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PubMed1984

Molecular mechanism of cataractogenesis: III. Toxic metabolites of oxygen as initiators of lipid peroxidation and cataract.

A free radical mechanism of cataractogenesis involving enzymatic and nonenzymatic reactions, is proposed. Supporting experimental evidence is briefly reviewed. H2O2, which is one of the toxic metabolites of oxygen, was significantly increased 2-3 fold in ocular humors in several experimental cataracts and in human senile cataract. Various cataractogenic agents were also found to increase H2O2 in ocular humors in vivo prior to cataract formation. Enzymatic defenses against O2-. and H2O2 provided by superoxide dismutase, catalase and glutathione peroxidase were impaired in cataracts. In some cataracts, catalase and superoxide dismutase were affected earlier. Malondialdehyde (MDA), a major breakdown product of lipid peroxides was significantly increased by 2-4-fold in human senile cataract, in cataracts induced in rabbit and rat, and in hereditary cataracts in mice. All the reactive species of O2 (O2-., H2O2, OH. and 1 delta gO2) may participate in initiating lipid peroxidation of lens in vitro. Various scavengers of these species were capable of preventing lenticular lipid peroxidation, amongst which OH. scavengers were found to be the most effective. Biological antioxidant, vitamin E afforded 44% prevention of lipid peroxidation in lens. The important observation was that vitamin E was therapeutically effective in about 50% of animals in arresting cataract induced in rabbit by 3-aminotriazole. In these rabbits, H2O2 and ascorbic acid of ocular humors and MDA of lens were close to normal. It is our working hypothesis that the carbonyl groups of MDA and amino groups of amino acids, proteins, nucleic acids and their bases, and phospholipids could interact in a cross-linking reaction producing high molecular weight aggregates by Schiff-base conjugate formation in addition to disulfide cross-linking of proteins, and finally resulting in cataract.

Animals↗
PubMed1983

[Leukocyte cytoskeleton under normal and pathological conditions].

Like other cells, leukocytes have the cellular skeleton comprising microtubules, actine, myosine, and intermediate filaments. Elements of the cellular skeleton are connected with receptors on the plasma membrane surface and determine the distribution density of these receptors. There is functional relationship between microtubules and actine filaments, in particular, microtubules determine uniform distribution of actine filaments in the cell cytoplasm. The basic principle of functioning of the cellular skeleton consists of the process of polymerization and reversible depolymerization of proteins forming components of the cellular skeleton. These processes are regulated by Ca2+, calmoduline, as well as by the ratio of cyclic adenosine monophosphate and guanidine monophosphate in the cell. The cellular skeleton determines the most important functions of leukocytes: their mobility, binding and absorption of various substances, processes of degranulation, fusion of granules with phagocytic vacuole. Cellular skeleton defects are accompanied by recurrent bacterial infections. Several such defects are known: leukocyte actine dysfunction syndrome, Chediak-Higashi syndrome, syndrome with marked increase in the content of cGMP and microtubules in leukocytes. In these syndromes, the therapeutic effect is achieved with the substances which regulate the level of cyclic nucleotides in leukocytes, among them large doses of ascorbic acid.

Arachidonic Acids↗
PubMed1980

Genetic disorders of glutathione and sulfur amino-acid metabolism. New biochemical insights and therapeutic approaches.

Important insights have recently been derived from studies of inborn human defects of sulfur metabolism. Metabolic lesions responsible for homocystinuria have been elucidated, with possible implications for understanding atherogenesis in the general population. The cause of cystinosis remains enigmatic, but important information has been gained on the origin of some stored cystine from degraded protein. Cysteamine and ascorbic acid deplete the cystine content of cystinotic fibroblasts in vitro, and clinical trials with these agents have been undertaken. Studies of patients with glutathione synthetase deficiency have provided new understanding of the roles of glutathione as in antioxidant and as a modulator of microtubule-related processes. Studies of patients with this disorder and glucose-6-phosphate dehydrogenase deficiency, in which the capacity to maintain glutathione in the reduced state is compromised, indicate that pharmacologic doses of vitamin E can correct certain functional consequences of an inadequate supply of reduced glutathione both in erythrocytes and polymorphonuclear leukocytes. Much remains to be learned about the mechanisms of membrane damage in these states of enhanced oxidative susceptibility.

Amino Acid Metabolism, Inborn Errors↗
PubMed2002

Fluctuation in therapeutic control associated with interchange of prednisolone tablet formulations: assessment of bioequivalence by dissolution test.

A 47-year-old woman received combination therapy with prednisolone (PSL), danazol, cepharanthin, ascorbic acid, and cimetidine for the treatment of idiopathic thrombocytopenic purpura. The platelet count was well controlled for over 1 year. Then the PSL tablet formulation was altered from Tablet A to Tablet B with the same treatment regimen, but the platelet counts fell drastically thereafter. However, the platelet counts recovered by changing the PSL tablet formulation back from Tablet B to Tablet A. In vitro dissolution testing was undertaken to assess bioequivalence between Tablet A and Tablet B. PSL in Tablet B was released more slowly compared with that in Tablet A regardless of the medium pH conditions, and the difference in the release rate between the two tablet formulations increased with increasing medium pH value. The difference exceeded the allowance limit (15%) for judgment of bioequivalence under conditions above pH 4, indicating that Tablet A and Tablet B might be nonbioequivalent. The intragastric pH of the patient was probably raised due to coadministration of cimetidine. Therefore the present results suggest that the disparity in the immunosuppressive effects between the two PSL tablet formulations was attributable to the difference in their dissolution behavior in the gastrointestinal tract. We consider that it is better to avoid interchanging PSL tablet formulations in clinical practice.

Chemistry, Pharmaceutical↗
PubMed2005

Wound healing in rat cornea: the role of electric currents.

Human corneal epithelial cells respond rapidly following injury to restore the integrity of the ocular surface. What stimulates and guides cells to move into the wound to heal? One candidate is the wound-induced electric field. Using vibrating probe techniques, we provide detailed temporal and spatial mapping of endogenous electric currents at rat corneal wounds. We find Cl- and Na+ are the major components of electric currents in rat corneal wounds. Na+ is the major component of ionic transport in the resting (nonwounded) rat cornea and of the wound center leakage current, whereas Cl- is a more important component of the endogenous electrical current at the wound edges. Enhancing or decreasing Cl- flow with clinically approved pharmacological agents such as aminophylline, ascorbic acid, or furosemide increased or decreased endogenous wound electric currents, respectively. These changes in wound currents correlated directly with the rate of wound healing in vivo. Thus, pharmacologically enhancing or decreasing wound-induced electric currents increased and decreased wound healing rate, respectively. This may have wide-reaching and novel therapeutic potential in the management of wound healing and may help explain some mechanistic aspects of the effects of some clinically used agents.

Aminophylline↗
PubMed2004

Effect of Rubia cordifolia, Fagonia cretica linn, and Tinospora cordifolia on free radical generation and lipid peroxidation during oxygen-glucose deprivation in rat hippocampal slices.

The major damaging factor during and after the ischemic/hypoxic insult is the generation of free radicals, which leads to apoptosis, necrosis, and ultimately cell death. Rubia cordifolia (RC), Fagonia cretica linn (FC), and Tinospora cordifolia (TC) have been reported to contain a wide variety of antioxidants and have been in use in the eastern system of medicine for various disorders. Hippocampal slices were subjected to oxygen-glucose deprivation (OGD) and divided into three groups, control, OGD, and OGD+drug treated. Cytosolic reduced glutathione (GSH), nitric oxide [NO, measured as nitrite (NO2)]. EPR was used to establish the antioxidant effect of RC, FC, and TC with respect to superoxide anion (O*2-), hydroxyl radicals (*OH), nitric oxide (NO) radical, and peroxynitrite anion (ONOO-) generated from pyrogallol, menadione, DETA-NO, and Sin-1, respectively. RT-PCR was performed for the three herbs to assess their effect on the expression of gamma-glutamylcysteine ligase (GCLC), iNOS, and GAPDH gene expression. All the three herbs were effective in elevating the GSH levels and expression of the GCLC. The herbs also exhibited strong free radical scavenging properties against reactive oxygen and nitrogen species as revealed by electron paramagnetic resonance spectroscopy, diminishing the expression of iNOS gene. RC, FC, and TC therefore attenuate oxidative stress mediated cell injury during OGD and exert the above effects at both the cytosolic as well as at gene expression levels and may be effective therapeutic tool against ischemic brain damage.

Animals↗
PubMedDate not supplied

Vitamin C supplementation in the patient with burns and renal failure.

Vitamin C supplementation is an important component of nutritional management in patients with burns. To supply appropriate vitamin C therapy, complications such as renal failure must be considered. An understanding of current vitamin regimens and potential metabolic sequelae can assist the practitioner in providing safe and therapeutic vitamin C doses.

Acute Kidney Injury↗
PubMed2006

Effects of transferrin receptor blockade on cancer cell proliferation and hypoxia-inducible factor function and their differential regulation by ascorbate.

Cellular iron is needed for cell survival and hydroxylation of hypoxia-inducible factor-1alpha (HIF-alpha) by prolyl hydroxylases (PHD). One mechanism of iron uptake is mediated by the cell surface transferrin receptor (TfR). Because iron is required for cell growth and suppression of HIF-alpha levels, we tested the effects of the two anti-TfR monoclonal antibodies (mAb) E2.3 and A27.15 on growth of breast cancer cells and induction of HIF-alpha and hypoxia-regulated genes. Treatment with both mAbs together synergistically inhibited cell proliferation in a dose-responsive manner by up to 80% following 8 days of exposure, up-regulated HIF-1alpha and HIF transcription targets, down-regulated TfR expression, and down-regulated cellular labile iron pool by 60%. Because combined treatment with anti-TfR mAbs resulted in the up-regulation of the hypoxia pathway, which may increase tumor angiogenesis, we analyzed the effects of ascorbate on cell viability and HIF-1alpha levels in cells treated with both anti-TfR mAbs together, as ascorbate has been shown to be required by PHD enzymes for full catalytic activity. Ascorbate at physiologic concentrations (25 micromol/L) suppressed HIF-1alpha protein levels and HIF transcriptional targets in anti-TfR mAb-treated cells but did not suppress the antiproliferative effect of the mAbs. These results indicate that the addition of ascorbate increased the activity of the PHD enzymes in down-regulating HIF but not the proliferation of iron-starved anti-TfR mAb-treated cells. The use of anti-TfR mAbs and ascorbate in inhibiting both cell proliferation and HIF-1alpha and angiogenesis under normoxic conditions may be of therapeutic use.

Antibodies, Monoclonal↗
PubMedDate not supplied

[Treatment of osteoporosis with a delayed-action sodium fluoride preparation].

40 patients with various types of osteoporosis, aged 17 to 76 years, were treated for 12 months with a new NaF-drug (Ossiplex-Retard, film tbl. 25 mg NaF plus 200 mg vitamine C). Daily dosage was 50-100 mg. Clinical symptoms, X-ray-status of the axial skeleton, alkaline serum phosphatase and the consumption of analgetics were used for assessment. 2/3 of the patients with presenile and steroid induced osteoporosis responded well to treatment, while those with osteogenesis imperfecta, idiopathic osteoporosis and plasmocytosis did not show clinical or radiological improvement. In senile osteoporosis, a physiological process of aging, should only be given NaF-treatment, if fractures without callus formation are present. Harmless side effects, (gastrointestinal intolerance in 15% and a painful tendoperiostosis syndrome in 12.5%), necessitated discontinuation of treatment in 3 cases. The NaF-drug with added vitamine C has less side effects than other NaF-containing compounds and should therefore be included as part of the therapeutical regimen of certain types of osteoporosis.

Adolescent↗
PubMed1989

A probe for intracellular concentrations of drugs: delayed fluorescence from acridine orange.

The aim of this work is to develop fluorescent probes that will indicate effective concentrations of therapeutic agents, or endogenous protectors, at important cellular sites. Acridine orange associates with nucleic acids and emits a 'delayed' fluorescence signal. This signal is quenched by oxidants such as oxygen, nitroaryl radiosensitizers, adriamycin and mitomycin-c, and reductants such as thiols, ascorbate and other radioprotectors. The quenching of the acridine orange delayed fluorescence reflects the effective concentration of these therapeutically-important oxidants and reductants near DNA. The relative concentration of basic radiosensitizers such as pimonidazole (Ro 03-8799) near the DNA is greater than that of misonidazole. Thiols quench the delayed fluorescence signal according to the degree of ionization of the thiol function; this may model the reactivity of thiols with guanine radical sites in DNA. Ascorbate and aminopyrine do not quench the delayed fluorescence from cells stained with acridine orange as these compounds are taken up by cells very inefficiently.

Acridine Orange↗
PubMed1996

The anti-oxidant properties of 5-aminosalicylic acid.

Oxidative damage to biological membranes is an important cause of tissue injury in inflammatory bowel disease. 5-Aminosalicylic Acid (5ASA) has therapeutic efficacy in Ulcerative colitis, which may be based on its antioxidant properties. We used Parinaric acid as a fluorescent marker of oxidation in an intestinal microvillous brush border membrane preparation. Various concentrations of the antioxidants 5ASA, ascorbate, and tocopherol were added, and oxidation was initiated from within the membrane by 2,2' azobis (2.4-dimethylvaleronitrile) (AMVN) and from solution by 2,2' azobis (2-amidinopropane) hydrochloride (AAPH). Tocopherol was able to inhibit oxidation from either source. Ascorbate was only able to inhibit oxidation initiated from solution. 5ASA was able to inhibit oxidation initiated from either site, and was more effective than tocopherol against AAPH, but similarly effective against AMVN. We postulate that water soluble 5ASA preferentially associates with membrane surface, allowing chain-breaking antioxidant activity when peroxidation is initiated within the membrane. Likewise, it is effective against aqueous oxidants because its position allows it to interact with AAPH before lipid peroxidation can be initiated as well as breaking the lipid peroxidation chain once it is initiated. This dual capacity may be important for therapeutic effect of 5ASA and may suggest other candidate antioxidants for clinical trials.

Amidines↗
PubMedDate not supplied

In vivo and in vitro antitumor effect of ascorbic acid, lysine, proline and green tea extract on human melanoma cell line A2058.

BACKGROUND: Melanoma, a very serious form of skin cancer, causes the most skin cancer-related deaths, due to metastasis. Structural changes in the extracellular matrix (ECM) are necessary for cell migration during tissue remodeling. MMPs, VEGF, Ki-67 (proliferative protein) and constituents of ECM play a critical role in angiogenesis, and are crucial in neoplastic invasion and metastasis. MATERIALS AND METHODS: The effect of a diet (NM) containing lysine, proline, arginine, ascorbic acid and green tea extract on the growth of tumors induced by implanting human melanoma A2058 cells in athymic nude mice was examined and, also, on the expression of MMPs, VEGF and Ki-67 in these tumors. The effect of NM in vitro on the melanoma A2058 cell line was tested by measuring: cell proliferation by the MTT assay, expression of MMPs by gelatinase zymography and invasion through Matrigel. RESULTS: Nutrient supplementation strongly suppressed the growth of tumors (by 57%)without adverse effects in nude mice. Histological studies supported these findings by showing inhibition of MMP-9 and VEGF secretion and mitotic index. In vitro, NM inhibited melanoma cell growth by 64% at 500 microg/ml and Matrigel invasion by 95% at 100 microg/ml NM. CONCLUSION: These results suggest that NM may have a therapeutic potential in melanoma.

Animals↗
PubMed1997

Oxygen free radicals and their clinical implications.

Reactive oxygen species (ROS) have been implicated in a variety of pathological processes. The generation of highly reactive oxygen metabolites is an integral feature of normal cellular metabolism (mitochondrial respiratory chain, phagocytosis, arachidonic acid metabolism, ovulation and fertilization), however their production can multiply during pathological circumstances. Free oxygen radicals act either on the extracellular matrix or directly upon cellular membranes themselves. The fundamental defense of the organism against ROS include scavenger enzymes (superoxide dismutase, catalase, glutathione peroxidase) and lipid- and water soluble antioxidant compound (ascorbic acid, glutathione, albumin, transferrin, etc.). Their role in ischemia-reperfusion models have now been comprehensively investigated and it has become clear that ROS is to be blamed for the bulk of post-ischemic injuries, hence the basis for newly established antioxidant therapy in such cases. Also more and more studies have concluded a pivotal role of ROS in degenerative and inflammatory conditions, post-radiation processes and aging. Therefore it seems as we are continuously shedding light on the crucial part played by these molecules regarding a wide range of pathologies, we are discovering new therapeutic windows that would clinically assist us in managing such conditions.

Aging↗
PubMed1980

[Studies of sulfhemoglobin formation by various drugs (4). Influences of various antidotes on chemically induced methemoglobinemia and sulfhemoglobinemia (author's transl)].

The influences of methylene blue (MB), thionine, ascorbic acid (ASA), sodium thiosulfate (STS), N-(2-mercaptopropionyl)-glycine (MPG) and reduced glutathione (GSH) on methemoglobin-(MHb)-emia and sulf-hemoglobin (SHb)-emia induced by 4-chloroaniline (4-Cl-A) i.p. were studied. Preventive or therapeutic effect on MHb-emia and preventive effect on SHb-emia in mice: MHb formation was inhibited by MB i.p. whether it was administered simultaneously with or after 4-Cl-A, but SHb formation was increased. Similar effects were seen with thionine. Both compounds proved to have MHb and SHb forming activities. STS or MPG, if administered i.p. simultaneously with 4-Cl-A, inhibited formation of MHb, but exerted no effect on delayed SHb formation. However, if administered i.p. or i.v. 120 minutes after 4-Cl-A when the peak of MHb formation had passed, there was a preventive effect on delayed SHb formation. GSH inhibited MHb formation and prevented SHb formation only when it was administered i.v. 120 minutes after 4-Cl-A. ASA did not inhibit MHb formation when it was administered either i.p. or i.v., but showed a preventive effect on SHb formation, if administered 120 minutes after 4-Cl-A. Combined i.v. administration of the corresponding doses to the clinical ones of MB and ASA 120 minutes after 4-Cl-A showed a therapeutic effect on MHb-emia and a preventive effect on SHb-emia. However, at higher dose levels, MB masked the preventive effect of ASA on SHb-emia. Therapeutic effect on SHb-emia in mice and rats: None of MB, STS, GSH and ASA proved to have any therapeutic effects for established SHb-emia. On the basis of these results, significance of clinical usage of drugs in the treatment of chemically induced MHb-emia and SHb-emia is discussed.

Aniline Compounds↗
PubMed1977

Lack of effect of methenamine in suppression of, or prophylaxis against, chronic urinary infection.

Methenamine is frequently prescribed for patients who have chronic urinary infection to suppress bacterial growth during active infection or to prevent recurrence once an infection has been brought under control. We have examined the effect of methenamine mandelate and ascorbic acid on bacteriuria in para- and quadriplegics from a spinal cord unit. Patients with indwelling urinary catheters and those on a program of intermittent catheterization were included. No suppressive or prophylactic effect of this regimen was observed in any of our patients. Methenamine does not appear to be an effective antimicrobial agent in subjects who have an indwelling urinary catheter or in patients with spinal cord injury who are on intermittent catheterization. Since there appears to be reason to question the efficacy of methenamine in situations in which it is usually prescribed, evidence should be sought for a therapeutic effect in other cases. If no benefit is observed, the drug should not be used.

Ascorbic Acid↗