to the normal ranges by the third kinetic trial (KT-3) following vitamin C supplementation. All of the decreases and increases in the individual and average vitamin C concentrations paralleled the observed decreases and increases in the daily vitamin C intake. None of the caffeine pharmacokinetic parameters evaluated changed significantly during the study. The mean rate constant of elimination was approximately 0.15 hr⁻¹, the average plasma half-life was approximately 4.5 hours, and the mean apparent volume of distribution was approximately 500 ml kg⁻¹ for all three kinetic trials. The average total body, renal, and metabolic clearances were approximately 76.9, 1.3, and 76.0 (ml hr⁻¹)kg⁻¹, respectively, for all three kinetic trials. With the exception of V and TBC, the various pharmacokinetic characteristics investigated were in general agreement with data reported for younger subjects. The average apparent volume of distribution determined at any of the kinetic trials was about 16% lower than the value reported for young, healthy subjects. Similarly, the mean total body clearance observed was about 21% lower than that observed in young, healthy subjects. Since the average elimination rate constant observed in these elderly subjects is similar to the values observed in younger subjects and since TBC is equal to the product of V times K, the reduced TBC observed in this study appears to be due to the reduction in V, rather than to a decrease in the intrinsic metabolic capacity of the liver with aging. No relationship between vitamin C intake and/or body levels and the pharmacokinetics of caffeine was observed. These results indicate that the elimination of caffeine in the elderly is not affected significantly by the concentrations of vitamin C achieved during the study.

The aim of this study was to examine whether vitamins E (200 IU) and C (1 g) in combination would influence exercise-induced lipid peroxidation to a greater extent than vitamin E (400 IU) alone. A placebo-controlled study was carried out on 7 collegiate cyclists who were supplemented with 1) vitamin C (1 g); 2) vitamins E (200 IU) and C (1 g); and vitamin E (400 IU) during 3 treatments, each 3 weeks in duration. The serum concentrations of hematocrit and MDA, one marker of lipid peroxidation, were measured immediately before, immediately after, and 24 hours after each exercise bout. After the vitamin C treatment, MDA serum concentration of the athletes (n=7) increased 85% above the baseline values of the placebo values, the vitamin E/C treatment showed a 29% increase, and the vitamin E treatment showed a 39% decrease. Pre- to post-exercise serum MDA levels increased 64% in the placebo group, a 29% increase in the vitamin C treatment group, a 23.2% increase in the vitamins E/C treatment group, and a 46.9% increase in the vitamin E treatment group. It is concluded that exercise-induced lipid peroxidation is more greatly influenced post-exercise by a combination of vitamins E (200 IU) and C (1 g), than by either vitamin C (1 g) alone, or vitamin E (400 IU) alone. / Department of Family and Consumer Sciences

Oxidative stress is the major driving force behind the aging process and many age-related diseases. However, direct experimental evidence of whether antioxidants, such as ascorbate (AA) and lipoic acid (LA) can slow the progression of aging process and/or reduce risks of developing degenerative disease is largely absent. This suggests a better understanding of the precise mechanism of how dietary micronutrient affect parameters of involved in cellular redox balance and aging are warranted. In this dissertation, young and old rats were used as our model to understand potential pro-oxidant events that contribute to increases in oxidative stress in various tissues and how antioxidants such as ascorbate and lipoic acid influence these events. Our major findings are that the age-related impairment of mitochondria and increased deposition of iron contribute significantly to heighten levels of oxidative stress, as evidenced by the resultant increases in the rates of oxidant appearance and in the levels of oxidative damage to DNA, lipids and proteins. We find that AA and LA strongly protected against transition metal-ion dependent increases in oxidative stress. AA effectively inhibited transition metal-mediated lipide peroxidation in human plasma. LA in its reduced form effectively binds iron and copper in a redox inactive manner and reversed chronically elevated levels of iron in the brain without removing enzyme bound transition metal ions. LA also significantly attenuated the age-related increase in oxidative stress associated with mitochondrial decay in the heart, as evidenced by the improvements in AA levels and glutathione redox status. The declines in tissue GSH levels in aged rats were strongly associated with the diminished γ-GCL activity (in parallel with decreased expression of the catalytic and modulatory subunits), and lowered Nrf2 expression and binding to ARE sequence in rat liver. Remarkably, all these events were effectively reversed by the administration of LA, modulating the parameters to return to the observed in young animals. The implications of this work open new avenues not only for further understanding of the aging process but also for possible strategies in its modulation by the micronutrients. / Graduation date: 2004

Graduation date: 2004

During extreme exercise, athletes experience increased inflammation that is similar to the acute phase response. Endurance athletes, distance runners in particular, are also more susceptible to compromised iron stores. This study evaluated inflammation, immune function and iron status in athletes completing a 50K ultramarathon. Twenty-two well-trained distance runners, 11 males and 11 females, were randomized in a double blind manner into--1) those who consumed 300 mg vitamin E and 1000 mg vitamin C (500 mg twice daily) or 2) placebos--for six weeks before and one week following a 50K ultramarathon race. Blood samples were obtained on 13 separate occasions throughout the study: before supplementation, during supplementation, the day before the race, pre-race, mid-race, immediately post-race, 2 hours following the race, and daily for six days following the race. Plasma levels of ascorbic acid and ��-tocopherol were measured by HPLC with electrochemical detection. Inflammatory cytokines, interleukin-6 (IL-6), tumor necrosis factor-�� (TNF-��), and interleukin-1�� (IL-1��) were measured using standard clinical assays. Each subject recorded immune function in an activity log and incidence of illness was tabulated as number of days ill. Ferritin was measured by enzyme immunoassay. Hemoglobin, hematocrit, and total-iron binding capacity (TIBC) and serum total iron were analyzed by standard procedures. Plasma concentrations of ascorbic acid and ��-tocopherol increased significantly in supplemented subjects (p<0.0001). Although the ultramarathon race elicited an inflammatory response, antioxidant supplementation did not alter the responses of IL-6 and TNF-��, which both increased from pre-race to mid-race, post- and post-2 h (Scheffe post-hoc analysis, p<0.0001) and returned to pre-race concentrations by 1 day after the race. Male supplemented subjects had lower IL-1�� concentrations compared to females consuming the supplement or to males consuming the placebo (ANCOVA, gender/time/treatment interaction; p<0.01) at mid-race (p<0.05 females, p<0.005 males), post 1 and 2 days (all p<0.002). Males had significantly higher ferritin levels than the female subjects (ANOVA, p<0.0001); supplementation resulted in lower ferritin concentrations at post-5 days (p<0.02, ANCOVA treatment time interaction, p<0.005). Supplementation did not reduce the days illness among those consuming antioxidants compared to those consuming the placebos. Ferritin not only increases during inflammation, it also is a measure of iron stores. Females had significantly lower levels of iron than the male subjects for each of the iron parameters measured (hemoglobin and hematocrit both p<0.0001, ferritin p<0.001, TIBC p<0.02) excluding serum total iron. The ferritin concentrations measured in the women were indicative of depleted iron stores (<12 ��g/l), and antioxidant supplementation increased hematocrit levels in the female subjects (p<0.05). This investigation indicates that female distance runners need to be aware of an increased susceptibility to iron depletion compared to their male counterparts. Antioxidant supplementation improved hematocrit levels (p<0.05) among female runners and may improve iron status among females with depleted stores. Although other investigations have suggested that antioxidant vitamins decrease exercise induced inflammation, no profound benefit of supplementation was found in this investigation though a response similar to the acute phase response was elicited by the ultramarathon race. Improvements in IL-i and ferritin in response to antioxidant supplementation may indicate that the supplementation was beneficial, but more research is needed to draw definitive conclusions. / Graduation date: 2003