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Redox concerns in the use of acellular hemoglobin-based therapeutic oxygen carriers: the role of plasma components.

Within the past decade, most research efforts in the red blood cell substitute area have revolved about the development of acellular hemoglobin-based oxygen carriers (HBOC) as clinical replacements and/or augmentation of human blood's carrying and delivery function. A major requirement for all HBOC is the maintenance of the heme-Fe+2 in this reduced state for normal physiological behavior. Oxidation of hemoglobin results in the formation of methemoglobin (heme-Fe+3). MetHb is unable to bind oxygen thus effectively lowering the carrying capacity of the Hb-based substitute. In addition, met Hb gives rise to free radicals that have the potential to cause endothelial and surrounding tissue damage. Results of this study suggest that the normal endogenous reducing agents of human plasma have the capacity to provide redox protection and stability to specific acellular-types of HBOC. The effectiveness of these reducing agents may be related to the formal reduction potential of the HBOC being considered. The choice of buffer for HBOC storage is critical and specific to the HBOC product.

Adult↗

NFkappaB decoy oligodeoxynucleotides ameliorates osteoporosis through inhibition of activation and differentiation of osteoclasts.

The transcription factor, nuclear factor-kappa B (NFkappaB), is believed to play a pivotal role in osteoclast formation. In this study, we focused on NFkappaB decoy oligodeoxynucleotides (ODN) as a new therapeutic strategy to attenuate osteoporosis. Tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts formed in mononuclear cells including osteoclast precursors from neonatal rabbit bone marrow were increased in the presence of 1,25-dihydroxyvitamin D3, whereas transfection of NFkappaB decoy ODN decreased the number of TRAP-positive cells and attenuated RANKL and M-CSF-induced osteoclast formation. NFkappaB decoy ODN also inhibited the activity of osteoclasts, as assessed by pit formation. In rat ovariectomized model of estrogen deficiency, continuous administration of NFkappaB decoy ODN attenuated the increase of TRAP activity, accompanied by a significant increase in calcium concentration in tibia and femur and decrease in urinary deoxypyridinoline. In additional osteoporosis model using vitamin C-deficient rat, inhibition of NFkappaB by decoy ODN dramatically improved the bone length, weight, density as assessed by dual-energy X-ray absorptiometry. Overall, inhibition of NFkappaB by decoy strategy prevented osteoporosis through the inhibition of bone resorption. Targeting of NFkappaB might be potential therapy in various bone metabolic diseases.

Absorptiometry, Photon↗

The selectivity and inhibition of AlkB.

AlkB is one of four proteins involved in the adaptive response to DNA alkylation damage in Escherichia coli and is highly conserved from bacteria to humans. Recent analyses have verified the prediction that AlkB is a member of the Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase family of enzymes. AlkB mediates repair of methylated DNA by direct demethylation of 1-methyladenine and 3-methylcytosine lesions. Other members of the Fe(II) and 2OG-dependent oxygenase family, including those involved in the hypoxic response, are targets for therapeutic intervention. Assays measuring 2OG turnover were used to investigate the selectivity of AlkB. 1-Methyladenosine, 1-methyl-2'-deoxyadenosine, 3-methylcytidine, and 3-methyl-2'-deoxycytidine all stimulated 2OG turnover by AlkB but were not demethylated indicating an uncoupling of 2OG and prime substrate oxidation and that oligomeric DNA is required for hydroxylation and subsequent demethylation. In contrast the equivalent unmethylated nucleosides did not stimulate 2OG turnover indicating that the presence of a methyl group in the substrate is important in initiating oxidation of 2OG. Stimulation of 2OG turnover by 1-methyladenosine was highly dependent on the presence of a reducing agent, ascorbate or dithiothreitol. Following the observation that AlkB is inhibited by high concentrations of 2OG, analogues of 2OG, including 2-mercaptoglutarate, were found to specifically inhibit AlkB. The flavonoid quercetin inhibits both AlkB and the 2OG oxygenase factor-inhibiting hypoxia-inducible factor (FIH) in vitro. FIH inhibition by quercetin occurs in the presence of excess iron indicating a specific interaction, while the inhibition of AlkB by quercetin is, predominantly, due to nonspecific iron chelation.

Ascorbic Acid↗

Epigallocatechin gallate can significantly decrease free oxygen radicals in the reperfusion injury in vivo.

OBJECTIVE: There is experimental evidence that oxygen-derived free radicals (Superoxide (O(2)(-))) play a key role in tissue damage in ischemia-reperfusion injury. Among various antioxidants tested in vitro, natural polyphenols like Epigallocatechine gallate (EGCG) show a 164-fold higher scavenging activity for O(2)(-) than ascorbic acid We therefore conducted an animal study in order to investigate the impact of EGCG on O(2)(-) production during reperfusion after defined periods of ischemia in the muscle tissue of the rat, using a recently developed cytochrome c-based biosensor for on-line in vivo monitoring of O(2)(-). MATERIALS AND METHODS: Femoral artery and vein were dissected below the inguinal ligament in male Wistar rats. The cytochrome c-based biosensor was placed in the gastrocnemius muscle. Ischemia was induced by clamping the femoral vessels. Ischemia times were either 60 (n = 14) or 120 (n = 14) minutes. Six animals in each group received 4 mg/kg body weight EGCG intravenously at the time of reperfusion, another six animals in each group served as controls (no treatment). Additionally, two animals in each group received the same volume of saline instead of EGCG. The current response of the biosensor corresponding to the O(2)(-) concentrations in vivo was recorded on a PC. The gastrocnemius muscles were harvested for histological evaluation. RESULTS: The average maximum O(2)(-) concentration after 60 minutes of ischemia was 188, 18 nmol/L (23 pA) compared to 90 nmol/L (11 pA) (P <.01) with EGCG application. The mean O(2)(-) value after 120 minutes was 220 nmol/L (27 pA) versus 135 nmol/L (16.5 pA) (P <.01) with EGCG, respectively. Histological analysis showed advanced muscle cell injury and neutrophil infiltration in the group without EGCG. No O(2)(-) reduction could be verified administering saline instead of EGCG. CONCLUSION: For the first time the scavenging activity of an antioxidant was verified in vivo on-line. EGCG significantly diminished O(2)(-) tissue concentrations after 60 or 120 minutes of ischemia by an average of nearly 50%, suggesting its therapeutic potential.

Animals↗

Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy.

A therapeutic trial with polyvitamins and dichloroacetate (DCA) in combination with thiamine in a 13-year-old girl with complex I deficiency is reported. The polyvitamin therapy included thiamine, riboflavin, ascorbate, coenzyme Q 10 and carnitine. This therapeutic regine was used over a period of 17 months without any effect. Although DCA lowered the lactate concentration in blood and CNS--measured by magnetic resonance spectroscopy--no clinical benefit was achieved. After 20 weeks of DCA therapy a distal polyneuropathy with areflexia developed although 100 mg thiamine daily as comedication was given from the beginning of DCA therapy. Nerve conduction velocity of the peroneal nerve was not detectable, sensible evoked potentials of the tibialis posterious nerve were normal. This side-effect resolved completely within 6 months after omission of DCA. Our observation suggests a direct toxic effect of DCA only on the peripheral nervous system in our patient since several cerebral MRI and magnetic resonance spectroscopy studies showed no abnormalities. CONCLUSION. DCA lowers the lactate concentration in children with complex I deficiency of the respiratory chain in a dose of 100 mg/kg body weight without clinical benefit. Reversible peripheral polyneuropathy may develop under DCA therapy despite thiamine medication.

Adolescent↗

Morphometric analysis of alveolar responses of F344 rats to subchronic inhalation of nitric oxide.

Nitric oxide (NO)*, the principal airborne pollutant generated from combustion processes such as gas stoves, tobacco smoke, and burning of fossil fuels, is being tested as a therapeutic agent in clinical trials. A prior morphometric study of rats exposed for 9 weeks to 0.5 parts per million (ppm) NO demonstrated focal degeneration of the alveolar interstitium and increased numbers of fenestrated alveolar septa (Mercer et al. 1995). The limited size and distribution of defects in this NO exposure did not alter alveolar surface area or other morphometric indicators of lung function, but were of interest as the responses to inhaled NO appeared to differ from those produced by other oxidants such as ozone (O3) and nitrogen dioxide (NO2). Nitric oxide exposures at the same concentration and duration as prior morphometric studies of O3 and NO2 were necessary in order to make a comparison. This was the purpose of the current study in which F344 rats were exposed for 6 weeks to air, 2 ppm NO, or 6 ppm NO. Following exposure, the lungs of NO- and air-exposed rats were preserved and prepared for electron microscopy. The lungs of replicate groups were lavaged and analyzed for protein content and antioxidants. Ultrastructural alterations due to exposure were determined by quantitative morphometric analyses and serial-section counts of the number of alveolar fenestrae. In contrast to the prior study of NO, there was no significant difference in the number of alveolar fenestrae/lung between control and NO-exposed groups. Morphometric analysis of the 6 ppm NO-exposure group demonstrated a significant increase from controls in the percentage of epithelial basement membrane covered by type II epithelial cells and a significant increase in the number of type II epithelial cells and airspace macrophages. At 2 ppm, only the percentage of epithelial basement membrane covered by type II epithelial cells was significant. No significant differences were found in lavage protein or in lavage ascorbic acid or glutathione content between clean-air controls and NO-exposed groups. Overall, the proinflammatory responses by type II epithelial cells and airspace macrophages following inhaled NO were comparable to those of O3 and NO2. These results, derived from experiments using significantly higher concentrations than in the prior study, demonstrate that inhaled NO produces a pattern of injury similar to that of other oxidants.

Administration, Inhalation↗

Effect of dexamethasone treatment on oxidative energy metabolism in rat liver mitochondria during postnatal developmental periods.

Dexamethasone--a potent synthetic glucocorticoid--has multiple therapeutic applications and is used in all age groups, as well as for antenatal and perinatal treatments. However, side-effects of dexamethasone treatment, including those on development, are becoming increasingly apparent. Since developmental processes are energy-dependent, we examined the effects of chronic dexamethasone treatment on oxidative energy metabolism in liver mitochondria from rats belonging to different developmental age groups. Dexamethasone treatment adversely affected the state 3 respiration rates in 2- and 3-week groups and in the adults with glutamate as the substrates, whereas for pyruvate + malate, the adverse effects were seen for the 3 week and the adult groups. Oxidation of succinate was severely impaired in all the age groups. For ascorbate + TMPD as the substrate, elevated respiration was noted for the 5-week group and the impaired oxidation was observed in adults. Dexamethasone treatment also resulted in site-specific uncoupling with the effect being seen predominantly in the 3- and 5-week and adult animals. The activity of dehydrogenases decreased in a manner comparable to the respiration rates. The mitochondrial cytochromes decreased in an age-dependent manner. The ATPase activity also decreased significantly. The results thus emphasize the adverse effects of dexamethasone treatment on mitochondrial energy metabolism especially in critical age groups.

Age Factors↗

The combined effect of citrate/ascorbate treatment in alkali-injured rabbit eyes.

The incidence of ulceration and perforation in the cornea of alkali-injured eyes is significantly reduced by treatment with trisodium citrate or sodium ascorbate. Topical citrate reduces the inflammatory response in the cornea by inhibiting polymorphonuclear leukocytes. Topical ascorbate elevates the depressed level of this vitamin in the alkali-injured cornea, reversing a scorbutic condition. The purpose of the current study was to determine whether combined treatment with topical citrate and ascorbate has an additional therapeutic value when compared with citrate alone. Adsorbotear without EDTA was used as the vehicle for both medications. Rabbit eyes were injured with 1N NaOH for 35 s using a 12-mm well and were rinsed. Group I (47 eyes) received two drops of 10% citrate every hour on the hour and Adsorbotear on the half-hour for 14 h/day. Group II (48 eyes) received two drops of 10% citrate every hour on the hour and 10% ascorbate every hour on the half-hour for 14 h/day. The citrate/ascorbate group had significantly fewer ulcerations during the experiment than did the group receiving citrate alone (2 of 48 versus 10 of 47, 0.01 less than p less than 0.02). Both anterior ulcers in the citrate/ascorbate group and five ulcers in the citrate group healed to no ulcer by the end of the experiment (0 of 48 versus 5 of 47, 0.02 less than p less than 0.05). The average depth of ulceration was significantly less for the citrate/ascorbate group (p less than 0.001). No descemetoceles or perforations were observed in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkalies↗

Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle.

OBJECTIVE: Although early administration of ascorbate has been shown to protect against the microvascular dysfunction in sepsis, it is not clear if a delayed introduction of ascorbate also yields beneficial effects. The main objective was to determine the therapeutic window for treatment of an animal model of sepsis with bolus injection of ascorbate. We also determined if sepsis per se affects urinary excretion of ascorbate. DESIGN: Prospective, controlled laboratory study. SETTING: Animal laboratory in a university-affiliated research institute. SUBJECTS: Male Sprague-Dawley rats, 300-400 g of body weight. INTERVENTIONS: Rats were made septic by cecal ligation and perforation (CLP) and volume resuscitated by continuous saline infusion. Ascorbate bolus (7.6 mg/100 g of body weight) or saline vehicle was injected intravenously at 1, 6, or 24 hrs after CLP. MEASUREMENTS AND MAIN RESULTS: At 24 hrs post-CLP, sepsis caused antidiuresis and decreased plasma ascorbate concentration, but it did not affect urinary excretion of ascorbate in rats that received only saline. Sepsis also caused maldistribution of capillary blood flow in skeletal muscle. This maldistribution of flow was prevented by ascorbate injected at 6 hrs post-CLP. At 48 hrs post-CLP, in addition to the flow maldistribution, sepsis caused systemic arterial hypotension and fever that were prevented by both immediate (1 hr post-CLP) and delayed injections of ascorbate (24 hrs post-CLP). CONCLUSION: Despite volume resuscitation, the present model of sepsis resulted in maldistribution of capillary blood flow within 24 hrs and hypotension within 48 hrs. Our finding that intravenous bolus of ascorbate can protect against these deficits even if delayed 6-24 hrs after the septic insult shows, for the first time, that ascorbate can reverse microcirculatory dysfunction after the onset of sepsis.

Analysis of Variance↗

A randomized, double-blind, placebo-controlled trial of supplementary vitamins E, C and their combination for treatment of haemodialysis cramps.

BACKGROUND: Muscle cramps that improve after carnitine or vitamin E therapies are common in haemodialysis (HD) patients. Because vitamin C participates in carnitine biosynthesis, and its levels are reduced in uraemia, subclinical vitamin C depletion may contribute to HD cramps. Our aim was to determine the effects of vitamins C, E and their combination on the frequency and intensity of HD cramps. METHODS: In this placebo-controlled, double-blind study, 60 HD-patients were randomized into four therapeutic groups. Each group (n=15) received six identical capsules daily for 8 weeks, containing one of the following: vitamin E (400 mg), vitamin C (250 mg), their combination, or placebo. RESULTS: The frequency and intensity of HD cramps decreased significantly in all three vitamin groups compared with the placebo group at the end of the trial, and compared with the pre-treatment values. At the end of the trial, vitamins E, C, their combination, and placebo produced cramp reductions of 54, 61, 97 and 7%, respectively. The percentage cramp reduction had no significant correlation with age, sex, aetiology of end-stage renal disease, serum electrolytes or HD duration, but showed a positive correlation (r=0.33, P=0.01) with the type of therapy. No vitamin-related adverse effects were encountered during the trial. CONCLUSION: Short-term treatment with the combination of vitamins E and C is safe and effective in reducing HD cramps; however, its safety for prolonged therapy has yet to be evaluated in HD patients.

Ascorbic Acid↗

[Intermittent high-dose vitamin C therapy in patients with HTLV-I-associated myelopathy].

The aim of this study was to determine the efficacy and safety of intermittent high-dose vitamin C therapy in patients with HTLV-I associated myelopathy (HAM). Seven HAM patients (4 men and 3 women, aged 36 to 81 years), who were repeatedly given a daily oral dose of 1.5 to 3.0 g of vitamin C (40 mg/kg/day) for 3 to 5 successive days followed by a two-day withdrawal period, were followed for a mean period of 9.7 +/- 5.8 months after the therapy. The therapeutic efficacy was evaluated by a 10-grade disability scoring (DS) system, short somatosensory evoked potentials (SSEP) elicited by tibial nerve stimulation and several immunological parameters before and at 2.0 to 14 months after the therapy. All HAM patients responded well to intermittent high-dose vitamin C therapy, 6 being excellent responders (DS improvement > or = 2 grades) and one being a good responder (DS improvement of one grade). The grade of DS was decreased at 9.7 +/- 5.8 months after the therapy from 5.9 +/- 1.6 (baseline) to 3.0 +/- 1.5 (p < 0.01), indicating an excellent clinical outcome. SSEPs were obtained before and after the therapy in 4 of the patients. On SSEP before therapy, all the patients showed abnormally prolonged P37 peak latency. N20 was not recorded in 2 patients. After the therapy, N20 appeared and prolonged P37 peak latency improved in 2 patients. Immunoglobulin concentrations, T-B lymphocyte subsets and HTLV-I antibody titer in serum did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

Consensus meeting on "Relevance of parenteral vitamin C in acute endothelial dependent pathophysiological conditions (EDPC)".

The 22 supersetnd Hohenheim Consensus Workshop took place in at the University of Stuttgart-Hohenheim. The subject of this conference was vitamin C and its role in the treatment of endothelial dysfunction. Scientists, who had published and reviewed scientific and regulatory papers on that topic were invited, among them basic researchers, toxicologists, clinicians and nutritionists. The participants were presented with eleven questions, which were discussed and answered at the workshop, with the aim of summarising the current state of knowledge. The explicatory text accompanying the short answers was produced and agreed on after the conference and was backed up by corresponding references. The therapeutic relevance of administration of the physiological antioxidant vitamin C in high parenteral doses in Endothelial Dependent Pathophysiological Conditions (EDPC) was discussed. Endothelial dysfunction is defined as including disturbed endothelial dependant relaxation of resistance vessels, breakdown of the microvascular endothelial barrier and/or loss of anti-adhesive function. It occurs in severe burn injury, intoxications, acute hyperglycemia, sepsis, trauma, and ischemic-reperfusion tissue injury and is induced by oxidative stress. Reduced plasma ascorbate levels are a hallmark of oxidative stress and occur in severe burns, sepsis, severe trauma, intoxication, chemotherapy/radiotherapy and organ transplantation. Vitamin C directly enhances the activity of nitric oxide synthase, the acyl CoA oxidase system and inhibits the actions of proinflammatory lipids. There is experimental evidence that parenteral high-dose vitamin C restores endothelial function in sepsis. In vitro, supraphysiological concentrations (> 1mM) of ascorbate restore nitric oxide bioavailability and endothelial function. Only parenterally, can enough vitamin C be administered to combat oxidative stress. There is no evidence that parenteral vitamin C exerts prooxidant effects in humans. Theoretical concerns in relation to competitive interactions between vitamin C and glucose cellular uptake are probably only relevant for oxidised vitamin C (dehydroascorbate).

Acute Disease↗

Pharmacoeconomic aspects of patients treated by hemodialysis.

Hemodialysis as a therapeutic procedure in patients being in the end-stage of renal failure has been used since the sixties of the 20th century. Generally speaking, the conservative drug therapy in patients treated by hemodialysis is complex, and economically it consummes as great proportion of financial expenses. The aim of the study was to perform an economic analysis of 101 patients, both sexes (37 females and 64 males, aged from 22 to 81 years) treated by hemodialysis, in respect of drug treatment costs. The total average cost of treatment medication represented 161,589 SKK/patient/year. Eighty one percent of total expenses were linked with the consumption on antianemic drugs (102,298.40 SKK/patient/year). The second most expensive drug group (9% of the total cost) were medications used in coincidence with hemodialysis complications (14,981 SKK/patient/year). Diuretic--furosemid was the most frequently used drug out of the category of antihypertensive medications (68% of patients), followed by beta-blockers (preparation Concor), calcium channel blockers (preparations Norvasc and Plendil) and angiotensin converting enzyme tritace inhibitors (ACEI, preparations Trirace, Enap, Prestarium), respectively. Only 27% of patients were treated by hypolipidemic drugs mostly by the preparations of Gevilon and Innogen. In the majority of patients (93%) preparations for the correction of calcium and phosphorus metabolisms such as Vitacalcin and Rocaltrol were administered, the latter being most expensive. Antianemic drugs have been used in all patients. In this category of preparations, those composing acid folate and erythropoetin were used most frequently. Alkaline supplementation of NaHCO, (bicarbonate) was used in 88% of patients. In order to prevent the development of thrombosis and other vascular complications, the drugs with antiaggregative effects were used (Ibustrin, Curantyl, Anopyrin). To prevent the manifestation of gastrointestinal adverse reactions, the administration of H2-antagonists have been preferred (Famosan, Quamtel). The group of "Other drugs" was represented by vitamins and drugs with anti-uratic effects (ascorbic acid--preparation Celaskon, tocopherol--preparation E-vitamin and Milurit). When summed together, the costs of therapy in patients treated by hemodialysis are three times higher compared with those in the pre-dialysis phase. In addition to the latter hemodialysis is associated with a large number of medical, psychic and social complications. In the presented pilot study the authors analysed the financial expenses coinciding with drug costs (direct loads) which are significant, but represent only a part of the pharmacoeconomic complexity. In the future it is necessary to perform a more complex pharmacoeconomic analysis in order to evaluate also other factors, such as the costs of hospitalization, dialysate solutions, technologys, salaries of the staff, etc. (Tab. 6, Ref. 37.).

Adult↗

Evaluation of the biochemical effects of administration of intravenous nutrients using erythrocyte ATP/ADP ratios.

Regardless of clinical diagnosis, many acutely and chronically sick patients benefit from intravenous vitamins and minerals, which are usually administered in multiple infusions before observing obvious benefit. We hypothesized this effect was due to improved cellular energy, and attempted to find laboratory evidence via this study. Two groups of patients, chosen at random, received a single infusion of vitamins and minerals in two different dose schedules. Controls received no treatment. Study subjects were patients who presented specifically for a nutritional therapeutic approach, and although all were treated with multiple infusions, a single infusion was selected at random for this study. Thirty patients received a single infusion of a lower dose nutritional formula, sometimes known as a Myer's Cocktail (MC), and 34 had a single infusion of a higher dose nutritional I/V (NIV). Immediately prior to and after the infusion, blood was drawn and an erythrocyte ATP/ADP ratio (EADR) was determined. The results showed that in both infusion groups if the EADR was initially low, it would increase. If it were initially high, it would decrease. This effect was not observed in control subjects. Pre-test EADR boxplot analyses, derived from the results of each protocol, showed these results were statistically predictable. An analysis of variation (ANOVA) calculation indicated the differences were significant. The family error rate used was 0.05. We conclude that this regression of the EADR to the mean, as a result of either of the two infusions and not seen in control subjects, is biochemically significant.

Adenosine Diphosphate↗

Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia.

Reduced levels of membrane essential polyunsaturated fatty acids (EPUFAs), namely, arachidonic acid (AA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acids (DHAs), and their association with psychopathology have been consistently reported in both chronic-medicated schizophrenic patients as well as in never-medicated patients soon after the first episode of psychosis. Past supplementation studies with either omega-6 or omega-3 or both EPUFAs generally in chronic-medicated-older patients have reported varying degrees of therapeutic effects, and have suggested that supplementation with primarily omega-3 EPUFAs (EPA>DHA) may be preferable. We report the supplementation with a mixture of EPA/DHA (180:120 mg) and antioxidants (vitamin E/C, 400 IU:500 mg) orally morning and evening to schizophrenic patients (N=33) for 4 months. The red blood cell (RBC) membrane fatty acid levels, plasma lipid peroxides and clinical measures were carried out by established procedures at pretreatment, posttreatment and after 4 months of postsupplementation period to determine the stability of treatment effects within patients. Levels of fatty acids and lipid peroxides were compared with their levels in normal controls (NC) (N=45).Posttreatment levels of RBC EPUFAs were significantly higher than pretreatment levels as well as levels in normal controls without any significant increase in plasma peroxides. Concomitantly, there was significant reduction in psychopathology based on reduction in individual total scores for brief psychiatric rating scale (BPRS) and positive and negative syndrome scale (PANSS), general psychopathology-PANSS and increase in Henrich's Quality of Life (QOL) Scale. The EPUFA levels returned to pretreatment levels after 4 months of supplementation washout. However, the clinical improvement was significantly retained. Future studies need be done in placebo-controlled trials and also with a comparison group supplemented with fatty acids alone in a larger number of patients, both chronic as well as never medicated, and for a longer duration of treatment while the dietary intake is monitored. This may establish the EPUFA supplementation a very effective treatment to improve the outcome for an extended period of time.

Adult↗

Impact of coronary endothelial function on the progression of cardiac transplant-associated arteriosclerosis: effect of anti-oxidant vitamins C and E.

BACKGROUND: Excessive vascular oxidant stress has been implicated in cardiac transplant-associated arteriosclerosis (TxAA). In a recent placebo-controlled study of 40 cardiac transplant recipients, vitamin C 500 mg twice a day and vitamin E 400 IU twice a day for 1 year retarded the progression of TxAA, as assessed by intravascular ultrasound (IVUS). Endothelial dysfunction is a key feature of TxAA and reflects oxidant stress. We hypothesized that coronary endothelial dysfunction portends greater TxAA progression and a larger therapeutic response to anti-oxidant vitamins. METHODS: In this pre-specified analysis, the 40 cardiac transplant recipients were categorized according to normal or abnormal coronary endothelial vasomotor function at baseline, as assessed by acetylcholine (10(-8) to 10(-6) mol/liter). The effect of anti-oxidant vitamins within these two groups of patients was assessed by the change in intimal index over 1 year using IVUS. RESULTS: With placebo (n = 21), the increase in intimal index was greater in the presence vs absence of endothelial dysfunction (11 +/- 3% vs 5 +/- 1%, p < 0.05). Among patients with endothelial dysfunction (n = 21), the intimal index increased 11 +/- 3% with placebo, but decreased -1 +/- 2% with vitamins (p = 0.002). Among patients with normal endothelial function (n = 14), the intimal index increased 5 +/- 1% with placebo and 1 +/- 1% with vitamins (p < 0.05). CONCLUSIONS: Endothelial dysfunction indicates rapid TxAA progression, even in the statin era. Although anti-oxidant vitamins reduce disease progression in patients with normal or abnormal endothelial function, the magnitude of benefit is larger in patients with endothelial dysfunction.

Antioxidants↗

Bioavailability and therapeutic efficacy of bivalent and trivalent iron preparations.

The bioavailability of iron on Fe(III)-hydroxide-polymaltose complex was compared intraindividually with that of Fe (II)-ascorbate (iron absorption) and a Fe (II)-sulphate quick release preparation (haemoglobin regeneration test). The study was carried out in a population of 16 healthy male volunteers, phlebotomized in weekly intervals until development of an iron deficiency anaemia in order to establish a test population with only small variations of their individual body iron status. Intestinal iron absorption in fasting state as measured by 59Fe whole body retention and simultaneous estimation from plasma iron tolerance curves was low for the 59Fe (III)-complex (1.2 +/- 0.1% (means +/- SD] as compared to the 59Fe (II)-ascorbate (43.7 +/- 7.1% (means +/- SD]. Iron administration together with a test meal did not affect the absorption from the 59Fe (II)-ascorbate, whereas the 59Fe (III)-complex showed a significant increase in absorption (8.8 +/- 4.7% (means +/- SD]. Haemoglobin (Hb) regeneration after 100 mg of iron as Fe (III)-complex and Fe (II)-sulphate administered during 28 days with meals amounted to a mean of 0.68 +/- 0.2 g/l and 1.1 +/- 0.3 g/l (means +/- SD) of total daily Hb-increase and a net-Hb-increase of 0.31 +/- 0.37 g/l and 0.79 +/- 0.36 g/l (means +/- SD), respectively. There was also a small but significant rise in serum ferritin during the oral treatment in both treatment groups. The results of Hb-regeneration after treatment with the Fe (III)-complex were in the range which could be expected from the absorption measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Hydrogen peroxide induced apoptosis in amnion-derived WISH cells is not inhibited by vitamin C.

Increased reactive oxygen species (ROS) have been identified as a potential cause of remodelling and apoptotic change in fetal membrane. Vitamin C has been suggested as a therapeutic agent to prevent ROS induced chorio-amnion apoptosis. The purpose of this study was to determine whether hydrogen peroxide (HP), a ROS, initiates apoptosis in the WISH cell model and whether vitamin C would inhibit HP induced apoptosis. HP induced apoptosis in WISH cells; as assessed by cytochrome-c release from mitochondria, Poly-(ADP-ribose)-Polymerase (PARP) cleavage, nuclear matrix protein (NMP) release and DNA fragmentation analysis. HP induced dose dependent release of cytochrome-c, PARP cleavage, NMP release, and DNA fragmentation. HP also increased PGE(2)release in parallel with apoptosis in WISH cells, in a manner similar to that reported with other apoptotic agents. Vitamin C pre-incubation caused cytochrome-c release earlier, and at lower HP doses, than HP alone. It had no effect on HP induced PARP cleavage, but enhanced DNA fragmentation, and induced NMP release on its own. Vitamin C partially suppressed dose dependent HP induced PGE(2)release. We conclude that HP causes apoptosis in WISH cells and vitamin C pre-incubation does not inhibit, and may accelerate and exacerbate, HP induced apoptosis.

Amnion↗